<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 Cefoxitin and can you explain it in depth? [/INST] Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.

History and discovery
Groups of researchers at Merck and Lilly discovered Cephamycin C while looking at penicillin-producing bacteria. This followed their discovery of erythromycin, another antibiotic. Cephamycin C was the first cephem discovered but while it was highly resistant to several beta-lactamases, as is its derivative cefoxitin, it was almost only effective against Gram negative bacteria. The scientists used chemically modified the compound to give cefoxitin, so titled due to its semi-synthetic nature. This new modification broadened its spectrum to include Gram positive bacteria. More than 300 modifications were made to it and tested on the cephalosporin base with methoxy groups at the 7-alpha position. Yet only cefoxitin retained its previous effectiveness against Gram negative bacteria, developed effectiveness against Gram positive bacteria, and resisted breakdown by beta-lactamase.Cefoxitin, and the cephamycin family as a whole, served as a branching point and impulsed the discovery of more classes of beta-lactams. This is in part due to their primary and early discovery in the broths studied.

Mechanism
Cefoxitin is a beta-lactam antibiotic which binds to penicillin binding proteins, or transpeptidases. By binding to PBPs, cefoxitin prevents the PBPs from forming the cross-linkages between the peptidoglycan layers that make up the bacterial cell wall, thereby interfering with cell wall synthesis. It is a strong beta-lactamase inducer, as are certain other antibiotics (such as imipenem). However, cefoxitin is a better substrate than imipenem for beta-lactamases.

Microbiological resistance
In the presence of cefoxitin, bacteria that make beta-lactamases will increase their production and secretion to cleave the beta lactam ring. As a cephamycin, cefoxitin is highly resistant to hydrolysis by some beta-lactamases, in part due to the presence of the 7-alpha-methoxy functional group (see skeletal formula above).Another more efficient form of resistance to cefoxitin is provided by the mecA gene in bacteria. This gene codes for an alternative penicillin binding protein, PBP2a. This PBP has a lower binding affinity for penicillin-based antibiotics such as cefoxitin and will continue to cross-link the peptidoglycan layers of the cell wall even in the presence of the beta-lactam antibiotics. MRSA, or methicillin-resistant Staphylococcus aureus is a strain that has acquired resistance to cefoxitin via this gene. For the purposes of detecting bacterial strains with the mecC gene, which like mecA codes for a different PBP, cefoxitin is more reliable than oxacillin because mecC does not correlate as strongly with oxacillin resistance.

Spectrum of bacterial susceptibility
Cefoxitins spectrum of in vitro antimicrobial activity includes a broad range of gram-negative and gram-positive bacteria, including anaerobes. It is inactive against most strains of Pseudomonas aeruginosa and many strains of Enterobacter cloacae. Staphylococci that are resistant to methicillin and oxacillin should also be considered clinically resistant to cefoxitin even if they test susceptible by in vitro methods.Major bacterial strains susceptible to cefoxitin include:
methicillin-susceptible Staphylococcus aureus
Streptococcus sp.
E. coli
Salmonella sp.
Proteus vulgaris
Flavobacterium sp.
Klebsiella sp.Major bacteria resistant to cefoxitin include:
methicillin-resistant Staphylococcus aureus
Enterococci
Listeria monocytogenes
Enterobacter sp.
Bacteroides sp.

Replacement and substitution
In a 2005 study, Fernandes et al. determined that cefoxitin serves as an appropriate replacement for methicillin in determining if some bacteria display methicillin resistance. Likewise, Funsun et al. found in a 2009 study that cefoxitin disk assays correctly identified all 60 mecA-positive Staphylococcus aureus, or MRSA isolates, to be resistant to cefoxitin.Due, in part, to the unavailability of methicillin in the United States, cefoxitin has replaced methicillin for disk diffusion tests, which determine the sensitivity of a bacterial specimen to a given antibiotic. Cefoxitin also yields more accurate results for disk diffusion tests. Interpretive criteria for determining susceptibility to cefoxitin via disk diffusion are greater than or equal to 22mm resulting in a "susceptible" result for Staphylococcus aureus and greater than or equal to 25mm for coagulase-negative staphylococci to be considered susceptible.The following are susceptibility data for several medically significant microorganisms, measured by minimum inhibitory concentration, which is an alternative, liquid medium test for susceptibility.

Escherichia coli: 0.2 μg/ml – 64 μg/ml
Haemophilus influenzae: 0.5 μg/ml – 12.5 μg/ml
Streptococcus pneumoniae: 0.2 μg/ml – 1 μg/ml

Uses in medicine
Cefoxitin is sold in three major IV doses, 1g, 2g, and 10g. It is usually given to adults every six to eight hours in 1g or 2g doses. Cefoxitin may interfere with tests detecting urine glucose and result in a false positive. As with any antibiotic, it should not be given to patients who are allergic to it.Cefoxitin is used to treat:
Skin infections, primarily due to Staphylococcus
Urinary tract infections
Bronchitis
Tonsillitis
Ear infections
Bacterial pneumonia
Sepsis
Bone and joint infections
Abdominal infections and abscesses
Perineum injuries
Pelvic inflammatory disease
Gonorrhea
Infections caused by susceptible bacteria mentioned earlierCefoxitin has many other uses; it may be given prior to surgery to prevent the development of surgical wound infections, and when used in third and fourth degree perineal injuries in women after giving vaginal birth, cefoxitin decreases infection rate at two and six weeks. However, the earlier and more times a child is exposed to cefoxitin, as with early and multiple exposure to many antibiotics, the greater the likelihood of developing inflammatory bowel disease later in life. This may be due in part to a decreased variety of microorganisms in the digestive system.It is also used to treat pelvic inflammatory disease, because it is a broad spectrum antibiotic. For outpatient treatment, oral antibiotics or those with less frequent dosing may be prescribed. As an effective alternative to penicilin and spectinomycin, and replacement for methicillin, cefoxitin is used to treat gonorrhea in both men and women with few side effects.

Side effects
Side effects for cefoxitin are regarded as mild. Common side effects include:

local tenderness or pain at the site of injection
skin color change, mild diarrhea
mild nausea
headache
loss of appetite
vaginal discharge and itching
swelling of feet or legs.While cefoxitin has not been associated with alcohol incompatibility like other members of the second generation cephalosporins class, it has been with a higher risk of coagulopathy, a bleeding disorder.This is not a comprehensive list and not intended to provide medical advice. If any of the previous side effects are severe, or if an allergic reaction takes place immediately contact your doctor.

Notable drug interactions
Contraindications
A contraindication means that the drug in question should not be used under particular circumstances. For cefoxitin, this includes patients who are hypersensitive to cephalosporin antibiotics.Patients with colitis, kidney disease, or liver disease are also advised not to take cefoxitin. However, some drug databases will considers the diseases means for caution rather than contraindications.

Major or Severe
Aside from the above-mentioned contraindications and diseases which require monitoring by a doctor, the live cholera and live typhoid vaccines are known to have a severe interaction with cefoxitin.Individuals on a low sodium diet, undergoing dialysis, or who have experienced seizures, particularly following antibiotic therapy, should also consult their physician prior to taking cefoxitin.

Moderate
Only take additional antibiotics, anticoagulants and blood thinners under doctor supervision. Cefoxitin may decrease the effectiveness of hormonal birth control. This increases the risk for pregnancy and a medical consult will help determine whether backup birth control methods should be used.

Minor
Minor drug interactions do not usually require a change in treatment. Your doctor may monitor specific events, such as bleeding, while taking cefoxitin. Two such minor interactions occur between cefoxitin and heparin as well as genistein.

Pharmacodynamic and pharmacokinetic data
Pharmocokinetic and pharmacodynamic data for cefoxitin are, as of 2013, considered limited and outdated. A few relatively recent studies have attempted to remedy that.
One such study was by the Hôpitaux de Paris in collaboration with the French Ministry of Health. However, while the clinical trials were completed in 2015, no study data have been published. The expected results from using cefoxitin over carbapenems, another type of antibiotic with a wider bacterial spectrum, included effective treatment of E. coli produce extended spectrum beta-lactamase, less selective pressure on the GI tract which better maintains balanced flora, and a lower treatment cost.This followed a 2012 French study on the same E. coli strain with CTX-M-15 extended release beta-lactamase. Lepeule et al. determined that in mice, the ideal pharmacodynamic target of fT>MIC=33%, where MIC is the minimum inhibitory concentration, was obtained with 200 mg/kg every four 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 Ravulizumab and can you explain it in depth? [/INST] Ravulizumab, sold under the brand name Ultomiris, is a humanized monoclonal antibody complement inhibitor medication designed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome. It is designed to bind to and prevent the activation of Complement component 5 (C5).Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell destruction, anemia (red blood cells unable to carry enough oxygen to tissues), blood clots, and impaired bone marrow function (not making enough blood cells). In paroxysmal nocturnal hemoglobinuria, proteins known as the complement system, which is part of the immune system, become overactive because of a genetic mutation and start to attack the patients own red blood cells. Ravulizumab, is a monoclonal antibody (a type of protein) designed to attach to the C5 protein, which is part of the complement system. By attaching to the C5 protein, the medicine blocks its effect and thereby reduces the destruction of red blood cells.The most common side effects are upper respiratory tract infection (nose and throat infection), nasopharyngitis (inflammation of the nose and throat) and headache. The most serious side effect is meningococcal infection, a bacterial infection caused by Neisseria meningitidis that can cause meningitis and sepsis.

