<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tizanidine and can you explain it in depth? [/INST] Tizanidine, sold under the brand name Zanaflex among others, is a medication that is used to treat muscle spasticity due to spinal cord injury or multiple sclerosis. Effectiveness appears similar to baclofen or diazepam. It is taken by mouth.Common side effects of Tizanidine include dry mouth, sleepiness, weakness, and dizziness. Serious side effects may include low blood pressure, liver problems, psychosis, and QT prolongation. It is unclear if use in pregnancy and breastfeeding is safe. It is an α2-adrenergic agonist and how it works is not entirely clear.Tizanidine was approved for medical use in the United States in 1996. It is available as a generic medication. In 2019, it was the 92nd most commonly prescribed medication in the United States, with more than 8 million prescriptions.

Medical uses
Tizanidine has been found to be as effective as other antispasmodic drugs and is more tolerable than baclofen and diazepam.

Side effects
Side effects include dizziness, drowsiness, weakness, nervousness, confusion, hallucinations, strange dreams, depression, vomiting, dry mouth, constipation, diarrhea, stomach pain, heartburn, increased muscle spasms, back pain, rash, sweating, and a tingling sensation in the arms, legs, hands, and feet.

Interactions
Concomitant use of tizanidine and moderate or potent CYP1A2 inhibitors (such as zileuton, certain antiarrhythmics (amiodarone, mexiletine, propafenone, verapamil), cimetidine, famotidine, aciclovir, ticlopidine and oral contraceptives) is contraindicated. Concomitant use of tizanidine with fluvoxamine, a potent CYP1A2 inhibitor in humans, resulted in a 33-fold increase in the tizanidine AUC (plasma drug concentration-time curve). For this reason both fluvoxamine and tizanidine should not be taken at the same time. Fluoroquinolone antibiotics such as moxifloxacin, levofloxacin, and ciprofloxacin should also be avoided due to an increased serum concentration of tizanidine when administered concomitantly. Tizanidine has the potential to interact with other central nervous system depressants. Alcohol should be avoided, particularly as it can upset the stomach. The CNS-depressant effects of tizanidine and alcohol are additive. Caution with the following interactions:
antibiotics such as enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, sparfloxacin, trovafloxacin, or norfloxacin;
blood pressure medications such as clonidine, guanabenz, guanfacine (Tenex), or methyldopa;
heart rhythm medications such as amiodarone (Cordarone, Pacerone), mexiletine (Mexitil), propafenone (Rhythmol), and verapamil (Calan, Covera, Isoptin).

Pharmacology
Tizanidine is an α2 receptor agonist closely related to clonidine. It has  approximately one tenth to one fifteenth of the pressure lowering effect of clonidine. The relation between the α2 receptor agonism and the spasmolytic action is still not fully understood.

Route of administration
Tizanidine is available as a tablet or capsule </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Zinc gluconate and can you explain it in depth? [/INST] Zinc gluconate is the zinc salt of gluconic acid.  It is an ionic compound consisting of two anions of gluconate for each zinc(II) cation. Zinc gluconate is a popular form for the delivery of zinc as a dietary supplement providing 14.35% elemental zinc by weight.
Gluconic acid is found naturally, and is industrially made by the fermentation of glucose, typically by Aspergillus niger, but also by other fungi, e.g. Penicillium, or by bacteria, e.g. Acetobacter, Pseudomonas and Gluconobacter. In its pure form, it is a white to off-white powder. It can also be made by electrolytic oxidation, although this is a more expensive process. The advantages are a lower microbiological profile, and a more complete reaction, yielding a product with a longer shelf life.

Zinc gluconate and the common cold
Zinc gluconate has been used in lozenges for treating the common cold. However, controlled trials with lozenges which include zinc acetate have found it has the greatest effect on the duration of colds.  Zinc has also been administered nasally for treating the common cold, but has been reported to cause anosmia in some cases.

Safety concerns
Instances of anosmia (loss of smell) have been reported with intranasal use of some products containing zinc gluconate. In September 2003, Zicam faced lawsuits from users who claimed that the product, a nasal gel containing zinc gluconate and several inactive ingredients, negatively affected their sense of smell and sometimes taste. Some plaintiffs alleged experiencing a strong and very painful burning sensation when they used the product. Matrixx Initiatives, Inc., the maker of Zicam, responded that only a small number of people had experienced problems and that anosmia can be caused by the common cold itself </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Alogliptin and can you explain it in depth? [/INST] Alogliptin, sold under the brand names Nesina and Vipidia,) is an oral anti-diabetic drug in the DPP-4 inhibitor (gliptin) class. Alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of hypoglycemia, and has relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in people whose diabetes cannot adequately be controlled with metformin alone.In April 2016, the U.S. Food and Drug Administration (FDA) added a warning about increased risk of heart failure. It was developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005.

Medical uses
Alogliptin is a dipeptidyl peptidase-4 inhibitor that decreases blood sugar similar to the other.

Side effects
Adverse events include mild hypoglycemia based on clinical studies. Alogliptin is not associated with increased weight, increased risk of cardiovascular events </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Dasiglucagon and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Promethazine and can you explain it in depth? [/INST] Promethazine is a first-generation antihistamine and antiemetic used to treat allergies, insomnia, and nausea. It may also help with some symptoms associated with the common cold and may also be used for sedating people who are agitated or anxious. Promethazine is available by mouth in syrup or tablet dosage forms, as a rectal suppository, or by injection into a muscle.Common side effects of promethazine include confusion and sleepiness; consumption of alcohol or other sedatives can make these symptoms worse. It is unclear if use of promethazine during pregnancy or breastfeeding is safe for the baby. Use of promethazine is not recommended in those less than two years old, due to potentially negative effects on breathing. Use of promethazine by injection into a vein is not recommended, due to potential skin damage. Promethazine is in the phenothiazine family of medications.Promethazine was made in the 1940s by a team of scientists from Rhône-Poulenc laboratories. It was approved for medical use in the United States in 1951. It is a generic medication and is available under many brand names globally. In 2019, it was the 174th most commonly prescribed medication in the United States, with more than 3 million prescriptions.

Medical uses
Promethazine has a variety of medical uses, including:

Sedation
For nausea and vomiting associated with anesthesia or chemotherapy. It is commonly used postoperatively as an antiemetic. The antiemetic activity increases with increased dosing; however, side effects also increase, which often limits maximal dosing.
For moderate to severe morning sickness and hyperemesis gravidarum: In the UK, promethazine is drug of first choice, being preferred as an older drug with which there is a greater experience of use in pregnancy (second in line being metoclopramide or prochlorperazine).
For allergies such as hay fever and together with other medications in anaphylaxis
To aid with symptoms of the common cold
Motion sickness, including space sickness
Hemolytic disease of the newborn
Anxiety before surgery

Side effects
Some documented side effects include:

Tardive dyskinesia, pseudoparkinsonism, acute dystonia (effects due to dopamine D2 receptor antagonism)
Confusion in the elderly
Drowsiness, dizziness, fatigue, more rarely vertigo
Known to have effects on serotonin and dopamine receptors.
Dry mouth
Nausea
Respiratory depression in patients under age of two and in those with severely compromised pulmonary function
Blurred vision, xerostomia, dry nasal passages, dilated pupils, constipation, and urinary retention. (due to cholinergic effects)
Chest discomfort/pressure (In children less than 2 years old)
AkathisiaLess frequent:

Cardiovascular side effects to include arrhythmias and hypotension
Neuroleptic malignant syndrome
Liver damage and cholestatic jaundice
Bone marrow suppression, potentially resulting in agranulocytosis, thrombocytopenia, and leukopenia
Depression of the thermoregulatory mechanism resulting in hypothermia/hyperthermiaRare side effects include:

SeizuresBecause of potential for more severe side effects, this drug is on the list to avoid in the elderly.  In many countries (including the US and UK), promethazine is contraindicated in children less than two years of age, and strongly cautioned against in children between two and six, due to problems with respiratory depression and sleep apnea.Promethazine is listed as one of the drugs of highest anticholinergic activity in a study of anticholinergenic burden, including long-term cognitive impairment.

