<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 Inebilizumab and can you explain it in depth? [/INST] Inebilizumab, sold under the brand name Uplizna, is a medication for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults.The most common adverse reactions include urinary tract infection, headache, joint pain (arthralgia), nausea and back pain.Inebilizumab is a humanized mAb that binds to and depletes CD19+ B cells including plasmablasts and plasma cells.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses
Inebilizumab is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with a particular antibody (patients who are anti-aquaporin-4 or AQP4 antibody positive).NMOSD is a rare autoimmune disorder in which immune system cells and autoantibodies attack and damage the optic nerves and spinal cord. NMOSD can be associated with antibodies that bind to a protein called aquaporin-4 (AQP4). Binding of the anti-AQP4 antibody appears to activate other components of the immune system, causing inflammation and damage to the central nervous system. Clinically, the disease is manifested with attacks/relapses that result in neurological impairment such as blindness, paraplegia, sensory loss, bladder dysfunction, and peripheral pain. The disability from each attack is cumulative, making NMOSD a chronically debilitating and potentially life-threatening disease.

Side effects
The label for inebilizumab includes a warning for infusion reactions, potential depletion of certain proteins (hypogammaglobulinemia), and potential increased risk of infection – including Progressive Multifocal Leukoencephalopathy, and potential reactivation of hepatitis B and tuberculosis.The most common adverse reactions in the NMOSD clinical trial were urinary tract infection, headache, joint pain (arthralgia), nausea and back pain.Women who are pregnant should not take inebilizumab because it may cause harm to a developing fetus or newborn baby. The FDA advises health care professionals to inform females of reproductive age to use effective contraception during treatment with inebilizumab and for six months after the last dose.Vaccination with live-attenuated or live vaccines is not recommended during treatment and should be administered at least four weeks prior to initiation of inebilizumab.

History
Inebilizumab was created from the research led by Thomas Tedder at Cellective Therapeutics, and development was continued by Viela Bio and MedImmune.Inebilizumab was approved for medical use in the United States in June 2020.The effectiveness of inebilizumab for the treatment of NMOSD was demonstrated in a clinical study (NCT02200770) of 230 adult participants that evaluated the efficacy and safety of intravenous inebilizumab. In the trial, 213 of the 230 participants had antibodies against AQP4 (anti-AQP4 antibody positive). During the 197-day study, the risk of an NMOSD relapse in the 161 anti-AQP4 antibody positive participants who were treated with inebilizumab was reduced by 77% when compared to the placebo treatment group. There was no evidence of a benefit in participants who were anti-AQP4 antibody negative. The primary efficacy endpoint was the time to the onset of the first adjudicated relapse on or before study day 197 evaluated by a blinded, independent, adjudication committee, who determined whether the attack met protocol-defined criteria. The trial was conducted at 82 sites in 24 countries (including the United States) in North and South America, Europe, Africa, Asia and Australia.The U.S. Food and Drug Administration (FDA) granted the application for inebilizumab orphan drug designation and granted approval of Uplizna to Viela Bio.

Society and culture
Legal status
In November 2021, 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 Uplizna, intended for the treatment of adults with neuromyelitis optica spectrum disorders (NMOSD) who are anti-aquaporin 4 immunoglobulin G (AQP4-IgG) seropositive. The applicant for this medicinal product is Viela Bio.

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

References
Further reading
Cree BA, Bennett JL, Kim HJ, Weinshenker BG, Pittock SJ, Wingerchuk DM,  et al </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 Bedaquiline and can you explain it in depth? [/INST] Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis. Specifically, it is used to treat multi-drug-resistant tuberculosis (MDR-TB) along with other medications for tuberculosis. It is used by mouth.Common side effects include nausea, joint pains, headaches, and chest pain. Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death. While harm during pregnancy has not been found, it has not been well studied in this population. It is in the diarylquinoline antimycobacterial class of medications. It works by blocking the ability of M. tuberculosis to make adenosine 5-triphosphate (ATP).Bedaquiline was approved for medical use in the United States in 2012. It is on the World Health Organizations List of Essential Medicines. The cost for six months is approximately US$900 in low-income countries, US$3,000 in middle-income countries, and US$30,000 in high-income countries.The public sector invested US$455–747 million in developing bedaquiline. This is thought to be 1.6× to 5.1× what the owner, Janssen Biotech, invested (estimated at US$90–240 million). If capitalized and risk-adjusted, these costs become US$647–1,201 million and US$292–772 million, respectively.

Medical uses
Its use was approved in December 2012 by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a Fast-Track accelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.As of 2013 both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for people with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.

Clinical trials
Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway. It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).

Side effects
The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel. Everyone on bedaquiline should have monitoring with a baseline and repeated ECGs. If a person has a QTcF of > 500 ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo. Ten deaths occurred in the bedaquiline group out of 79, while two occurred in the placebo group, out of 81. Of the 10 deaths on bedaquiline, one was due to a motor vehicle accident, five were judged as due to progression of the underlying tuberculosis and three were well after the person had stopped receiving bedaquiline. However, there is still significant concern for the higher mortality in people treated with bedaquiline, leading to the recommendation to limit its use to situations where a four drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval, and the placement of a prominent black box warning.

Drug interactions
Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the liver enzyme responsible for oxidative metabolism of the drug. Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experiencedSince bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided. Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.

Mechanism of action
Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. It is the first member of a new class of drugs called the diarylquinolines </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 Yasmin 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 Fenofibrate and can you explain it in depth? [/INST] Fenofibrate (sold under the brand names Tricor, Fenobrat etc.), is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces to the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes.Common side effects include liver problems, breathing problems, abdominal pain, muscle problems, and nausea. Serious side effects may include toxic epidermal necrolysis, rhabdomyolysis, gallstones, and pancreatitis. Use during pregnancy and breastfeeding is not recommended. It works by  multiple mechanisms.It was patented in 1969, and came into medical use in 1975. It is available as a generic medication. In 2019, it was the 87th most commonly prescribed medication in the United States with more than 8 million prescriptions.

Medical uses
Fenofibrate is mainly used for primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate may slow the progression of diabetic retinopathy and the need for invasive treatment such as laser therapy in patients with type 2 diabetes with pre-existing retinopathy. It was initially indicated for diabetic retinopathy in patients with type 2 diabetes and diabetic retinopathy in Australia. The large scale, international FIELD and ACCORD-Eye trials found that fenofibrate therapy reduced required laser treatment for diabetic retinopathy by 1.5% over 5 years, as well as reducing progression by 3.7% over 4 years.  Further studies looking at the role of fenofibrate in the progression of diabetic retinopathy as the primary outcome is warranted to understand its role in this condition. Although no statistically significant cardiovascular risk benefits were identified in these trials, benefits may accrue to add on therapy to patients with high triglyceride dyslipidaemia currently taking statin medications.Fenofibrate appears to reduce the risk of below ankle amputations in patients with Type 2 diabetes without microvascular disease. The FIELD study reported that fenofibrate at doses of 200 mg daily, reduced the risk for any amputation by 37% independent of glycaemic control, presence or absence of dyslipidaemia and its lipid-lowering mechanism of action. However, the cohort of participants who underwent amputations were more likely to have had previous cardiovascular disease (e.g. angina, myocardial infarction), longer duration of diabetes and had baseline neuropathy.Fenofibrate has an off-label use as an added therapy of high blood uric acid levels in people who have gout.It is used in addition to diet to reduce elevated low-density lipoprotein cholesterol (LDL), total cholesterol, triglycerides (TG), and apolipoprotein B (apo B), and to increase high-density lipoprotein cholesterol (HDL) in adults with primary hypercholesterolemia or mixed dyslipidemia.

Severe hypertriglyceridemia type IV or V
It is used in tandem with diet for treatment of adults with severe hypertriglyceridemia. Improving glycemic control in diabetics showing fasting chylomicronemia usually reduces the need for pharmacologic intervention.Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications.Additionally, in 2016, the FDA filed "Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed Release Capsules" noting "the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events. Consistent with this conclusion, FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn."