Medical uses
In the United States, ravulizumab is indicated for the treatment of adults and children one month of age and older with paroxysmal nocturnal hemoglobinuria and for the treatment of adults and children one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).In the European Union, ravulizumab is indicated in the treatment of adults with paroxysmal nocturnal haemoglobinuria:

in people with haemolysis with clinical symptom(s) indicative of high disease activity
in people who are clinically stable after having been treated with eculizumab for at least the past six months.

Names
Ravulizumab is the International Nonproprietary Name (INN).

History
Ravulizumab was developed by Alexion Pharmaceuticals, Inc. It was engineered from eculizumab to have a longer-lasting effect.Ravulizumab was approved by the US Food and Drug Administration (FDA) in December 2018. In April 2019, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the granting of a conditional marketing authorization for ravulizumab </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 Elagolix/estradiol/norethindrone acetate and can you explain it in depth? [/INST] Elagolix/estradiol/norethindrone acetate, sold under the brand name Oriahnn, is a fixed-dose combination medication used to treat heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. It contains elagolix, a gonadotropin-releasing hormone (GnRH) receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin. It is taken by mouth. Oriahnn is co-packaged as a combination of elagolix/estradiol/norethindrone acetate capsules with elagolix capsules.The most common side effects include hot flushes (sudden feelings of warmth), headache, fatigue and irregular vaginal bleeding.

Medical uses
Fibroids are benign (non-cancerous) muscle tumors of the uterus that can cause heavy menstrual bleeding, pain, bowel or bladder problems and infertility. Some women may not experience any symptoms, but many do, including heavy bleeding with periods. Fibroids can occur at any age but are most common in women 35 to 49 years of age. They typically resolve after menopause but are a leading reason for hysterectomy (surgical removal of the uterus) in the United States when they cause severe symptoms.Elagolix/estradiol/norethindrone acetate is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

Adverse effects
Elagolix/estradiol/norethindrone acetate may cause bone loss over time, and the loss in some women may not be completely recovered after stopping treatment. Because bone loss may increase the risk for fractures, women should not take elagolix/estradiol/norethindrone acetate for more than 24 months.The drug label for the combination includes a boxed warning about the risk of vascular events (strokes) and thrombotic or thromboembolic disorders (blood clots), especially in women at increased risk for these events.

History
Elagolix/estradiol/norethindrone acetate was approved for medical use in the United States in May 2020.The efficacy of elagolix/estradiol/norethindrone acetate was established in two clinical trials in which a total of 591 premenopausal women with heavy menstrual bleeding received the drug or placebo for six months. Heavy menstrual bleeding at baseline was defined as having at least two menstrual cycles with greater than 80 mL (about a third of a cup) of menstrual blood loss (MBL). The primary endpoint was the proportion of women who achieved MBL volume less than 80 mL at the final month and 50% or greater reduction in MBL volume from the start of the study (baseline) to the final month. In the first study, 68.5% of participants who received elagolix/estradiol/norethindrone acetate achieved this endpoint (compared to 8.7% of participants who received placebo) </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 Benznidazole and can you explain it in depth? [/INST] Benznidazole is an antiparasitic medication used in the treatment of Chagas disease. While it is highly effective in early disease this decreases in those who have long-term infection. It is the first-line treatment given its moderate side effects compared to nifurtimox. It is taken by mouth.Side effects are fairly common. They include rash, numbness, fever, muscle pain, loss of appetite, and trouble sleeping. Rare side effects include bone marrow suppression which can lead to low blood cell levels. It is not recommended during pregnancy or in people with severe liver or kidney disease. Benznidazole is in the nitroimidazole family of medication and works by the production of free radicals.Benznidazole came into medical use in 1971. It is on the World Health Organizations List of Essential Medicines. As of 2012, Laboratório Farmacêutico do Estado de Pernambuco, a government run pharmaceutical company in Brazil was the only producer.

Medical uses
Benznidazole has a significant activity during the acute phase of Chagas disease, with a success rate of up to 80%. Its curative capabilities during the chronic phase are, however, limited. Some studies have found parasitologic cure (a complete elimination of T. cruzi from the body) in children during the early stage of the chronic phase, but overall failure rate in chronically infected individuals is typically above 80%.Some studies indicate treatment with benznidazole during the chronic phase, even if incapable of producing parasitologic cure because it reduces electrocardiographic changes and delays worsening of the clinical condition of the patient.Benznidazole has proven to be effective in the treatment of reactivated  T. cruzi  infections caused by immunosuppression, such as in people with AIDS or in those under immunosuppressive therapy related to organ transplants.

Children
Benznidazole can be used in children, with the same 5–7 mg/kg per day weight-based dosing regimen that is used to treat adult infections. A formulation for children up to two years of age is available. It was added to the WHO Essential Medicines List for Children in 2013. Children are found to be at a lower risk of adverse events compared to adults, possibly due to increased hepatic clearance of the drug. The most prevalent adverse effects in children were found to be gastrointestinal, dermatologic, and neurologic in nature. However, the incidence of severe dermatologic and neurologic adverse events is lower in the pediatric population compared to adults. It use for Chagas in children was approved by the FDA in the US in 2017.

Pregnant women
Studies in animals have shown that benznidazole can cross the placenta. Due to its potential for teratogenicity, use of benznidazole in pregnancy is not recommended.

Side effects
Side effects tend to be common and occur more frequently with increased age. The most common adverse reactions associated with benznidazole are allergic dermatitis and peripheral neuropathy. It is reported that up to 30% of people will experience dermatitis when starting treatment. Benznidazole may cause photosensitization of the skin, resulting in rashes. Rashes usually appear within the first 2 weeks of treatment and resolve over time. In rare instances, skin hypersensitivity can result in exfoliative skin eruptions, edema, and fever. Peripheral neuropathy may occur later on in the treatment course and is dose dependent. It is not permanent, but takes time to resolve.Other adverse reactions include anorexia, weight loss, nausea, vomiting, insomnia, and dysguesia, and bone marrow suppression. Gastrointestinal symptoms usually occur during the initial stages of treatment and resolves over time. Bone marrow suppression has been linked to the cumulative dose exposure.

Contraindications
Benznidazole should not be used in people with severe liver and/or kidney disease. Pregnant women should not use benznidazole because it can cross the placenta and cause teratogenicity.

Pharmacology
Mechanism of action
Benznidazole is a nitroimidazole antiparasitic with good activity against acute infection with Trypanosoma cruzi, commonly referred to as Chagas disease. Like other nitroimidazoles, benznidazoles main mechanism of action is to generate radical species which can damage the parasites DNA or cellular machinery. The mechanism by which nitroimidazoles do this seems to depend on whether or not oxygen is present. This is particularly relevant in the case of Trypanosoma species, which are considered facultative anaerobes.Under anaerobic conditions, the nitro group of nitroimidazoles is believed to be reduced by the pyruvate:ferredoxin oxidoreductase complex to create a reactive nitro radical species. The nitro radical can then either engage in other redox reactions directly or spontaneously give rise to a nitrite ion and imidazole radical instead. The initial reduction takes place because nitroimidazoles are better electron acceptors for ferredoxin than the natural substrates. In mammals, the principal mediators of electron transport are NAD+/NADH and NADP+/NADPH, which have a more positive reduction potential and so will not reduce nitroimidazoles to the radical form. This limits the spectrum of activity of nitroimidazoles so that host cells and DNA are not also damaged. This mechanism has been well-established for 5-nitroimidazoles such as metronidazole, but it is unclear if the same mechanism can be expanded to 2-nitroimidazoles (including benznidazole).In the presence of oxygen, by contrast, any radical nitro compounds produced will be rapidly oxidized by molecular oxygen, yielding the original nitroimidazole compound and a superoxide anion in a process known as "futile cycling" </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 TENEX 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 Nateglinide 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 Esketamine and can you explain it in depth? [/INST] Esketamine, also known as (S)-ketamine or S(+)-ketamine, is the S(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand names Spravato (for depression), Ketanest (for anesthesia), among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.It is specifically used as a therapy for treatment-resistant depression (TRD) and for major depressive disorder (MDD) with co-occurring suicidal ideation or behavior. Its effectiveness for depression is modest and similar to that of other antidepressants. Esketamine is used by infusion into a vein for anesthesia and under direct medical supervision as a nasal spray once or twice weekly for depression.Adverse effects of esketamine include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Less often, esketamine can cause bladder problems. Esketamine acts primarily as a N-methyl-D-aspartate (NMDA) receptor antagonist but also has other actions.In the form of racemic ketamine, esketamine was first synthesized in 1962 and introduced for medical use as an anesthetic in 1970. Enantiopure esketamine was introduced for medical use as an anesthetic in 1997 and as an antidepressant in 2019. It is used as an anesthetic in the European Union and as an antidepressant in the United States and Canada. Due to misuse liability as a dissociative hallucinogen, esketamine is a controlled substance.

Medical uses
Anesthesia
Esketamine is a general anesthetic and is used for similar indications as ketamine. Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.

