<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 Oxytocin (medication) and explain in detail? [/INST] Synthetic oxytocin, sold under the brand name Pitocin among others, is a medication made from the peptide oxytocin. As a medication, it is used to cause contraction of the uterus to start labor, increase the speed of labor, and to stop bleeding following delivery. For this purpose, it is given by injection either into a muscle or into a vein.Oxytocin is also available in intranasal spray form for psychiatric, endocrine and weight management use as a supplement. Intranasal oxytocin works on a different pathway than injected oxytocin, primarily along the olfactory nerve crossing the brain blood barrier to the olfactory lobe in the brain, where dense magnocellular oxytocin neurons receive the dose application.
The use of synthetic oxytocin as an injectable medication for inducing childbirth can result in excessive contraction of the uterus that can risk the health of the baby. Common side effects in the mother include nausea and a slow heart rate. Serious side effects include rupture of the uterus and with excessive dose, water intoxication. Allergic reactions including anaphylaxis may also occur.The natural occurrence of oxytocin was discovered in 1906. It is on the World Health Organizations List of Essential Medicines.

Medical uses
An intravenous infusion of oxytocin is used to induce labor and to support labor in case of slow childbirth if the oxytocin challenge test fails. Whether a high dose is better than a standard dose for labor induction is unclear. It has largely replaced ergometrine as the principal agent to increase uterine tone in acute postpartum hemorrhage. Oxytocin is also used in veterinary medicine to facilitate birth and to stimulate milk release.
The tocolytic agent atosiban (Tractocile) acts as an antagonist of oxytocin receptors. It is registered in many countries for use in suppressing premature labor between 24 and 33 weeks of gestation. It has fewer side effects than drugs previously used for this purpose (such as ritodrine, salbutamol and terbutaline).Oxytocin has not been found to be useful for improving breastfeeding success.

Contraindications
Oxytocin injection (synthetic) is contraindicated in any of these conditions:
Substantial cephalopelvic disproportion
Unfavorable fetal position or presentation (e.g., transverse lies) undeliverable without conversion before delivery
Obstetric emergencies where maternal or fetal risk-to-benefit ratio favors surgery
Fetal distress when delivery is not imminent
Umbilical cord prolapse
Uterine activity fails to progress adequately
Hyperactive or hypertonic uterus
Vaginal delivery is contraindicated (e.g., invasive cervical carcinoma, active genital herpes infection, total placenta previa, vasa previa, cord presentation or prolapse)
Uterine or cervical scarring from previous cesarean section or major cervical or uterine (e.g., transfundal) surgery
Unengaged fetal head
History of hypersensitivity to oxytocin or any ingredient in the formulation

Side effects
Oxytocin is relatively safe when used at recommended doses, and side effects are uncommon. These maternal events have been reported:
Subarachnoid hemorrhage
Increased blood pressure
Cardiac arrhythmia including increased or decreased heart rate, and premature ventricular contraction
Impaired uterine blood flow
Pelvic hematoma
Afibrinogenemia
Anaphylaxis
Nausea and vomiting
Increase fetal blood flowExcessive dosage or long-term administration (over a period of 24 hours or longer) has been known to result in tetanic uterine contractions, uterine rupture, postpartum hemorrhage, and water intoxication, sometimes fatal.
Oxytocin was added to the Institute for Safe Medication Practicess list of High Alert Medications in Acute Care Settings in 2012. The list includes medications that have a high risk for harm if administered incorrectly.During pregnancy, increased uterine motility has led to decreased heart rate, cardiac arrhythmia, seizures, brain damage, and death in the fetus or neonate.Use is linked to an increased risk of postpartum depression in the mother.Certain learning and memory functions are impaired by centrally administered oxytocin. Also, systemic oxytocin administration can impair memory retrieval in certain aversive memory tasks. However, oxytocin does seem to facilitate learning and memory specifically for social information </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 Rosiglitazone and explain in detail? [/INST] Rosiglitazone (trade name Avandia) is an antidiabetic drug in the thiazolidinedione class. It works as an insulin sensitizer, by binding to the PPAR in fat cells and making the cells more responsive to insulin. It is marketed by the pharmaceutical company GlaxoSmithKline (GSK) as a stand-alone drug or for use in combination with metformin or with glimepiride. First released in 1999, annual sales peaked at approximately $2.5-billion in 2006; however, following a meta-analysis in 2007 that linked the drugs use to an increased risk of heart attack, sales plummeted to just $9.5-million in 2012. The drugs patent expired in 2012.It was patented in 1987 and approved for medical use in 1999. Despite rosiglitazones effectiveness at decreasing blood sugar in type 2 diabetes mellitus, its use decreased dramatically as studies showed apparent associations with increased risks of heart attacks and death.  Adverse effects alleged to be caused by rosiglitazone were the subject of over 13,000 lawsuits against GSK; as of July 2010, GSK had agreed to settlements on more than 11,500 of these suits.
Some reviewers recommended rosiglitazone be taken off the market, but an FDA panel disagreed, and it remains available in the U.S. From November 2011 until November 2013, the federal government did not allow Avandia to be sold without a prescription from a certified doctor; moreover, patients were required to be informed of the risks associated with its use, and the drug had to be purchased by mail order through specified pharmacies. In 2013, the FDA lifted its earlier restrictions on rosiglitazone after reviewing the results of a 2009 trial which failed to show increased heart attack risk.In Europe, the European Medicines Agency (EMA) recommended in September 2010 that the drug be suspended because the benefits no longer outweighed the risks. It was withdrawn from the market in the UK, Spain and India in 2010, and in New Zealand and South Africa in 2011.

Medical uses
Rosiglitazone was approved for glycemic control in people with type 2 diabetes, as measured by glycated haemoglobin A1c (HbA1c) as a surrogate endpoint, similar to that of other oral antidiabetic drugs. The controversy over adverse effects has dramatically reduced the use of rosiglitazone.Published studies did not provide evidence that outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by rosiglitazone.

Adverse effects
Heart failure
One of the safety concerns identified before approval was fluid retention. Moreover, the combination of rosiglitazone with insulin resulted in a higher rate of congestive heart failure. In Europe there were contraindications for use in heart failure and combination with insulin.A meta analysis of all trials from 2010 and 2019 confirmed a higher risk of heart failure and a double risk when rosiglitazone was administered as add-on therapy to insulin. Two meta-analyses of real life cohort studies found a higher risk of heart failure compared to pioglitazone. There were 649 excess cases of heart failure every 100,000 patients who received rosiglitazone rather than pioglitazone.