COVID-19
In August 2021, researchers in the UK and Italy reported laboratory findings that fenofibrate can significantly reduce SARS-CoV-2 infection in vitro.

Contraindications
Fenofibrate is contraindicated in:
Patients with severe renal impairment, including those receiving dialysis (2.7-fold increase in exposure, and increased accumulation during chronic dosing in patients with estimated glomerular filtration rate < 30 mL/min)
Patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function test abnormalities
Patients with preexisting gallbladder disease
Nursing mothers
Hypothyreosis
Patients with known hypersensitivity to fenofibrate or fenofibric acid

Adverse effects
The most common adverse events (>3% of patients with coadministered statins) are

Precautions
When fenofibrate and a statin are given as combination therapy, it is recommended that fenofibrate be given in the morning and the statin at night, so that the peak dosages do not overlap.Musculoskeletal

Myopathy and rhabdomyolysis; increased risk when coadminstered with a statin, particularly in the elderly and patients with diabetes, kidney failure, hypothyroidismHepatotoxicity

Can increase serum transaminases; liver tests should be monitored periodicallyNephrotoxicity

Can increase serum creatinine levels; renal function should be monitored periodically in patients with chronic kidney diseaseBiliary

Can increase cholesterol excretion into the bile, leading to risk of cholelithiasis; if suspected, gallbladder studies are indicated. See "Interaction" section under Bile acid sequestrantCoagulation/Bleeding

Exercise caution in concomitant treatment with oral Coumadin anticoagulants (e.g. warfarin). Adjust the dosage of Coumadin to maintain the prothrombin time/INR at desired level to prevent bleeding complications.

Overdose
"There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care is indicated, including monitoring of vital signs and observation of clinical status". Additionally, hemodialysis should not be considered as an overdose treatment option because fenofibrate heavily binds to plasma proteins and does not dialyze well.

Interactions
These drug interactions with fenofibrate are considered major and may need therapy modifications:

Bile acid sequestrants (e.g. cholestyramine, colestipol, etc.): If taken together, bile acid resins may bind to fenofibrate, resulting in a decrease in fenofibrate absorption. To maximize absorption, patients need to separate administration by at least 1 h before or 4 h to 6 h after taking the bile acid sequestrant.
Immunosuppressants (e.g. ciclosporin or tacrolimus): An increased risk of renal dysfunction exists with concomitant use of immunosuppressants and fenofibrate </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 Flucytosine and can you explain it in depth? [/INST] Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious Candida infections and cryptococcosis. It may be used by itself or with other antifungals for chromomycosis. Flucytosine is used by mouth and by injection into a vein.Common side effects include bone marrow suppression, loss of appetite, diarrhea, vomiting, and psychosis. Anaphylaxis and other allergic reactions occasionally occur. It is unclear if use in pregnancy is safe for the baby. Flucytosine is in the fluorinated pyrimidine analogue family of medications. It works by being converted into fluorouracil inside the fungus, which impairs its ability to make protein.Flucytosine was first made in 1957. It is on the World Health Organizations List of Essential Medicines. As of 2016, in the United States the medication cost about US$2,000 per day while in the United Kingdom it is about US$22 per day. It is not available in much of the developing world.

Medical uses
Flucytosine by mouth is used for the treatment of serious infections caused by susceptible strains of Candida or Cryptococcus neoformans. It can also be used for the treatment of chromomycosis (chromoblastomycosis), if susceptible strains cause the infection. Flucytosine must not be used as a sole agent in life-threatening fungal infections due to relatively weak antifungal effects and fast development of resistance, but rather in combination with amphotericin B and/or azole antifungals such as fluconazole or itraconazole. Minor infections such as candidal cystitis may be treated with flucytosine alone. In some countries, treatment with slow intravenous infusions for no more than a week is also a therapeutic option, particular if the disease is life-threatening.
Serious fungal infections may occur in those who are immunocompromised. These people benefit from combination therapy including flucytosine, but the incidence of side-effects of a combination therapy, particular with amphotericin B, may be higher.

Pregnancy and breastfeeding
In animal models (rats), flucytosine has been found to be teratogenic. Sufficient human data does not exist. Pregnant women should be given flucytosine only if the potential benefits exceed the potential harm to the fetus.
It is not known if flucytosine is distributed in human breast milk. Given the potential risk to the child, the patient should not breastfeed during treatment with flucytosine.

Children
The efficacy and safety in patients under 18 years of age has not been determined.

Side effects
Patients treated with drugs compromising bone marrow function (e.g. cytostatics) should be treated carefully. Blood cell counts should be taken very frequently.
Patients with renal disease should receive flucytosine cautiously and in reduced doses. Guidelines for proper dosing exist. Serum level determinations are mandatory for these patients.
All patients receiving flucytosine should be under strict medical supervision.
Hematological, renal and liver function studies should be done frequently during therapy (initially daily, twice a week for the rest of treatment).
Patients with preexisting bone marrow depression and liver impairment should be treated with caution.
Antiproliferative actions on bone marrow and GI tissue: Due to the drugs preference for rapidly proliferating tissues, bone marrow depression (anemia, leukopenia, pancytopenia, or even rarely agranulocytosis) may occur. Aplastic anemia has also been seen. Bone marrow toxicity can be irreversible and may cause death, particularly in immunocompromised patients. GI toxicity may be severe or rarely fatal and consists of anorexia, abdominal bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcer, GI hemorrhage, nausea, vomiting, and ulcerative colitis.
Liver function: Elevations of liver enzymes and bilirubin, hepatic dysfunction, jaundice and, in one patient, liver necrosis have all been seen. Some fatal cases have been reported; however, the majority of cases was reversible.
Renal function: Increased BUN and serum creatinine have been noted. Crystalluria (formation of crystals and excretion in the urine) and acute kidney injury have also been seen.
Adverse central nervous system effects are frequent and include confusion, hallucinations, psychosis, ataxia, hearing loss, headache, paresthesia, parkinsonism, peripheral neuropathy, vertigo and sedation.
Skin reactions: Rash, pruritus, and photosensitivity have all been noticed. Toxic epidermal necrolysis (Lyells syndrome) may also be encountered and may be life-threatening.
Anaphylaxis: Sometimes cases of anaphylaxis consisting of diffuse erythema, pruritus, conjunctival injection, fever, abdominal pain, edema, hypotension and bronchospastic reactions are observed.It is not known if flucytosine is a human carcinogen. The issue has been raised because traces of 5-fluorouracil, which is a known carcinogen, are found in the colon resulting from the metabolization of flucytosine.

Interactions
Flucytosine may increase the toxicity of amphotericin B and vice versa, although the combination may be life-saving and should be used whenever indicated (e.g., cryptococcal meningitis). The cytostatic cytarabine inhibits the antimycotic activity of flucytosine.

Overdose
Symptoms and their severities are unknown, because flucytosine is used under close medical supervision, but expected to be an excess of the usually encountered side effects on the bone marrow, gastrointestinal tract, liver and kidney function. Vigorous hydration and hemodialysis may be helpful in removing the drug from the body. Hemodialysis is particular useful in patients with impaired renal function.

Pharmacology
Mechanisms of action
Two major mechanisms of action have been elucidated:

Flucytosine is intrafungally converted into the cytostatic fluorouracil which undergoes further steps of activation and finally interacts as 5-fluorouridinetriphosphate with RNA biosynthesis thus disturbing the building of certain essential proteins.
Flucytosine also undergoes conversion into 5-fluorodeoxyuridinemonophosphate which inhibits fungal DNA synthesis.

Spectrum of susceptible fungi and resistance
Flucytosine is active in vitro as well as in vivo against some strains of Candida and Cryptococcus. Limited studies demonstrate that flucytosine may be of value against infections with Sporothrix, Aspergillus, Cladosporium, Exophiala, and Phialophora.
Resistance is quite commonly seen as well in treatment-naive patients and under current treatment with flucytosine. In different strains of Candida resistance has been noted to occur in 1 to 50% of all specimens obtained from patients.

