<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Erythromycin and explain in detail? [/INST] Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, as well as to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.Common side effects include abdominal cramps, vomiting, and diarrhea. More serious side effects may include Clostridium difficile colitis, liver problems, prolonged QT, and allergic reactions. It is generally safe in those who are allergic to penicillin. Erythromycin also appears to be safe to use during pregnancy. While generally regarded as safe during breastfeeding, its use by the mother during the first two weeks of life may increase the risk of pyloric stenosis in the baby. This risk also applies if taken directly by the baby during this age. It is in the macrolide family of antibiotics and works by decreasing bacterial protein production.Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 215th most commonly prescribed medication in the United States, with more than two million prescriptions.

Medical uses
Erythromycin can be used to treat bacteria responsible for causing infections of the skin and upper respiratory tract, including Streptococcus, Staphylococcus, Haemophilus and Corynebacterium genera. The following represents MIC susceptibility data for a few medically significant bacteria:
Haemophilus influenzae: 0.015 to 256 μg/ml
Staphylococcus aureus: 0.023 to 1024 μg/ml
Streptococcus pyogenes: 0.004 to 256 μg/ml
Corynebacterium minutissimum: 0.015 to 64 μg/mlIt may be useful in treating gastroparesis due to this promotility effect. It has been shown to improve feeding intolerances in those who are critically ill. Intravenous erythromycin may also be used in endoscopy to help clear stomach contents.

Available forms
Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, enteric-coated capsules, non enteric-coated tablets, non enteric-coated capsules, and injections.
The following erythromycin combinations are available for oral dosage:
erythromycin base (capsules, tablets)
erythromycin estolate (capsules, oral suspension, tablets),  contraindicated during pregnancy
erythromycin ethylsuccinate (oral suspension, tablets)
erythromycin stearate (oral suspension, tablets)For injection, the available combinations are:
erythromycin gluceptate
erythromycin lactobionateFor ophthalmic use:

erythromycin base (ointment)

Adverse effects
Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are very common because erythromycin is a motilin agonist. Because of this, erythromycin tends not to be prescribed as a first-line drug.
More serious side effects include arrhythmia with prolonged QT intervals, including torsades de pointes, and reversible deafness. Allergic reactions range from urticaria to anaphylaxis. Cholestasis, Stevens–Johnson syndrome, and toxic epidermal necrolysis are some other rare side effects that may occur.
Studies have shown evidence both for and against the association of pyloric stenosis and exposure to erythromycin prenatally and postnatally. Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants. Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.Erythromycin estolate has been associated with reversible hepatotoxicity in pregnant women in the form of elevated serum glutamic-oxaloacetic transaminase and is not recommended during pregnancy. Some evidence suggests similar hepatotoxicity in other populations.It can also affect the central nervous system, causing psychotic reactions, nightmares, and night sweats.

Interactions
Erythromycin is metabolized by enzymes of the cytochrome P450 system, in particular, by isozymes of the CYP3A superfamily. The activity of the CYP3A enzymes can be induced or inhibited by certain drugs (e.g., dexamethasone), which can cause it to affect the metabolism of many different drugs, including erythromycin. If other CYP3A substrates — drugs that are broken down by CYP3A — such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor)—are taken concomitantly with erythromycin, levels of the substrates increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated.
Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4. Hence, erythromycin should not be administered to people using these drugs, or drugs that also prolong the QT interval. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline, which is used mostly in asthma, is also contraindicated.
Erythromycin and doxycycline can have a synergistic effect when combined and kill bacteria (E. coli) with a higher potency than the sum of the two drugs together. This synergistic relationship is only temporary. After approximately 72 hours, the relationship shifts to become antagonistic, whereby a 50/50 combination of the two drugs kills less bacteria than if the two drugs were administered separately.It may alter the effectiveness of combined oral contraceptive pills because of its effect on the gut flora. A review found that when erythromycin was given with certain oral contraceptives, there was an increase in the maximum serum concentrations and AUC of estradiol and dienogest.Erythromycin is an inhibitor of the cytochrome P450 system, which means it can have a rapid effect on levels of other drugs metabolised by this system, e.g., warfarin.

Pharmacology
Mechanism of action
Erythromycin displays bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations. By binding to the 50s subunit of the bacterial  rRNA complex, protein synthesis and subsequent structure and function processes critical for life or replication are inhibited. Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied, thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action.
Erythromycin increases gut motility by binding to Motillin receptor, thus it is a Motillin receptor agonist in addition to its antimicrobial properties.

Pharmacokinetics
Erythromycin is easily inactivated by gastric acid; therefore, all orally administered formulations are given as either enteric-coated or more-stable salts or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released.

Metabolism
Most of erythromycin is metabolised by demethylation in the liver by the hepatic enzyme CYP3A4. Its main elimination route is in the bile with little renal excretion, 2%-15% unchanged drug. Erythromycins elimination half-life ranges between 1.5 and 2.0 hours and is between 5 and 6 hours in patients with end-stage renal disease.  Erythromycin levels peak in the serum 4 hours after dosing; ethylsuccinate peaks 0.5-2.5 hours after dosing, but can be delayed if digested with food.Erythromycin crosses the placenta and enters breast milk.  The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding. Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients.

Chemistry
Composition
Standard-grade erythromycin is primarily composed of four related compounds known as erythromycins A, B, C, and D. Each of these compounds can be present in varying amounts and can differ by lot. Erythromycin A has been found to have the most antibacterial activity, followed by erythromycin B. Erythromycins C and D are about half as active as erythromycin A. Some of these related compounds have been purified and can be studied and researched individually.

Synthesis
Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were  made to synthesize it in the laboratory. The presence of 10 stereogenic carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task. Complete syntheses of erythromycins’ related structures and precursors such as 6-deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials. Woodward successfully completed the synthesis of erythromycin A.

Erythromycin related compounds
History
In 1949 Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer at Eli Lilly. Aguilar managed to isolate erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to Saccharopolyspora erythraea) found in the samples. Aguilar received no further credit or compensation for his discovery.
The scientist was allegedly promised a trip to the company’s manufacturing plant in Indianapolis, but it was never fulfilled. In a letter to the company’s president, Aguilar wrote: “A leave of absence is all I ask as I do not wish to sever my connection with a great company which has given me wonderful breaks in life.” The request was not granted.Aguilar reached out to Eli Lilly again in 1993, requesting royalties from sales of the drug over the years, intending to use them to put up a foundation for poor and sickly Filipinos. This request was also denied. He died in September of the same year.Lilly filed for patent protection on the compound which was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected). Erythromycin was formerly also called Ilotycin.
The antibiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.
Scientists at Chugai Pharmaceuticals discovered an erythromycin-derived motilin agonist called mitemcinal that is believed to have strong prokinetic properties (similar to erythromycin) but lacking antibiotic properties. Erythromycin is commonly used off-label for gastric motility indications such as gastroparesis. If mitemcinal can be shown to be an effective prokinetic agent, it would represent a significant advance in the gastrointestinal field, as treatment with this drug would not carry the risk of unintentional selection for antibiotic-resistant bacteria.