Pharmacology
Promethazine, a phenothiazine derivative, is structurally different from the neuroleptic phenothiazines, with similar but different effects. It acts primarily as a strong antagonist of the H1 receptor (antihistamine) and a moderate mACh receptor antagonist (anticholinergic), and also has weak to moderate affinity for the 5-HT2A, 5-HT2C, D2, and α1-adrenergic receptors, where it acts as an antagonist at all sites, as well. New studies have shown that promethazine acts as a strong non-competitive selective NMDA receptor antagonist; which might promote sedation in addition with the strong antihistaminergic effects of the H1 receptor, but also as a weaker analgesic. It does not however affect the AMPA receptors.Another notable use of promethazine is as a local anesthetic, by blockage of sodium channels.

Chemistry
Solid promethazine hydrochloride is a white to faint-yellow,  practically odorless, crystalline powder. Slow oxidation may occur upon prolonged exposure to air, usually causing blue discoloration. Its hydrochloride salt is freely soluble in water and somewhat soluble in alcohol </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ciprofloxacin and can you explain it in depth? [/INST] Ciprofloxacin is a fluoroquinolone antibiotic used to treat a number of bacterial infections. This includes bone and joint infections, intra abdominal infections, certain types of infectious diarrhea, respiratory tract infections, skin infections, typhoid fever, and urinary tract infections, among others. For some infections it is used in addition to other antibiotics. It can be taken by mouth, as eye drops, as ear drops, or intravenously.Common side effects include nausea, vomiting, and diarrhea. Severe side effects include an increased risk of tendon rupture, hallucinations, and nerve damage. In people with myasthenia gravis, there is worsening muscle weakness. Rates of side effects appear to be higher than some groups of antibiotics such as cephalosporins but lower than others such as clindamycin. Studies in other animals raise concerns regarding use in pregnancy. No problems were identified, however, in the children of a small number of women who took the medication. It appears to be safe during breastfeeding. It is a second-generation fluoroquinolone with a broad spectrum of activity that usually results in the death of the bacteria.Ciprofloxacin was patented in 1980 and introduced in 1987. It is on the World Health Organizations List of Essential Medicines. The World Health Organization classifies ciprofloxacin as critically important for human medicine. It is available as a generic medication. In 2019, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions.

Medical uses
Ciprofloxacin is used to treat a wide variety of infections, including infections of bones and joints, endocarditis, gastroenteritis, malignant otitis externa, respiratory tract infections, cellulitis, urinary tract infections, prostatitis, anthrax, and chancroid.Ciprofloxacin only treats bacterial infections; it does not treat viral infections such as the common cold. For certain uses including acute sinusitis, lower respiratory tract infections and uncomplicated gonorrhea, ciprofloxacin is not considered a first-line agent.
Ciprofloxacin occupies an important role in treatment guidelines issued by major medical societies for the treatment of serious infections, especially those likely to be caused by Gram-negative bacteria, including Pseudomonas aeruginosa.  For example, ciprofloxacin in combination with metronidazole is one of several first-line antibiotic regimens recommended by the Infectious Diseases Society of America for the treatment of community-acquired abdominal infections in adults. It also features prominently in treatment guidelines for acute pyelonephritis, complicated or hospital-acquired urinary tract infection, acute or chronic prostatitis, certain types of endocarditis, certain skin infections, and prosthetic joint infections.In other cases, treatment guidelines are more restrictive, recommending in most cases that older, narrower-spectrum drugs be used as first-line therapy for less severe infections to minimize fluoroquinolone-resistance development. For example, the Infectious Diseases Society of America recommends the use of ciprofloxacin and other fluoroquinolones in urinary tract infections be reserved to cases of proven or expected resistance to narrower-spectrum drugs such as nitrofurantoin or trimethoprim/sulfamethoxazole. The European Association of Urology recommends ciprofloxacin as an alternative regimen for the treatment of uncomplicated urinary tract infections, but cautions that the potential for "adverse events have to be considered".Although approved by regulatory authorities for the treatment of respiratory infections, ciprofloxacin is not recommended for respiratory infections by most treatment guidelines due in part to its modest activity against the common respiratory pathogen Streptococcus pneumoniae.  "Respiratory quinolones" such as levofloxacin, having greater activity against this pathogen, are recommended as first line agents for the treatment of community-acquired pneumonia in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). Similarly, ciprofloxacin is not recommended as a first-line treatment for acute sinusitis.Ciprofloxacin is approved for the treatment of gonorrhea in many countries, but this recommendation is widely regarded as obsolete due to resistance development.

Pregnancy
In the United States ciprofloxacin is pregnancy category C. This category includes drugs for which no adequate and well-controlled studies in human pregnancy exist, and for which animal studies have suggested the potential for harm to the fetus, but potential benefits may warrant use of the drug in pregnant women
despite potential risks. An expert review of published data on experiences with ciprofloxacin use during pregnancy by the Teratogen Information System concluded therapeutic doses during
pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state no risk exists. Exposure to quinolones, including levofloxacin, during the first-trimester is not associated with an increased risk of stillbirths, premature births, birth defects, or low birth weight.Two small post-marketing epidemiology studies of mostly short-term, first-trimester exposure found that fluoroquinolones did not increase risk of major malformations, spontaneous abortions, premature birth, or low birth weight. The label notes, however, that these studies are insufficient to reliably evaluate the definitive safety or risk of less common defects by ciprofloxacin in pregnant women and their developing fetuses.

Breastfeeding
Fluoroquinolones have been reported as present in a mothers milk and thus passed on to the nursing child. The U.S. Food and Drug Administration (FDA) recommends that because of the risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Children
Oral and intravenous ciprofloxacin are approved by the FDA for use in children for only two indications due to the risk of permanent injury to the musculoskeletal system:

Inhalational anthrax (postexposure)
Complicated urinary tract infections and pyelonephritis due to Escherichia coli, but never as first-line agents.Current recommendations by the American Academy of Pediatrics note the systemic use of ciprofloxacin in children should be restricted to infections caused by multidrug-resistant pathogens or when no safe or effective alternatives are available.

Spectrum of activity
Its spectrum of activity includes most strains of bacterial pathogens responsible for community-acquired pneumonias, bronchitis, urinary tract infections, and gastroenteritis. Ciprofloxacin is particularly effective against Gram-negative bacteria (such as Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, and Pseudomonas aeruginosa), but is less effective against Gram-positive bacteria (such as methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis) than newer fluoroquinolones.

Bacterial resistance
As a result of its widespread use to treat minor infections readily treatable with older, narrower spectrum antibiotics, many bacteria have developed resistance to this drug in recent years, leaving it significantly less effective than it would have been otherwise.Resistance to ciprofloxacin and other fluoroquinolones may evolve rapidly, even during a course of treatment. Numerous pathogens, including enterococci, Streptococcus pyogenes and Klebsiella pneumoniae (quinolone-resistant) now exhibit resistance. Widespread veterinary usage of the fluoroquinolones, particularly in Europe, has been implicated. Meanwhile, some Burkholderia cepacia, Clostridium innocuum and Enterococcus faecium strains have developed resistance to ciprofloxacin to varying degrees.Fluoroquinolones had become the class of antibiotics most commonly prescribed to adults in 2002. Nearly half (42%) of those prescriptions in the U.S. were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection, according to a study supported in part by the Agency for Healthcare Research and Quality. Additionally, they were commonly prescribed for medical conditions that were not even bacterial to begin with, such as viral infections, or those to which no proven benefit existed.

Contraindications
Contraindications include:
Taking tizanidine at the same time
Use by those who are hypersensitive to any member of the quinolone class of antimicrobial agents
Use by those who are diagnosed with myasthenia graves, as muscle weakness may be exacerbatedCiprofloxacin is also considered to be contraindicated in children (except for the indications outlined above), in pregnancy, to nursing mothers, and in people with epilepsy or other seizure disorders.
Caution may be required in people with Marfan syndrome or Ehlers-Danlos syndrome.

Adverse effects
Adverse effects can involve the tendons, muscles, joints, nerves, and the central nervous system.Rates of adverse effects appear to be higher than with some groups of antibiotics such as cephalosporins but lower than with others such as clindamycin. Compared to other antibiotics some studies find a higher rate of adverse effects while others find no difference.In clinical trials most of the adverse events were described as mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Some adverse effects may be permanent. Ciprofloxacin was stopped because of an adverse event in 1% of people treated with the medication by mouth. The most frequently reported drug-related events, from trials of all formulations, all dosages, all drug-therapy durations, and for all indications, were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%). Other adverse events occurred at rates of <1%.