Heart attacks
The relative risk of ischemic cardiac events seen in pre-approval trials of rosiglitazone was similar to that of comparable drugs, but there was increased LDL cholesterol, LDL/HDL cholesterol ratio, triglycerides and weight.In 2005, at the insistence of the World Health Organization, GSK performed a meta-analysis of all 37 trials involving use of rosiglitazone, finding a hazard ratio of 1.29 (0.99 to 1.89).
In 2006 the GSK updated the analysis, now including 42 trials and showing a hazard ratio of 1.31 (1.01 to 1.70). A large observational study comparing patients treated with rosiglitizone with patients treated with other diabetes therapies was performed at the same time and found a relative risk of 0.93 (95% C.I. 0.8 to 1.1) for those treated with rosiglitazone.  The information was passed to the FDA and posted on the company website, but not otherwise published. GSK provided these analyses to the FDA, but neither the company nor the FDA warned prescribers or patients of the hazard. According to the FDA, the Agency did not issue a safety bulletin because the results of the meta analysis conflicted with those of the observational study and with the results of the ADOPT trial.A meta-analysis in May 2007 reported the use of rosiglitazone was associated with a 1.4 fold increased risk of heart attack and a numerically higher (but non-significant) increase in risk of death from all cardiovascular diseases against control. It contained 42 trials of which 27 were unpublished. Another meta analysis of 4 trials with follow-up longer than 1 year found similar results. Nissens meta analysis was criticized in a 2007 article by George Diamond et al. in the Annals of Internal Medicine.  The authors concluded that Nissens analysis had excluded trials with important data on the cardiovascular profile of rosiglitazone, had inappropriately combined trials of greatly differing design, and had inappropriately excluded trials with no cardiovascular events. The authors concluded that no firm conclusion could be drawn regarding whether rosiglitazone increased or decreased cardiovascular risk.  Investigators from the Cochrane Collaboration published a meta-analysis of their own on the use of rosiglitazone in Type II diabetes, concluding there was not sufficient evidence to show any health benefit for rosiglitazone.  Noting the recent publication by Nissen, they repeated their meta analysis including only the trials included in the Nissen study that dealt with Type II diabetics. (The Nissen study included some trials in people with other disorders.) They did not find a statistically significant increase in cardiovascular events, but noted that all of the cardiovascular endpoints they analyzed showed a non-significant trend toward worse outcomes in the rosiglitazone arms.In July 2007 the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee.  FDA scientist Joy Mele presented a meta analysis examining the cardiovascular risk of rosiglitazone in completed clinical trials.  The study found an overall 1.4x increase in risk of cardiovascular ischemic events relative to the control arms. The results were heterogenous, with clear evidence of increased risk relative to placebo but not relative to other diabetes treatments and higher risk associated with combinations of rosiglitazone with insulin or metformin. Based on the 1.4x increased risk relative to control groups, FDA scientist David Graham presented an analysis suggesting that rosiglitazone had caused 83,000 excess heart attacks between 1999 and 2007.: 4  The advisory panel voted 20 : 3 that the evidence available indicated that rosiglitazone increased the risk of cardiovascular events and 22 : 1 that the overall risk:benefit ratio of rosiglitazone justified its continued marketing in the United States. The FDA placed restrictions on the drug, including adding a boxed warning about heart attacks, but did not withdraw it.In 2000 a study to address the concerns regarding cardiovascular safety was requested by the European Medicines Agency (EMA). GSK agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed that rosiglitazone was non-inferior to treatment with metformin or a sulfonylurea with respect to the rate of cardiovascular events and cardiovascular death. European regulators concluded that due in part to design limitations, the results neither proved nor eliminated concerns of excess cardiovascular risk.In February 2010, the FDAs associate director of drug safety, recommended rosiglitazone be taken off the market. In June 2010, they published a retrospective study comparing roziglitazone to pioglitazone, the other thiazolidinedione marketed in the United States and concluded rosiglitazone was associated with "an increased risk of stroke, heart failure, and all-cause mortality and an increased risk of the composite of AMI, stroke, heart failure, or all-cause mortality in patients 65 years or older". The number needed to harm with roziglitazone was sixty. Graham argued rosiglitazone caused 500 more heart attacks and 300 more heart failures than its main competitor.
Two meta analyses released in 2010, one incorporating 56 trials and a second incorporating 164 trials reached conflicting conclusions. Nissen et al. found again an increased risk for heart infarction against control, but no increased risk for cardiovascular death. Mannucci et al. found no statistically significant increase in cardiac events but a significant increase in heart failure. A 2011 drug class review found an increased risk of cardiovascular adverse events.A meta-analysis of 16 observational studies released in March, 2011, compared rosiglitazone to pioglitazone, finding support for greater cardiovascular safety for pioglitazone. The meta-analysis involved 810 000 patients taking rosiglitazone or pioglitazone. The study suggests 170 excess myocardial infarctions, 649 excess cases of heart failure, and 431 excess deaths for every 100 000 patients who receive rosiglitazone rather than pioglitazone. This was confirmed by another meta-analysis involving 945 286 patients in 8 retrospective cohort studies, most in the US.In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007.

Death
There was no difference in all cause and vascular death in a meta-analysis of 4 trials against controls.  Two meta-analyses of cohort studies found excess deaths against pioglitazone.

Stroke
An retrospective observational study performed using Medicare data found that patients treated with rosiglitazone had a 27% higher risk of stroke compared to those treated with pioglitazone.

Bone fractures
GlaxoSmithKline reported a greater incidence of fractures of the upper arms, hands and feet in female diabetics given rosiglitazone compared with those given metformin or glyburide.
The information was based on data from the ADOPT trial The same increase has been found with pioglitazone (Actos), another thiazolidinedione.
A meta-analysis of 10 RCTs, involving 13,715 patients and including both rosiglitazone- and pioglitazone-treated patients, showed an overall 45% increased risk of fracture with thiazolidone use compared with placebo or active comparator. It doubled the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.

Hypoglycaemia
The risk of hypoglycaemia is reduced with thiazolidinediones when compared with sulfonylureas; the risk is similar to the risk with metformin (high strength of evidence).

Weight gain
Both thiazolidinediones cause a similar degree of weight gain to that caused by sulfonylureas (moderate strength of evidence).