Depression
Esketamine is approved under the brand name Spravato in the form of a nasal spray added to a conventional antidepressant as a therapy for treatment-resistant depression (TRD) as well as major depressive disorder (MDD) associated with suicidal ideation or behavior in adults in the United States. In the clinical trials that led to approval of esketamine, TRD was defined as MDD with inadequate response to at least two different conventional antidepressants. The nasal spray formulation of esketamine used for depression delivers two sprays containing a total of 28 mg esketamine and doses of 56 mg (2 devices) to 84 mg (3 devices) are used. The recommended dosage of Spravato is 56 mg on day 1, 56 or 84 mg twice per week during weeks 1 to 4, 56 or 84 mg once per week during weeks 5 to 8, and 56 or 84 mg every 2 weeks or once weekly during week 9 and thereafter. Dosing is individualized to the least frequent dosing necessary to maintain response or remission. Spravato is administered under the supervision of a healthcare provider and patients are monitored for at least 2 hours during each treatment session. Due to concerns about sedation, dissociation, and misuse, esketamine is available for treatment of depression only from certified providers through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called Spravato REMS.Five clinical studies of esketamine for TRD (TRANSFORM-1, -2, and -3, and SUSTAIN-1 and -2) were submitted to and evaluated by the FDA when approval of esketamine for treatment of TRD was sought by Janssen Pharmaceuticals. Of these five studies, three were short-term (4-week) efficacy studies (the TRANSFORM studies). Two of these three studies (TRANSFORM-1 and -3) did not find a statistically significant antidepressant effect of esketamine relative to placebo. In the one positive short-term efficacy study (TRANSFORM-2), there was a 4.0-point difference between esketamine and placebo on the Montgomery–Åsberg Depression Rating Scale (MADRS) after 4 weeks of treatment (P = 0.020). This scale ranges from 0 to 60 and the average score of the participants at the start of the study was about 37.0 in both the esketamine and placebo groups. The total change in score after 4 weeks was –19.8 points in the esketamine group and –15.8 points in the placebo group. This corresponded to a percentage change in MADRS score from baseline of –53.5% with esketamine and –42.4% with placebo (a difference and reduction of depression score of –11.1% potentially attributable to the pharmacological action of esketamine) in these patient samples. Placebo showed 80.0% of the antidepressant effect of esketamine for TRD in this study and hence approximately 20.0% of the antidepressant response was attributable to esketamine. In the two negative short-term efficacy trials that did not reach statistical significance (TRANSFORM-1 and -3), the differences in MADRS reductions between esketamine and placebo were –3.2 (P = 0.088) and –3.6 (P = 0.059) after 4 weeks of treatment.

The 4.0-point additional reduction in MADRS score with esketamine over placebo in the single positive efficacy trial corresponds to less than "minimal improvement" and has been criticized as being below the threshold for clinically meaningful change. A difference of at least 6.5 points was originally suggested by the trial investigators to be a reasonable threshold for clinical significance. In other literature, MADRS reductions have been interpreted as "very much improved" corresponding to 27–28 points, "much improved" to 16–17 points, and "minimally improved" to 7–9 points. It has additionally been argued that the small advantage in scores with esketamine may have been related to an enhanced placebo response in the esketamine group due to functional unblinding caused by the psychoactive effects of esketamine. In other words, it is argued that the study was not truly a double-blind controlled trial. Dissociation was experienced as a side effect by a majority of participants who received esketamine (61–75% with esketamine and 5–12% with placebo; ~7-fold difference) and "severe" dissociation was experienced by 25%. Deblinding and expectancy confounds are problems with studies of hallucinogens for psychiatric indications in general. The FDA normally requires at least two positive short-term efficacy studies for approval of antidepressants, but this requirement was loosened for esketamine and a relapse-prevention trial was allowed to fill the place of the second efficacy trial instead. This is the first time that the FDA is known to have made such an exception and the decision has been criticized as lowering regulatory standards. In the relapse-prevention trial (SUSTAIN-2), the rate of depression relapse was significantly lower with esketamine continued than with it discontinued and replaced with placebo in esketamine-treated stable responders and remitters (51% rate reduction in remitters and 70% reduction in responders).

Esketamine was approved for the treatment of MDD with co-occurring suicidal ideation or behavior on the basis of two short-term (4-week) phase 3 trials (ASPIRE-1 and -2) of esketamine nasal spray added to a conventional antidepressant. The primary efficacy measure was reduction in MADRS total score after 24 hours following the first dose of esketamine. In both trials, MADRS scores were significantly reduced with esketamine relative to placebo at 24 hours. The mean MADRS scores at baseline were 39.4 to 41.3 in all groups and the MADRS reductions at 24 hours were –15.9 and –16.0 with esketamine and –12.0 and –12.2 with placebo, resulting in mean differences between esketamine and placebo of –3.8 and –3.9. The secondary efficacy measure in the trials was change in Clinical Global Impression of Suicidal Severity - Revised (CGI-SS-r) 24 hours after the first dose of esketamine. The CGI-SS-r is a single-item scale with scores ranging from 0 to 6. Esketamine was not significantly effective in reducing suicidality relative to placebo on this measure either at 24 hours or after 25 days. At 24 hours, CGI-SS-r scores were changed by –1.5 with esketamine and –1.3 with placebo, giving a non-significant mean difference between esketamine and placebo of –0.20. Hence, while efficacious in reducing depressive symptoms in people with depression and suicidality, antisuicidal effects of esketamine in such individuals have not been demonstrated.Expectations were initially very high for ketamine and esketamine for treatment of depression based on early small-scale clinical studies, with discovery of the rapid and ostensibly robust antidepressant effects of ketamine described by some authors as "the most important advance in the field of psychiatry in the past half century". According to a 2018 review, ketamine showed more than double the antidepressant effect size over placebo of conventional antidepressants in the treatment of depression based on the preliminary evidence available at the time (Cohens d = 1.3–1.7 for ketamine, Cohens d = 0.8 for midazolam (active placebo), and Cohens d = 0.53–0.81 for conventional antidepressants). However, the efficacy of ketamine/esketamine for depression declined dramatically as studies became larger and more methodologically rigorous. The effectiveness of esketamine for the indication of TRD is described as "modest" and is similar in magnitude to that of other antidepressants for treatment of MDD. The comparative effectiveness of ketamine and esketamine in the treatment of depression has not been adequately characterized. A January 2021 meta-analysis reported that ketamine was similarly effective to esketamine in terms of antidepressant effect size (SMD for depression score of –1.1 vs. –1.2) but more effective than esketamine in terms of response and remission rates (RR = 3.01 vs. RR = 1.38 for response and RR = 3.70 vs. RR = 1.47 for remission). A September 2021 Cochrane review found that ketamine had an effect size (SMD) for depression at 24 hours of –0.87, with very low certainty, and that esketamine had an effect size (SMD) at 24 hours of –0.31, based on moderate-certainty evidence. However, these meta-analyses have involved largely non-directly-comparative studies with dissimilar research designs and patient populations. Only a single clinical trial has directly compared ketamine and esketamine for depression as of May 2021. This study reported similar antidepressant efficacy as well as tolerability and psychotomimetic effects between the two agents. However, the study was small and underpowered, and more research is still needed to better-characterize the comparative antidepressant effects of ketamine and esketamine. Preliminary research suggests that arketamine, the R(−) enantiomer of ketamine, may also have its own independent antidepressant effects and may contribute to the antidepressant efficacy of racemic ketamine, but more research likewise is needed to evaluate this possibility.In February 2019, an outside panel of experts recommended in a 14–2 vote that the FDA approve the nasal spray version of esketamine for TRD, provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after. The approval of esketamine for TRD by the FDA was controversial due to limited and mixed evidence of efficacy and safety. In January 2020, esketamine was rejected by the National Health Service (NHS) of Great Britain. The NHS questioned the benefits of the medication for depression and claimed that it was too expensive. People who have been already using esketamine were allowed to complete treatment if their doctors considered this necessary.Spravato debuted to a cost of treatment of US$32,400 per year when it launched in the United States in March 2019. The Institute for Clinical and Economic Review (ICER), which evaluates cost effectiveness of drugs analogously to the National Institute for Health and Care Excellence (NICE) in the United Kingdom, declined to recommend esketamine for depression due to its steep cost and modest efficacy, deeming it not sufficiently cost-effective.Esketamine is the second drug to be approved for TRD by the FDA, following olanzapine/fluoxetine (Symbyax) in 2009. Other agents, like the atypical antipsychotics aripiprazole (Abilify) and quetiapine (Seroquel), have been approved for use in the adjunctive therapy of MDD in people with a partial response to treatment. In a meta-analysis conducted internally by the FDA during its evaluation of esketamine for TRD, the FDA reported a standardized mean difference (SMD) of esketamine for TRD of 0.28 using the three phase 3 short-term efficacy trials conducted by Janssen. This was similar to an SMD of 0.26 for olanzapine/fluoxetine for TRD and lower than SMDs of 0.35 for aripiprazole and 0.40 for quetiapine as adjuncts for MDD. These drugs are less expensive than esketamine and may serve as more affordable alternatives to it for depression with similar effectiveness.

Adverse effects
The most common adverse effects of esketamine for depression (≥5% incidence) include dissociation, dizziness, sedation, nausea, vomiting, vertigo, numbness, anxiety, lethargy, increased blood pressure, and feelings of drunkenness. Long-term use of esketamine has been associated with bladder disease.