Society and culture
Cost
It is available as a generic medication.In the United States in 2014 the price increased to seven dollars per tablet.The price of Erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015. In 2017, a Kaiser Health News study found that the per-unit cost of dozens of generics doubled or even tripled from 2015 to 2016, increasing spending by the Medicaid program. Due to price increases by drug manufacturers, Medicaid paid on average $2,685,330 more for Erythromycin in 2016 compared to 2015 (not including rebates) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pimecrolimus and explain in detail? [/INST] Pimecrolimus is an immunomodulating agent of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis (however, Galderma has been promoting the compound in Canada since early 2007) under the trade name Elidel.

Medical uses
It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis,  cutaneous lupus erythematosus, oral lichen planus,  vitiligo, and psoriasis </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is DTaP-IPV/Hib vaccine and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Fosphenytoin and explain in detail? [/INST] Fosphenytoin, also known as fosphenytoin sodium, and sold under the brand name Cerebyx among others, is a water-soluble phenytoin prodrug that is administered intravenously to deliver phenytoin, potentially more safely than intravenous phenytoin. It is used in the acute treatment of convulsive status epilepticus.
Fosphenytoin was developed in 1996. On 18 November 2004, Sicor (a subsidiary of Teva) received a tentative approval letter from the United States Food and Drug Administration for a generic version of fosphenytoin.

Medical uses
Fosphenytoin is approved in the United States for the short-term (five days or fewer) treatment of epilepsy when more widely used means of phenytoin administration are not possible or are ill-advised, such as endotracheal intubation, status epilepticus or some other type of repeated seizures; cluster seizure, vomiting, and/or the patient is unalert or not awake or both.

Other
In 2003, it was reported that even though anticonvulsants are often very effective in mania, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect.

Metabolism
One millimole of phenytoin is produced for every millimole of fosphenytoin administered; the hydrolysis of fosphenytoin also yields phosphate and formaldehyde, the latter of which is subsequently metabolized to formate, which is in turn metabolized by a folate dependent mechanism.

Side effects
Side effects are similar to intravenous phenytoin and include hypotension, cardiac arrhythmias, CNS adverse events (nystagmus, dizziness, sedation/somnolence, ataxia and stupor), and local dermatological reactions </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Amlodipine/celecoxib and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Fludarabine and explain in detail? [/INST] Fludarabine is a purine analogue and antineoplastic agent.   It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate,
sold under the brand name Fludara among others.  It is a chemotherapy medication used in the treatment of leukemia and lymphoma. These include chronic lymphocytic leukemia, non-Hodgkins lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. It is given by injection into a vein or by mouth.Common side effects include nausea, diarrhea, fever, rash, shortness of breath, numbness, vision changes, and feeling tired. Severe side effects include brain dysfunction, low blood cell counts, and lung inflammation. Use in pregnancy will likely result in harm to the fetus. Fludarabine is in the purine analog family of medications and works by interfering with the duplication of DNA.Fludarabine was approved for medical use in the United States in 1991. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone.
Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas.  As part of the FLAG or FLAMSA regimen, fludarabine is used together with cytarabine and granulocyte colony-stimulating factor in the treatment of acute myeloid leukaemia.  Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to allogeneic stem cell transplant.

Side effects
Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infections. People who have been treated with fludarabine will usually be asked to take co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis jiroveci pneumonia </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Sarecycline and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Busulfan and explain in detail? [/INST] Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, Otsuka America Pharmaceutical, Inc.) is a chemotherapy drug in use since 1959. It is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate.

History
Busulfan was approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML) in 1999.  Busulfan was the mainstay of the chemotherapeutic treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib, though it is still in use to a degree as a result of the drugs relative low cost.

Indications
Busulfan is used in pediatrics and adults in combination with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemias, lymphomas, and myeloproliferative disorders.  Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities.
The drug was recently used in a study to examine the role of platelet-transported serotonin in liver regeneration.

Availability
Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet. After 2002, a great interest has appeared for intravenous presentations of busulfan. Busulfex is supplied as an intravenous solution with 6 mg/ml busulfan.  Busulfex has proved equally effective as oral busulfan, with presumedly less toxic side effects. Pharmacokinetic and dynamic studies support this use, that has prompted its usage in transplantation regimes, particularly in frail patients. Fludarabine + busulfan is a typical example of this use.

Side effects
Toxicity may include interstitial pulmonary fibrosis ("busulfan lung"), hyperpigmentation, seizures, hepatic (veno-occlusive disease) (VOD) or sinusoidal obstruction syndrome (SOS), emesis, and wasting syndrome. Busulfan also induces thrombocytopenia, a condition of lowered blood platelet count and activity, and sometimes medullary aplasia.  Seizures and VOD are serious concerns with busulfan therapy and prophylaxis is often utilized to avoid these effects.  Hepatic VOD is a dose-limiting toxicity. Symptoms of VOD include weight gain, elevated bilirubin, painful hepatomegaly, and edema. The reason busulfan causes VOD is mostly unknown and can be deadly.  Ursodiol may be considered for prophylaxis of veno-occlusive disease.
Antiemetics are often administered prior to busulfan to prevent vomiting (emesis).
Phenytoin may be used concurrently to prevent the seizures. Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.Busulfan is listed by the IARC as a Group 1 carcinogen.