Eye damage
Both rosiglitazone and pioglitazone have been suspected of causing macular edema, which damages the retina of the eye and causes partial blindness. Blindness is also a possible effect of diabetes, which rosiglitazone is intended to treat. One report documented several occurrences and recommended discontinuation at the first sign of vision problems. A retrospective cohort study showed an association between the use of thiazolidinediones and the incidence of diabetic macular edema (DME). Both use was associated with a 2,3 higher risk at 1 year and at 10 year follow-up, rising to 3 if associated with insulin.

Hepatotoxicity
Moderate to severe acute hepatitis has occurred in several adults who had been taking the drug at the recommended dose for two to four weeks. Plasma rosiglitazone concentrations may be increased in people with existing liver problems.

Contraindications
Both rosiglitazone and pioglitazone are contraindicated in people with NYHA Class III and IV heart failure. They are not recommended for use in heart failure.In Europe rosiglitazone was contraindicated for heart failure or history of heart failure with regard to all NYHA stages, for combined use with insulin and for acute coronary syndrome. The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.

Pharmacology
Rosiglitazone is a member of the thiazolidinedione class of drugs. Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. They work by binding to the peroxisome proliferator-activated receptors (PPARs). PPARs are transcription factors that reside in the nucleus and become activated by ligands such as thiazolidinediones. Thiazolidinediones enter the cell, bind to the nuclear receptors, and alter the expression of genes. The several PPARs include PPARα, PPARβ/δ, and PPARγ. Thiazolidinediones bind to PPARγ.
PPARs are expressed in fat cells, cells of the liver, muscle, heart, and inner wall (endothelium) and smooth muscle of blood vessels. PPARγ is expressed mainly in fat tissue, where it regulates genes involved in fat cell (adipocyte) differentiation, fatty acid uptake and storage, and glucose uptake. It is also found in pancreatic beta cells, vascular endothelium, and macrophages Rosiglitazone is a selective ligand of PPARγ and has no PPARα-binding action. Other drugs bind to PPARα.
Rosiglitazone also appears to have an anti-inflammatory effect in addition to its effect on insulin resistance. Nuclear factor kappa-B (NF-κB), a signaling molecule, stimulates the inflammatory pathways. NF-κB inhibitor (IκB) downregulates the inflammatory pathways. When patients take rosiglitazone, NF-κB levels fall and IκB levels increase.

History
Rosiglitazone was approved by the US FDA in 1999 and by the EMA in 2000;  the EMA however required two postmarketing studies on longterm adverse effects, one for chronic heart failure and the other for cardiovascular effects.

Society and culture
Sales
US sales of the drug were of $2.2 billion in 2006. Sales in 2Q 2007 down 22% compared to 2006. 4Q 2007 sales down to $252 million.Though sales have gone down since 2007 due to safety concerns, Avandia sales for 2009 totalled $1.2 billion worldwide.

Lawsuits
According to analysts from UBS, 13,000 suits had been filed by March 2010. Included among those suing: Santa Clara County, California, which claims to have spent $2 million on rosiglitazone between 1999 and 2007 at its public hospital and is asking for "triple damages".
In May 2010, GlaxoSmithKline (GSK) reached settlement agreements for some of the cases against the company, agreeing to pay $60 million to resolve 700 suits. In July 2010, GSK reached settlement agreements to close another 10,000 of the lawsuits against it, agreeing to pay about $460 million to settle these suits.In 2012, the U.S. Justice Department announced GlaxoSmithKline had agreed to plead guilty and pay a $3 billion fine, in part for withholding the results of two studies of the cardiovascular safety of Avandia between 2001 and 2007. The settlement stems from claims made by four employees of GlaxoSmithKline, including a former senior marketing development manager for the company and a regional vice president, who tipped off the government about a range of improper practices from the late 1990s to the mid-2000s.

United States investigations
GlaxoSmithKline was being investigated by the FDA and the US Congress regarding Avandia.
Senators Democrat Max Baucus and Republican Charles Grassley filed a report urging GSK to withdraw Avandia in 2008 due to the side effects. The report noted the drug caused 500 avoidable heart attacks a month, and Glaxo officials sought to intimidate doctors who criticized the drug. It also said GSK continued to sell and promote the drug despite knowing the increased risk of heart attacks and stroke.The Senate Finance Committee, in a panel investigation, revealed emails from GSK company officials that suggest the company downplayed scientific findings about safety risks dating back to 2000. It was also alleged by the committee that the company initiated a "ghostwriting campaign", whereby GSK sought outside companies to write positive articles about Avandia to submit to medical journals. GSK defended itself by presenting data that its own tests found Avandia to be safe, although an FDA staff report showed the conclusions were flawed.On July 14, 2010, after two days of extensive deliberations, the FDA panel investigating Avandia came to a mixed vote. Twelve members of the panel voted to take the drug off the market, 17 recommended to leave it on but with a more revised warning label, and three voted to keep it on the market with the current warning label. The panel has come to some controversy, however; on July 20, 2010, one of the panelists was discovered to have been a paid speaker for GlaxoSmithKline, arousing questions of a conflict of interest. This panel member was one of the three who voted to keep Avandia on the market with no additional warning labels.In 2011 the FDA has decided on revising its prescribing information and medication guides for all rosilitazone containing medicines. The US label for rosiglitazone (Avandia, GlaxoSmithKline) and all rosiglitazone-containing medications (Avandamet and Avandaryl) now include the additional safety information and restrictions. The revised labels restrict use to patients already taking a rosiglitazone-containing medicine or to new patients who are unable to achieve adequate glycemic control on other diabetes medications and to those, who in consultation with their healthcare provider, have decided not to take Actos (pioglitazone) or other pioglitazone-containing medicines for medical reasons.In June 2013 an FDA Advisory Committee reviewed all available data, including a re-adjudicated RECORD trial, found no evidence of increased cardiovascular risk with Avandia, and voted to remove the restrictions on Avandia marketing in the United States.  In November 2013, the US FDA removed these marketing restrictions on the product. Under the FDAs instruction, Avandias maker, GlaxoSmithKline, had funded the Duke Clinical Research Institute to re-analyze the raw data from the study. At the 2010 panel, three panelists voted that the existing warnings were good enough; two were back in 2013. Seven voted to make those warnings more onerous, and five of them returned. But of the 10 who voted to restrict Avandias use, only four returned. And of the 12 who voted in 2010 to withdraw Avandia from the market, only three came back.