Pharmacology
Pharmacodynamics
Esketamine is approximately twice as potent an anesthetic as racemic ketamine.In mice, the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine. The usefulness of arketamine over esketamine has been supported by other researchers.Esketamine inhibits dopamine transporters eight times more than arketamine. This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients. Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly. This is however in contradiction with arketamine being devoid of psychotomimetic side effects.Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in the frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing. However, another study found no difference between racemic ketamine and esketamine on the patients level of vigilance. Interpretation of this finding is complicated by the fact that racemic ketamine is 50% esketamine.

Pharmacokinetics
Esketamine is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows the elimination of esketamine.

History
Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries. In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such. Esketamine received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016. In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States </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 VIII and can you explain it in depth? [/INST] Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the F8 gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disorder. Factor VIII is produced in liver sinusoidal cells and endothelial cells outside the liver throughout the body. This protein circulates in the bloodstream in an inactive form, bound to another molecule called von Willebrand factor, until an injury that damages blood vessels occurs. In response to injury, coagulation factor VIII is activated and separates from von Willebrand factor. The active protein (sometimes written as coagulation factor VIIIa) interacts with another coagulation factor called factor IX. This interaction sets off a chain of additional chemical reactions that form a blood clot.Factor VIII participates in blood coagulation; it is a cofactor for factor IXa, which, in the presence of Ca2+ and phospholipids, forms a complex that converts factor X to the activated form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.People with high levels of factor VIII are at increased risk for deep vein thrombosis and pulmonary embolism. Copper is a required cofactor for factor VIII and copper deficiency is known to increase the activity of factor VIII.There is a formulation as a medication that is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.

Genetics
Factor VIII was first characterized in 1984 by scientists at Genentech. The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII presents an interesting primary structure, as another gene (F8A1) is embedded in one of its introns.

Structure
Factor VIII protein consists of six domains: A1-A2-B-A3-C1-C2, and is homologous to factor V.
The A domains are homologous to the A domains of the copper-binding protein ceruloplasmin.  The C domains belong to the  phospholipid-binding discoidin domain family, and the C2 domain mediate membrane binding.Activation of factor VIII to factor VIIIa is done by cleavage and release of the B domain. The protein is now divided to a heavy chain, consisting of the A1-A2 domains, and a light chain, consisting of the A3-C1-C2 domains. Both form non-covalently a complex in a calcium-dependent manner. This complex is the pro-coagulant factor VIIIa.

Physiology
FVIII is a glycoprotein procofactor.  Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver </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 Voxelotor and can you explain it in depth? [/INST] Voxelotor, sold under the brand name Oxbryta, is a medication used for the treatment of sickle cell disease. Developed by Global Blood Therapeutics, voxelotor is the first hemoglobin oxygen-affinity modulator. Voxelotor has been shown to have disease-modifying potential by increasing hemoglobin levels and decreasing hemolysis indicators in sickle cell patients. It has a safe profile in sickle cell patients and healthy volunteers, without any dose-limiting toxicity.In November 2019, voxelotor received accelerated approval in the United States for the treatment of sickle cell disease (SCD) for those twelve years of age and older </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 Sodium fluoride and can you explain it in depth? [/INST] Sodium fluoride (NaF) is an inorganic compound with the formula NaF. It is used in trace amounts in the fluoridation of drinking water, in toothpaste, in metallurgy, and as a flux. It is a colorless or white solid that is readily soluble in water. It is a common source of fluoride in the production of pharmaceuticals and is used to prevent dental cavities.
In 2017, it was the 247th most commonly prescribed medication in the United States, with more than one million prescriptions.

Uses
Dental caries
Fluoride salts are often added to municipal drinking water (as well as to certain food products in some countries) for the purpose of maintaining dental health. The fluoride enhances the strength of teeth by the formation of fluorapatite, a naturally occurring component of tooth enamel. Although sodium fluoride is used to fluoridate water and is the standard by which other water-fluoridation compounds are gauged, hexafluorosilicic acid (H2SiF6) and its salt sodium hexafluorosilicate (Na2SiF6) are more commonly used additives in the United States.

Osteoporosis
Fluoride supplementation has been extensively studied for the treatment of postmenopausal osteoporosis. This supplementation does not appear to be effective; even though sodium fluoride increases bone density, it does not decrease the risk of fractures.

Medical imaging
In medical imaging, fluorine-18-labelled sodium fluoride (USP, sodium fluoride F18) is one of the oldest tracers used in positron emission tomography (PET), having been in use since the 1960s. Relative to conventional bone scintigraphy carried out with gamma cameras or SPECT systems, PET offers more sensitivity and spatial resolution. Fluorine-18 has a half-life of 110 min, which requires it to be used promptly once produced; this logistical limitation hampered its adoption in the face of the more convenient technetium-99m-labelled radiopharmaceuticals. However fluorine-18 is generally considered to be a superior radiopharmaceutical for skeletal imaging. In particular it has a high and rapid bone uptake accompanied by very rapid blood clearance, which results in a high bone-to-background ratio in a short time. Additionally the annihilation photons produced by decay of 18F have a high energy of 511 keV  compared to the 140 keV photons of 99mTc.

Chemistry
Sodium fluoride has a variety of specialty chemical applications in synthesis and extractive metallurgy. It reacts with electrophilic chlorides including acyl chlorides, sulfur chlorides, and phosphorus chloride. Like other fluorides, sodium fluoride finds use in desilylation in organic synthesis. Sodium fluoride can be used to produce fluorocarbons via the Finkelstein reaction; this process has the advantage of being simple to perform on a small scale but is rarely used on an industrial scale due to the existence of more effective techniques (e.g. Electrofluorination, Fowler process).

Other uses
Sodium fluoride is used as a cleaning agent (e.g., as a "laundry sour").Sodium fluoride can be used in a nuclear molten salt reactor.
Over a century ago, sodium fluoride was used as a stomach poison for plant-feeding insects. Inorganic fluorides such as fluorosilicates and sodium fluoride complex magnesium ions as magnesium fluorophosphate. They inhibit enzymes such as enolase that require Mg2+ as a prosthetic group. Thus, fluoride poisoning prevents phosphate transfer in oxidative metabolism.

Safety
The lethal dose for a 70 kg (154 lb) human is estimated at 5–10 g.Fluorides, particularly aqueous solutions of sodium fluoride, are rapidly and quite extensively absorbed by the human body.Fluorides interfere with electron transport and calcium metabolism. Calcium is essential for maintaining cardiac membrane potentials and in regulating coagulation. High ingestion of fluoride salts or hydrofluoric acid may result in fatal arrhythmias due to profound hypocalcemia. Chronic over-absorption can cause hardening of bones, calcification of ligaments, and buildup on teeth. Fluoride can cause irritation or corrosion to eyes, skin, and nasal membranes.Sodium fluoride is classed as toxic by both inhalation (of dusts or aerosols) and ingestion.  In high enough doses, it has been shown to affect the heart and circulatory system. For occupational exposures, the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health have established occupational exposure limits at 2.5 mg/m3 over an eight-hour time-weighted average.In the higher doses used to treat osteoporosis, plain sodium fluoride can cause pain in the legs and incomplete stress fractures when the doses are too high; it also irritates the stomach, sometimes so severely as to cause peptic ulcer disease. Slow-release and enteric-coated versions of sodium fluoride do not have significant gastric side effects, and have milder and less frequent complications in the bones </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 Kinneret 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 Trifarotene 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 Docetaxel and can you explain it in depth? [/INST] Docetaxel (DTX or DXL), sold under the brand name Taxotere among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer, head and neck cancer, stomach cancer, prostate cancer and non-small-cell lung cancer. It may be used by itself or along with other chemotherapy medication. It is given by slow injection into a vein.Common side effects include hair loss, cytopenia (low blood cell counts), numbness, shortness of breath, nausea, vomiting, and muscle pains. Other severe side effects include allergic reactions and future cancers. Docetaxel induced pneumotoxicity is also a well recognized adverse effect which has to be identified timely and treated after withholding the drug  Side effects are more common in people with liver problems. Use during pregnancy may harm the baby. Docetaxel is in the taxane family of medications. It works by disrupting the normal function of microtubules and thereby stopping cell division.Docetaxel was patented in 1986 and approved for medical use in 1995. It is on the World Health Organizations List of Essential Medicines. Docetaxel is available as a generic medication.

Medical uses
Docetaxel is used in the treatment of various cancers, including breast, lung, prostate, gastric, head and neck, and ovarian cancer. Clinical data have shown docetaxel to have cytotoxic activity against breast, colorectal, lung, ovarian, prostate, liver, renal, gastric, and head and neck cancers and melanoma. In hormone-refractory prostate cancer docetaxel improves life expectancy and overall life quality.The optimal dose scheduling of taxanes remains unconfirmed, but most studies find significant mortality benefit following either a three-week or a one-week administration schedule.  While a 2010 article in Current Clinical Pharmacology states, "weekly administration has emerged as the optimal schedule," the official docetaxel package insert recommends administration every three weeks.

Outcomes
Treatment with docetaxel increases survival time in people with certain types of cancer. While some clinical trials show median survival times to be increased by approximately only three months, the range of survival time is large. Many people survive beyond five years with treatment from docetaxel, however it is difficult to attribute these findings directly to treatment with docetaxel. Improved median survival time and response indicates that docetaxel slows metastatic cancer progression and can lead to disease-free survival. Conjunctive treatment of prednisone with docetaxel has been shown to lead to improved survival rate as well as improved quality of life and reduction of pain compared with treatments with mitoxantrone.As well as inhibiting mitosis, the presence of docetaxel has been found to lead to the phosphorylation of the oncoprotein bcl-2, which leads to apoptosis of cancer cells that had previously blocked the apoptotic inducing mechanism, leading to tumour regression. Enhanced effects of radiation therapy when combined with docetaxel has been observed in mice. Docetaxel has also been found to have greater cellular uptake and is retained longer intracellularly than paclitaxel allowing docetaxel treatment to be effective with a smaller dose, leading to fewer and less severe adverse effects.