Dosing, administration, and pharmacokinetics
As an adjunct therapy with cyclophosphamide for conditioning prior to bone marrow transplantation in adults and children >12 kg, intravenous (IV) busulfan (Bulsulfex) is dosed at 0.8 mg/kg every six hours for 16 doses (four days).  IV busulfan is usually administered over two hours.  Both IV and oral formulations require prophylactic antiemetic agents administered prior to the busulfan dose and scheduled antiemetics administered thereafter. Oral bioavailability of busulfan shows a large interindividual variation. Taking busulfan on an empty stomach is recommended to reduce the risk of nausea and emesis.
Peak plasma concentrations are achieved within one hour of oral administration.  About 30% of the drug is bound to plasma proteins, such as albumin.
Busulfan therapeutic drug monitoring is completed based on trough (pre-dose) levels with a target six-hour area under the curve (AUC) of between 900 and 1500 micromolxmin.  AUCs (six-hour) >1500 micromolxmin are associated with hepatic VOD and subsequent dose reduction should be considered.  AUCs (six-hour) <900 micromolxmin are associated with incomplete bone marrow ablation and subsequent dose escalation should be considered.  Dose adjustments are performed using first order kinetics, such that the adjusted dose = current dose × (target AUC/actual AUC).

Drug interactions
Busulfan is metabolized via glutathione conjugation in the liver to inactive metabolites.  Itraconazole can decrease busulfan clearance by up to 25%, resulting in AUC levels >1500 micromolxmin and increased risk of hepatic VOD.  Concomitant use of acetaminophen within 72 hours of busulfan use can reduce busulfan clearance (resulting in increased busulfan AUC), as acetaminophen is also metabolized via glutathione and may deplete stores </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cetrorelix and explain in detail? [/INST] Cetrorelix (INN, BAN), or cetrorelix acetate (USAN, JAN), sold under the brand name Cetrotide, is an injectable gonadotropin-releasing hormone (GnRH) antagonist. A synthetic decapeptide, it is used in assisted reproduction to inhibit premature luteinizing hormone surges The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition, cetrorelix can be used to treat hormone-sensitive cancers of the prostate and breast (in pre-/perimenopausal women) and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). It is administered as either multiple 0.25 mg daily subcutaneous injections or as a single-dose 3 mg subcutaneous injection. The duration of the 3 mg single dose is four days; if human chorionic gonadotropin (hCG) is not administered within four days, a daily 0.25 mg dose is started and continued until hCG is administered.

Medical uses
Cetrorelix is marketed by Merck Serono for use in in-vitro fertilization in all countries except Japan, where it is marketed by Shionogi and Nippon Kayaku. Aeterna Zentaris receives royalties on these sales and retains rights to develop cetrorelix for other indications. In IVF use it is injected daily after follicle stimulation has been initiated and evidence of follicle maturation is approaching; given daily it prevents an endogenous LH surge that would trigger an untimely ovulation prior to the hCG administration by the treating physician. As an alternative to the GnRH antagonist, also a GnRH agonist could be given, but agonist have to be started earlier to overcome the agonistic effect. Cetrorelix can be mixed with follitropin alpha without compromising their reported safety and efficacy.

Contraindications
The use of cetrorelix is contraindicated in severe renal impairment. It is not intended for women aged 65 years or older. Use in women with severe allergic conditions is not recommended. Use with caution in women with active allergies or history of allergies.

Research
Cetrorelix was under development for the treatment of benign prostatic hyperplasia, premenopausal breast cancer, endometriosis, ovarian cancer, prostate cancer, and uterine fibroids, but development for these indications was discontinued.A study published in Nature Medicine found a link between hormonal imbalance in the womb and Polycystic ovary syndrome (PCOS), specifically prenatal exposure to anti-Müllerian hormone.  For the study, the researchers injected pregnant mice with AMH so that they had a higher than normal concentration of the hormone. Indeed, they gave birth to daughters who later developed PCOS-like tendencies. These included problems with fertility, delayed puberty, and erratic ovulation. To reverse it, the researchers dosed the polycystic mice with cetrorelix, which made the symptoms to go away </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cysteamine and explain in detail? [/INST] Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A.  The intermediate pantetheine is broken down into cysteamine and pantothenic acid.  It is the biosynthetic precursor to the neurotransmitter hypotaurine.It is a stable aminothiol, i.e., an organic compound containing both an amine and a thiol functional groups.  Cysteamine is a white, water-soluble solid.  It is often used as salts of the ammonium derivative [HSCH2CH2NH3]+ including the hydrochloride, phosphocysteamine, and bitartrate.As a medication, cysteamine, sold under the brand name Cystagon among others, is indicated to treat cystinosis.

Medical uses
Cysteamine is used to treat cystinosis.  It is available by mouth (capsule and extended release capsule) and in eye drops.When applied topically it can scavenge free radicals and lighten skin thats been darkened as a result of post-inflammatory hyperpigmentation, sun exposure and Melasma. Tentative evidence suggests that it may be a more effective depigmentation agent than hydroquinone, retinoids and topical corticosteroids in individuals with chronic skin discoloration. Topical application of cysteamine cream has also demonstrated similar efficacy to intradermal tranexamic acid injections for the treatment of Melasma but with much fewer adverse effects.

Adverse effects
Topical use
The most important adverse effect related to topical use might be skin irritation. However its significantly better tolerated than alternative skin lightening treatments with similar efficacy.

Oral use
The label for oral formulations of cysteamine carry warnings about symptoms similar to Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms including  seizures, lethargy, somnolence, depression, and encephalopathy, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension that can cause  headache, tinnitus, dizziness, nausea, double or blurry vision, loss of vision, and pain behind the eye or pain with eye movement.The main side effects are Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension (IIH). IIH can cause headache, ringing in the ears, dizziness, nausea, blurry vision, loss of vision, and pain behind the eye or with eye movement.Additional adverse effects of oral cysteamine include bad breath, skin odor, vomiting, nausea, stomach pain, diarrhea, and loss of appetite.The drug is in pregnancy category C; the risks of cysteamine to a fetus are not known but it harms babies in animal models at doses less than those given to people.For eye drops, the most common adverse effects are  sensitivity to light, redness, and eye pain, headache, and visual field defects.

Interactions
There are no drug interactions for normal capsules or eye drops, but the extended release capsules should not be taken with drugs that affect stomach acid like proton pump inhibitors or with alcohol, as they can cause the drug to be released too quickly.  It doesnt inhibit any cytochrome P450 enzymes.

Pharmacology
People with cystinosis lack a functioning transporter (cystinosin) which transports cystine from the lysosome to the cytosol. This ultimately leads to buildup of cystine in lysosomes, where it crystallizes and damages cells </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dacomitinib and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Netarsudil and explain in detail? [/INST] Netarsudil, sold under the brand name Rhopressa among others, is a medication for the treatment of glaucoma.  In the United States, in December 2017, the Food and Drug Administration (FDA) approved a 0.02% ophthalmic solution for the lowering of elevated intraocular pressure in people with open-angle glaucoma or ocular hypertension. The European Medicines Agency approved it in 2019 for the same uses under the brand name Rhokiinsa.The FDA considers it to be a first-in-class medication.