Tendon problems
Ciprofloxacin includes a boxed warning in the United States due to an increased risk of tendinitis and tendon rupture, especially in people who are older than 60 years, people who also use corticosteroids, and people with kidney, lung, or heart transplants. Tendon rupture can occur during therapy or even months after discontinuation of the medication. One study found that fluoroquinolone use was associated with a 1.9-fold increase in tendon problems. The risk increased to 3.2 in those over 60 years of age and to 6.2 in those over the age of 60 who were also taking corticosteroids. Among the 46,766 quinolone users in the study, 38 (0.08%) cases of Achilles tendon rupture were identified.

Cardiac arrhythmia
The fluoroquinolones, including ciprofloxacin, are associated with an increased risk of cardiac toxicity, including QT interval prolongation, torsades de pointes, ventricular arrhythmia, and sudden death.

Nervous system
Because Ciprofloxacin is lipophilic, it has the ability to cross the blood-brain barrier. The 2013 FDA label warns of nervous system effects. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold, and may cause other central nervous system adverse effects. Headache, dizziness, and insomnia have been reported as occurring fairly commonly in postapproval review articles, along with a much lower incidence of serious CNS adverse effects such as tremors, psychosis, anxiety, hallucinations, paranoia, and suicide attempts, especially at higher doses. Like other fluoroquinolones, it is also known to cause peripheral neuropathy that may be irreversible, such as weakness, burning pain, tingling or numbness.

Cancer
Ciprofloxacin is active in six of eight in vitro assays used as rapid screens for the detection of genotoxic effects, but is not active in in vivo assays of genotoxicity. Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (about 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m2). Results from photo co-carcinogenicity testing indicate ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control.

Other
The other black box warning is that ciprofloxacin should not be used in people with myasthenia gravis due to possible exacerbation of muscle weakness which may lead to breathing problems resulting in death or ventilator support. Fluoroquinolones are known to block neuromuscular transmission. There are concerns that fluoroquinolones including ciprofloxacin can affect cartilage in young children.Clostridium difficile-associated diarrhea is a serious adverse effect of ciprofloxacin and other fluoroquinolones; it is unclear whether the risk is higher than with other broad-spectrum antibiotics.A wide range of rare but potentially fatal adverse effects reported to the U.S. FDA or the subject of case reports includes aortic dissection, toxic epidermal necrolysis, Stevens–Johnson syndrome, low blood pressure, allergic pneumonitis, bone marrow suppression, hepatitis or liver failure, and sensitivity to light. The medication should be discontinued if a rash, jaundice, or other sign of hypersensitivity occurs.Children and the elderly are at a much greater risk of experiencing adverse reactions.

Overdose
Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach by induced vomiting or gastric lavage, as well as administration of antacids containing magnesium, aluminium, or calcium to reduce drug absorption. Renal function and urinary pH should be monitored. Important support includes adequate hydration and urine acidification if necessary to prevent crystalluria. Hemodialysis or peritoneal dialysis can only remove less than 10% of ciprofloxacin. Ciprofloxacin may be quantified in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.

Interactions
Ciprofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.
Ciprofloxacin should not be taken with antacids containing magnesium or aluminum, highly buffered drugs (sevelamer, lanthanum carbonate, sucralfate, didanosine), or with supplements containing calcium, iron, or zinc. It should be taken two hours before or six hours after these products. Magnesium or aluminum antacids turn ciprofloxacin into insoluble salts that are not readily absorbed by the intestinal tract, reducing peak serum concentrations by 90% or more, leading to therapeutic failure. Additionally, it should not be taken with dairy products or calcium-fortified juices alone, as peak serum concentration and the area under the serum concentration-time curve can be reduced up to 40%. However, ciprofloxacin may be taken with dairy products or calcium-fortified juices as part of a meal.Ciprofloxacin inhibits the drug-metabolizing enzyme CYP1A2 and thereby can reduce the clearance of drugs metabolized by that enzyme. CYP1A2 substrates that exhibit increased serum levels in ciprofloxacin-treated patients include tizanidine, theophylline, caffeine, methylxanthines, clozapine, olanzapine, and ropinirole. Co-administration of ciprofloxacin with the CYP1A2 substrate tizanidine (Zanaflex) is contraindicated due to a 583% increase in the peak serum concentrations of tizanidine when administered with ciprofloxacin as compared to administration of tizanidine alone. Use of ciprofloxacin is cautioned in patients on theophylline due to its narrow therapeutic index. The authors of one review recommended that patients being treated with ciprofloxacin reduce their caffeine intake. Evidence for significant interactions with several other CYP1A2 substrates such as cyclosporine is equivocal or conflicting.The Committee on Safety of Medicines and the FDA warn that central nervous system adverse effects, including seizure risk, may be increased when NSAIDs are combined with quinolones. The mechanism for this interaction may involve a synergistic increased antagonism of GABA neurotransmission.Altered serum levels of the antiepileptic drugs phenytoin and carbamazepine (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.Ciprofloxacin is a potent inhibitor of CYP1A2, CYP2D6, and CYP3A4.

Mechanism of action
Ciprofloxacin is a broad-spectrum antibiotic of the fluoroquinolone class. It is active against some Gram-positive and many Gram-negative bacteria. It functions by inhibiting a type II topoisomerase (DNA gyrase) and topoisomerase IV, necessary to separate bacterial DNA, thereby inhibiting cell division. Bacterial DNA fragmentation will occur as a result of inhibition of the enzymes.

Pharmacokinetics
Ciprofloxacin for systemic administration is available as immediate-release tablets, extended-release tablets, an oral suspension, and as a solution for intravenous administration. When administered over one hour as an intravenous infusion, ciprofloxacin rapidly distributes into the tissues, with levels in some tissues exceeding those in the serum.  Penetration into the central nervous system is relatively modest, with cerebrospinal fluid levels normally less than 10% of peak serum concentrations.  The serum half-life of ciprofloxacin is about 4–6 hours, with 50–70% of an administered dose being excreted in the urine as unmetabolized drug. An additional 10% is excreted in urine as metabolites.  Urinary excretion is virtually complete 24 hours after administration. Dose adjustment is required in the elderly and in those with renal impairment.Ciprofloxacin is weakly bound to serum proteins (20–40%). It is an inhibitor of the drug-metabolizing enzyme cytochrome P450 1A2, which leads to the potential for clinically important drug interactions with drugs metabolized by that enzyme.Ciprofloxacin is about 70% orally available when administered orally, so a slightly higher dose is needed to achieve the same exposure when switching from IV to oral administrationThe extended release oral tablets allow once-daily administration by releasing the drug more slowly in the gastrointestinal tract. These tablets contain 35% of the administered dose in an immediate-release form and 65% in a slow-release matrix.  Maximum serum concentrations are achieved between 1 and 4 hours after administration. Compared to the 250- and 500-mg immediate-release tablets, the 500-mg and 1000-mg XR tablets provide higher Cmax, but the 24‑hour AUCs are equivalent.
Ciprofloxacin immediate-release tablets contain ciprofloxacin as the hydrochloride salt, and the XR tablets contain a mixture of the hydrochloride salt as the free base.

Chemical properties
Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance.Ciprofloxacin hydrochloride (USP) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C17H18FN3O3HCl•H2O.

Usage
Ciprofloxacin is the most widely used of the second-generation quinolones. In 2010, over 20 million prescriptions were written, making it the 35th-most commonly prescribed generic drug and the 5th-most commonly prescribed antibacterial in the U.S.

History
The first members of the quinolone antibacterial class were relatively low-potency drugs such as nalidixic acid, used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine. In 1979, the publication of a patent filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of norfloxacin, and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency. In the aftermath of this disclosure, several other pharmaceutical companies initiated research and development programs with the goal of discovering additional antibacterial agents of the fluoroquinolone class.
The fluoroquinolone program at Bayer focused on examining the effects of very minor changes to the norfloxacin structure. In 1983, the company published in vitro potency data for ciprofloxacin, a fluoroquinolone antibacterial having a chemical structure differing from that of norfloxacin by the presence of a single carbon atom. This small change led to a two- to 10-fold increase in potency against most strains of Gram-negative bacteria.  Importantly, this structural change led to a four-fold improvement in activity against the important Gram-negative pathogen Pseudomonas aeruginosa, making ciprofloxacin one of the most potent known drugs for the treatment of this intrinsically antibiotic-resistant pathogen.The oral tablet form of ciprofloxacin was approved in October 1987, just one year after the approval of norfloxacin. In 1991, the intravenous formulation was introduced. Ciprofloxacin sales reached a peak of about 2 billion euros in 2001, before Bayers patent expired in 2004, after which annual sales have averaged around €200 million.The name probably originates from the International Scientific Nomenclature: ci- (alteration of cycl-) + propyl + fluor- + ox- + az- + -mycin.