Breast cancer
Docetaxel and paclitaxel have comparable efficacy metastatic breast cancer but paclitaxel has less severe side effects. Additionally, it has been noted that docetaxel is prone to cellular drug resistance via a variety of different mechanisms.

Monitoring and combination use
Docetaxel is administered via a one-hour infusion every three weeks over ten or more cycles. Treatment is given under the supervision of an oncologist. Strict monitoring of blood cell counts, liver function, serum electrolytes, serum creatinine, heart function, oxygen saturation and fluid retention is required detect adverse reactions and toxicity so that treatment can be modified or terminated if necessary.Premedication with corticosteroids is recommended before each administration of docetaxel to reduce fluid retention and hypersensitive reactions. Other medications will often be given to aid pain management and other symptoms. The treatment of breast cancer with doxorubicin and cyclophosphamide is enhanced by adjuvant treatment with docetaxel. Docetaxel is also used in combination with capecitabine, a DNA synthesis inhibitor.

Side effects
Docetaxel is a cytotoxic chemotherapeutic agent. As with all chemotherapy, adverse effects are common, and many side effects have been documented. Because docetaxel is a cell-cycle-specific agent, it is cytotoxic to all dividing cells in the body. This includes tumour cells as well as hair follicles, bone marrow and other germ cells. For this reason, common chemotherapy side effects such as hair loss occur; sometimes this can be permanent. North west France are conducting a survey to establish exactly how many people are affected in this way. Independent studies show it could be as high as 6.3%, which puts it in the common and frequent classification.Haematological adverse effects include neutropenia (95.5%), anaemia (90.4%), febrile neutropenia (11.0%) and thrombocytopenia (8.0%). Deaths due to toxicity accounted for 1.7% of the 2045 patients, and incidence was increased (9.8%) in patients with elevated baseline liver function tests (liver dysfunction).Taxane-induced pneumotoxicity is rare. However, 1–5% of patients taking docetaxel may develop severe pneumotoxicity. Patients may develop exertional breathlessness and desaturation which needs to be detected early. Chest X-Ray may show bilateral opacities and High Resolution CT chest may reveal Organizing Pneumonia (OP) pattern or Non-Specific Organizing Pneumonia (NSIP) pattern or a combination. Docetaxel-induced DPLD is a fatal adverse effect, which can be managed by the cessation of the drug and starting on steroids in adequate doses.Observations of severe side effects in the above 40 phase II and phase III studies were also recorded.
Many more side effects have been reported for conjunctive and adjuvant treatment with docetaxel as well as rare post-marketing events.

Contraindications and patient factors
Docetaxel is contraindicated for use with patients with a baseline neutrophil count less than 1500 cells/µL, a history of severe hypersensitivity reactions to docetaxel or polysorbate 80, severe liver impairment and pregnant or breast-feeding women.Side effects are experienced more frequently by patients of 65 years or older, but dosage is usually not decreased. Kidney failure is thought not to be a significant factor for docetaxel dosage adjustment. Patients with hepatic insufficiency resulting in serum bilirubin greater than the upper limit of normal (ULN) should not be administered docetaxel, though this is not a stated contraindication. Dosage should be reduced by 20% in people who develop grade 3 or 4 diarrhea following exposure to docetaxel, hepatotoxicity defined by liver enzymes at levels greater than five times the ULN, and grade 2 palmer-planter toxicity.Paediatric trials of docetaxel have been limited, and so safety of use in patients under 16 years has not been established.

Pregnancy
Based on the limited data available, docetaxel appears to be safe in pregnancy if administered during the second and third trimesters; however, maternal and fetal risks should be weighed against benefits to determine the appropriate course of action.
As with all chemotherapeutic agents, docetaxel administered to pregnant animals causes a variety of embryofetal toxicities, including death, when given during the period of organogenesis. Yet adequate studies investigating maternal and fetal effects in humans are lacking. One small systematic review that examined the use of taxanes to treat breast cancer in pregnancy showed that, out of 19 patients, only three congenital malformations occurred. Two cases of cerebral ventriculomegaly observed in the study were documented prior to the administration of chemotherapy, suggesting an alternate cause of congenital malformation. The third case involved pyloric stenosis in an infant whose mother received a combination regimen of docetaxel, doxorubicin, cyclophosphamide and paclitaxel; because the fetus was exposed to multiple drugs in utero, it remains difficult to identify docetaxel as the causative teratogenic agent. Further studies are needed to better assess the safety of docetaxel in pregnancy and determine appropriate dosing in pregnant women.

Drug interactions
Drug interactions may be the result of altered pharmacokinetics or pharmacodynamics due to one of the drugs involved.  Cisplatin, dexamethasone, doxorubicin, etoposide, and vinblastine are all potentially co-administered with docetaxel and did not modify docetaxel plasma binding in phase II studies. Cisplatin is known to have a complex interaction with some CYPs and has in some events been shown to reduce docetaxel clearance by up to 25%. Anticonvulsants induce some metabolic pathways relevant to docetaxel. CYP450 and CYP3A show increased expression in response to the use of anticonvulsants and the metabolism of docetaxel metabolite M4 is processed by these CYPs. A corresponding increase in clearance of M4 by 25% is observed in patients taking phenytoin and phenobarbital, common anticonvulsants.
Erythromycin, ketoconazole and cyclosporine are CYP3A4 inhibitors and therefore inhibit the metabolic pathway of docetaxel. When used with anticonvulsants, which induce CYP3A4, an increased dose of docetaxel may be required.Pre-treatment with corticosteroids has been used to decrease hypersensitivity reactions and oedema in response to docetaxel and has shown no effect on the pharmacokinetics of docetaxel. The efficacy of docetaxel was improved by treatment with oral capecitabine, and after more than 27 months follow-up the survival benefit has been confirmed. Doxorubicin was combined with docetaxel in one study of 24 patients and resulted in an increased AUC of docetaxel by 50 to 70%, indicating doxorubicin may affect the disposition of docetaxel. Etoposide has also been shown to decrease docetaxel clearance, though patient numbers for this observation have been low.Prednisone given with docetaxel led to improved survival, quality of life and pain management in patients with hormone-refractory prostate cancer.

Chemistry
Docetaxel is of the chemotherapy drug class; taxane, and is a semi-synthetic analogue of paclitaxel (Taxol), an extract from the bark of the rare Pacific yew tree, Taxus brevifolia. Due to scarcity of paclitaxel, extensive research was carried out leading to the formulation of docetaxel – an esterified product of 10-deacetyl baccatin III, which is extracted from the renewable and more readily available leaves of the European yew tree.
Docetaxel differs from paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas paclitaxel has an acetate ester, and a tert-butyl carbamate ester exists on the phenylpropionate side chain instead of the benzamide in paclitaxel. The carbon 10 functional group change causes docetaxel to be more water-soluble than paclitaxel.

Formulations and compositions
Docetaxel is a white powder and is the active ingredient available in 20 mg and 80 mg Taxotere single-dose vials of concentrated anhydrous docetaxel in polysorbate 80. The solution is a clear brown-yellow containing 40 mg docetaxel and 1040 mg polysorbate 80 per mL. 20 mg Taxotere is distributed in a blister carton containing one single-dose vial of Taxotere (docetaxel) preparation in 0.5 mL sterile pyrogen-free anhydrous polysorbate 80, and a single dose Taxotere solvent vial containing 1.5 mL 13% ethanol in saline to be combined and diluted in a 250 mL infusion bag containing 0.9% sodium chloride or 5% glucose for administration. 80 mg Taxotere is supplied identically but with 2.0 mL polysorbate 80 and 6.0 mL 13% ethanol in saline. The docetaxel and solvent vials are combined to give a solution of 10 mg/mL and the required dose is drawn from this solution. Vials have an overfill to compensate for liquid loss during preparation, foaming, adhesion to vial walls and the dead volume. 20 mg vials may be stored for 24 months below 25 °C away from light and 80 mg vials for 26 months in the same conditions.Recently Sanofi has got approval for one-vial formulation. With this one-vial formulation, the preparation of the infusion solution is simplified by eliminating the first dilution step.
The two-vial and one-vial formulations contain the same drug substance, docetaxel trihydrate, and the same excipients (ethanol, polysorbate 80 and citric acid).
The one-vial formulation is administered as an aqueous intravenous solution that contains the same drug substance in the same concentration as the already approved two-vial formulation. The same grade, quality, and quantity of polysorbate 80 are present in the infusion solution of both formulations. The only difference between these two formulations is the quantity of ethanol.