Contraindications
Netarsudil has no contraindications apart from known hypersensitivity to the drug.

Adverse effects
The most common side effects are hyperaemia (increased blood flow associated with redness, in 51% of patients) in the conjunctiva, cornea verticillata (drug deposits in the cornea, in 17%), and eye pain (in 17%). All other side effects occur in fewer than 10% of people. Hypersensitivity reactions occur in fewer than 1%.

Overdose
Overdosing netarsudil is unlikely because concentrations in the body are so low that they are generally not detectable.

Interactions
No interaction studies have been done. The European label recommends to apply other eye drops at least five minutes before, and eye ointments at least five minutes after netarsudil drops.

Pharmacology
Mechanism of action
This drugs mechanism of action is not entirely clear. It inhibits the enzyme rho kinase. This appears to increase outflow of aqueous humor through the trabecular meshwork, and also to reduce pressure in the veins of the episcleral layer. The drug also inhibits the norepinephrine transporter.

Pharmacokinetics
After instillation into the eye, netarsudil is cleaved by esterases in the cornea to AR-13503, which is the active metabolite </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Evinacumab and explain in detail? [/INST] Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 slows the function of certain enzymes that break down fats in the body. Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol.  Evinacumab was approved for medical use in the United States in February 2021.Regeneron invented evinacumab using the companys VelocImmune® technology, a proprietary genetically-engineered mouse platform endowed with a genetically-humanized immune system to produce optimized fully-human monoclonal antibodies.

History
The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH). In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo. Participants were taking other lipid-lowering therapies as well.The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24. At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.The U.S. Food and Drug Administration (FDA) granted the application for evinacumab orphan drug, breakthrough therapy, and priority review designations. The FDA granted approval of Evkeeza to Regeneron Pharmaceuticals, Inc.

Society and culture
Legal status
On 22 April 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 under exceptional circumstances for the medicinal product Evkeeza, intended for the treatment of adult and adolescent patients aged 12 years and older with homozygous familial hypercholesterolaemia (HoFH). The applicant for this medicinal product is Regeneron Ireland Designated Activity Company (DAC). Evinacumab was approved for medical use in the European Union in June 2021.

References
Further reading
Dewey FE, Gusarova V, Dunbar RL, ODushlaine C, Schurmann C, Gottesman O,  et al </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Latanoprost and explain in detail? [/INST] Latanoprost, sold under the brand name Xalatan among others, is a medication used to treat increased pressure inside the eye. This includes ocular hypertension and open angle glaucoma. It is applied as eye drops to the eyes. Onset of effects is usually within four hours, and they last for up to a day.Common side effects include blurry vision, redness of the eye, itchiness, and darkening of the iris. Latanoprost is in the prostaglandin analogue family of medications. It works by increasing the outflow of aqueous fluid from the eyes through the uveoscleral tract.Latanoprost was approved for medical use in the United States in 1996. It is on the World Health Organizations List of Essential Medicines. Latanoprost is available as a generic medication. In 2019, it was the 77th most commonly prescribed medication in the United States with more than 9 million prescriptions. It is available as a combination with netarsudil and with timolol.

Medical uses
Open-angle glaucoma
In people with ocular hypertension (intraocular pressure (IOP) ≥21 mm Hg) including open-angle glaucoma, treatment with latanoprost reduced IOP levels by 22 to 39% over 1 to 12 months’ treatment. Latanoprost was more effective than timolol 0.5% twice daily in 3 of 4 large (n = 163 to 267) randomised, double-blind trials. Latanoprost demonstrated a stable long-term IOP-lowering effect in 1- or 2-year continuations of these trials, with no sign of diminishing effect during prolonged treatment. The UKGTS trial found that latanoprost treatment results in more than halved risk of sight loss.Meta-analysis suggests that latanoprost is more effective than timolol in lowering intraocular pressure (IOP). However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified.

Closed-angle glaucoma
Patients who had elevated IOP despite iridotomy and/or iridectomy (including patients of Asian descent), latanoprost was significantly more effective than timolol in two double-blind, monotherapy trials (8.2 and 8.8 mm Hg vs 5.2 and 5.7 mm Hg for latanoprost vs timolol at 12 and 2 weeks, respectively).

Adverse effects
Listed from most to least common:
> 5–15%: blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased (brown) pigmentation of the iris (causing heterochromia), punctate epithelial keratopathy
4%: cold or upper respiratory tract infections, flu-like syndrome
1–4%: dry eyes, excessive tearing, eye pain, lid crusting, lid edema, lid erythema (hyperemia), lid pain, photophobia
1–2%: chest pain, allergic skin reactions, arthralgia, back pain, myalgia
< 1 % (only severe or life-threatening effects): asthma, herpes keratitis, iritis, keratitis, retinal artery embolus, retinal detachment, toxic epidermal necrolysis, uveitis, vitreous hemorrhage from diabetic retinopathy
A single case report links latanoprost use to the progression of keratoconus.Research suggests that wiping the eye with an absorbent pad after the administration of eye drops can result in shorter eyelashes and a lesser chance of hyperpigmentation in the eyelid, compared to not wiping off excess fluid.

Pregnancy
Use in pregnant women is limited due to high incidence of abortion shown in animal experiments. Because of this, latanoprost is classified as risk factor C (adverse events were observed in animal reproduction studies at maternally toxic doses) according to United States Food and Drug Administrations use-in-pregnancy ratings. Drug excretion in breast milk is unknown.

Interactions
Interactions are similar to other prostaglandin analogs. Paradoxically, the concomitant use of latanoprost and bimatoprost or other prostaglandins may result in increased intraocular pressure.
Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce or increase the effect of latanoprost.

Pharmacology
Mechanism of action
Like tafluprost and travoprost, latanoprost is an ester prodrug that is activated to the free acid in the cornea. Also like the related drugs, latanoprost acid is an analog of prostaglandin F2α that acts as a selective agonist at the prostaglandin F receptor.  Prostaglandins increase the scleras permeability to aqueous fluid </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cyclobenzaprine and explain in detail? [/INST] Cyclobenzaprine (sold under the brand name Flexeril, among others) is a medication used for muscle spasms from musculoskeletal conditions of sudden onset. It is not useful in cerebral palsy. It is taken by mouth. Use is not recommended for more than a few weeks.Common side effects include headache, feeling tired, dizziness, and dry mouth. Serious side effects may include an irregular heartbeat. There is no evidence of harm in pregnancy, but it has not been well studied in this population. It should not be used with an MAO inhibitor. How it works is unclear.Cyclobenzaprine was approved for medical use in the United States in 1977. It is available as a generic medication. In 2020, it was the 39th most commonly prescribed medication in the United States, with more than 16 million prescriptions. It was not available in the United Kingdom as of 2012.