Pharmacokinetic data
Flucytosine is well absorbed (75 to 90%) from the gastrointestinal tract. Intake with meals slows the absorption, but does not decrease the amount absorbed. Following an oral dose of 2 grams peak serum levels are reached after approximately 6 hours. The time to peak level decreases with continued therapy. After 4 days peak levels are measured after 2 hours. The drug is eliminated renally. In normal patients flucytosine has reportedly a half-life of 2.5 to 6 hours. In patients with impaired renal function higher serum levels are seen and the drug tends to accumulate. The drug is mainly excreted unchanged in the urine (90% of an oral dose) and only traces are metabolized and excreted in the feces. Therapeutic serum levels range from 25 to 100 μg/ml. Serum levels in excess of 100 μg are associated with a higher incidence of side effects </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 Methyclothiazide 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 1-Docosanol 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 Felodipine 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 Pramlintide 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 Dicycloverine and can you explain it in depth? [/INST] Dicycloverine, also known as dicyclomine, sold under the brand name Bentyl in the US, is a medication that is used to treat spasms of the intestines such as occur in irritable bowel syndrome. It is taken by mouth or by injection into a muscle. While it has been used in baby colic and enterocolitis, evidence does not support these uses.Common side effects include dry mouth, blurry vision, weakness, sleepiness, and lightheadedness. Serious side effects may include psychosis and breathing problems in babies. Use in pregnancy appears to be safe while use during breastfeeding is not recommended. How it works is not entirely clear.Dicycloverine was approved for medical use in the United States in 1950. It is available as a generic medication. In 2019, it was the 165th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Dicyclomine is used to treat the symptoms of irritable bowel syndrome, specifically hypermotility, in adults. As of 2016, clinical guidelines recommended dicycloverine and other antispasmodics for IBS with diarrhea as a first line treatment.

Contraindications
This medicine should not be used for people who have an obstructive GI or urinary condition, severe ulcerative colitis, reflux, any unstable cardiac condition, glaucoma, myasthenia gravis, and anyone who is acutely bleeding.It should not be given to children or infants with colic due to the risks of convulsions, difficult breathing, irritability, and restlessness, and there is little evidence to support the efficacy in such use in any case.Because dicycloverine is known to impair thinking and coordination, people taking the drug should avoid driving or operating machinery.The effect on the baby during pregnancy or breastfeeding is not well understood.

Adverse effects
Dicycloverine can cause a range of anticholinergic side effects such as dry mouth, nausea, blurred vision, dizziness, confusion, severe constipation, stomach pain, heart palpitations, difficulty urinating, and seizures.

Pharmacology
Dicycloverine blocks the action of acetylcholine on cholinergic receptors on smooth muscles in the GI tract, relaxing the smooth muscle.

History
Dicycloverine was first synthesized chemically in the United States circa 1945 by scientists at William S. Merrell Company.It was first marketed in 1952 for gastrointestinal disorders, including colic in infants. The INN name "dicycloverine" was recommended in 1959. It was included in the combination drug for morning sickness called Bendectin, along with doxylamine and vitamin B6 which was launched in the US 1956; dicyclomine was removed from the formulation in 1976 after Merrell determined that it added no value </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 Naphazoline/pheniramine and can you explain it in depth? [/INST] Naphazoline/pheniramine, sold under the brand name Naphcon-A among others, is a combination eye drop used to help the symptoms of allergic conjunctivitis such as from hay fever. It contains naphazoline and pheniramine. It is used as an eye drop </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 Relugolix and can you explain it in depth? [/INST] Relugolix, sold under the brand names Orgovyx and Relumina and as one component of Myfembree, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uterine fibroids in women. It is also under development for use in the treatment of endometriosis. It is taken by mouth once per day.Side effects of relugolix include menstrual abnormalities, hot flashes, excessive sweating, headache, and decreased bone mineral density. Relugolix is a GnRH antagonist, or an antagonist of the gonadotropin-releasing hormone receptor. Unlike most other GnRH modulators, but similarly to elagolix (brand name Orilissa), relugolix is a non-peptide, small-molecule compound and is orally active. It suppresses sex hormone levels to the postmenopausal or castrate range in both women and men with administration once per day.As of February 2019, relugolix is in phase III clinical trials for endometriosis. It was approved for use for the treatment of uterine fibroids in Japan in January 2019, and for the treatment of prostate cancer in the United States in December 2020.

Medical uses
Relugolix is approved in the United States for the treatment of prostate cancer in men and in Japan for the treatment of uterine fibroids (uterine leiomyoma) in women. It is used at a dosage of 120 mg once daily by mouth in the treatment of prostate cancer (after a single 360 mg loading dose on the first day of therapy) and at a dosage of 40 mg once daily in the treatment of uterine fibroids.

Available forms
Relugolix is available in the form of 40 and 120 mg oral tablets.

Side effects
The main side effects of relugolix for uterine fibroids include abnormal uterine bleeding (24.6–48.6% vs. 6.3% for placebo), hot flashes (42.8–45.5% vs. 0% for placebo), heavy menstrual bleeding (12.1–49.3% vs. 9.4% for placebo), headache (12.3–15.2%), and excessive sweating (9.4–15.2% vs. 0% for placebo). In addition, decreased bone mineral density occurs with relugolix (21.7% decrease by week 12, 24.4% decrease by week 24).

Pharmacology
Pharmacodynamics
Relugolix is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR), with a half-maximal inhibitory concentration (IC50) of 0.12 nM.A dosage of relugolix of 40 mg once per day has been found to suppress estradiol levels to postmenopausal levels (<20 pg/mL) within 24 hours in premenopausal women. In the control group of women, estradiol levels fluctuated between 50 and 250 pg/mL. Estradiol levels have been found to return to normal concentrations within 4 weeks of discontinuation of relugolix in premenopausal women. The medication additionally suppresses levels of progesterone, luteinizing hormone, and follicle-stimulating hormone in premenopausal women. Relugolix at a dosage of 40 mg or more once per day has been found to reduce testosterone levels to sustained castrate levels (<20 ng/dL) in men. It additionally suppresses luteinizing hormone and follicle-stimulating hormone levels in men.Lower doses of relugolix (<40 mg/day) are under investigation for achieving partial sex hormone suppression in the treatment of endometriosis and uterine fibroids. This is intended to reduce the incidence and severity of menopausal symptoms such as hot flushes and decreased bone mineral density that are secondary to estrogen deficiency.

Pharmacokinetics
A single 40-mg oral dose of relugolix has been found to result in peak levels of relugolix of 29 ng/mL (47 nmol/L) after 1.5 hours. Steady-state levels are reached within 7 days with 40 mg/day relugolix administration. There is an approximate 2-fold accumulation of relugolix by 2 weeks of continuous administration. Food diminishes the oral bioavailability of relugolix by about 50%.Relugolix is a substrate for P-glycoprotein, which may have a limiting effect on its absorption and distribution. The plasma protein binding of relugolix is approximately 68 to 71% over a concentration range of 0.05 to 5 μg/mL.Relugolix is not a substrate for CYP3A4. The elimination half-life of relugolix is 36 to 65 hours across a dosage range of 20 to 180 mg/day. There is moderate to high interindividual variability in systemic exposure to relugolix.Relugolix is excreted mainly in feces (83%) and to a small degree in urine (4%). Only about 6% of a dose of relugolix is excreted unchanged.

Chemistry
Relugolix is a non-peptide, small-molecule compound, and is structurally distinct from GnRH analogues. It is an N-phenylurea derivative.