Society and culture
Cost
It is available as a generic medication and not very expensive. At least one company, Turtle Pharma Private Limited provides industrial-size amounts

Generic equivalents
On 24 October 2001, the Prescription Access Litigation (PAL) project filed suit to dissolve an agreement between Bayer and three of its competitors which produced generic versions of drugs (Barr Laboratories, Rugby Laboratories, and Hoechst-Marion-Roussel) that PAL claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating its price and supply. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayers patent had expired, the United States District Court for the Eastern District of New York granted Bayers and the other defendants motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law, in effect upholding Bayers agreement with its competitors.

Available forms
Ciprofloxacin for systemic administration is available as immediate-release tablets, as extended-release tablets, as an oral suspension, and as a solution for intravenous infusion. It is also available for local administration as eye drops and ear drops.

Litigation
A class action was filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the U.S. Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged they developed serious adverse effects from taking ciprofloxacin in the aftermath of the anthrax attacks in 2001 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Midazolam and can you explain it in depth? [/INST] Midazolam, sold under the brand name Versed among others, is a benzodiazepine medication used for anesthesia and procedural sedation, and to treat severe agitation. It works by inducing sleepiness, decreasing anxiety, and causing a loss of ability to create new memories. The drug does not cause an individual to become unconscious, merely to be sedated. It is also useful for the treatment of prolonged (lasting over 5 minutes) seizures. Midazolam can be given by mouth, intravenously, by injection into a muscle, by spraying into the nose, or through the cheek. When given intravenously, it typically begins working within five minutes; when injected into a muscle, it can take fifteen minutes to begin working. Effects last between one and six hours.
Side effects can include a decrease in efforts to breathe, low blood pressure, and sleepiness. Tolerance to its effects and withdrawal syndrome may occur following long-term use. Paradoxical effects, such as increased activity, can occur especially in children and older people. There is evidence of risk when used during pregnancy but no evidence of harm with a single dose during breastfeeding. It belongs to the benzodiazepine class of drugs and works by increasing the activity of the GABA neurotransmitter in the brain.Midazolam was patented in 1974 and came into medical use in 1982. It is on the World Health Organizations List of Essential Medicines. Midazolam is available as a generic medication. In many countries, it is a controlled substance.

Medical uses
Seizures
Midazolam is sometimes used for the acute management of prolonged seizures. Long-term use for the management of epilepsy is not recommended due to the significant risk of tolerance (which renders midazolam and other benzodiazepines ineffective) and the significant side effect of sedation. A benefit of midazolam is that in children it can be given in the cheek or in the nose for acute seizures, including status epilepticus. Midazolam is effective for status epilepticus or when intravenous access cannot be obtained, and has advantages of being water-soluble, having a rapid onset of action and not causing metabolic acidosis from the propylene glycol vehicle (which is not required due to its solubility in water), which occurs with other benzodiazepines.Drawbacks include a high degree of breakthrough seizures—due to the short half-life of midazolam—in over 50% of people treated, as well as treatment failure in 14–18% of people with refractory status epilepticus. Tolerance develops rapidly to the anticonvulsant effect, and the dose may need to be increased by several times to maintain anticonvulsant therapeutic effects. With prolonged use, tolerance and tachyphylaxis can occur and the elimination half-life may increase, up to days. Buccal and intranasal midazolam may be both easier to administer and more effective than rectally administered diazepam in the emergency control of seizures.

Procedural sedation
Intravenous midazolam is indicated for procedural sedation (often in combination with an opioid, such as fentanyl), preoperative sedation, for the induction of general anesthesia, and for sedation of people who are ventilated in critical care units. Midazolam is superior to diazepam in impairing memory of endoscopy procedures, but propofol has a quicker recovery time and a better memory-impairing effect. It is the most popular benzodiazepine in the intensive care unit (ICU) because of its short elimination half-life, combined with its water solubility and its suitability for continuous infusion. However, for long-term sedation, lorazepam is preferred due to its long duration of action, and propofol has advantages over midazolam when used in the ICU for sedation, such as shorter weaning time and earlier tracheal extubation.Midazolam is sometimes used in neonatal intensive care units. When used, additional caution is required in newborns; midazolam should not be used for longer than 72 hours due to risks of tachyphylaxis, and the possibility of development of a benzodiazepine withdrawal syndrome, as well as neurological complications. Bolus injections should be avoided due to the increased risk of cardiovascular depression, as well as neurological complications.
Midazolam is also sometimes used in newborns who are receiving mechanical ventilation, although morphine is preferred, owing to its better safety profile for this indication.Sedation using midazolam can be used to relieve anxiety and manage behaviour in children undergoing dental treatment.

Agitation
Midazolam, in combination with an antipsychotic drug, is indicated for the acute management of schizophrenia when it is associated with aggressive or out-of-control behaviour.

End of life care
In the final stages of end-of-life care, midazolam is routinely used at low doses via subcutaneous injection to help with agitation, restlessness or anxiety in the last hours or days of life. At higher doses during the last weeks of life, midazolam is considered a first line agent in palliative continuous deep sedation therapy when it is necessary to alleviate intolerable suffering not responsive to other treatments, but the need for this is rare.

Administration
Routes of administration of midazolam can be oral, intranasal, buccal, intravenous, and intramuscular.

Contraindications
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or other drug-dependent individuals or those with comorbid psychiatric disorders. Additional caution is required in critically ill patients, as accumulation of midazolam and its active metabolites may occur. Kidney or liver impairments may slow down the elimination of midazolam leading to prolonged and enhanced effects. Contraindications include hypersensitivity, acute narrow-angle glaucoma, shock, hypotension, or head injury. Most are relative contraindications.

Side effects
Side effects of midazolam in the elderly are listed above. People experiencing amnesia as a side effect of midazolam are generally unaware their memory is impaired, unless they had previously known it as a side effect.Long-term use of benzodiazepines has been associated with long-lasting deficits in memory, and show only partial recovery six months after stopping benzodiazepines. It is unclear whether full recovery occurs after longer periods of abstinence. Benzodiazepines can cause or worsen depression. Paradoxical excitement occasionally occurs with benzodiazepines, including a worsening of seizures. Children and elderly individuals or those with a history of excessive alcohol use and individuals with a history of aggressive behavior or anger are at increased risk of paradoxical effects. Paradoxical reactions are particularly associated with intravenous administration. After nighttime administration of midazolam, residual hangover effects, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely and may increase the risk of falls and hip fractures. Sedation, respiratory depression and hypotension due to a reduction in systematic vascular resistance, and an increase in heart rate can occur. If intravenous midazolam is given too quickly, hypotension may occur. A "midazolam infusion syndrome" may result from high doses, is characterised by delayed arousal hours to days after discontinuation of midazolam, and may lead to an increase in the length of ventilatory support needed.In rare susceptible individuals, midazolam has been known to cause a paradoxical reaction, a well-documented complication with benzodiazepines. When this occurs, the individual may experience anxiety, involuntary movements, aggressive or violent behavior, uncontrollable crying or verbalization, and other similar effects. This seems to be related to the altered state of consciousness or disinhibition produced by the drug. Paradoxical behavior is often not recalled by the patient due to the amnesia-producing properties of the drug. In extreme situations, flumazenil can be administered to inhibit or reverse the effects of midazolam.  Antipsychotic medications, such as haloperidol, have also been used for this purpose.Midazolam is known to cause respiratory depression. In healthy humans, 0.15 mg/kg of midazolam may cause respiratory depression, which is postulated to be a central nervous system (CNS) effect. When midazolam is administered in combination with fentanyl, the incidence of hypoxemia or apnea becomes more likely.Although the incidence of respiratory depression/arrest is low (0.1–0.5%) when midazolam is administered alone at normal doses, the concomitant use with CNS acting drugs, mainly analgesic opiates, may increase the possibility of hypotension, respiratory depression, respiratory arrest, and death, even at therapeutic doses. Potential drug interactions involving at least one CNS depressant were observed for 84% of midazolam users who were subsequently required to receive the benzodiazepine antagonist flumazenil. Therefore, efforts directed toward monitoring drug interactions and preventing injuries from midazolam administration are expected to have a substantial impact on the safe use of this drug.