Medical use
Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions. After sustaining an injury, muscle spasms to stabilize the affected body part occur, which may increase pain to prevent further damage. Cyclobenzaprine is used to treat such muscle spasms associated with acute, painful musculoskeletal conditions. It decreases pain in the first two weeks, peaking in the first few days, but has no proven benefit after two weeks. Since no benefit is proven beyond that, therapy should not be continued long-term. It is the best-studied muscle relaxer. It is not useful for spasticity due to neurologic conditions such as cerebral palsy.A 2004 review found benefit for fibromyalgia symptoms, with a reported number needed to treat of 4.8 (meaning that 1 person out of every 4.8 benefits from treatment) for pain reduction, but no change in fatigue or tender points. A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome. It may also be used along with other treatments for tetanus.

Side effects
Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%). Drowsiness and dry mouth appear to intensify with increasing dose. The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamine, serotonin, and muscarinic receptors.Agitation is a common side effect observed, especially in the elderly. Some experts believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment. In general, the National Committee for Quality Assurance recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.Dysphagia, a life-threatening side-effect, may rarely occur. Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants.

Overdose
The most common effects of overdose are drowsiness and tachycardia. Rare but potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low blood pressure, seizures, and neuroleptic malignant syndrome. Life-threatening overdose is rare, however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats. The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs.

Interactions
Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndrome when cyclobenzaprine was taken with the serotonergic drugs duloxetine or phenelzine.These substances may interact with cyclobenzaprine:

Central nervous system  depressants (e.g. alcohol, opioids, benzodiazepines, nonbenzodiazepines, phenothiazines,  carbamates, barbiturates, major tranquilizers)
Monoamine oxidase inhibitors taken within two weeks of cyclobenzaprine may result in serious, life-threatening side effects.Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery.

Pharmacology
Cyclobenzaprine is a centrally acting muscle relaxant. Cyclobenzaprine is a 5-HT2 receptor antagonist; it relieves muscle spasm through action on the central nervous system at the brain stem, rather than targeting the peripheral nervous system or muscles themselves.

Pharmacodynamics
Pharmacokinetics
Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. The half-life of the drug is 18 hours and it has a plasma clearance of 0.7 litres per minute.

Comparison to other medications
Cyclobenzaprine has been found to be not inferior to tizanidine, orphenadrine, and carisoprodol in the treatment of acute lower back pain, although none have been proven to be effective for long-term use (beyond two weeks of treatment) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ranibizumab and explain in detail? [/INST] Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related macular degeneration (AMD, also ARMD), diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion.
Ranibizumab was developed by Genentech and marketed by them in the United States, and elsewhere by Novartis, under the brand name Lucentis.Ranibizumab (Lucentis) was approved for medical use in the United States in June 2006. Ranibizumab (Susvimo) was approved for medical use in the United States in October 2021.

Medical uses
In the United States, ranibizumab is indicated for the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization.In the European Union, ranibizumab is indicated for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to diabetic macular edema, proliferative diabetic retinopathy, visual impairment due to macular edema secondary to retinal vein occlusion, and visual impairment due to choroidal neovascularisation.It is often used for age-related wet macular degeneration. Its effectiveness is similar to that of bevacizumab and aflibercept. A 2017 systematic review update found that while ranibizumab and bevacizumab provide similar functional outcomes in diabetic macular edema, there is low-certainty evidence suggesting that ranibizumab is more effective in reducing central retinal thickness than bevacizumab.

Side effects
A 2014 Cochrane review did not find a difference between bevacizumab and ranibizumab in deaths or total severe side effects when used for macular degeneration. There, however, was not a lot of evidence, and thus this conclusion is not that certain.Ranibizumab does appear to result in a lower risk of stomach and intestinal problems. It is also associated with a low rate of eye related side effects.The most common side effects in clinical trials were conjunctival haemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation.
Although there is a theoretical risk for arterial thromboembolic events in people receiving VEGF-inhibitors by intravitreal injection, the observed incidence rate was low (< 4%) and similar to that seen with placebo.
Serious adverse events related to the injection procedure occurred with an incidence rate of less than 1% and included endophthalmitis, retinal detachment, and traumatic cataracts. Other serious ocular adverse events observed among ranibizumab-treated patients (incidence rate < 1%) included intraocular inflammation and blindness.

Interactions
No significant interactions are known.

Pharmacology
Ranibizumab is a monoclonal antibody that inhibits angiogenesis by inhibiting vascular endothelial growth factor A, a mechanism similar to that of Bevacizumab.

Society & culture
Economics
Its effectiveness is similar to that of bevacizumab. Its rates of side effects also appear similar. However, ranibizumab typically costs $2,000 a dose, while the equivalent dose of bevacizumab typically costs $50.In November 2010, The New York Times reported that Genentech began offering secret rebates to about 300 ophthalmologists in an apparent inducement to get them to use more ranibizumab rather than their less expensive bevacizumab.  This may have been in anticipation of the results of the CATT clinical trial, which was sponsored by the National Eye Institute, and compared the relative safety and efficacy of ranibizumab and bevacizumab in treating AMD. In 2008, bevacizumab cost Medicare only $20 million for about 480,000 injections, while ranibizumab cost Medicare $537 million for only 337,000 injections. A small study showed no superior effect of ranibizumab versus bevacizumab in direct comparison.
The initial results of the larger Comparison of Age-related Macular Degeneration Treatments Trials (CATT) trial were published in the New England Journal of Medicine in May 2011 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tolazamide and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Thyroid-stimulating hormone and explain in detail? [/INST] Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

Physiology
Hormone levels
TSH (with a half-life of about an hour) stimulates the thyroid gland to secrete the hormone thyroxine (T4), which has only a slight effect on metabolism. T4 is converted to triiodothyronine (T3), which is the active hormone that stimulates metabolism. About 80% of this conversion is in the liver and other organs, and 20% in the thyroid itself.TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development, as well as in response to stress.
The hypothalamus, in the base of the brain, produces thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary gland to produce TSH.
Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release.
The concentration of thyroid hormones (T3 and T4) in the blood regulates the pituitary release of TSH; when  T3 and T4 concentrations are low, the production of TSH is increased, and, conversely, when T3 and T4 concentrations are high,  TSH production is decreased. This is an example of a negative feedback loop. Any inappropriateness of measured values, for instance a low-normal TSH together with a low-normal T4 may signal tertiary (central) disease and a TSH to TRH pathology. Elevated reverse T3 (RT3) together with low-normal TSH and low-normal T3, T4 values, which is regarded as indicative for euthyroid sick syndrome, may also have to be investigated for chronic subacute thyroiditis (SAT) with output of subpotent hormones. Absence of antibodies in patients with diagnoses of an autoimmune thyroid in their past would always be suspicious for development to SAT even in the presence of a normal TSH because there is no known recovery from autoimmunity.
For clinical interpretation of laboratory results it is important to acknowledge that TSH is released in a pulsatile manner resulting in both circadian and ultradian rhythms of its serum concentrations.