European investigations
In 2000 a study to address the concerns regarding cardiovascular safety was requested by the EMA, and the makers agreed to perform post-marketing a long-term cardiovascular morbidity/mortality study in patients on rosiglitazone in combination with a sulfonylurea or metformin: the RECORD study. The results as published in 2009 showed non-inferiority with regard to cardiovascular events and cardiovascular death when the treatment with rosiglitazone was compared with metformin or a sulfonylurea. For myocardial infarction, there was a non-statistically significant increase in risk. In their assessment, the European regulators acknowledged weaknesses of the study, such as an unexpectedly low rate of cardiovascular events and the open-label design, which may lead to reporting bias. They found that the results were inconclusive. The European Medicines Agency recommended on 23 September 2010 that Avandia be suspended from the European market.According to a probe by the British Medical Journal in September 2010, the United Kingdoms Commission on Human Medicines recommended to the Medicines and Healthcare Products Regulatory Agency (MHRA) back in July 2010, to withdraw Avandia sale because its "risks outweigh its benefits". Additionally, the probe revealed that in 2000, members of the European panel in charge of reviewing Avandia prior to its approval had concerns about the long-term risks of the drug.

New Zealand
Rosiglitazone was withdrawn from the New Zealand market April 2011 because Medsafe concluded the suspected cardiovascular risks of the medicine for patients with type 2 diabetes outweigh its benefits.

South Africa
A notice issued by the Medicines Control Council of South Africa on July 5, 2011, stated that it had resolved on July 3, 2011, to withdraw all rosiglitazone-containing medicines from the South African market due to safety risks. It disallowed all new prescriptions of Avandia.

Controversy and response
Following the reports in 2007 that Avandia can significantly increase the risk of heart attacks, the drug has been controversial. A 2010 article in Time uses the Avandia case as evidence of a broken FDA regulatory system that "may prove criminal as well as fatal". It details the disclosure failures, adding, "Congressional reports revealed that GSK sat on early evidence of the heart risks of its drug, and that the FDA knew of the dangers months before it informed the public." It reports, "the FDA is investigating whether GSK broke the law by failing to fully inform the agency of Avandias heart risks", according to deputy FDA commissioner Dr. Joshua Sharfstein </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 Sargramostim and explain in detail? [/INST] Sargramostim (tradename Leukine) is a recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) that functions as an immunostimulator.

Medical uses
Sargramostim is primarily used for myeloid reconstitution after autologous or allogeneic bone marrow transplantation. It is also used to treat neutropenia induced by chemotherapy during the treatment of acute myeloid leukemia.  It also used as a medical countermeasure for treating people who have been exposed to sufficient radiation to suppress bone marrow myelogenesis.It is administered via intravenous infusion.

Contraindications
Sargramostim should not be used in people with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product and for concomitant use with chemotherapy and radiotherapy.There is a formulation with benzyl alcohol, which is toxic to babies; other formulations should be used.  Sargramostim has not been tested in pregnant women but appears to be toxic to fetuses. There is no data as to whether sargramostim is expressed in breast milk.

Adverse effects
Some people have experienced anaphylaxis when given the drug; and infusion reactions have occurred as well, including edema, capillary leak syndrome, a build up of fluid around the lungs and around the heart. Irregular heart rhythms have occurred, especially in people with a history of that problem </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 Ponatinib and explain in detail? [/INST] Ponatinib (trade name Iclusig  eye-KLOO-sig, previously AP24534) is an oral drug developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL).  It is a multi-targeted tyrosine-kinase inhibitor.  Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib.  Ponatinib has been designed to be effective against these types of tumors.The United States Food and Drug Administration approved the drug as a candidate in December 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels". This suspension was partially lifted on Dec. 20, 2013 with ponatinib being issued revised prescribing information, a new "Black Box Warning" and a "Risk Evaluation and Mitigation Strategy" in place to better evaluate the risks and benefits of using the drug.
In the US it can cost $138,000 a year, which has been criticized.

Approvals and indications
Ponatinib was approved by the US FDA on December 14, 2012, for patients with resistant or intolerant CML and Ph+ ALL, based on results of the PACE phase II trial reported days earlier at the annual ASH meeting. Because the approval was under the FDA Accelerated Approval program the applicant was required to carry out additional studies. Based on these additional studies, the FDA granted in 2016 full approval and updated the label to include patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia for whom no other tyrosine kinase inhibitor therapy is indicated. Approval was also granted for T315I-positive and T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia.

Adverse effects
The United States Food and Drug Administration issued a partial clinical hold on new trial enrollment for ponatinib on October 9, 2013, due to an increased number of blood clots observed in patients taking the drug. The EPIC trial was later canceled on October 18. Subsequent studies of 449 patients treated during 4 years with ponatinib for chronic phase chronic myelogenous leukemia found the following adverse reactions. 150 Patients experienced cardiac vascular (21% of patients), peripheral vascular (12%), and cerebrovascular (9%) arterial occlusive events. Venous thromboembolic events occurred in 6% of patients. The most common all-grade adverse events included hypertension (69%), rash (63%), abdominal pain (48%), fatigue (47%), headache (43%), arterial ischemia (42%), dry skin (42%), constipation (41%), arthralgia (32%), nausea (28%), pyrexia (26%), peripheral neuropathy (24%), myalgia (24%), pain in extremity (23%), back pain (21%), and diarrhea (20%). In addition, there have been reported cases of the posterior reversible encephalopathy syndrome. Recently, an analogue of ponatinib was developed that retained anti-tumor efficacy but had reduced cardiovascular toxicity in experimental models.

Clinical trials
In 2010 ARIAD announced result from a Phase I study of ponatinib in patients with resistant and refractory chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). The study demonstrated that in chronic-phase CML patients treated with ponatinib, 66 percent of patients in the trial achieved a major cytogenetic response, including 100 percent of patients who also had a T315I mutation.The PACE (Ponatinib Ph+ ALL and CML Evaluation) pivotal phase II trial started enrolling patients in September 2010 and is designed to provide definitive clinical data for regulatory approval in this setting.  Good results were reported in December 2012.The EPIC (Evaluation of Ponatinib versus Imatinib in CML) phase-III trial began in June 2012  and was halted on October 18, 2013.

Mechanism of action
The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL. CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases such as accelerated or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors </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 Tipranavir and explain in detail? [/INST] Tipranavir (TPV), or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer Ingelheim under the trade name Aptivus  AP-tiv-əs </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 Provera 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 Desipramine and explain in detail? [/INST] Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.