Pregnancy and breastfeeding
Midazolam, when taken during the third trimester of pregnancy, may cause risk to the neonate, including benzodiazepine withdrawal syndrome, with possible symptoms including hypotonia, apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Symptoms of hypotonia and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth. Other neonatal withdrawal symptoms include hyperexcitability, tremor, and gastrointestinal upset (diarrhea or vomiting). Breastfeeding by mothers using midazolam is not recommended.

Elderly
Additional caution is required in the elderly, as they are more sensitive to the pharmacological effects of benzodiazepines, metabolise them more slowly, and are more prone to adverse effects, including drowsiness, amnesia (especially anterograde amnesia), ataxia, hangover effects, confusion, and falls.

Tolerance, dependence, and withdrawal
A benzodiazepine dependence occurs in about one-third of individuals who are treated with benzodiazepines for longer than 4 weeks, which typically results in tolerance and benzodiazepine withdrawal syndrome when the dose is reduced too rapidly. Midazolam infusions may induce tolerance and a withdrawal syndrome in a matter of days. The risk factors for dependence include dependent personality, use of a benzodiazepine that is short-acting, high potency and long-term use of benzodiazepines. Withdrawal symptoms from midazolam can range from insomnia and anxiety to seizures and psychosis. Withdrawal symptoms can sometimes resemble a persons underlying condition. Gradual reduction of midazolam after regular use can minimise withdrawal and rebound effects. Tolerance and the resultant withdrawal syndrome may be due to receptor down-regulation and GABAA receptor alterations in gene expression, which causes long-term changes in the function of the GABAergic neuronal system.Chronic users of benzodiazepine medication who are given midazolam experience reduced therapeutic effects of midazolam, due to tolerance to benzodiazepines. Prolonged infusions with midazolam results in the development of tolerance; if midazolam is given for a few days or more a withdrawal syndrome can occur. Therefore, preventing a withdrawal syndrome requires that a prolonged infusion be gradually withdrawn, and sometimes, continued tapering of dose with an oral long-acting benzodiazepine such as clorazepate dipotassium. When signs of tolerance to midazolam occur during intensive care unit sedation the addition of an opioid or propofol is recommended. Withdrawal symptoms can include irritability, abnormal reflexes, tremors, clonus, hypertonicity, delirium and seizures, nausea, vomiting, diarrhea, tachycardia, hypertension, and tachypnea. In those with significant dependence, sudden discontinuation may result in withdrawal symptoms such as status epilepticus.

Overdose
A midazolam overdose is considered a medical emergency and generally requires the immediate attention of medical personnel. Benzodiazepine overdose in healthy individuals is rarely life-threatening with proper medical support; however, the toxicity of benzodiazepines increases when they are combined with other CNS depressants such as alcohol, opioids, or tricyclic antidepressants. The toxicity of benzodiazepine overdose and the risk of death are also increased in the elderly and those with obstructive pulmonary disease or when used intravenously. Treatment is supportive; activated charcoal can be used within an hour of the overdose. The antidote for an overdose of midazolam (or any other benzodiazepine) is flumazenil. While effective in reversing the effects of benzodiazepines it is not used in most cases as it may trigger seizures in mixed overdoses and benzodiazepine dependent individuals.Symptoms of midazolam overdose can include:

Detection in body fluids
Concentrations of midazolam or its major metabolite, 1-hydroxymidazolam glucuronide, may be measured in plasma, serum, or whole blood to monitor for safety in those receiving the drug therapeutically, to confirm a diagnosis of poisoning in hospitalized patients, or to assist in a forensic investigation of a case of fatal overdosage. Patients with renal dysfunction may exhibit prolongation of elimination half-life for both the parent drug and its active metabolite, with accumulation of these two substances in the bloodstream and the appearance of adverse depressant effects.

Interactions
Protease inhibitors, nefazodone, sertraline, grapefruit, fluoxetine, erythromycin, diltiazem, clarithromycin inhibit the metabolism of midazolam, leading to a prolonged action. St Johns wort, rifapentine, rifampin, rifabutin, phenytoin enhance the metabolism of midazolam leading to a reduced action. Sedating antidepressants, antiepileptic drugs such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opioids, antipsychotics and alcohol enhance the sedative effects of midazolam. Midazolam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with midazolam results in a reduced elimination rate of midazolam. St Johns wort decreases the blood levels of midazolam. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations.

Pharmacology
Midazolam is a short-acting benzodiazepine in adults with an elimination half-life of 1.5–2.5 hours. In the elderly, as well as young children and adolescents, the elimination half-life is longer. Midazolam is metabolised into an active metabolite alpha1-hydroxymidazolam. Age-related deficits, renal and liver status affect the pharmacokinetic factors of midazolam as well as its active metabolite. However, the active metabolite of midazolam is minor and contributes to only 10 percent of biological activity of midazolam. Midazolam is poorly absorbed orally, with only 50 percent of the drug reaching the bloodstream. Midazolam is metabolised by cytochrome P450 (CYP) enzymes and by glucuronide conjugation. The therapeutic as well as adverse effects of midazolam are due to its effects on the GABAA receptors; midazolam does not activate GABAA receptors directly but, as with other benzodiazepines, it enhances the effect of the neurotransmitter GABA on the GABAA receptors (↑ frequency of Cl− channel opening) resulting in neural inhibition. Almost all of the properties can be explained by the actions of benzodiazepines on GABAA receptors. This results in the following pharmacological properties being produced: sedation, induction of sleep, reduction in anxiety, anterograde amnesia, muscle relaxation and anticonvulsant effects.

History
Midazolam is among about 35 benzodiazepines currently used medically, and was synthesized in 1975 by Walser and Fryer at Hoffmann-LaRoche, Inc in the United States. Owing to its water solubility, it was found to be less likely to cause thrombophlebitis than similar drugs. The anticonvulsant properties of midazolam were studied in the late 1970s, but not until the 1990s did it emerge as an effective treatment for convulsive status epilepticus. As of 2010, it is the most commonly used benzodiazepine in anesthetic medicine. In acute medicine, midazolam has become more popular than other benzodiazepines, such as lorazepam and diazepam, because it is shorter lasting, is more potent, and causes less pain at the injection site. Midazolam is also becoming increasingly popular in veterinary medicine due to its water solubility. In 2018 it was revealed the CIA considered using Midazolam as a "truth serum" on terrorist suspects in project "Medication".

Society and culture
Cost
Midazolam is available as a generic medication.

Availability
Midazolam is available in the United States as a syrup or as an injectable solution.Dormicum brand midazolam is marketed by Roche as white, oval, 7.5-mg tablets in boxes of two or three blister strips of 10 tablets, and as blue, oval, 15-mg tablets in boxes of two (Dormonid 3x) blister strips of 10 tablets. The tablets are imprinted with "Roche" on one side and the dose of the tablet on the other side. Dormicum is also available as 1-, 3-, and 10-ml ampoules at a concentration of 5 mg/ml. Another manufacturer, Novell Pharmaceutical Laboratories, makes it available as Miloz in 3- and 5-ml ampoules. Midazolam is the only water-soluble benzodiazepine available. Another maker is Roxane Laboratories; the product in an oral solution, Midazolam HCl Syrup, 2 mg/ml clear, in a red to purplish-red syrup, cherry in flavor. It becomes soluble when the injectable solution is buffered to a pH of 2.9–3.7. Midazolam is also available in liquid form. It can be administered intramuscularly, intravenously, intrathecally, intranasally, buccally, or orally.

Legal status
In the Netherlands, midazolam is a List II drug of the Opium Law.
Midazolam is a Schedule IV drug under the Convention on Psychotropic Substances. In the United Kingdom, midazolam is a Schedule 3/Class C controlled drug. In the United States, midazolam (DEA number 2884) is on the Schedule IV list of the Controlled Substances Act as a non-narcotic agent with low potential for abuse.