History
Relugolix was first described in 2004. It superseded sufugolix (developmental code name TAK-013), which was developed by the same researchers. Relugolix was approved for the treatment of uterine fibroids in Japan on 8 January 2019. It was the second orally active GnRH antagonist to be introduced for medical use, following elagolix (brand name Orilissa) in July 2018. Relugolix was approved for the treatment of prostate cancer in the United States on 18 December 2020.The FDA approved relugolix based on evidence from a clinical trial (NCT03085095) of 930 participants 48 to 97 years old with advanced prostate cancer. The trial was conducted at 155 sites in the United States, Canada, and countries in South America, Europe and the Asia Pacific region. All participants in the trial had advanced prostate cancer. Participants were randomly assigned to receive either one relugolix tablet daily (on the first day they received three tables) or an active control (leuprolide acetate) which was given as an injection under the skin every three months. The participants and healthcare providers were aware of which treatment was being given. The treatment lasted for 48 weeks. The efficacy of relugolix was assessed by the percentage of participants who achieved and maintained low testosterone level equal to castration.

Society and culture
Names
Relugolix is the generic name of the drug and its INN, USAN, and JAN. It is also known by its former developmental code names RVT-601 and TAK-385.Relugolix is sold under the brand name Orgovyx for the treatment of prostate cancer and under the brand name Relumina for the treatment of uterine fibroids.  Relugolix compounded with ethinyl estradiol and norethindrone is sold under the brand name Myfembree for the treatment of uterine fibroids.

Availability
Relugolix is available in the United States and in Japan.

Legal status
On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Orgovyx, intended for the treatment of prostate cancer. The applicant for this medicinal product is Myovant Sciences Ireland Limited.

Research
Relugolix is under development by Myovant Sciences and Takeda for the treatment of uterine fibroids in countries besides Japan such as the United States. Relugolix is also under development for the treatment of endometriosis in the United States and other countries.

References
Further reading
Markham, Anthony (April 2019). "Relugolix: First Global Approval". Drugs. 79 (6): 675–679. doi:10.1007/s40265-019-01105-0. ISSN 0012-6667. PMID 30937733. S2CID 89616869.
Elsharoud, A.; Ali, M.; Al-Hendy, A. (2019). "Relugolix. GnRH (LHRH) receptor antagonist, Treatment of uterine fibroids, Treatment of endometriosis-related pain, Treatment of prostate cancer". Drugs of the Future. 44 (2): 131. doi:10.1358/dof.2019.44.2.2927590. ISSN 0377-8282 </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 Sonata and can you explain it in depth? [/INST] Sonata (; Italian: [soˈnaːta], pl. sonate; from Latin and Italian: sonare [archaic Italian; replaced in the modern language by suonare], "to sound"), in music, literally means a piece played as opposed to a cantata (Latin and Italian cantare, "to sing"), a piece sung.: 17  The term evolved through the history of music, designating a variety of forms until the Classical era, when it took on increasing importance. Sonata is a vague term, with varying meanings depending on the context and time period. By the early 19th century, it came to represent a principle of composing large-scale works. It was applied to most instrumental genres and regarded—alongside the fugue—as one of two fundamental methods of organizing, interpreting and analyzing concert music. Though the musical style of sonatas has changed since the Classical era, most 20th- and 21st-century sonatas still maintain the same structure.
The term sonatina, pl. sonatine, the diminutive form of sonata, is often used for a short or technically easy sonata.

Instrumentation
In the Baroque period, a sonata was for one or more instruments almost always with continuo. After the Baroque period most works designated as sonatas specifically are performed by a solo instrument, most often a keyboard instrument, or by a solo instrument accompanied by a keyboard instrument.
Sonatas for a solo instrument other than keyboard have been composed, as have sonatas for other combinations of instruments.

History
Baroque
In the works of Arcangelo Corelli and his contemporaries, two broad classes of sonata were established, and were first described by Sébastien de Brossard in his Dictionaire de musique (third edition, Amsterdam, ca. 1710): the sonata da chiesa (that is, suitable for use in church), which was the type "rightly known as Sonatas", and the sonata da camera (proper for use at court), which consists of a prelude followed by a succession of dances, all in the same key.: 21, 40  Although the four, five, or six movements of the sonata da chiesa are also most often in one key, one or two of the internal movements are sometimes in a contrasting tonality.The sonata da chiesa, generally for one or more violins and bass, consisted normally of a slow introduction, a loosely fugued allegro, a cantabile slow movement, and a lively finale in some binary form suggesting affinity with the dance-tunes of the suite. This scheme, however, was not very clearly defined, until the works of Arcangelo Corelli when it became the essential sonata and persisted as a tradition of Italian violin music.
The sonata da camera consisted almost entirely of idealized dance-tunes. On the other hand, the features of sonata da chiesa and sonata da camera then tended to be freely intermixed. Although nearly half of Bachs 1,100 surviving compositions, arrangements, and transcriptions are instrumental works, only about 4% are sonatas.The term sonata is also applied to the series of over 500 works for harpsichord solo, or sometimes for other keyboard instruments, by Domenico Scarlatti, originally published under the name Essercizi per il gravicembalo (Exercises for the Harpsichord). Most of these pieces are in one binary-form movement only, with two parts that are in the same tempo and use the same thematic material, though occasionally there will be changes in tempo within the sections. They are frequently virtuosic, and use more distant harmonic transitions and modulations than were common for other works of the time. They were admired for their great variety and invention.
Both the solo and trio sonatas of Vivaldi show parallels with the concerti he was writing at the same time. He composed over 70 sonatas, the great majority of which are of the solo type; most of the rest are trio sonatas, and a very small number are of the multivoice type.The sonatas of Domenico Paradies are mild and elongated works with a graceful and melodious little second movement included.

Classical period
The practice of the Classical period would become decisive for the sonata; the term moved from being one of many terms indicating genres or forms, to designating the fundamental form of organization for large-scale works. This evolution stretched over fifty years. The term came to apply both to the structure of individual movements (see Sonata form and History of sonata form) and to the layout of the movements in a multi-movement work. In the transition to the Classical period there were several names given to multimovement works, including divertimento, serenade, and partita, many of which are now regarded effectively as sonatas. The usage of sonata as the standard term for such works began somewhere in the 1770s. Haydn labels his first piano sonata as such in 1771, after which the term divertimento is used sparingly in his output. The term sonata was increasingly applied to either a work for keyboard alone (see piano sonata), or for keyboard and one other instrument, often the violin or cello. It was less and less frequently applied to works with more than two instrumentalists; for example, piano trios were not often labelled sonata for piano, violin, and cello.
Initially the most common layout of movements was:

Allegro, which at the time was understood to mean not only a tempo, but also some degree of "working out", or development, of the theme.
A middle movement, most frequently a slow movement: an Andante, an Adagio or a Largo; or less frequently a Minuet or Theme and Variations form.
A closing movement was generally an Allegro or a Presto, often labeled Finale. The form was often a Rondo or Minuet.However, two-movement layouts also occur, a practice Haydn uses as late as the 1790s. There was also in the early Classical period the possibility of using four movements, with a dance movement inserted before the slow movement, as in Haydns Piano sonatas No. 6 and No. 8. Mozarts sonatas were also primarily in three movements. Of the works that Haydn labelled piano sonata, divertimento, or partita in Hob XIV, seven are in two movements, thirty-five are in three, and three are in four; and there are several in three or four movements whose authenticity is listed as "doubtful." Composers such as Boccherini would publish sonatas for piano and obbligato instrument with an optional third movement—–in Boccherinis case, 28 cello sonatas.
But increasingly instrumental works were laid out in four, not three movements, a practice seen first in string quartets and symphonies, and reaching the sonata proper in the early sonatas of Beethoven. However, two- and three-movement sonatas continued to be written throughout the Classical period: Beethovens opus 102 pair has a two-movement C major sonata and a three-movement D major sonata. Nevertheless, works with fewer or more than four movements were increasingly felt to be exceptions; they were labelled as having movements "omitted," or as having "extra" movements.
Thus, the four-movement layout was by this point standard for the string quartet, and overwhelmingly the most common for the symphony. The usual order of the four movements was:

An allegro, which by this point was in what is called sonata form, complete with exposition, development, and recapitulation.
A slow movement, an Andante, an Adagio or a Largo.
A dance movement, frequently Minuet and trio or—especially later in the classical period—a Scherzo and trio.
A finale in faster tempo, often in a sonata–rondo form.When movements appeared out of this order they would be described as "reversed", such as the scherzo coming before the slow movement in Beethovens 9th Symphony. This usage would be noted by critics in the early 19th century, and it was codified into teaching soon thereafter.
It is difficult to overstate the importance of Beethovens output of sonatas: 32 piano sonatas, plus sonatas for cello and piano or violin and piano, forming a large body of music that would over time increasingly be thought essential for any serious instrumentalist to master.