Active regions
A model based on electron crystallographic density and nuclear magnetic resonance deconvolution has been proposed to explain the binding of docetaxel to β-tubulin. In this T-shaped/butterfly model, a deep hydrophobic cleft exists near the surface of the β-tubulin where three potential hydrogen bonds and multiple hydrophobic contacts bind to docetaxel. The hydrophobic pocket walls contain helices H1, H6, H7 and a loop between H6 and H7 that form hydrophobic interactions with the 3’-benzamido phenyl, 3’-phenyl, and the 2-benzoyl phenyl of docetaxel. 3’-phenyl also has contact with β-sheets B8 and B10. The C-8 methyl of docetaxel has Van der Waals interactions with two residues, Thr-276 and Gln-281 near the C-terminal end of β-tubulin. Docetaxels O-21 experiences electrostatic attraction to Thr-276 and the C-12 methyl has proximity with Leu-371 on the loop between B9 and B10.

Pharmacokinetics
Absorption and distribution
Oral bioavailability has been found to be 8% ±6% on its own and, when co-administered with cyclosporine, bioavailability increased to 90% ± 44%. In practice, docetaxel is administered intravenously only to increase dose precision. Evaluation of docetaxel pharmacokinetics in phase II and III clinical studies were with 100 mg/m2 dosages given over one-hour infusions every three weeks.Docetaxel was shown to be greater than 98% plasma protein bound independent of concentration at 37 °C and pH 7.4 Docetaxels plasma protein binding includes lipoproteins, alpha1 acid glycoprotein and albumin. Alpha1 acid glycoprotein is the most variable of these proteins inter-individually, especially in cancer patients and is therefore the main determinant of docetaxels plasma binding variability. Docetaxel interacted little with erythrocytes and was unaffected by the polysorbate 80 in its storage medium. Polysorbate 80 may be the cause of hypersensitivity reasons in taxanes as recent studies indicated.The concentration-time profile of docetaxel was consistent with a three-compartment pharmacokinetic model. An initial, relatively rapid decline, with an α half-life of mean 4.5 minutes is representative of distribution to peripheral compartments from the systemic circulation. A β half-life of mean 38.3 minutes and a relatively slow γ half-life of mean 12.2 hours represent the slow efflux of docetaxel from the peripheral compartment.Administration a 100 mg/m2 dose over a one-hour infusion gave a mean total body clearance of 21 L/h/m2 and a mean steady state volume of distribution of 73.8 L/m2 or 123 L based on the mean BSA (body surface area) of 1.68 m2. Area under the plasma concentration-time curve had a mean value of 2.8 mg.h/L. The Cmax of docetaxel was found to be 4.15 ± 1.35 mg/L. Increased dose resulted in a linear increase of the area under the concentration-time curve and so it is concluded that dose is directly proportional to plasma concentration.

Metabolism and excretion
Docetaxel is mainly metabolised in the liver by the cytochrome P450 CYP3A4 and CYP3A5 subfamilies of isoenzymes. Metabolism is principally oxidative and at the tert-butylpropionate side chain, resulting first in an alcohol docetaxel (M2), which is then cyclised to three further metabolites (M1, M3 and M4). M1 and M3 are two diastereomeric hydroxyoxazolidinones and M4 is an oxazolidinedione. Phase II trials of 577 patients showed docetaxel clearance is related to body surface area and to hepatic enzyme and alpha1 acid glycoprotein plasma levels. The following model represents docetaxel clearance in humans:

where CL is total body clearance (L/h), BSA is total body surface area (m2), AAG and ALB represent alpha1 acid glycoprotein and albumin plasma concentrations (g/L) respectively, and AGE is the patients age (years). HEP12 represents a measure of hepatic dysfunction, affecting clearance of docetaxel. This final model accounted for a modest proportion of patients and identified most of the patients varying from the model (population median of CL = 35.6 L/h) as having hepatic dysfunction, indicating hepatic function as the most unpredictable factor with regards to clearance variability.Patients with significant hepatic dysfunction had an approximately 30% decrease in clearance of docetaxel and were also at a higher risk of toxicity poisoning from docetaxel treatment. Clearance has been shown from population pharmacokinetic studies to decrease significantly with age, increased alpha1 acid glycoprotein and albumin concentrations and decreased body surface area.Renal impairment is unlikely to affect metabolism or excretion of docetaxel as renal excretion contributes less than 5% of elimination. Limited data is available for docetaxel use in children with dosage between 55 and 75 mg/m2. Two paediatric studies have taken place that show a mean clearance of 33 L/h/m2 and concentration-time profiles best fitted by a two-compartmental model of distribution and elimination. Mean distribution half-life was 0.09 hours and mean elimination half-life was 1.4 hours in paediatric studies.Biodistribution of 14C-labelled docetaxel in three patients showed the bulk of the drug to be metabolised and excreted in bile to the faeces. Of the radioactively labelled docetaxel administered, 80% was eliminated to the faeces with 5% in the urine over seven days, an indication that urinary excretion of docetaxel is minimal. Saliva contributed minimal excretion and no excretion was detected through pulmonary means. The terminal half-life of docetaxel was determined as approximately 86 hours, through prolonged plasma sampling, contrary to the clinically stated terminal half-life of 10–18 hours.

Mechanism of action
Molecular target
Docetaxel binds to microtubules reversibly with high affinity and has a maximum stoichiometry of 1 mole docetaxel per mole tubulin in microtubules. This binding stabilizes microtubules and prevents depolymerisation from calcium ions, decreased temperature and dilution, preferentially at the plus end of the microtubule. Docetaxel has been found to accumulate to higher concentration in ovarian adenocarcinoma cells than kidney carcinoma cells, which may contribute to the more effective treatment of ovarian cancer by docetaxel. It has also been found to lead to the phosphorylation of oncoprotein bcl-2, which is apoptosis-blocking in its oncoprotein form.

Modes of action
The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule depolymerisation/disassembly in the absence of GTP. This leads to a significant decrease in free tubulin, needed for microtubule formation and results in inhibition of mitotic cell division between metaphase and anaphase, preventing further cancer cell progeny.Because microtubules do not disassemble in the presence of docetaxel, they accumulate inside the cell and cause initiation of apoptosis. Apoptosis is also encouraged by the blocking of apoptosis-blocking bcl-2 oncoprotein. Both in vitro and in vivo analysis show the anti-neoplastic activity of docetaxel to be effective against a wide range of known cancer cells, cooperate with other anti-neoplastic agents activity, and have greater cytotoxicity than paclitaxel, possibly due to its more rapid intracellular uptake.The main mode of therapeutic action of docetaxel is the suppression of microtubule dynamic assembly and disassembly, rather than microtubule bundling leading to apoptosis, or the blocking of bcl-2.

Cellular responses
Docetaxel exhibits cytotoxic activity on breast, colorectal, lung, ovarian, gastric, renal and prostate cancer cells </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 Fondaparinux and can you explain it in depth? [/INST] Fondaparinux (trade name Arixtra) is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by GlaxoSmithKline. A generic version developed by Alchemia is marketed within the US by Dr. Reddys Laboratories.

Medical uses
Clinically, it is used for the prevention of deep vein thrombosis in patients who have had orthopedic surgery as well as for the treatment of deep vein thrombosis and pulmonary embolism.Fondaparinux is similar to enoxaparin in reducing the risk of ischemic events at nine days, but it substantially reduces major bleeding and improves long-term mortality and morbidity.It has been investigated for use in conjunction with streptokinase.

Comparison to other agents
One potential advantage of fondaparinux over LMWH or unfractionated heparin is that the risk for heparin-induced thrombocytopenia (HIT) is substantially lower. Furthermore, there have been case reports of fondaparinux being used to anti-coagulate patients with established HIT as it has no affinity for PF4 </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 Zafirlukast and can you explain it in depth? [/INST] Zafirlukast is an orally administered leukotriene receptor antagonist (LTRA) used for the chronic treatment of asthma. While zafirlukast is generally well tolerated, headache and stomach upset often occur. Some rare side effects can occur, which can be life-threatening, such as liver failure. Churg-Strauss syndrome has been associated with zafirlukast, but the relationship isnt thought to be causative in nature. Overdoses of zafirlukast tend to be self-limiting.
Zafirlukast, like other LTRAs, works by inhibiting the immune system. Through its action on inflammatory cells in the lungs, zafirlukast reduces the production of inflammatory mediators that are implicated in the pathogenesis of asthma. Zafirlukast is extensively hepatically metabolized by an enzyme called CYP2C9. Zafirlukast inhibits the action of CYP3A4, leading to drug-drug interactions with other drugs that are metabolized by CYP3A4. Genetic differences in LTC4 synthase and CYP2C9 may predict how a person reacts to zafirlukast treatment.
Zafirlukast (brand name Accolate) was the first cysteinyl leukotriene receptor antagonist approved in the United States. It is now approved in many other countries under other brand names.

Medical uses
Zafirlukast is FDA-approved for the prevention and treatment of asthma in adults and children older than 5 years old. Like other leukotriene receptor antagonists, zafirlukast is thought to be useful for the long-term treatment of asthma, but it is generally less effective than inhaled glucocorticoids as monotherapy (which are the standard of care) or long-acting beta-2 agonists in combination therapy. Notably, zafirlukast is ineffective in the event of an acute asthma attack.

Available forms
There are two dosage forms for zafirlukast, notable for their age-adjustments. The 20 mg tablet is for adults and children older than age 12, whereas the 10 mg tablet is for children between the ages of 5 and 12. Tablets should be stored at room temperature, out of direct sunlight, and away from sources of moisture.Tablets are for oral administration only.

Specific populations
Pediatrics
As a general rule, leukotriene receptor antagonists like zafirlukast are more effective in children that are younger and whose asthma is less atopic. Atopy refers to a predisposition towards developing allergic conditions, including asthma, hay fever, and eczema.