Medical uses
Desipramine is primarily used for the treatment of depression. It may also be useful to treat symptoms of attention-deficit hyperactivity disorder (ADHD). Evidence of benefit is only in the short term, and with concerns of side effects its overall usefulness is not clear. Desipramine at very low doses is also used to help reduce the pain associated with functional dyspepsia. It has also been tried, albeit with little evidence of effectiveness, in the treatment of cocaine dependence. Evidence for usefulness in neuropathic pain is also poor.

Side effects
Desipramine tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive or memory impairments.

Overdose
Desipramine is particularly toxic in cases of overdose, compared to other antidepressants. Any overdose or suspected overdose of desipramine is considered to be a medical emergency and can result in death without prompt medical intervention.

Pharmacology
Pharmacodynamics
Desipramine is a very potent and relatively selective norepinephrine reuptake inhibitor (NRI), which is thought to enhance noradrenergic neurotransmission. Based on one study, it has the highest affinity for the norepinephrine transporter (NET) of any other TCA, and is said to be the most noradrenergic and the most selective for the NET of the TCAs. The observed effectiveness of desipramine in the treatment of ADHD was the basis for the development of the selective NRI atomoxetine and its use in ADHD.Desipramine has the weakest antihistamine and anticholinergic effects of the TCAs. It tends to be slightly activating/stimulating rather than sedating, unlike most others TCAs. Whereas other TCAs are useful for treating insomnia, desipramine can cause insomnia as a side effect due to its activating properties. The drug is also not associated with weight gain, in contrast to many other TCAs </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 Quinapril and explain in detail? [/INST] Quinapril, sold under the brand name Accupril among others, is a medication used to treat high blood pressure (hypertension), heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth.Common side effects include headaches, dizziness, feeling tired, and cough. Serious side effects may include liver problems, low blood pressure, angioedema, kidney problems, and high blood potassium. Use in pregnancy and breastfeeding is not recommended. It is an ACE inhibitor and works by decreasing renin-angiotensin-aldosterone system activity.Quinapril was patented in 1980 and came into medical use in 1989 </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 Propofol and explain in detail? [/INST] Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Its uses include the starting and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. It is also used for status epilepticus if other medications have not worked. It is given by injection into a vein, and the maximum effect takes about two minutes to occur and typically lasts five to ten minutes. Propofol is also used for medical assistance in dying in Canada.The medication appears to be safe for use during pregnancy but has not been well studied for use in this case. It is not recommended for use during a cesarean section. It is not a pain medication, so opioids such as morphine may also be used; however, whether or not they are always needed is not clear. Propofol is believed to work at least partly via a receptor for GABA.Propofol was discovered in 1977 and approved for use in the United States in 1989. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. It has been referred to as milk of amnesia (a play on "milk of magnesia"), because of the milk-like appearance of the intravenous preparation, and because of its tendency to suppress memory recall. Propofol is also used in veterinary medicine for anesthesia.

Medical uses
Anesthesia
To induce general anesthesia, propofol is the drug used almost exclusively, having largely replaced sodium thiopental. It can also be administered as part of an anesthesia maintenance technique called total intravenous anesthesia, using either manually programmed infusion pumps or computer-controlled infusion pumps in a process called target controlled infusion (TCI). Propofol is also used to sedate individuals who are receiving mechanical ventilation but not undergoing surgery, such as patients in the intensive care unit. In critically ill patients, propofol is superior to lorazepam both in effectiveness and overall cost. Propofol is relatively inexpensive compared to medications of similar use due to shorter ICU stay length. One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is because studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation. Propofol has also been suggested as a sleep aid in critically ill adults in the ICU; however, the effectiveness of this medicine at replicating the mental and physical aspects of sleep for people in the ICU is not clear.Propofol can be run through a peripheral IV or central line. Propofol is frequently paired with fentanyl (for pain relief) in intubated and sedated people. The two drugs are compatible in IV form.

Procedural sedation
Propofol is safe and effective for gastrointestinal endoscopy procedures. Its use in these settings results in a faster recovery compared to midazolam. It can also be combined with opioids or benzodiazepines. Because of its rapid induction and recovery time, propofol is also widely used for sedation of infants and children undergoing MRI. It is also often used in combination with ketamine with minimal side effects.

Assisted death in Canada
A lethal dose of propofol is used for medical assistance in dying in Canada to quickly induce deep coma and death, but rocuronium is always given—even when patient dies as a result of propofol injection. Delivery order of IV medication is as follows:Step 1: Midazolam 10–20 mg given as 2−4ml of 5 mg/ml preparation for pre-anesthesia, induces sleep in 1−2 minutes.
Step 2: Lidocaine 40 mg given as 4ml of 1% preparation to reduce possible burning in peripheral vein caused by propofol. Pause to allow effect.
Step 3: Propofol 1000 mg given as 100ml of 10 mg/ml preparation. Loss of consciousness occurs within 10 seconds and coma occurs in 1–2 minutes. Death may result from the propofol but rocuronium is still given.
Step 4: Rocuronium 200 mg given as 20ml of 10 mg/ml preparation to induce respiratory arrest. Cardiac arrest subsequently follows about 5 minutes later due to hypoxia.

COVID-19
In March 2021, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for Propofol‐Lipuro 1% to maintain sedation via continuous infusion in people older than sixteen with suspected or confirmed COVID-19 who require mechanical ventilation in an intensive care unit ICU setting. In the circumstances of this public health emergency, it would not be feasible to require healthcare providers to seek to limit Fresenius Propoven 2% Emulsion or Propofol-Lipuro 1% only to be used for patients with suspected or confirmed COVID-19; therefore, this authorization does not limit use to such patients.

Other uses
Executions
The US state of Missouri added propofol to its execution protocol in April 2012. However, Governor Jay Nixon halted the first execution by the administration of a lethal dose of propofol in October 2013 following threats from the European Union to limit the drugs export if it were used for that purpose.  The United Kingdom had already banned the export of medicines or veterinary medicines containing propofol to the United States.