Romantic period
In the early 19th century, the current usage of the term sonata was established, both as regards form per se, and in the sense that a fully elaborated sonata serves as a norm for concert music in general, which other forms are seen in relation to. From this point forward, the word sonata in music theory labels as much the abstract musical form as particular works. Hence there are references to a symphony as a sonata for orchestra. This is referred to by William Newman as the sonata idea.
Among works expressly labeled sonata for the piano, there are the three of Frédéric Chopin, those of Felix Mendelssohn, the three of Robert Schumann, Franz Liszts Sonata in B minor, and later the sonatas of Johannes Brahms and Sergei Rachmaninoff.
In the early 19th century, the sonata form was defined, from a combination of previous practice and the works of important Classical composers, particularly Haydn, Mozart, Beethoven, but composers such as Clementi also. It is during this period that the differences between the three- and the four-movement layouts became a subject of commentary, with emphasis on the concerto being laid out in three movements, and the symphony in four.
Ernest Newman wrote in the essay "Brahms and the Serpent":

That, perhaps, will be the ideal of the instrumental music of the future; the way to it, indeed, seems at last to be opening out before modern composers in proportion as they discard the last tiresome vestiges of sonata form. This, from being what it was originally, the natural mode of expression of a certain eighteenth century way of thinking in music, became in the nineteenth century a drag upon both individual thinking and the free unfolding of the inner vital force of an idea, and is now simply a shop device by which a bad composer may persuade himself and the innocent reader of textbooks that he is a good one.

After the Romantic period
The role of the sonata as an extremely important form of extended musical argument would inspire composers such as Hindemith, Prokofiev, Shostakovich, Tailleferre, Ustvolskaya, and Williams to compose in sonata form, and works with traditional sonata structures continue to be composed and performed.

Scholarship and musicology
Sonata idea or principle
Research into the practice and meaning of sonata form, style, and structure has been the motivation for important theoretical works by Heinrich Schenker, Arnold Schoenberg, and Charles Rosen among others; and the pedagogy of music continued to rest on an understanding and application of the rules of sonata form as almost two centuries of development in practice and theory had codified it.
The development of the classical style and its norms of composition formed the basis for much of the music theory of the 19th and 20th centuries. As an overarching formal principle, sonata was accorded the same central status as Baroque fugue; generations of composers, instrumentalists, and audiences were guided by this understanding of sonata as an enduring and dominant principle in Western music. The sonata idea begins before the term had taken on its present importance, along with the evolution of the Classical periods changing norms. The reasons for these changes, and how they relate to the evolving sense of a new formal order in music, is a matter to which research is devoted. Some common factors which were pointed to include: the shift of focus from vocal music to instrumental music; changes in performance practice, including the loss of the continuo.Crucial to most interpretations of the sonata form is the idea of a tonal center; and, as the Grove Concise Dictionary of Music puts it: "The main form of the group embodying the sonata principle, the most important principle of musical structure from the Classical period to the 20th century: that material first stated in a complementary key be restated in the home key".(The sonata idea has been thoroughly explored by William Newman in his monumental three-volume work Sonata in the Classic Era (A History of the Sonata Idea), begun in the 1950s and published in what has become the standard edition of all three volumes in 1972.

20th-century theory
Heinrich Schenker argued that there was an Urlinie or basic tonal melody, and a basic bass figuration. He held that when these two were present, there was basic structure, and that the sonata represented this basic structure in a whole work with a process known as interruption.As a practical matter, Schenker applied his ideas to the editing of the piano sonatas of Beethoven, using original manuscripts and his own theories to "correct" the available sources. The basic procedure was the use of tonal theory to infer meaning from available sources as part of the critical process, even to the extent of completing works left unfinished by their composers. While many of these changes were and are controversial, that procedure has a central role today in music theory, and is an essential part of the theory of sonata structure as taught in most music schools.

Notable sonatas
Baroque (c. 1600 – c. 1760)
Johann Sebastian Bach
Sonatas for solo violin (BWV 1001, 1003 and 1005)
Sonatas for flute and continuo (BWV 1034, 1035)
Trio sonatas: for organ (BWV 525–530); for violin and harpsichord (BWV 1014–1019); for viola da gamba and harpsichord (BWV 1027–1029); for flute and harpsichord (BWV 1030, 1032); for flute, violin and continuo (Sonata sopril Soggetto Reale included in The Musical Offering)
Heinrich Ignaz Franz Biber
Rosary Sonatas
George Frideric Handel
Sonata for Violin and Continuo in D major (HWV 371)
Giuseppe Tartini
Devils Trill Sonata
Domenico Scarlatti
List of solo keyboard sonatas by Domenico Scarlatti

Classical (c. 1760 – c. 1830)
Wolfgang Amadeus Mozart
Piano Sonata No. 8 in A minor (K. 310)
Piano Sonata No. 11 in A major (K. 331/300i)
Piano Sonata No. 12 in F major (K. 332)
Piano Sonata No. 13 in B-flat major (K. 333)
Piano Sonata No. 14 in C minor (K. 457)
Piano Sonata No. 15 in F major (K. 533/494)
Piano Sonata No. 16 in C major (K. 545)
Sonata in A for Violin and Keyboard (K. 526)
Franz Joseph Haydn
Sonata No. 1 in C major, Hob. XVI:1 – Piano Sonata No. 62, Hob.XVI:52
Franz Schubert
Sonata in C minor, D. 958
Sonata in A major, D. 959
Sonata in B♭ major, D. 960

Romantic (c. 1795 – c. 1900)
Ludwig van Beethoven
Piano Sonata No. 8 "Pathétique"
Piano Sonata No. 14 "Moonlight" (Sonata quasi una fantasia)
Piano Sonata No. 17 "Tempest"
Piano Sonata No. 19 "Leichte"
Piano Sonata No. 21 "Waldstein"
Piano Sonata No. 23 "Appassionata"
Piano Sonata No. 29 "Hammerklavier"
Piano Sonata No. 32 in C minor, Op. 111
Violin Sonata No. 5 "Spring"
Violin Sonata No. 9 "Kreutzer"
Cello Sonata No. 1 in F major Op. 5
Cello Sonata No. 2 in G minor Op. 5
Cello Sonata No. 3 in A major Op. 69
Johannes Brahms
Cello Sonata No. 1
Cello Sonata No. 2
Clarinet Sonatas No. 1 and No.2
Violin Sonata No. 1
Violin Sonata No. 2
Violin Sonata No. 3
Johannes Brahms, Albert Dietrich, and Robert Schumann
F-A-E Sonata
Frédéric Chopin
Piano Sonata No. 2 in B♭ minor
Piano Sonata No. 3 in B minor
Paul Dukas
Piano Sonata in E-flat minor (1900)
George Enescu
Sonata No. 1 for violin and piano in D major, Op. 2 (1897)
Sonata No. 2 for violin and piano in F minor, Op. 6 (1899)
Edvard Grieg
Three sonatas for Violin and Piano
Franz Liszt
Sonata after a Reading of Dante (Fantasia Quasi Sonata)
Sonata in B minor
Robert Schumann
Violin Sonata No. 1 in A minor, Op. 105