Geriatrics
The hepatic clearance of zafirlukast is impaired in adults 65 years of age and older, resulting in a 2–3 fold increase in the maximum plasma concentration and the total area under the curve. Zafirlukast may increase the risk for infections (7.0% vs 2.9%, zafirlukast vs. placebo incidence respectively), especially lower respiratory tract infections, in older adults, though the infections noted were not severe.

Pregnancy
Zafirlukast is considered to be "pregnancy category B." This is due, in part, to the wide safety margin of zafirlukast in animal studies investigating teratogenicity. No teratogenicity has been observed in doses up to 2000 mg/kg/day in cynomolgus monkeys, representing an equivalent 20x exposure of the maximum recommended daily oral dose in human adults. However, spontaneous abortions occurred in cynomolgus monkeys at 2000 mg/kg/day, though the dose itself was maternally toxic.

Lactation
There is limited research on the use of zafirlukast in women whom are breastfeeding. Based on data from the manufacturer, it is expected that 0.6% of the maternal weight-adjusted dose would reach a breastfed infant, though the effects in the infant are unknown.

Renal impairment
Renal impairment does not appear to affect the pharmacokinetic profile of zafirlukast.

Hepatic impairment
The hepatic clearance of zafirlukast is impaired by significant hepatic impairment. Cirrhosis of the liver can result in an increase in the maximum plasma concentration and the total area under the curve (a measure of drug exposure) by 50–60%.

Contraindications
Zafirlukast is contraindicated in people that are hypersensitive or allergic to it.

Adverse effects
Zafirlukast is generally well tolerated, though headache and gastrointestinal (GI) upset can occur. The incidence of headache is between 12 and 20%, which is similar to the incidence of headache found in patients taking placebos in the studies that lead to zafirlukasts approval. GI upset may include nausea, stomach discomfort/pain, and diarrhea. GI complaints can be lessened by taking zafirlukast with food, though this can dramatically impair the amount of drug that gets absorbed into the body (see the section on drug-food interactions below).Other common side effects include flu-like symptoms, sleep disturbances (abnormal dreams, insomnia), hallucinations, and daytime drowsiness.

Neuropsychiatric effects
Neuropsychiatric side effects have been reported with the use of zafirlukast and other LTRAs. While some side effects are less severe (e.g. abnormal dreams), others are more serious (e.g. hallucinations, tremor, suicidality). These effects were discovered through post-marketing reports, as the initial trials were not designed to monitor for neuropsychiatric side effects.

Hepatotoxicity
Zafirlukast can also cause rare but serious side effects like acute liver injury. Zafirlukast-induced hepatotoxicity generally occurs within the first 2–6 months of initiating therapy, though cases have been reported up to 13 months after starting zafirlukast. Zafirlukast-induced hepatotoxicity is characterized by a spectrum of liver damage symptoms, including fatigue, nausea, and right upper quadrant pain followed by dark urine, jaundice and pruritus. Liver enzyme elevations are common, and the pattern usually reflects hepatocellular damage, resembling acute viral hepatitis. It is unclear how the hepatotoxicity occurs, but it may be due to a metabolic intermediate of zafirlukast, since it is metabolized in the liver through the enzyme CYP2C9. When it does occur it can be fatal, and reexposure with zafirlukast may result in a worse injury. Switching zafirlukast to another medication in the same class (e.g. montelukast) or in the related class of 5-lipoxygenase inhibitors can be attempted, but caution should be employed.According to the "Dear Health Care Provider" letter from AstraZeneca, zafirlukast-induced hepatotoxicity has occurred predominantly in females.

Churg-Strauss syndrome
Several cases of Churg-Strauss syndrome, also known as allergic angiitis and granulomatosis, have been reported with the use of zafirlukast, montelukast, pranlukast, and other asthma medications. When Churg-Strauss syndrome occurs, it tends to occur in people with long-standing asthma and sinus inflammation, chronic oral corticosteroid use, and the recent initiation of a new anti-asthma therapy (like zafirlukast) in conjunction with tapering the corticosteroids. While the exact etiology of the development of Churg-Strauss symptoms in proximity to initiating zafirlukast is unknown, it is thought that withdrawal of chronic corticosteroids "unmasks" the previously undetected disease. Because corticosteroid withdrawal often happens while starting a new anti-asthma medication (like zafirlukast), this explains the rare but notable association. These cases may represent misdiagnosed asthma, as Churg-Strauss syndrome can induce symptoms of airway obstruction that are akin to an acute asthma exacerbation. As these asthma-like symptoms are reduced by zafirlukast, the symptoms of Churg-Strauss (e.g. neuropathy) increase due to the lack of the broader, anti-inflammatory coverage that the steroid was providing.

Overdose
The highest overdose reported with zafirlukast is 200 mg. All overdose patients have survived. Symptoms reported included rash and upset stomach.

Interactions
Drug-drug interactions
Zafirlukast is an inhibitor of the hepatic drug-metabolizing enzyme cytochrome P450 family 3 subfamily A member 4 (CYP3A4). Zafirlukast may increase the concentration of drugs that are metabolized through CYP3A4, such as the anticoagulant medication warfarin and the antiepileptic drugs phenytoin and carbamazepine.

Drug-food interactions
The oral absorption (bioavailability) of zafirlukast is decreased by 40% when it is taken with high fat or high protein meals. To avoid this interaction, zafirlukast should be taken on an empty stomach. An empty stomach is classified as an hour before, or two hours after, consuming a meal.

Pharmacology
Pharmacodynamics
Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLT1), a receptor found throughout the smooth muscle of the lungs, within interstitial lung macrophages (white blood cells that operate in the interstitial space of the lungs), and rarely in epithelial cells. CystLT1 is a receptor for a specific class of leukotrienes that contain the amino acid cysteine. These cysteinyl leukotrienes include leukotriene C4, leukotriene D4, and leukotriene E4, all of which are produced by inflammatory cells like eosinophils, basophils, and macrophages in the lungs. Through their action on CysLT1 these leukotrienes can trigger bronchoconstriction, a state in which the bronchial passages of the lungs constrict, leading to the characteristic, reactive airway symptoms associated with bronchial asthma. The other pro-inflammatory effects of leukotrienes, such as their inhibition of mucus clearance and their stimulation of mucus secretion and edema, are thought to play a role in the characteristic symptoms of allergic rhinitis (also called hay fever). By inhibiting the action of these specific leukotrienes, zafirlukast is thought to exert an anti-inflammatory effect against leukotriene-mediated inflammatory conditions.

Pharmacokinetics
Absorption
Zafirlukast is rapidly absorbed into the bloodstream following oral administration, reaching peak plasma levels within 3 hours of taking the dose. The peak plasma level is the maximum concentration of zafirlukast in the blood.

Distribution
Zafirlukast is moderately distributed into the bodys tissues, with an apparent steady state volume of distribution of 70 liters. Zafirlukast is highly plasma protein bound, 99% bound to albumin. Albumin is the most abundant protein found in human plasma and is capable of carrying and transporting drugs (like zafirlukast) throughout the body. In vivo research indicates that zafirlukast has low blood-brain barrier penetration. The blood-brain barrier is a protective system that prevents many chemicals from entering the brain.

Metabolism
Zafirlukast undergoes extensive hepatic metabolism into inactive metabolites.  Zafirlukast is primarily metabolized by the enzyme CYP2C9 to a hydroxylated metabolite.

Elimination
Zafirlukast is primarily cleared through biliary excretion at a rate of 20 liters/hour. Zafirlukast is undetectable in urine. The mean terminal half-life ranges 8–16 hours, following linear kinetics up to doses of 80 mg.

Pharmacogenomics
LTC4 synthase
Genetic polymorphisms in the LTC4 synthase promoter may predict response to zafirlukast. The single-nucleotide polymorphism (SNP) A444C (the wild-type DNA base adenine, at the 444th position on the gene, is mutated; cytosine is there instead), which is associated with a severe asthma phenotype, has been shown to decrease the clinical response to zafirlukast (both when the genetic alteration was heterozygous or homozygous).

CYP2C9
Zafirlukast is metabolized through the hepatic enzyme CYP2C9 </s>


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<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 Tolcapone and can you explain it in depth? [/INST] Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinsons disease (PD).  It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries.
In comparison with entacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate the blood–brain barrier, acting both in the central nervous system and in the periphery. However, entacapone is less toxic for the liver.

Medical uses
Tolcapone is used in the treatment of Parkinsons disease as an adjunct to levodopa/carbidopa or levodopa/benserazide medications. Levodopa is a prodrug for dopamine, which reduces Parkinson symptoms; carbidopa and benserazide are aromatic L-amino acid decarboxylase (AADC) inhibitors.Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations.

Contraindications
Combining tolcapone with non-selective monoamine oxidase inhibitors such as phenelzine or tranylcypromine is contraindicated. Tolcapone is also contraindicated for people with liver diseases or increased liver enzymes.

Side effects
Tolcapone has demonstrated significant liver toxicity (hepatotoxicity) that limits the drugs utility. Entacapone is an alternative, largely since it has a more favorable toxicity profile.
The hepatotoxicity can be related to elevated levels of transaminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored. No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation.Other side effects regard the increase in dopaminergic activity, including digestive symptoms. Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of levodopa. This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms.Digestive symptoms include nausea and diarrhea; further dopaminergic side effects include orthostatic hypotension, dry mouth, sweating and dizziness.  Tolcapone causes more severe diarrhea than entacapone; this was the most common reason for therapy termination in studies. Urine discoloration comes from yellow tolcapone metabolites being excreted in the urine and is harmless.