Subunits
TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit.

The α (alpha) subunit (i.e., chorionic gonadotropin alpha) is nearly identical to that of human chorionic gonadotropin (hCG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The α subunit is thought to be the effector region responsible for stimulation of adenylate cyclase (involved the generation of cAMP). The α chain has a 92-amino acid sequence.
The β (beta) subunit (TSHB) is unique to TSH, and therefore determines its receptor specificity. The β chain has a 118-amino acid sequence.

The TSH receptor
The TSH receptor is found mainly on thyroid follicular cells. Stimulation of the receptor increases T3 and T4 production and secretion. This occurs through stimulation of six steps in thyroid hormone synthesis: (1) Up-regulating the activity of the sodium-iodide symporter (NIS) on the basolateral membrane of thyroid follicular cells, thereby increasing intracellular concentrations of iodine (iodine trapping). (2) Stimulating iodination of thyroglobulin in the follicular lumen, a precursor protein of thyroid hormone. (3) Stimulating the conjugation of iodinated tyrosine residues. This leads to the formation of thyroxine (T4) and triiodothyronine (T3) that remain attached to the thyroglobulin protein. (4) Increased endocytocis of the iodinated thyroglobulin protein across the apical membrane back into the follicular cell. (5) Stimulation of proteolysis of iodinated thyroglobulin to form free thyroxine (T4) and triiodothyronine (T3). (6) Secretion of thyroxine (T4) and triiodothyronine (T3) across the basolateral membrane of follicular cells to enter the circulation. This occurs by an unknown mechanism.Stimulating antibodies to the TSH receptor mimic TSH and cause Graves disease. In addition, hCG shows some cross-reactivity to the TSH receptor and therefore can stimulate production of thyroid hormones. In pregnancy, prolonged high concentrations of hCG can produce a transient condition termed gestational hyperthyroidism. This is also the mechanism of trophoblastic tumors increasing the production of thyroid hormones.

Applications
Diagnostics
Reference ranges for TSH may vary slightly, depending on the method of analysis, and do not necessarily equate to cut-offs for diagnosing thyroid dysfunction. In the UK, guidelines issued by the Association for Clinical Biochemistry suggest a reference range of 0.4–4.0 µIU/mL (or mIU/L). The  National Academy of Clinical Biochemistry (NACB) stated that it expected the reference range for adults to be reduced to 0.4–2.5 µIU/mL, because research had shown that adults with an initially measured TSH level of over 2.0 µIU/mL had "an increased odds ratio of developing hypothyroidism over the [following] 20 years, especially if thyroid antibodies were elevated".TSH concentrations in children are normally higher than in adults. In 2002, the NACB recommended age-related reference limits starting from about 1.3 to 19 µIU/mL for normal-term infants at birth, dropping to 0.6–10 µIU/mL at 10 weeks old, 0.4–7.0 µIU/mL at 14 months and gradually dropping during childhood and puberty to adult levels, 0.3–3.0 µIU/mL.: Section 2

Diagnosis of disease
TSH concentrations are measured as part of a thyroid function test in patients suspected of having an excess (hyperthyroidism) or deficiency (hypothyroidism) of thyroid hormones. Interpretation of the results depends on both the TSH and T4 concentrations. In some situations measurement of T3 may also be useful.

A TSH assay is now also the recommended screening tool for thyroid disease.  Recent advances in increasing the sensitivity of the TSH assay make it a better screening tool than free T4.

Monitoring
The therapeutic target range TSH level for patients on treatment ranges between 0.3 and 3.0 μIU/mL.For hypothyroid patients on thyroxine, measurement of TSH alone is generally considered sufficient. An increase in TSH above the normal range indicates under-replacement or poor compliance with therapy. A significant reduction in TSH suggests over-treatment. In both cases, a change in dose may be required. A low or low-normal TSH value may also signal pituitary disease in the absence of replacement.For hyperthyroid patients, both TSH and T4 are usually monitored. In pregnancy, TSH measurements do not seem to be a good marker for the well-known association of maternal thyroid hormone availability with offspring neurocognitive development.TSH distribution progressively shifts toward higher concentrations with age.

Difficulties with interpretation of TSH measurement
Heterophile antibodies (which include human anti-mouse antibodies (HAMA) and Rheumatoid Factor (RF)), which bind weakly to the test assays animal antibodies, causing a higher (or less commonly lower) TSH result than the actual true TSH level. Although the standard lab assay panels are designed to remove moderate levels of heterophilic antibodies, these fail to remove higher antibody levels </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Brinzolamide and explain in detail? [/INST] Brinzolamide (trade names Azopt, Alcon Laboratories, Befardin, Fardi Medicals, ) is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
Brinzolamide was approved as a generic medication in the United States in November 2020.

Chemistry
Brinzolamide is a carbonic anhydrase inhibitor (specifically, carbonic anhydrase II). Carbonic anhydrase is found primarily in erythrocytes (but also in other tissues including the eye). It exists as a number of isoenzymes, the most active of which is carbonic anhydrase II (CA-II).

Indications
Use for the treatment of open-angle glaucoma and raised intraocular pressure due to either excess aqueous humor production or inadequate drainage of the humor via the trabecular meshwork.

Pharmacodynamics
Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion and thus lowers the intraocular pressure in the anterior chamber, presumably by reducing the rate of formation of bicarbonate ions with subsequent reduction in sodium and fluid transport; this may alleviate the effects of open-angle glaucoma.