Marketing authorization
In 2011, the European Medicines Agency (EMA) granted a marketing authorisation for a buccal application form of midazolam, sold under the brand name Buccolam. Buccolam was initially approved for the treatment of prolonged, acute, convulsive seizures in people from three months to less than 18 years of age. This was the first application of a paediatric-use marketing authorisation.

Use in executions
The drug has been introduced for use in executions by lethal injection in certain jurisdictions in the United States in combination with other drugs. It was introduced to replace pentobarbital after the latters manufacturer disallowed that drugs use for executions. Midazolam acts as a sedative but will fail to render the condemned prisoner unconscious, at which time vecuronium bromide and potassium chloride are administered, stopping the prisoners breathing and heart, respectively. Since the condemned prisoner is not unconscious but merely sedated, two very different things, those following two drugs can cause extreme pain and panic in the soon to die prisoner.Midazolam has been used as part of a three-drug cocktail, with vecuronium bromide and potassium chloride in Florida and Oklahoma prisons.  Midazolam has also been used along with hydromorphone in a two-drug protocol in Ohio and Arizona.The usage of midazolam in executions became controversial after condemned inmate Clayton Lockett apparently regained consciousness and started speaking midway through his 2014  execution when the state of Oklahoma attempted to execute him with an untested three-drug lethal injection combination using 100 mg of midazolam. Prison officials reportedly discussed taking him to a hospital before he was pronounced dead of a heart attack 40 minutes after the execution began. An observing doctor stated that Locketts vein had ruptured. It is not clear whether his death was caused by one or more of the drugs or by a problem in the administration procedure, nor is it clear what quantities of vecuronium bromide and potassium chloride were released to his system before the execution was cancelled.

Notable incidents
The state of Florida used midazolam to execute William Frederick Happ in October 2013.The state of Ohio used midazolam in the execution of Dennis McGuire in January 2014; it took McGuire 24 minutes to die after the procedure started, and he gasped and appeared to be choking during that time, leading to questions about the dosing and timing of the drug administration, as well as the choice of drugs.The execution of Ronald Bert Smith in the state of Alabama on 8 December 2016, "went awry soon after (midazolam) was administered"
again putting the effectiveness of the drug in question.In October 2016, the state of Ohio announced that it would resume executions in January 2017, using a formulation of midazolam, vecuronium bromide, and potassium chloride, but this was blocked by a Federal judge. On 26 July 2017, Ronald Phillips was executed with a three-drug cocktail including midazolam after the Supreme Court refused to grant a stay. Prior to this, the last execution in Ohio had been that of Dennis McGuire. Murderer Gary Ottes lawyers unsuccessfully challenged his Ohio execution, arguing that midazolam might not protect him from serious pain when the other drugs are administered. He died without incident in about 14 minutes on 13 September 2017.On 24 April 2017, the state of Arkansas carried out a double-execution of Jack Harold Jones, 52, and Marcel Williams, 46. The state of Arkansas attempted to execute eight people before its supply of midazolam expired on 30 April 2017. Two of them were granted a stay of execution, and another, Ledell T. Lee, 51, was executed on 20 April 2017.On 28 October 2021, the state of Oklahoma executed inmate John Marion Grant, 60, using midazolam as part of its three-drug cocktail hours after the U.S. Supreme Court ruled to lift a stay of execution for Oklahoma death row inmates. The execution was the states first since 2015. Witnesses to the execution said that when the first drug, midazolam, began to flow at 4:09 p.m., Grant started convulsing about two dozen times and vomited. Grant continued breathing, and a member of the execution team wiped the vomit off his face. At 4:15 p.m., officials said Grant was unconscious, and he was pronounced dead at 4:21 p.m.

Legal challenges
In Glossip v. Gross, attorneys for three Oklahoma inmates argued that midazolam could not achieve the level of unconsciousness required for surgery, meaning severe pain and suffering was likely. They argued that midazolam was cruel and unusual punishment and thus contrary to the Eighth Amendment to the United States Constitution. In June 2015, the U.S </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Verteporfin and can you explain it in depth? [/INST] Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular degeneration. Verteporfin accumulates in these abnormal blood vessels and, when stimulated by nonthermal red light with a wavelength of 689 nm in the presence of oxygen, produces highly reactive short-lived singlet oxygen and other reactive oxygen radicals, resulting in local damage to the endothelium and blockage of the vessels.Verteporfin is also used off-label for the treatment of central serous retinopathy.

Administration
Verteporfin is usually injected intravenously into the largest arm vein. It is injected at a dose of 6 mg/m2 and light-activated. It is usually is given 15 minutes before laser treatment. This dose can be repeated 4 times per year.

Contraindications
Porphyria.

Side effects
Most common side effects are blurred vision, headache, and local effects at the injection site. Also, photosensitivity; it is strictly advised to avoid exposure to sunlight and unscreened lighting until 48 hours after verteporfin administration.Dogs and rats have been treated with inactivated daily doses 32–70 times higher than the dose advised for humans. The 4 weeks of treatment resulted in mild extravascular hemolysis and hematopoiesis in the animals.

Interactions
Verteporfin is known to interact with the herbal remedy feverfew (Tanacetum parthenium), the latter of which seems to act as an antagonist to verteporfin for unknown reasons. Taking the two substances simultaneously is inadvisable.Verteporfin does not appear to be metabolized by Cytochrome P450 enzymes, therefore not affecting Cytochrome P450 metabolism of other drugs.

Shortages
In May 2020, a low manufacturing capacity caused disruption. This effected the usage of verteporfin among providers and patients in Europe. The EMA expected normal manufacturing to return by the first quarter 2022.

Potential against scarring
Verteporfin is FDA approved. Verteporfin is a YAP pathway inhibitor. Verteporfin displays a wide spectrum of anti-fibrotic properties </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Naltrexone/bupropion and can you explain it in depth? [/INST] Naltrexone/bupropion, sold under the brand name Contrave among others, is a fixed-dose combination medication for the management of chronic obesity in adults in combination with a reduced-calorie diet and increased physical activity. It contains naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant. It is taken by mouth. Both medications have individually shown some evidence of effectiveness in weight loss, and the combination has been shown to have some synergistic effects on weight.In September 2014, a sustained release formulation of the drug was approved for marketing in the United States under the brand name Contrave. The combination was subsequently approved in the European Union in the spring of 2015, where it is sold under the name Mysimba. It was approved in Canada under the Contrave brand name in 2018.

Medical uses
Naltrexone/bupropion is indicated, as an adjunct to a reduced-calorie diet and increased physical activity, for the management of weight in adults with an initial body mass index (BMI) of:
30 kg/m2 (obese), or
27 kg/m2 to < 30 kg/m2, (overweight) in the presence of one or more weight-related comorbidities, like type 2 diabetes, dyslipidaemia, or controlled high blood pressure

Available forms
Each Contrave tablet contains 8 mg naltrexone and 90 mg bupropion. Once full dosing is reached (after 4 weeks of administration), the total dosage of Contrave for overweightness or obesity is two tablets twice daily or 32 mg naltrexone and 360 mg bupropion per day.

Contraindications
The manufacturer recommends against its use in people that have/are:
History of seizures
History of an eating disorder such as bulimia nervosa or anorexia nervosa
Taking opioid pain medicines, taking medicines to stop opioid addiction, or are in opiate withdrawal
Taking an MAOI or have taken an MAOI in the last 14 days
Pregnant
Abruptly stopped using: alcohol, benzodiazepines, barbiturates, or antiepileptic drugs

Adverse effects
The U.S. Food and Drug Administration (FDA) has put a boxed warning onto this medicine because it may affect mood and increase the likelihood of suicidal thoughts in people under 25 years old. This is attributed to the bupropion component, as antidepressants have been associated with increased risk of suicidal thoughts, but not suicide, and only in people younger than 25.The safety and effectiveness in children under the age of 18 has not been studied.

Mechanism of action
Individually, naltrexone and bupropion each target pathways in the central nervous system that influence appetite and energy use.

Bupropion is a reuptake inhibitor and releasing agent of both norepinephrine and dopamine, and a nicotinic acetylcholine receptor antagonist, and it activates proopiomelanocortin (POMC) neurons in the hypothalamus which give an effect downstream, resulting in loss of appetite and increased energy output. The POMC is regulated by endogenous opioids via opioid-mediated negative feedback.
Naltrexone is a pure opioid antagonist, which further augments bupropions activation of the POMC.Combined, naltrexone/bupropion has an effect on the reward pathway that results in reduced food craving. In 2009, Monash University physiologist Michael Cowley was awarded one of Australias top research honors, the Commonwealth Science Ministers Prize for Life Scientist of the Year, in recognition of his elucidation of these pathways, which led to the development of the combination medication.