20th-century and contemporary (c. 1910–present)
Samuel Barber
Cello Sonata Op. 6
Piano Sonata Op. 26 (1949)
Jean Barraqué
Piano Sonata (1950–52)
Béla Bartók
Sonata for Two Pianos and Percussion
Sonata for Piano (1926)
Sonata for Solo Violin
Sonata No. 1 for Violin and Piano
Sonata No. 2 for Violin and Piano
Alban Berg
Sonata for Piano, Op. 1
Leonard Bernstein
Sonata for Clarinet and Piano
Pierre Boulez
Piano Sonata No. 1
Piano Sonata No. 2
Piano Sonata No. 3
Benjamin Britten
Sonata for Cello and Piano, Op. 65
John Cage
Sonata for Unaccompanied Clarinet
Sonatas and Interludes for Prepared Piano (1946–48)
Claude Debussy
Sonata No. 1, for cello and piano (1915)
Sonata No. 2, for flute, viola and harp (1915)
Sonata No. 3, for violin and piano (1916–1917)
George Enescu
Sonata No. 3 for violin and piano, in A minor, dans le caractère populaire roumain Op. 25 (1926)
Sonata No. 2 for cello and piano in C major, Op. 26, No. 2 (1935)
Piano Sonata No. 1 in F♯ minor, Op. 24, No. 1 (1924)
Piano Sonata No. 3 in D major, Op. 24, No. 3 (1933–1935)
Karel Goeyvaerts
Sonata for Two Pianos, Op. 1
Hans Werner Henze
Royal Winter Music, Guitar Sonatas No. 1 and 2
Paul Hindemith
Sonata for Viola and Piano, Op. 11, No. 4 (1919)
Charles Ives
Piano Sonata No. 2, Concord, Mass., 1840–60
Leoš Janáček
1. X. 1905 (Janáčeks Sonata for Piano)
Ben Johnston
Sonata for Microtonal Piano
György Ligeti
Sonata, for solo cello (1948/1953)
Darius Milhaud
Sonata for flute, oboe, clarinet, and piano, Op. 47 (1918)
Sergei Prokofiev
Piano Sonatas—six juvenile (1904, 1907, 1907, 1907–08, 1908, 1908–09)
Piano Sonata No. 1 in F minor, Op. 1 (1907–09)
Piano Sonata No. 2 in D minor, Op. 14 (1912)
Piano Sonata No. 3 in A minor, Op. 28 (1907–17)
Piano Sonata No. 4 in C minor, Op. 29 (1917)
Piano Sonata No. 5 in C major (original version), Op. 38 (1923)
Violin Sonata No. 1 in F minor, Op. 80 (1938–46)
Piano Sonata No. 6 in A major, Op. 82 (1939–40)
Piano Sonata No. 7 in B-flat major, Stalingrad, Op. 83 (1939–42)
Piano Sonata No. 8 in B-flat major, Op. 84 (1939–44)
Flute Sonata in D major, Op. 94 (1943)
Violin Sonata No. 2 in D major, Op. 94 bis (1943)
Piano Sonata No. 9 in C major, Op. 103 (1947)
Sonata for Solo Violin (Unison Violins) in D major, Op. 115
Cello Sonata in C major, Op. 119
Sonata for Solo Cello in C-sharp minor, Op. 133
Piano Sonata No. 5 in C major (revised version), Op. 135 (1952–53)
Sergei Rachmaninoff
Piano Sonata No. 2 in B-flat minor, Op. 36 (1913, revised in 1931)
Sonata for Cello and Piano in G minor, Op. 19 (1901)
Alexander Scriabin
Piano Sonata No. 2 (Sonata-Fantasy)
Piano Sonata No. 3
Piano Sonata No. 4
Piano Sonata No. 5
Piano Sonata No. 6
Piano Sonata No </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 Lactitol and can you explain it in depth? [/INST] Lactitol is a sugar alcohol used as a replacement bulk sweetener for low calorie foods with 30–40% of the sweetness of sucrose. It is also used medically as a laxative. Lactitol is produced by two manufacturers, Danisco and Purac Biochem.

Applications
Lactitol is used in a variety of low food energy or low fat foods. High stability makes it popular for baking. It is used in sugar-free candies, cookies (biscuits), chocolate, and ice cream, with a sweetness of 30–40% that of sucrose. Lactitol also promotes colon health as a prebiotic. Because of poor absorption, lactitol only has 2–2.5 kilocalories (8.4–10.5 kilojoules) per gram, compared to 4 kilocalories (17 kJ) per gram for typical saccharides. Hence, lactitol is about 60% as caloric as typical saccharides.

Medical
Lactitol is listed as an excipient in some prescription drugs.Lactitol is a laxative and is used to prevent or treat constipation, e.g., under the trade name Importal.In February 2020, Lactitol was approved for use in the United States as an osmotic laxative for the treatment of chronic idiopathic constipation (CIC) in adults.Lactitol in combination with Ispaghula husk is an approved combination for idiopathic constipation as a laxative and is used to prevent or treat constipation.

Safety and health
Lactitol, erythritol, sorbitol, xylitol, mannitol, and maltitol are all sugar alcohols. The U.S. Food and Drug Administration (FDA) classifies sugar alcohols as "generally recognized as safe" (GRAS). They are approved as food additives, and are recognized as not contributing to tooth decay or causing increases in blood glucose. Lactitol is also approved for use in foods in most countries around the world.Like other sugar alcohols, lactitol causes cramping, flatulence, and diarrhea in some individuals who consume it </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 Stavudine and can you explain it in depth? [/INST] Stavudine (d4T), sold under the brand name Zerit among others, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other potential exposure. However, it is not a first-line treatment. It is given by mouth.Common side effects include headache, diarrhea, vomiting, rash, and peripheral nerve problems. Severe side effects include high blood lactate, pancreatitis, and an enlarged liver. It is not generally recommended in pregnancy. Stavudine is in the nucleoside analog reverse-transcriptase inhibitor (NRTI) class of medication.Stavudine was first described in 1966 and approved for use in the United States in 1994. It is available as a generic medication.

Medical uses
Stavudine is used in the treatment of HIV-1 infection, but is not a cure. It is not normally recommended as initial treatment. Stavudine can also reduce the risk of developing HIV-1 infection after coming into contact with the virus either at work (e.g., needlestick) or through exposure to infected blood or other bodily fluids. It is always used in combination with other HIV medications for the better control of the infection and a reduction in HIV complications.The World Health Organization (WHO) recommends stavudine to be phased out to due to its high toxicity levels. If the drug must be used, it is recommended to use low dosages to reduce the occurrence of side effects; however, a 2015 Cochrane review found no clear advantage between high and low dosage regimens.

Pregnancy and breastfeeding
Stavudine has been demonstrated to affect the fetus in animal studies but no data are available from human studies. Pregnant women should therefore be given stavudine only if the potential benefits outweigh the potential harm to the fetus. Additionally, there have been case reports of fatal lactic acidosis in pregnant women receiving combination therapy of stavudine and didanosine with other antiviral agents.The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, in order to avoid the risk of HIV transmission through breast milk. There is also evidence that stavudine gets into animal breast milk, although no data are available for human breast milk.

Children
Stavudine is safe for use in children infected with HIV from birth through adolescence.  Adverse effects and safety profile are the same as adults.

Elderly
There is no data available for stavudine use in HIV-infected adults aged 65 years or older.  However, among 12,000 people over the age of 65, 30% developed peripheral neuropathy.  Additionally, since the elderly are more likely to have decreased renal function, they are more likely to develop toxic side effects.