Recreational use
Recreational use of the drug via self-administration has been reported but is relatively rare due to its potency and the level of monitoring required for safe use — critically, a steep dose-response curve makes recreational use of propofol very dangerous, and deaths from self-administration continue to be reported.  The short-term effects sought via recreational use include mild euphoria, hallucinations, and disinhibition.Recreational use of the drug has been described among medical staff, such as anesthetists who have access to the drug. It is reportedly more common among anesthetists on rotations with short rest periods, as usage generally produces a well-rested feeling. Long-term use has been reported to result in addiction.Attention to the risks of off-label use of propofol increased in August 2009 due to the Los Angeles County coroners conclusion that music icon Michael Jackson died from a mixture of propofol and the benzodiazepine drugs lorazepam, midazolam, and diazepam on 25 June 2009. According to a 22 July 2009 search warrant affidavit unsealed by the district court of Harris County, Texas, Jacksons physician, Conrad Murray, administered 25 milligrams of propofol diluted with lidocaine shortly before Jacksons death. Even so, as of 2016, propofol was not on a US Drug Enforcement Administration schedule.

Side effects
One of propofols most common side effects is pain on injection, especially in smaller veins. This pain arises from activation of the pain receptor, TRPA1, found on sensory nerves and can be mitigated by pretreatment with lidocaine. Less pain is experienced when infused at a slower rate in a large vein (antecubital fossa). Patients show considerable variability in their response to propofol, at times showing profound sedation with small doses[1].
Additional side effects include low blood pressure related to vasodilation, transient apnea following induction doses, and cerebrovascular effects. Propofol has more pronounced hemodynamic effects relative to many intravenous anesthetic agents. Reports of blood pressure drops of 30% or more are thought to be at least partially due to inhibition of sympathetic nerve activity. This effect is related to the dose and rate of propofol administration. It may also be potentiated by opioid analgesics.Propofol can also cause decreased systemic vascular resistance, myocardial blood flow, and oxygen consumption, possibly through direct vasodilation. There are also reports that it may cause green discolouration of the urine.Although propofol is heavily used in the adult ICU setting, the side effects associated with propofol seem to be of greater concern in children. In the 1990s, multiple reported deaths of children in ICUs associated with propofol sedation prompted the FDA to issue a warning.As a respiratory depressant, propofol frequently produces apnea. The persistence of apnea can depend on factors such as premedication, dose administered, and rate of administration, and may sometimes persist for longer than 60 seconds.  Possibly as the result of depression of the central inspiratory drive, propofol may produce significant decreases in respiratory rate, minute volume, tidal volume, mean inspiratory flow rate, and functional residual capacity.Diminishing cerebral blood flow, cerebral metabolic oxygen consumption, and intracranial pressure are also characteristics of propofol administration.  In addition, propofol may decrease intraocular pressure by as much as 50% in patients with normal intraocular pressure.A more serious but rare side effect is dystonia. Mild myoclonic movements are common, as with other intravenous hypnotic agents. Propofol appears to be safe for use in porphyria, and has not been known to trigger malignant hyperpyrexia.Propofol is also reported to induce priapism in some individuals, and has been observed to suppress REM sleep stage and to worsen the poor sleep quality in some patients.Rare side effects include:
Anxiety.
changes in vision.
cloudy urine.
coughing up blood.
delirium or hallucinations.
difficult urination.
difficulty swallowing.
dry eyes, mouth, nose, or throat.As with any other general anesthetic agent, propofol should be administered only where appropriately trained staff and facilities for monitoring are available, as well as proper airway management, a supply of supplemental oxygen, artificial ventilation, and cardiovascular resuscitation.Because of its lipid base, some hospital facilities require the IV tubing (of continuous propofol infusions) to be changed after 12 hours. This is a preventive measure against microbial growth and infection.

Propofol infusion syndrome
A rare, but serious, side effect is propofol infusion syndrome. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes in combination with catecholamines and/or corticosteroids.

Interactions
The respiratory effects of propofol are increased if given with other respiratory depressants, including benzodiazepines.

Pharmacology
Pharmacodynamics
Propofol has been proposed as having several mechanisms of action, both through potentiation of GABAA receptor activity and therefore acting as a GABAA receptor positive allosteric modulator, thereby slowing the channel-closing time. At high doses, propofol may be able to activate GABAA receptors in the absence of GABA, behaving as a GABAA receptor agonist as well. Propofol analogs have been shown to also act as sodium channel blockers. Some research has also suggested that the endocannabinoid system may contribute significantly to propofols anesthetic action and to its unique properties. An EEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brains information integration capacity.

Pharmacokinetics
Propofol is highly protein-bound in vivo and is metabolised by conjugation in the liver.
The half-life of elimination of propofol has been estimated to be between 2 and 24 hours. However, its duration of clinical effect is much shorter, because propofol is rapidly distributed into peripheral tissues. When used for IV sedation, a single dose of propofol typically wears off within minutes. Propofol is versatile; the drug can be given for short or prolonged sedation, as well as for general anesthesia. Its use is not associated with nausea as is often seen with opioid medications. These characteristics of rapid onset and recovery along with its amnestic effects have led to its widespread use for sedation and anesthesia.

History
John B. Glen, a veterinarian and researcher at Imperial Chemical Industries (ICI) spent 13 years developing propofol, an effort which led to the awarding to him of the prestigious 2018 Lasker Award for clinical research. Propofol was originally developed as ICI 35868.  It was chosen for development after extensive evaluation and structure–activity relationship studies of the anesthetic potencies and pharmacokinetic profiles of a series of ortho-alkylated phenols.First identified as a drug candidate in 1973, clinical trials followed in 1977, using a form solubilised in cremophor EL. However, due to anaphylactic reactions to cremophor, this formulation was withdrawn from the market and subsequently reformulated as an emulsion of a soya oil/propofol mixture in water. The emulsified formulation was relaunched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan.  The currently available preparation is 1% propofol, 10% soybean oil, and 1.2% purified egg phospholipid as an emulsifier, with 2.25%  glycerol as a tonicity-adjusting agent, and sodium hydroxide to adjust the pH. Diprivan contains EDTA, a common chelation agent, that also acts alone (bacteriostatically against some bacteria) and synergistically with some other antimicrobial agents. Newer generic formulations contain sodium metabisulfite or benzyl alcohol as antimicrobial agents </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 Mitotane and explain in detail? [/INST] Mitotane, sold under the brand name Lysodren, is a steroidogenesis inhibitor and cytostatic antineoplastic medication which is used in the treatment of adrenocortical carcinoma and Cushings syndrome. It is a derivative of the early insecticide DDT and an isomer of p,p-DDD (4,4-dichlorodiphenyldichloroethane) and is also known as 2,4-(dichlorodiphenyl)-2,2-dichloroethane (o,p-DDD).