Pharmacokinetics
Absorption
The recommended frequency for topical application is two times per day. Following ocular instillation, the suspension is systemically absorbed to some degree; however the plasma concentrations are low and generally below the limits of detection (less than 10 ng/mL) due to extensive binding by tissues and erythrocytes </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Carboprost and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Rocuronium bromide and explain in detail? [/INST] Rocuronium bromide (brand names Zemuron, Esmeron) is an aminosteroid non-depolarizing  neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly required for surgery or mechanical ventilation </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Trimethoprim/polymyxin and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Fluocinolone acetonide and explain in detail? [/INST] Fluocinolone acetonide is a corticosteroid primarily used in dermatology to reduce skin inflammation and relieve itching. It is a synthetic hydrocortisone derivative. The fluorine substitution at position 9 in the steroid nucleus greatly enhances its activity </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Peramivir and explain in detail? [/INST] Peramivir (trade name Rapivab) is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.In October 2009, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the use of peramivir based on safety data from phase I, phase II, and limited phase III trial data. The emergency use authorization for peramivir expired in June 2010. On 19 December 2014, the FDA approved peramivir to treat influenza infection in adults.

History
An intramuscular (IM) peramivir phase II study for seasonal influenza in 2008–2009 found no effect for the primary endpoint of improvement in the median time to alleviation of symptoms in subjects with confirmed, acute, uncomplicated influenza infection versus placebo.
In October 2009, it was reported that the experimental antiviral drug peramivir had been "life-saving" effective in intravenous treating 8 serious cases of swine flu. On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for peramivir, allowing the use of the drug in intravenous form for hospitalized patients only in cases where the other available methods of treatment are ineffective or unavailable; for instance, if oseltamivir resistance develops and a person is unable to take zanamivir via the inhaled route. The U.S. government (department of Health and Human Services) gave BioCryst Pharmaceuticals more than $77 million to finish the Phase III clinical development of peramivir. In 2009 the department of Health and Human Services had already given about $180 million to the program. Biocryst also donated 1200 courses of treatment to the US department of Health and Human Services. The Emergency Use Authorization expired on June 23, 2010.
In 2011 a phase III trial found the median durations of influenza symptoms were the same with 1 intravenous injection of peramivir against 5 days of oral oseltamivir for people with seasonal influenza virus infection.In 2012 BioCryst reported that it should halt enrollment on its study for intravenous peramivir in potentially life-threatened people after an interim analysis led trial monitors to conclude that it would be futile to continue and the trial should be terminated. The difference between peramivir and control group (oral oseltamivir) for the primary endpoint, clinical or virologic, was small. In 2013 the Biomedical Advanced Research and Development Authority (BARDA/HHS) released new funding under the current $234.8 million contract to enable completion of a New Drug Application filing for intravenous (IV) peramivir.According to a research report published in June 2011, a new variant of swine flu had emerged in Asia with a genetic adaptation (a S247N neuraminidase mutation) giving some resistance to oseltamivir and zanamivir, but no significant reduction in sensitivity to peramivir. But a H274Y virus mutation showed resistance to oseltamivir and peramivir, but not to zanamivir, and only in N1 neuraminidases. Ultimately 3.2% (19/599) of A(H1N1)pdm09 viruses collected between 2009 and 2012 had highly reduced peramivir inhibition due to the H275Y NA mutation.BioCryst Pharmaceuticals submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for intravenous peramivir in December 2013. Peramivir (Rapivab) was approved for intravenous administration in December 2014.

References
External links
"Peramivir" </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ezetimibe/atorvastatin and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ibrexafungerp and explain in detail? [/INST] Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC) (vaginal yeast infection). It is taken by mouth. An estimated 75% of women will have at least one episode and 40 to 45% will have two or more episodes in their lifetime.Ibrexafungerp is a triterpenoid antifungal. It acts via inhibition of glucan synthase, which prevents formation of the fungal cell wall.Ibrexafungerp was approved for medical use in the United States in June 2021. It is the first approved drug in a novel antifungal class.

Medical uses
Ibrexafungerp is indicated for the treatment of adult and postmenarchal pediatric females with vulvovaginal candidiasis (VVC).

Pharmacology
Pharmacodynamics
Ibrexafungerp is a triterpenoid antifungal agent. It acts via inhibition of the enzyme glucan synthase, which is involved in the formation of 1,3-β-D-glucan—an essential component of the fungal cell wall. The compound has concentration-dependent fungicidal activity against Candida species.

Pharmacokinetics
Ibrexafungerp has a time to maximal concentrations of 4 to 6 hours. It is metabolized by hydroxylation via CYP3A4 and subsequently by glucuronidation and sulfation. The medication has an elimination half-life of approximately 20 hours.

References
Further reading
Azie N, Angulo D, Dehn B, Sobel JD (September 2020). "Oral Ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis". Expert Opin Investig Drugs. 29 (9): 893–900. doi:10.1080/13543784.2020.1791820. PMID 32746636.
Davis MR, Donnelley MA, Thompson GR (July 2020). "Ibrexafungerp: A novel oral glucan synthase inhibitor". Med Mycol. 58 (5): 579–592. doi:10.1093/mmy/myz083. PMID 31342066.
Petraitis V, Petraitiene R, Katragkou A, Maung BB, Naing E, Kavaliauskas P,  et al. (May 2020). "Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-β-d-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis" </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wera and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Indapamide and explain in detail? [/INST] Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are available. The thiazide-like diuretics (indapamide and chlorthalidone) reduce risk of major cardiovascular events and heart failure in hypertensive patients compared with hydrochlorothiazide with a comparable incidence of adverse events. Both thiazide diuretics and thiazide-like diuretics are effective in reducing risk of stroke. Both drug classes appear to have comparable rates of adverse effects as other antihypertensives such as angiotensin II receptor blockers and dihydropyridine calcium channel blockers and lesser prevalence of side-effects when compared to ACE-inhibitors and non-dihydropyridine calcium channel blockers.It was patented in 1968 and approved for medical use in 1977 </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Alcon and explain in detail? [/INST] Alcon is an American Swiss medical company specializing in eye care products with headquarters in Geneva, Switzerland, and incorporated in Fribourg, Switzerland. Alcon began as a US company and its US subsidiary’s  headquarters remain in Fort Worth, Texas, where the Alcon division of the company was founded.
Alcon was a subsidiary of Novartis until April 9, 2019, when the company completed a shareholder approved 100% spinoff of Alcon eye care devices business from Novartis.