History
Orexigen submitted a New Drug Application (NDA) for this drug combination to the U.S. Food and Drug Administration (FDA) on 31 March 2010. Having paid a fee under the Prescription Drug User Fee Act, Orexigen was given a deadline for the FDA to approve or reject the drug of 31 January 2011. On 7 December 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave, and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study. Subsequently, on 2 February 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Pemigatinib and can you explain it in depth? [/INST] Pemigatinib, sold under the brand name Pemazyre, is an anti-cancer medication used for the treatment of bile duct cancer (cholangiocarcinoma). Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.Pemigatinib belongs to a group of medicines called protein kinase inhibitors. It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs). FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells. By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer.The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin. Ocular (eye) toxicity is also a risk of pemigatinib. Additional common adverse reactions include rash, anemia, epistaxis, serous retinal detachment, extremity pain, dyspepsia, blurred vision, peripheral edema, and dizziness.

Medical uses
Pemigatinib is indicated for the treatment of adults with locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement that have progressed after at least one prior line of systemic therapy. In the United States it is also indicated for the treatment of relapsed or refractory myeloid/lymphoid neoplasms (MLNs) with fibroblast growth factor receptor 1 (FGFR1) rearrangement.Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine. Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2).

History
Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment. The trial was conducted at 67 sites in the United States, Europe, and Asia. During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects. To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks. The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate). The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response. Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer.The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority review, breakthrough therapy and orphan drug designations. The FDA granted approval of Pemazyre to Incyte Corporation.On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer. On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2. On 28 January 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 conditional marketing authorization for the medicinal product Pemazyre, intended for the second-line treatment of advanced or metastatic cholangiocarcinoma characterized by fusion or rearrangements of fibroblast growth factor receptor 2. The applicant for this medicinal product is Incyte Biosciences Distribution B.V. Pemigatinib was approved for medical use in the European Union in March 2021.Efficacy was evaluated in FIGHT-203 (NCT03011372), a multicenter open-label, single-arm trial that included 28 participants with relapsed or refractory MLNs with FGFR1 rearrangement. Eligible participants were either not candidates for or have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or after a disease modifying therapy (e.g., chemotherapy). Pemigatinib was administered until disease progression, unacceptable toxicity, or until participants were able to receive allo-HSCT.

Society and culture
Names
Pemigatinib is the international nonproprietary name (INN).

References
Further reading
Roskoski R (January 2020) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cetacaine and can you explain it in depth? [/INST] Cetacaine is a topical anesthetic that contains the active ingredients benzocaine (14%), butamben (2%), and tetracaine hydrochloride (2%). Cetacaine also contains small amounts of benzalkonium chloride at 0.5% and 0.005% of cetyl dimethyl ethyl ammonium bromide all in a bland water-soluble base. Although Cetacaine has been widely used in the medical and dental fields, it has yet to be officially approved by the FDA. Cetacaine is produced by the company Cetylite Industries, Inc. and they provide Cetacaine in three forms: liquid, gel, and spray.

Medical uses
Cetacaine is a benzocaine-based anesthetic that also contains other active ingredients that include butamben and tetracaine hydrochloride. The main use for this drug is to produce anesthesia to mucous membranes to numb and help control the pain in that area. The spray form of Cetacaine is also used to help prevent gagging in the patient. The anesthetic effect of Cetacaine can be expected to take effect in about 30 seconds and last between 30–60 minutes depending on location and application amount. Cetacaine can and has been used for surgeries that include bronchi, ear, esophagus, larynx, mouth, nose, pharynx, rectal, and vaginal procedures. These procedures can include periodontal treatment, pre-probing, pre-scaling/root planning procedures, pre-injection, and laser dentistry.

Available forms
The dosage should be applied directly to the site where anesthesia is required. The dosage should be modified according to the patient and there has not been a dosage specified for children.Spray: Cetacaine spray should be applied for only one second and dosage should not exceed an application spray longer than 2 seconds.
Gel: Use a cotton swab to apply 200 mg to the needed area and the dosage should not exceed 400 mg.
Liquid: Apply 200 mg either directly or by using cotton applicator to the location and the dosage should not exceed 400 mg.

Adverse effects
Cetacaine has been known to cause adverse effects in the patients it has been administered to. These include hypersensitivity in the form of anaphylaxis, dermatitis, erythema, pruritus which can lead to oozing and vesiculation. There have also been accounts of rashes, edema, urticarial and other allergic symptoms as well as methemoglobinemia. Other adverse effects can include: tremors, twitching, dizziness, confusion, hypo-tension, vomiting, euphoria, and blurred or double vision.

Pregnancy and breastfeeding
It has not been determined of Cetacaine has any adverse defects on the formation of the fetus or if it is transferred through breastfeeding. It is recommended that professional advise should be taken in these regards.

Pharmacology
Mechanism of action
Cetacaine acts quickly in about 30 seconds and can last between 30–60 minutes. This is due to benzocaine causing the immediate anesthetic effect, while butamben and tetracaine hydrochloride causes the extended effect of Cetacaine.The actual mechanism for the onset of anesthesia is unknown, but it is believed that the active ingredients reversibly block nerve conduction therefore causing the numbing sensation. This stabilizes the neuron and prevents signals from being transferred.

Pharmacokinetics
The rate of absorption through the skin and after diffusing in and back out of the nerve membrane it is metabolized by plasma cholinesterase and then excreted in urine.

Contraindications
This product should not be used to cover a large area for anesthetic affect causing an adverse reaction. The liquid and other forms of Cetacaine should not be administered via injection or used under dentures, on eyes or with patients with a cholinesterase deficiency.

Interactions
Cetacaine can have interaction with other drugs being taken by patients one of the interactions that can lead to methemoglobinemia is the interaction with sodium nitrate as well as prilocaine, which can lead to severe illness or death. As well as others listed on the referenced site.

History
The marketing start date for Cetacaine was January 1, 1960, but benzocaine was first produced in 1890 by German scientist 1890 by Eduard Ritsert. Cetacaine is mainly used in the dental field but has seen use as well in the medical field when dealing with small surgeries on or around mucus membranes </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Methyldopa and can you explain it in depth? [/INST] Methyldopa, sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.Common side effects include sleepiness. More severe side effects include red blood cell breakdown, liver problems, and allergic reactions. Methyldopa is in the alpha-2 adrenergic receptor agonist family of medication. It works by stimulating the brain to decrease the activity of the sympathetic nervous system.Methyldopa was discovered in 1960. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Methyldopa is used in the clinical treatment of the following disorders:

Hypertension (or high blood pressure)
Gestational hypertension (or pregnancy-induced hypertension) and pre-eclampsia.

Side effects
Methyldopa is capable of inducing a number of adverse side effects, which range from mild to severe. Nevertheless, they are generally mild when the dose is less than 1 gram per day. Side effects may include:

Psychological
Depression or even suicidal ideation, as well as nightmares
Apathy or anhedonia, as well as dysphoria
Anxiety, especially of the social anxiety variant
Decreased alertness, awareness, and wakefulness
Impaired attention, focus, and concentration
Decreased desire, drive, and motivation
Fatigue or lethargy or malaise or lassitude
Sedation or drowsiness or somnolence or sleepiness
Agitation or restlessness
Cognitive and memory impairment
Derealization or depersonalization, as well as mild psychosis
Sexual dysfunction including impaired libido, desire, and drive
Physiological
Dizziness, lightheadedness, or vertigo
Miosis or pupil constriction
Xerostomia or dry mouth
Gastrointestinal disturbances such as diarrhea or constipation
Headache or migraine
Myalgia or muscle aches, arthralgia or joint pain, or paresthesia ("pins and needles")
Restless legs syndrome (RLS)
Parkinsonian symptoms such as muscle tremors, rigidity, hypokinesia, or balance or postural instability
Akathisia, ataxia, dyskinesia as well as even tardive dyskinesia, or dystonia
Bells palsy or facial paralysis
Sexual dysfunction consisting of impaired erectile dysfunction or anorgasmia
Hyperprolactinemia or excess prolactin, gynecomastia/breast enlargement in males, or amenorrhoea or absence of menstrual cycles in females
Bradycardia or decreased heart rate
Hypotension or decreased blood pressure (though this may also be considered a therapeutic benefit)
Orthostatic hypotension (also known as postural hypotension)
Hepatitis, hepatotoxicity, or liver dysfunction or damage
Pancreatitis or inflammation of the pancreas
Warm autoimmune hemolytic anemia or deficiency in red blood cells (RBCs)
Myelotoxicity or bone marrow suppression, potentially leading to thrombocytopenia or blood platelet deficiency or leukopenia or white blood cell (WBC) deficiency
Hypersensitivity such as lupus erythematosus, myocarditis, or pericarditis
Lichenoid reactions such as skin lesions or rashes
Pallor

Rebound/withdrawal
Rebound hypertension via withdrawal on account of tolerance upon the abrupt discontinuation of methyldopa has been reported.