Medical uses
Mitotane has been produced by Bristol Myers Squibb but it is marketed as an orphan drug for adrenocortical carcinoma due to the small number of patients in need of it. Its main use is in those patients who have persistent disease despite surgical resection, those who are not surgical candidates, or those who have metastatic disease. In a 2007 retrospective study of 177 patients from 1985 to 2005 showed a significant increase in the recurrence-free interval after radical surgery followed by mitotane when compared to surgery alone. The drug is also sometimes used in the treatment of Cushings syndrome.

Side effects
The use of mitotane is unfortunately limited by side effects, which, as reported by Schteinberg et al., include anorexia and nausea (88%), diarrhea (38%), vomiting  (23%), decreased memory and ability to concentrate (50%), rash (23%), gynecomastia (50%), arthralgia (19%), and leukopenia (7%).

Pharmacology
Pharmacodynamics
Mitotane is an inhibitor of the adrenal cortex. It acts as an inhibitor of cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), and also of 11β-hydroxylase (CYP11B1), 18-hydroxylase (aldosterone synthase, CYP11B2), and 3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent. In addition, mitotane has direct and selective cytotoxic effects on the adrenal cortex, via an unknown mechanism, and thereby induces permanent adrenal atrophy similarly to DDD.

Chemistry
Analogues of mitotane include aminoglutethimide, amphenone B, and metyrapone.

History
Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma.

Society and culture
Generic names
Mitotane is the generic name of the drug and its INN, USAN, BAN, and JAN.

Brand names
Mitotane has been sold under the brand name Lysodren.

Veterinary use
Mitotane is also used to treat Cushings disease (pituitary-dependent Cushings syndrome) in dogs. The medication is used in the controlled destruction of adrenal tissue, leading to a decrease in cortisol production.

References
External links
V. P </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 Clarithromycin and explain in detail? [/INST] Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others. Clarithromycin can be taken by mouth as a pill or liquid.Common side effects include nausea, vomiting, headaches, and diarrhea. Severe allergic reactions are rare. Liver problems have been reported. It may cause harm if taken during pregnancy. It is in the macrolide class and works by slowing down bacterial protein synthesis.Clarithromycin was developed in 1980 and approved for medical use in 1990. It is on the World Health Organizations List of Essential Medicines. Clarithromycin is available as a generic medication. It is made from erythromycin and is chemically known as 6-O-methylerythromycin.

Medical uses
Clarithromycin is primarily used to treat a number of bacterial infections including pneumonia, Helicobacter pylori, and as an alternative to penicillin in strep throat. Other uses include cat scratch disease and other infections due to bartonella, cryptosporidiosis, as a second line agent in Lyme disease and toxoplasmosis. It may also be used to prevent bacterial endocarditis in those who cannot take penicillin. It is effective against upper and lower respiratory tract infections, skin and soft tissue infections and helicobacter pylori infections associated with duodenal ulcers.

Spectrum of bacterial susceptibility
Aerobic Gram-positive bacteria

Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenesAerobic Gram-negative bacteria

Haemophilus parainfluenzae
Haemophilus influenzae
Moraxella catarrhalisHelicobacter

Helicobacter pyloriMycobacteria
Mycobacterium avium complex consisting of:

Mycobacterium avium avium
Mycobacterium intracellulareOther bacteria

Chlamydia pneumoniae
Mycoplasma pneumoniaeSafety and effectiveness of clarithromycin in treating clinical infections due to the following bacteria have not been established in adequate and well-controlled clinical trials:Aerobic Gram-positive bacteria

Streptococcus agalactiae
Streptococcus (Groups C, F, G)
Viridans group streptococciAerobic Gram-negative bacteria

Bordetella pertussis
Legionella pneumophila
Pasteurella multocidaAnaerobic Gram-positive bacteria

Clostridium perfringens
Peptococcus Niger
Cutibacterium acnesAnaerobic Gram-negative bacteria

Prevotella melaninogenica (formerly Bacteroides melaninogenicus)

Contraindications
Clarithromycin should not be taken by people who are allergic to other macrolides or inactive ingredients in the tablets, including microcrystalline cellulose, croscarmelose sodium, magnesium stearate, and povidone
Clarithromycin should not be used by people with a history of cholestatic jaundice and/or liver dysfunction associated with prior clarithromycin use.
Clarithromycin should not be used in the setting of hypokalaemia (low blood potassium)
Use of clarithromycin with the following medications: cisapride, pimozide, astemizole, terfenadine, ergotamine, ticagrelor, ranolazine or dihydroergotamine is not recommended.
It should not be used with colchicine in people with kidney or liver impairment.
Concomitant use with cholesterol medications such as lovastatin or simvastatin.
Hypersensitivity to clarithromycin or any component of the product, erythromycin, or any macrolide antibiotics.
QT prolongation or ventricular cardiac arrhythmias, including torsade de pointes.

Side effects
The most common side effects are gastrointestinal: diarrhea (3%), nausea (3%), abdominal pain (3%), and vomiting (6%). It also can cause headaches, insomnia, and abnormal liver function tests.  Allergic reactions include rashes and anaphylaxis.  Less common side effects (<1%) include extreme irritability, hallucinations (auditory and visual), dizziness/motion sickness, and alteration in senses of smell and taste, including a metallic taste.  Dry mouth, panic attacks, and nightmares have also been reported, albeit less frequently.

Cardiac
In February 2018, the FDA issued a Safety Communication warning with respect to an increased risk for heart problems or death with the use of clarithromycin, and has recommended that alternative antibiotics be considered in those with heart disease.Clarithromycin can lead to a prolonged QT interval. In patients with long QT syndrome, cardiac disease, or patients taking other QT-prolonging medications, this can increase risk for life-threatening arrhythmias.In one trial, the use of short-term clarithromycin treatment was correlated with an increased incidence of deaths classified as sudden cardiac deaths in stable coronary heart disease patients not using statins. Some case reports suspect it of causing liver disease.

Liver and kidney
Clarithromycin has been known to cause jaundice, cirrhosis, and kidney problems, including kidney failure.

Central nervous system
Common adverse effects of clarithromycin in the central nervous system include dizziness, headaches.  Rarely, it can cause ototoxicity, delirium and mania.

Infection
A risk of oral candidiasis and vaginal candidiasis, due to the elimination of the yeasts natural bacterial competitors by the antibiotic, has also been noted.