Adverse events
Common side effects
Nausea
Vomiting
Diarrhea
Headache
Upset stomachSevere side effects
Peripheral neuropathy
Lactic acidosis
Pancreatitis
Hepatotoxicity
Hepatomegaly with steatosis
Lipoatrophy/lipodystrophy (fat redistribution/accumulation)Individuals are monitored for the development of these serious adverse effects. The development of peripheral neuropathy is shown to be dose related, and may be resolved if the drug is discontinued. Individuals with advanced HIV-1 disease, a history of peripheral neuropathy, or individuals on other drugs that have association with neuropathy develop this side effect more often.Stavudine has been shown in laboratory test to be genotoxic, but with clinical doses its carcinogenic effects are non-existent. Hyperlactatemia,  bone mineral density (BMD) loss, reduction in limb fat and an increase in triglycerides were found when administered in high dosages. It is also one of the most likely antiviral drugs to cause lipodystrophy, and for this reason it is no longer considered an appropriate treatment for most patients in developed countries.
HLA-B*4001 may be used as a genetic marker to predict which patients will develop stavudine-associated lipodystrophy, to avoid or shorten the duration of stavudine according to a study in Thailand.It is still used as first choice in first line therapy in resource poor settings such as in India. Only in case of development of peripheral neuropathy or pregnancy is it changed to the next choice, zidovudine. Safety and effectiveness of dosage titration was not reported in treatment naive patients. It was only reported in those patients with sustained virologic suppression. These findings are not generalized to Stavudine used in ART naive patients who have high viral loads.
On Monday 30 November 2009, the World Health Organization stated that "[The WHO] recommends that countries phase out the use of Stavudine, or d4T, because of its long-term, irreversible side-effects. Stavudine is still widely used in first-line therapy in developing countries due to its low cost and widespread availability. Zidovudine (AZT) or tenofovir (TDF) are recommended as less toxic and equally effective alternatives."

Mechanism of action
Stavudine is a nucleoside analog of thymidine. It is phosphorylated by cellular kinases into an active triphosphate. Stavudine triphosphate inhibits HIVs reverse transcriptase by competing with the natural substrate, thymidine triphosphate. Reverse transcriptase is the enzyme the virus uses to make a DNA copy of its RNA in order to insert its genetic material into the hosts DNA. Upon incorporation into the DNA strand, stavudine triphosphate causes termination of DNA replication.

Pharmacokinetics
Absorption: Stavudine has rapid absorption and good oral bioavailability  (F = 0.86).Distribution: Stavudine does not bind to proteins in the blood.Metabolism: The clearance of stavudine is affected minimally by hepatic metabolism. Oxidation and glucuronidation produce minor metabolites.Elimination: Stavudine is mostly eliminated in the urine and mostly in its unchanged form.

Drug interactions
Simultaneous use of zidovudine is not recommended, as it can inhibit the intracellular phosphorylation of stavudine. Other anti-HIV drugs do not possess this property.
Stavudine is not protein-bound nor does it inhibit the major cytochrome P450 isoforms. Thus, significant drug interactions with drugs metabolized through these pathways or drugs that are protein-bound are unlikely.

History
Stavudine was first created by Jerome Horwitz in the 1960s and was originally named D4T. When the AIDS epidemic occurred in the 1980s, William Prusoff and Dr. Tai-Shun Lin discovered the anti-HIV properties of Stavudine </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 Selexipag and can you explain it in depth? [/INST] Selexipag, sold under the brand name Uptravi, is a medication developed by Actelion for the treatment of pulmonary arterial hypertension (PAH). Selexipag and its active metabolite, ACT-333679 (or MRE-269, the free carboxylic acid), are agonists of the prostacyclin receptor, which leads to vasodilation in the pulmonary circulation. It is taken by mouth or administered intravenously.

Contraindications
In Europe, use of selexipag together with strong inhibitors of the liver enzyme CYP2C8, such as gemfibrozil, is contraindicated because it increases concentrations of selexipag twofold, and its active metabolite 11-fold, potentially leading to more adverse effects.

Adverse effects
The adverse effects of selexipag are similar to those of intravenous prostacyclins used for pulmonary arterial hypertension. Common side effects include headache and jaw pain. An increased risk for hyperthyroidism has also been noted in people taking selexipag.

Pharmacology
Mechanism of action
Selexipag and its active metabolite ACT-333679 act on the prostacyclin receptor of lung tissue, with the latter being 37-fold more potent. They are selective for the prostacyclin receptor. Binding to this receptor leads to three major effects: increased vasodilation of the arteries, decreased cell proliferation and inhibition of platelet aggregation, all beneficial in the treatment of pulmonary arterial hypertension.

Pharmacokinetics
Selexipag is quickly absorbed from the gut and hydrolyzed in the intestines and the liver to ACT-333679 by carboxylesterases </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 Folinic acid and can you explain it in depth? [/INST] Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to treat folate deficiency that results in anemia, and methanol poisoning. It is taken by mouth, injection into a muscle, or injection into a vein.Side effects may include trouble sleeping, allergic reactions, or fever. Use in pregnancy or breastfeeding is generally regarded as safe. When used for anemia it is recommended that pernicious anemia as a cause be ruled out first. Folinic acid is a form of folic acid that does not require activation by dihydrofolate reductase to be useful to the body.Folinic acid was first made in 1945. It is on the World Health Organizations List of Essential Medicines.

Medical use
Folinic acid is given following methotrexate as part of a total chemotherapeutic plan, where it may protect against bone marrow suppression or gastrointestinal mucosa inflammation. No apparent effect is seen on pre-existing methotrexate-induced nephrotoxicity. Folinic acid can be taken as a pill (orally) or injected into a vein (intravenously) or muscle (intramuscularly).While not specifically an antidote for methotrexate, folinic acid may also be useful in the treatment of acute methotrexate overdose. Different dosing protocols are used, but folinic acid should be redosed until the methotrexate level is less than 5 x 10−8 M.Additionally, folinic acid is sometimes used to reduce the side effects of methotrexate in rheumatoid arthritis patients. This includes reductions in nausea, abdominal pain, abnormal liver blood tests, and mouth sores.Folinic acid is also used in combination with the chemotherapy agent 5-fluorouracil in treating colon cancer. In this case, folinic acid is not used for "rescue" purposes; rather, it enhances the effect of 5-fluorouracil by inhibiting thymidylate synthase.
Folinic acid is also sometimes used to prevent toxic effects of high doses of antimicrobial dihydrofolate reductase inhibitors such as trimethoprim and pyrimethamine.  It may be prescribed in the treatment of toxoplasmosis retinitis, in combination with the folic acid antagonists pyrimethamine and sulfadiazine.
Folinic acid is also used in the treatment of cerebral folate deficiency, a syndrome in which the use of folic acid cannot normalize cerebrospinal fluid levels of 5-MTHF.

Side effects
Folinic acid should not be administered intrathecally. This may produce severe adverse effects or even death.In cancer patients, rare hypersensitivity reactions to folinic acid have been described.

Drug interactions
Fluorouracil: Folinic acid may increase the toxicity associated with fluorouracil if the two are administered together. Some adverse effects that have occurred, particularly in elderly patients, include severe enterocolitis, diarrhea, and dehydration.Sulfamethoxazole-trimethoprim: A potential drug interaction exists with concomitant use of sulfamethoxazole-trimethoprim and folinic acid. Folinic acid has been shown to decrease the efficacy of sulfamethoxazole-trimethoprim in the treatment of Pneumocystis jirovecii (formerly known as Pneumocystis carinii), a common cause of pneumonia in AIDS patients.

Mechanism of action
Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., 5,10-methylenetetrahydrofolate, 5-methyltetrahydrofolate), thus has vitamin activity equivalent to that of folic acid. Since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate. This is the classical view of folinic acid rescue therapy.  In 1980s, however, folinic acid was found to reactivate the dihydrofolate reductase itself even when methotrexate exists.
Although the mechanism is not very clear, the polyglutamylation of methotrexate and dihydrofolate in malignant cells is considered to play an important role in the selective reactivation of dihydrofolate reductase by folinic acid in normal cells.Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so some normal DNA replication processes can proceed.
Folinic acid has dextro- and levorotary isomers. Both levoleucovorin (the levorotary isomer) and racemic folinic acid (a mixture of both isomers) have similar efficacy and tolerability. Levoleucovorin was approved by the FDA in 2008.