Interactions
While increase of dopamine levels is a desired interaction, tolcapone can theoretically also increase the levels of other drugs metabolised by COMT, such as the AADC inhibitors carbidopa and benzerazide, as well as methyldopa, dobutamine, apomorphine, adrenaline, and isoprenaline. In studies, a slight interaction with benzerazide was seen, but not with carbidopa. Other interactions with this group of drugs have not been studied. A related type of theoretical interactions is with drugs that increase catecholamine concentrations, such as monoamine oxidase (MAO) inhibitors and noradrenaline reuptake inhibitors; these also showed only slight effects in practice. Combination with non-selective MAO inhibitors might be dangerous.Due to its affinity to the liver enzyme CYP2C9, interactions with drugs being metabolised by this enzyme are also possible, but unlikely. No interaction with tolbutamide, a 2C9 substrate, was observed in studies.

Pharmacology
Mechanism of action
Tolcapone selectively and reversibly binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the three catecholamines, including levodopa. It thereby prevents the 3-O-methylation of levodopa by COMT in the periphery, which produces 3-O-methyldopa, a major metabolite that competes with levodopa to cross the blood–brain barrier. More of the levodopa that is administered reaches the CNS. Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity. Thus, tolcapone improves the bioavailability and reduces the clearance of levodopa and subsequently dopamine from the CNS.

The strength of the binding affinity of tolcapone, represented by the inhibition constant Ki (2.5 nM), can be thought of as the dissociation constant for enzyme and inhibitor complex kinetics. Maximum catalytic activity denotes the efficacy of tolcapone (Vmax = 58.4 pmol/min·mg).

Pharmacokinetics
Tolcapone is quickly absorbed from the gut to about 85%. It has an absolute bioavailability of 65%, which is only slightly decreased when taken with food. The substance reaches highest blood plasma concentrations after about two hours. When in the bloodstream, it is almost completely (>99.9%) bound to plasma proteins, primarily albumin. The main inactivation step is glucuronidation; other processes are methylation by COMT, hydroxylation by CYP3A4 and CYP2A6 with subsequent oxidation to a carboxylic acid, and possibly a minor path with reduction to an amine with subsequent acetylation.The half-life of tolcapone is two to three hours, the volume of distribution (Vd) being 0.3 L/kg (21 L in an average 70 kg person). 60% of the metabolites are excreted via the urine and 40% via the feces. Only 0.5% of the drug are excreted in unchanged form via the urine.

99% of tolcapone is in monoanionic form in the body because the physiological pH is 7.4. Tolcapone penetrates the blood–brain barrier much better than two other nitrocatechols, nitecapone and entacapone, because it has higher lipophilicity due to its R-substituent. Partition coefficients quantify the ability of the molecule to cross the blood–brain barrier. LogPIdce= 0.2, –1.4, –0.4 for tolcapone, nitecapone and entacopone respectively.  Partition coefficients in this case were measured in 1,2-dichloroethane/H2O solution which caused molecules to be in ionized form. There is no current explanation for how these charged molecules permeate the blood–brain barrier.

Chemistry
Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25 g/mol. It melts at 143 to 146 °C (289 to 295 °F), is practically insoluble in water and acids but soluble in 0.1 M aqueous sodium hydroxide solution. The pKa values are 4.5 and 10.6 for the two phenyl groups; and the maximum absorption is at 268 nm (in 0.1 M hydrochloric acid / ethanol). Its chemical name is 3,4-dihydroxy-4-methyl-5-nitrobenzophenone.

Synthesis
A synthesis of tolcapone proposed in 2008, begins with a Grignard reaction between a benzaldehyde derivative and p-tolyl magnesium bromide. The alcohol thus produced is then converted to a ketone using sodium t-butoxide. The benzyl protecting group is removed by palladium-catalyzed hydrogenation in the presence of ammonium formate. A nitro group is introduced at the 5-position adjacent to the hydroxyl group unmasked in the cleavage of the benzyl ether. The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol.

History
Tolcapone was introduced into the European market in August 1997, and subsequently into the United States market in March 1998. Liver toxicity was reported in four people who were administered tolcapone, three people died due to complications </s>


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<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 Cabotegravir and can you explain it in depth? [/INST] Cabotegravir, sold under the brand name Vocabria among others, is a antiretroviral medication used for the treatment of HIV/AIDS. It is available in the form of tablets and as an intramuscular injection, as well as in an injectable combination with rilpivirine under the brand name Cabenuva.It is an integrase inhibitor with a carbamoyl pyridone structure similar to that of dolutegravir.In December 2021, the U.S. Food and Drug Administration approved cabotegravir for pre-exposure prophylaxis (PrEP) in at-risk people under the brand name Apretude.

Medical uses
Cabotegravir in combination with rilpivirine is indicated for the treatment of human immunodeficiency virus type-1 (HIV-1) in adults. The combination injection is intended for maintenance treatment of adults who have undetectable HIV levels in the blood (viral load less than 50 copies/mL) with their current antiretroviral treatment, and when the virus has not developed resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors. The tablets are used to check whether a person tolerates the treatment before the injection therapy is started.The two medicines are the first antiretroviral drugs that come in a long-acting injectable formulation.Cabotegravir (Apretude) is indicated for use in at-risk people weighing at least 35 kilograms (77 lb) for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV.

Contraindications and interactions
Cabotegravir must not be combined with the drugs rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenytoin or phenobarbital, which induce the enzyme UGT1A1. These drugs significantly decrease cabotegravir concentrations in the body and thus may reduce its effectiveness. Additionally, they induce the enzyme CYP3A4, which leads to reduced rilpivirine concentrations in the body. Additionally, patients who are breastfeeding or plan to breastfeed should not take Cabotegravir because it is not known if it will pass within the breast milk.

Adverse effects
The most common side effects of the injectable combination therapy with rilpivirine are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). For the tablets, headache and a hot feeling were slightly less frequent. Less common side effects (under 10%) for both formulations are depressive disorders, insomnia, and rashes.

Pharmacology
Mechanism of action
Cabotegravir is an integrase strand transfer inhibitor. This means it blocks the HIVs enzyme integrase, thereby preventing its genome from being integrated into the human cells DNA. As this is a necessary step for the virus to replicate, its further spread is hampered.

Pharmacokinetics
When taken by mouth, cabotegravir reaches highest blood plasma levels after three hours. Taking the drug together with food slightly increases its concentrations in the blood, but this is not clinically relevant. After injection into the muscle, cabotegravir is slowly absorbed into the bloodstream, reaching its highest blood plasma levels after about seven days.Over 99% of the substance are bound to plasma proteins. The drug is inactivated in the body by glucuronidation, mainly by the enzyme UGT1A1, and to a much lesser extent by UGT1A9. More than 90% of the circulating substance are the unchanged cabotegravir, however. The biological half-life is 41 hours for the tablets and 5.6 to 11.5 weeks for the injection.Elimination has only been studied for oral administration: Most of the drug is eliminated via the faeces in unchanged form (47%). It is not known how much of this amount comes from the bile, and how much was not absorbed in the first place. (The bile actually contains the glucuronide, but this could be broken up again in the gut lumen to give the parent substance that is observed in the faeces.) To a lesser extent it is excreted via the urine (27%), almost exclusively as the glucuronide.

Pharmacogenomics
UGT1A1 poor metabolizers have 1.3- to 1.5-fold increased cabotegravir concentrations in the body. This is not considered clinically significant.

Chemistry
Cabotegravir is a white to off-white, crystalline powder that is practically insoluble in aqueous solutions under pH 9, and slightly soluble above pH 10. It is slightly acidic with a pKa of 7.7 for the enolic acid and 1.1 (calculated) for the carboxamide. The molecule has two asymmetric carbon atoms; only one of the four possible configurations is present in the medication.

Formulation
In studies, the agent was packaged into nanoparticles (GSK744LAP) conferring a biological half-life of 21 to 50 days following a single dose. The marketed injection achieves its long half-life not via nanoparticles but with a suspension of the free cabotegravir acid. The tablets contain cabotegravir sodium salt.

History
Cabotegravir was examined in the clinical trials HPTN 083 and HPTN 084. In 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vocabria intended for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with rilpivirine injection. The EMA also recommended marketing authorization be given for rilpivirine and cabotegravir injections to be used together for the treatment of people with HIV-1 infection. Cabotegravir was approved for medical use in the European Union in December 2020.

Society and culture
Names
Cabotegravir is the United States Adopted Name (USAN) and the international nonproprietary name (INN).

Research
Pre-exposure prophylaxis
In 2020, results for some studies were released showing success in using injectable cabotegravir for long-acting pre-exposure prophylaxis (PrEP) with greater efficacy than the emtricitabine/tenofovir combination being widely used for PrEP at the time.The safety and efficacy of cabotegravir to reduce the risk of acquiring HIV were evaluated in two randomized, double-blind trials that compared cabotegravir to emtricitabine/tenofovir, a once daily oral medication for HIV PrEP. Trial 1 included HIV-uninfected men and transgender women who have sex with men and have high-risk behavior for HIV infection </s>


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