Pregnancy and breastfeeding
Clarithromycin should not be used in pregnant women except in situations where no alternative therapy is appropriate. Clarithromycin can cause potential hazard to the fetus hence should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. For lactating mothers it is not known whether clarithromycin is excreted in human milk.

Interactions
Clarithromycin inhibits a liver enzyme, CYP3A4, involved in the metabolism of many other commonly prescribed drugs. Taking clarithromycin with other medications that are metabolized by CYP3A4 may lead to unexpected increases or decreases in drug levels.
A few of the common interactions are listed below.

Colchicine
Clarithromycin has been observed to have a dangerous interaction with colchicine as the result of inhibition of CYP3A4 metabolism and P-glycoprotein transport. Combining these two drugs may lead to fatal colchicine toxicity, particularly in people with chronic kidney disease.

Statins
Taking clarithromycin concurrently with certain statins (a class of drugs used to reduce blood serum cholesterol levels) increases the risk of side effects, such as muscle aches and muscle break down (rhabdomyolysis).

Calcium channel blockers
Concurrent therapy with calcium channel blocker may increase risk of low blood pressure, kidney failure, and death, compared to pairing calcium channel blockers with azithromycin, a drug similar to clarithromycin but without CYP3A4 inhibition. Administration of clarithromycin in combination with verapamil have been observed to cause low blood pressure, low heart rate, and lactic acidosis.

Carbamazepine
Clarithromycin may double the level of carbamazepine in the body by reducing its clearance, which may lead to toxic symptoms of carbamazepine, such as double vision, loss of voluntary body movement, and nausea, as well as hyponatremia.

HIV medications
Depending on the combination of medications, clarithromycin therapy could be contraindicated, require changing doses of some medications, or be acceptable without dose adjustments. For example, clarithromycin may lead to decreased zidovudine concentrations.

Mechanism of action
Clarithromycin prevents bacteria from multiplying by acting as a protein synthesis inhibitor. It binds to 23S rRNA, a component of the 50S subunit of the bacterial ribosome, thus inhibiting the translation of peptides.

Pharmacokinetics
Unlike erythromycin, clarithromycin is acid-stable, so can be taken orally without having to be protected from gastric acids. It is readily absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, clarithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of clarithromycin are released; its concentration in the tissues can be over 10 times higher than in plasma. Highest concentrations are found in liver, lung tissue, and stool.

Metabolism
Clarithromycin has a fairly rapid first-pass metabolism in the liver. Its major metabolites include an inactive metabolite, N-desmethylclarithromycin, and an active metabolite, 14-(R)-hydroxyclarithromycin. Compared to clarithromycin, 14-(R)-hydroxyclarithromycin is less potent against mycobacterial tuberculosis and the Mycobacterium avium complex. Clarithromycin (20%-40%) and its active metabolite (10%-15%) are excreted in urine. Of all the drugs in its class, clarithromycin has the best bioavailability at 50%, which makes it amenable to oral administration.
Its elimination half-life is about 3 to 4 hours with 250 mg administered every 12 h, but increased to 5 to 7 h with 500 mg administered every 8 to 12 h </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 Dextran and explain in detail? [/INST] Dextran is a complex branched glucan (polysaccharide derived from the condensation of glucose), originally derived from wine. IUPAC defines dextrans as "Branched poly-α-d-glucosides of microbial origin having glycosidic bonds predominantly C-1 → C-6". Dextran chains are of varying lengths (from 3 to 2000 kilodaltons).
The polymer main chain consists of α-1,6 glycosidic linkages between glucose monomers, with branches from α-1,3 linkages. This characteristic branching distinguishes a dextran from a dextrin, which is a straight chain glucose polymer tethered by α-1,4 or α-1,6 linkages.

Occurrence
Dextran was discovered by Louis Pasteur as a microbial product in wine, but mass production was only possible after the development by Allene Jeanes of a process using bacteria. Dental plaque is rich in dextrans.  Dextran is a complicating contaminant in the refining of sugar because it elevates the viscosity of sucrose solutions and fouls plumbing.Dextran is now produced from sucrose by certain lactic acid bacteria of the family lactobacillus.  Species include Leuconostoc mesenteroides and Streptococcus mutans. The structure of dextran produced depends not only on the family and species of the bacterium but on the strain.  They are separated by fractional precipitation from protein-free extracts using ethanol.  Some bacteria coproduce fructans, which can complicate isolation of the dextrans.

Uses
Dextran 70 is on the WHO Model List of Essential Medicines, the most important medications needed in a health system.Medicinally it is used as an antithrombotic (antiplatelet), to reduce blood viscosity, and as a volume expander in hypovolaemia.

Microsurgery
These agents are used commonly by microsurgeons to decrease vascular thrombosis. The antithrombotic effect of dextran is mediated through its binding of erythrocytes, platelets, and vascular endothelium, increasing their electronegativity and thus reducing erythrocyte aggregation and platelet adhesiveness. Dextrans also reduce factor VIII-Ag Von Willebrand factor, thereby decreasing platelet function. Clots formed after administration of dextrans are more easily lysed due to an altered thrombus structure (more evenly distributed platelets with coarser fibrin). By inhibiting α-2 antiplasmin, dextran serves as a plasminogen activator, so possesses thrombolytic features.
Outside of these features, larger dextrans, which do not pass out of the vessels, are potent osmotic agents, thus have been used urgently to treat hypovolemia. The hemodilution caused by volume expansion with dextran use improves blood flow, thus further improving patency of microanastomoses and reducing thrombosis. Still, no difference has been detected in antithrombotic effectiveness in comparison of intra-arterial and intravenous administration of dextran.
Dextrans are available in multiple molecular weights ranging from 3 kDa to 2 MDa.  The larger dextrans (>60,000 Da) are excreted poorly from the kidney, so remain in the blood for as long as weeks until they are metabolized. Consequently, they have prolonged antithrombotic and colloidal effects. In this family, dextran-40 (MW: 40,000 Da), has been the most popular member for anticoagulation therapy. Close to 70% of dextran-40 is excreted in urine within the first 24 hours after intravenous infusion, while the remaining 30% are retained for several more days.

Other medical uses
Dextran is used in some eye drops as a lubricant. and in certain intravenous fluids to solubilize other factors, such as iron (in a solution known as Iron Dextran).
Intravenous solutions with dextran function both as volume expanders and means of parenteral nutrition. Such a solution provides an osmotically neutral fluid that once in the body is digested by cells into glucose and free water </s>