History
Folinic acid was discovered as a needed growth factor for the bacterium Leuconostoc citrovorum in 1948, by Sauberlich and Baumann. This resulted in it being called "citrovorum factor," meaning citrovorum growth factor. It had an unknown structure, but was found to be a derivative of folate that had to be metabolized in the liver before it could support growth of L </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 Physostigmine and can you explain it in depth? [/INST] Physostigmine (also known as eserine from éséré, the West African name for the Calabar bean) is a highly toxic parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean and the fruit of the Manchineel tree.
The chemical was synthesized for the first time in 1935 by Percy Lavon Julian and Josef Pikl. It is available in the U.S. under the trade names Antilirium and Isopto Eserine, and as eserine salicylate and eserine sulfate. Today, physostigmine is most commonly used for its medicinal value. However, before its discovery by Sir Robert Christison in 1846, it was much more prevalent as an ordeal poison. The positive medical applications of the drug were first suggested in the gold medal-winning final thesis of Thomas Richard Fraser at the University of Edinburgh in 1862.

Medical uses
Physostigmine is used to treat glaucoma and delayed gastric emptying. Because it enhances the transmission of acetylcholine signals in the brain and can cross the blood–brain barrier, physostigmine salicylate is used to treat anticholinergic poisoning (that is, poisoning by substances that interfere with the transmission of acetylcholine signaling, such as atropine, scopolamine, and other anticholinergic drug overdoses). It is also used to reverse neuromuscular blocking. Physostigmine is the antidote of choice for Datura stramonium poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine. It has also been used as an antidote for poisoning with GHB, but is poorly effective and often causes additional toxicity, so is not a recommended treatment. It can also be used as an antidote for dimenhydrinate poisoning.It has been shown to improve long-term memory, and was once explored as a therapy for Alzheimers disease, but in clinical trials it was not shown to confer convincing benefits, and it led to very common moderate to severe side-effects such as nausea, vomiting, diarrhea, loss of appetite, abdominal pain, and tremors, resulting in a high rate of withdrawal. Physostigmines poor tolerability led to it being abandoned in favor of later acetylcholinesterase inhibitors, three of which are currently in use: donepezil, galantamine, and rivastigmine. Recently, it has begun to be used in the treatment of orthostatic hypotension.
Recently, physostigmine has been proposed as an antidote for intoxication with gamma hydroxybutyrate (GHB, a potent sedative-hypnotic agent that can cause loss of consciousness, loss of muscle control, and death). Physostigmine may counteract GHB by producing a nonspecific state of arousal. However, not enough scientific evidence shows physostigmine properly treats GHB toxicity. Furthermore, lower doses of GHB produce a stronger action at the GHB receptor than at the GABAB-receptor, resulting in a stimulating effect which would act synergistically with physostigmine and produce hyperstimulation when the GHB blood levels begin to drop.
Physostigmine also has other proposed uses: it could reverse undesired side effects of benzodiazepines such as diazepam, alleviating anxiety and tension. Another proposed use of physostigmine is to reverse the effects of barbiturates (any of a group of barbituric acids derived for use as sedatives or hypnotics).

Pharmacology
Physostigmine acts by interfering with the metabolism of acetylcholine. It is a reversible inhibitor of acetylcholinesterase, the enzyme responsible for the breakdown of acetylcholine in the synaptic cleft of the neuromuscular junction. It indirectly stimulates both nicotinic and muscarinic acetylcholine receptors. Physostigmine has an LD50 of 3 mg/kg in mice.

Bioactivity
Physostigmine functions as an acetylcholinesterase inhibitor. Its mechanism is to prevent the hydrolysis of acetylcholine by acetylcholinesterase at the transmitted sites of acetylcholine. This inhibition enhances the effect of acetylcholine, making it useful for the treatment of cholinergic disorders and myasthenia gravis. More recently, physostigmine has been used to improve the memory of Alzheimers patients due to its potent anticholinesterase activity. However, its drug form, physostigmine salicylate, has poor bioavailability.
Physostigmine also has a miotic function, causing pupillary constriction. It is useful in treating mydriasis. Physostigmine also increases outflow of the aqueous humor in the eye, making it useful in the treatment of glaucoma.

Side effects
An overdose can cause cholinergic syndrome. Other side effects may include nausea, vomiting, diarrhea, anorexia, dizziness, headache, stomach pain, sweating, dyspepsia, and seizures. The carbamate functional group readily hydrolyses in water, and in bodily conditions. The metabolite thus formed from physostigmine and some other alkaloids (e.g. cymserine) is eseroline, which research has suggested may be neurotoxic to humans. Death can occur rapidly following overdose as a result of respiratory arrest and paralysis of the heart.

Synthesis
Physostigmine has two stereocenters—the two carbons where the five-membered rings join—so any attempt at the total synthesis must pay attention to obtaining the correct stereoisomer. The 71 syntheses of physostigmine yield 33 racemic mixtures and 38 products of a single enantiomer. The first total synthesis of physostigmine was achieved by Julian and Pikl in 1935. The main goal of Julians formal physostigmine synthesis was to prepare the key compound (L)-eseroline (compound 10 in the adjacent diagram), the conversion of which to physostigmine would be straightforward. In one of his earlier works Julian synthesized the ring of physostigmine from 1-methyl-3-formyl-oxindole as starting material, which was discovered by Paul Friedländer. However, the starting material was expensive, and the reduction of a nitrile to an amine (similar to the reaction of compound 6 to give compound 7 in the diagram) with sodium and alcohol did not proceed in good yield. In his second work “Studies in the Indole Series III,” he had improved the yield of amine from nitrile significantly by using palladium and hydrogen. Although he succeeded in the synthesis of the target compound, the route had several drawbacks. First, the chemical resolution of compound 8 is unreliable, and the chemical resolution of rac-eserethole gives optically pure product only after eight recrystallizations of its tartrate salt. Second, the reductive amination going from compound 8 to compound 9 requires a large amount of Na. In the years since this initial work, many other groups have used a variety of approaches to construct the ring system and showcase new synthetic methods.

Biosynthesis
Physostigmine biosynthesis is proposed from tryptamine methylation and post-heterocyclization catalyzed by an unknown enzyme:

History
The Calabar bean
The Efik people, living in Cross River State and the Ibibio people in Akwa Ibom State, in what is now the south-south of Nigeria, were the first to come in contact with physostigmine, the active ingredient in the Calabar bean. The Calabar bean, or chopping nut, was very prevalent in Efik culture as an ordeal poison. Individuals accused of witchcraft would drink the white, milky extract of the bean, made by crushing the bean in a mortar and soaking the remains in water. If the accused died, it was considered proof of their use of witchcraft. If they lived, usually due to vomiting up the poison, then they were declared innocent and sent free.

Western medicines discovery
In 1846, European missionaries arrived in what was referred to as Old Calabar, now part of Nigeria. These missionaries wrote about the use of the Calabar bean as a test for witchcraft. These beans eventually made their way back to Scotland, the home of these particular missionaries, where in 1855 Robert Christison, a toxicologist, tested the toxicity of the poison on himself by eating one. He survived to document the experience. The bean was studied throughout the 1860s by a few different Edinburgh scientists, including Douglas Argyll Robertson who wrote a paper on the use of Calabar bean extract on the eye and was the first to use it medicinally, and Thomas Richard Fraser, who researched how to best extract the active principle, which was later determined to be physostigmine. Fraser also studied the antagonism between physostigmine and atropine extremely rigorously, at a time when the concept of antagonism had little if any experimental support. Frasers research is still the basis of todays knowledge about the interactions between atropine and physostigmine at many different and specific doses. Physostigmines first use as a treatment for glaucoma was by Ludwig Laqueur in 1876 </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 Nizatidine and can you explain it in depth? [/INST] Nizatidine is a histamine H2 receptor antagonist that inhibits stomach acid production, and is commonly used in the treatment of peptic ulcer disease and gastroesophageal reflux disease.It was patented in 1980 and approved for medical use in 1988 </s>