History
The US division of Alcon was founded as an independent company in 1945 in Fort Worth, Texas, USA. Since the current Swiss company that grew from multiple mergers retained the Alcon name, it is important to differentiate the former US company (now a subsidiary) from the much larger company that bears the same Alcon name. Alcon has not existed as a US-based company since 1977.
The original US company Alcon started as a small pharmacy in Fort Worth and was named for its founders, pharmacists Robert Alexander and William Conner. Conner and Alexander focused on sterile ophthalmic products.
Nestlé of Switzerland purchased Alcon in 1977. Alcon expanded its manufacturing capability with new plants in South America and Europe and drastically increased its investment in research.
In 1979, Alcon acquired Texas Pharmacal Company which became Dermatological Products of Texas (and is now DPT Laboratories).In 1984, Alcon founded the Technical Excellence Award to promote achievements in R&D excellence and has awarded it to more than 100 recipients. The Alcon product line has expanded from pharmaceuticals to the surgical arena </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Extended cycle combined hormonal contraceptive and explain in detail? [/INST] Extended or continuous cycle combined oral contraceptive pills are a packaging of combined oral contraceptive pills (COCPs) that reduce or eliminate the withdrawal bleeding that would occur once every 28 days in traditionally packaged COCPs.  It works by reducing the frequency of the pill-free or placebo days.  Extended cycle use of COCPs may also be called menstrual suppression,  although other hormonal medications or medication delivery systems (hormonal intrauterine devices—IUDs) may also be used to suppress menses.  Any brand of combined oral contraceptive pills can be used in an extended or continuous manner by simply discarding the placebo pills; this is most commonly done with monophasic pills in which all of the pills in a package contain the same fixed dosing of a synthetic estrogen and a progestin in each active pill.Other combined hormonal contraceptives (those containing both an estrogen and a progestin) may also be used in an extended or continuous cycle. For example, the NuvaRing vaginal ring and the contraceptive patch have been studied for extended cycle use, and the monthly combined injectable contraceptive may similarly eliminate bleeding.

History
Before the advent of modern contraceptives, reproductive age women spent most of their time either pregnant or nursing.  In modern Western society, women typically have about 450 periods during their lives, as compared to about 160 formerly.Although it was evident that the pill could be used to suppress menstruation for arbitrary lengths of time, the original regimen was designed to produce withdrawal bleeding every four weeks to mimic the menstrual cycle.

Usage
When a woman takes COCP, the hormones in the pills prevent both ovulation and shedding of the endometrium (menstruation).  Traditionally, COCPs are packaged with 21 active (hormone-containing) pills and 7 placebo pills.  During the week of placebo pills, withdrawal bleeding occurs and simulates an average 28-day menstrual cycle.  The placebo pills are not required for pregnancy protection, and with any monophasic COCP the placebo pills may be discarded, and the next pack of active pills may be started to prevent the withdrawal bleeding.  With bi- and tri-phasic pills, skipping the placebo week results in a sudden change in hormone levels, which may cause irregular spotting or flow.
(Monophasic pills offer the same dose of estrogen and progestogen whereas multiphasic pills have varying doses from day to day; see formulations for details.)
Recently, several pharmaceutical companies have gained FDA approval to package COCPs for the intended use of reducing the frequency of or eliminating withdrawal bleeding.

Clinical indications
Extended or continuous use of COCPs has been used for many years to treat endometriosis, dysmenorrhea, and menstruation-associated symptoms.  Some studies have suggested that women who experience premenstrual-type symptoms during the placebo (hormone-free) week of traditionally packaged COCPs may experience significantly fewer symptoms when placed on extended cycle COCP regimens.More recently, personal preference to avoid menstruation has also become a common reason for use.  Personal preference is the most common reason extended cycle or continuous use COCPs are prescribed to adolescents.  The Society for Menstrual Cycle Research holds that this use of COCPs does not have sufficient safety studies to justify promotion as a lifestyle choice (as opposed to medical indications), and criticizes what it perceives as negative portrayals of normal menstrual cycles in promotional literature for extended and continuous COCP use.Womens satisfaction with their contraception, compliance in taking the pills on time, and discontinuation rates are not significantly different between traditional and extended cycle regimens.

Side effects
With all extended-cycle COCPs, breakthrough bleeding is the most common side effect, although it tends to decrease over time.  In a 12-month study of a continuous COCP regimen, 59% of women experienced no bleeding in months six through twelve and 79% of women experienced no bleeding in month twelve.  Extended or continuous use of COCPs or other combined hormonal contraceptives carries the same risk of side effects and medical risks as traditional COCP use.

Ad campaign
One of the early extended-cycle COCPs, Seasonale, was marketed with the campaign, "Fewer periods.  More possibilities."  In December 2004, Barr Pharmaceuticals was warned by the FDA concerning these television advertisements. As the warning stated, "By omitting and minimizing the risks associated with Seasonale, the TV ad misleadingly suggests that Seasonale is safer than has been demonstrated by substantial evidence or substantial clinical experience." Although clinical studies had proven Seasonale to be effective in preventing pregnancy, the FDA felt the commercial advertisements omitted the common side effects of irregular vaginal bleeding or spotting.

Brands
Seasonale is produced by Duramed Pharmaceuticals, a subsidiary of Barr Pharmaceuticals; Barr Pharmaceuticals also produces the same medicine as a generic called Jolessa.  Quasense is the generic version produced by Watson Pharmaceuticals.  Seasonale contains 30 micrograms of ethinylestradiol and 150 micrograms of levonorgestrel in each active pill. Seasonale reduces the frequency of menstrual periods from thirteen per year to four per year by changing the regimen of active pills from 21 to 84. Each package has 84 active pills and seven placebo pills to be taken at the end of the active cycle. It was first developed by Barr Pharmaceuticals, in collaboration with Eastern Virginia Medical School, under an agreement. The U.S. Food and Drug Administration (FDA) approved Seasonale in the United States on September 5, 2003.  Barr Pharmaceuticals, its manufacturer, claimed at the time of Seasonales approval that it would cost one dollar per pill. Health Canada approved Seasonale in July 2007, and Paladin Labs began distributing it in Canada on January 4, 2008.Seasonique, also produced by Duramed Pharmaceuticals, has active pills and packaging identical to Seasonale, but replaces the placebo week with a low-dosage week of estrogen.
Lybrel is produced by Wyeth Pharmaceuticals.  It contains 90 µg levonorgestrel and 20 µg ethinylestradiol in each pill, and is designed to be taken continuously with no placebos. The FDA approved Lybrel for human consumption on May 22, 2007.

References
Further reading
Elsimar M. Coutinho; Sheldon J </s>