Mechanism of action
The mechanism of action of methyldopa is not fully clear. Although it is a centrally acting sympathomimetic, it does not block reuptake or transporters. It may reduce the dopaminergic and serotonergic transmission in the peripheral nervous system and it indirectly affects norepinephrine (noradrenaline) synthesis. Methyldopa acts on alpha-2 adrenergic receptors, which are found on the pre synaptic nerve terminal </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Estradiol/progesterone and can you explain it in depth? [/INST] Estradiol/progesterone (E2/P4), sold under the brand names Bijuva and Juvenum, is a combined estrogen and progestogen medication which is used in the treatment of menopausal symptoms in postmenopausal women. It contains estradiol, an estrogen, and progesterone, a progestogen, and is available in both oral and intramuscular formulations. E2/P4 differs from other estrogen–progestogen formulations in that the sex-hormonal agents used are bioidentical.
Bijuva (formerly TX-001HR/TX-12-001HR) is an oral combination of estradiol (E2), an estrogen, and progesterone (P4), a progestogen, which was developed by TherapeuticsMD and is approved in the United States for the treatment of menopausal symptoms in women. It is also under development for the treatment of endometrial hyperplasia in women. The medication contains 2 mg solubilized E2 and 200 mg P4 in each gelatin capsule </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Almotriptan and can you explain it in depth? [/INST] Almotriptan  (trade name Axert and others) is a triptan medication discovered and developed by Almirall for the treatment of heavy migraine headache.
It was patented in 1992 and approved for medical use in 2000.

Medical uses
Almotriptan is prescribed to treat the acute headache phase of migraine attacks with or without aura. Almotriptan is the only oral triptan approved in the US for the treatment of migraine in adolescent from 12 to 17 years of age.

Efficacy
The efficacy and tolerability of almotriptan has been studied in numerous randomised, controlled trials totaling more than 4800 adults with either moderate or severe attacks of migraine. Its efficacy is significantly more effective than placebo and alleviates nausea, photophobia and phonophobia linked to migraine attacks. Almotriptan has similar efficacy as a standard dose of sumatriptan, another triptan drug, and fewer adverse effects.

Contraindications
As with other triptans, almotriptan should not be used in patients with a history, symptoms or signs of ischaemic heart disease (myocardial infarction, angina pectoris, documented silent ischaemia, Prinzmetals angina) or severe hypertension and uncontrolled mild or moderate hypertension.
Other contraindications are previous cerebrovascular accident (CVA) or transient ischaemic attack (TIA), peripheral vascular disease, severe hepatic impairment, concomitant administration of ergotamine, ergotamine derivatives (including methysergide) and other 5-HT1B/D agonists.

Side effects
Almotriptan has proved to have an adverse effects profile similar to placebo when used following the Summary of Product Characteristics instructions (see references).

Pharmacology
Mechanism of action
Like all triptans, almotriptan has a high and specific affinity for serotonin 5-HT1B/1D receptors. Binding of the drug to the receptor leads to vasoconstriction of the cranial (brain) blood vessels and thus affects the redistribution of blood flow. Almotriptan significantly increases cerebral blood flow and reduces blood flow through extracerebral cranial vessels. Even though it affects cranial blood vessels a single standard dose of almotriptan has no clinically significant effect on blood pressure or heart rate in both young and elderly healthy volunteers. Larger doses seem to slightly increase blood pressure but not beyond clinical relevance.

Pharmacokinetics
Almotriptan has linear pharmacokinetics up to the 16-fold standard dose. Its biological half-life is 3 hours, and its bioavailability 70%.
Cmax is observed 1.5–4 hours after oral administration, and approximately 50% of the drug is excreted unchanged in the urine </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Procarbazine and can you explain it in depth? [/INST] Procarbazine is a chemotherapy medication used for the treatment of Hodgkins lymphoma and brain cancers. For Hodgkins it is often used together with chlormethine, vincristine, and prednisone while for brain cancers such as glioblastoma multiforme it is used with lomustine and vincristine. It is typically taken by mouth.Common side effect include low blood cell counts and vomiting. Other side effects include tiredness and depression. It is not recommended in people with severe liver or kidney problems. Use in pregnancy is known to harm the baby. Procarbazine is in the alkylating agents family of medication. How it works is not clearly known.Procarbazine was approved for medical use in the United States in 1969. It is on the World Health Organizations List of Essential Medicines. In the United Kingdom a month of treatment cost the National Health Service 450 to 750 pounds.

Medical uses
When used to treat Hodgkins lymphoma, it is often delivered as part of the BEACOPP regimen that includes bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (tradename Oncovin), prednisone, and procarbazine. The first combination chemotherapy developed for Hodgkins lymphoma (HL), MOPP also included procarbazine (ABVD has supplanted MOPP as standard first line treatment for HL, with BEACOPP as an alternative for advanced/unfavorable HL) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Doxercalciferol and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Gemcitabine and can you explain it in depth? [/INST] Gemcitabine, with brand names including Gemzar, is a chemotherapy medication. It treats cancers including testicular cancer, breast cancer, ovarian cancer, non-small cell lung cancer, pancreatic cancer, and bladder cancer. It is administered by intravenous infusion. It acts against neoplastic growth, and it inhibits the replication of Orthohepevirus A, the causative agent of Hepatitis E, through upregulation of interferon signaling.Common side effects include bone marrow suppression, liver and kidney problems, nausea, fever, rash, shortness of breath, mouth sores, diarrhea, neuropathy, and hair loss.  Use during pregnancy will likely result in fetal harm. Gemcitabine is in the nucleoside analog family of medication. It works by blocking the creation of new DNA, which results in cell death.Gemcitabine was patented in 1983 and was approved for medical use in 1995. Generic versions were introduced in Europe in 2009 and in the US in 2010. It is on the WHO Model List of Essential Medicines.

Medical uses
Gemcitabine treats various carcinomas. It is used as a first-line treatment alone for pancreatic cancer, and in combination with cisplatin for advanced or metastatic bladder cancer and advanced or metastatic non-small cell lung cancer. It is used as a second-line treatment in combination with carboplatin for ovarian cancer and in combination with paclitaxel for breast cancer that is metastatic or cannot be surgically removed.It is commonly used off-label to treat cholangiocarcinoma and other biliary tract cancers.It is given by intravenous infusion at a chemotherapy clinic.

Contraindications and interactions
Taking gemcitabine can also affect fertility in men and women, sex life, and menstruation. Women taking gemcitabine should not become pregnant, and pregnant and breastfeeding women should not take it.As of 2014, drug interactions had not been studied.

Adverse effects
Gemcitabine is a chemotherapy drug that works by killing any cells that are dividing. Cancer cells divide rapidly and so are targeted at higher rates by gemcitabine, but many essential cells also divide rapidly, including cells in skin, the scalp, the stomach lining, and bone marrow, resulting in adverse effects.: 265 The gemcitabine label carries warnings that it can suppress bone marrow function and cause loss of white blood cells, loss of platelets, and loss of red blood cells, and that it should be used carefully in people with liver, kidney, or cardiovascular disorders. People taking it should not take live vaccines. The warning label also states it may cause posterior reversible encephalopathy syndrome, that it may cause capillary leak syndrome, that it may cause severe lung conditions like pulmonary edema, pneumonia, and adult respiratory distress syndrome, and that it may harm sperm.More than 10% of users develop adverse effects, including difficulty breathing, low white and red blood cells counts, low platelet counts, vomiting and nausea, elevated transaminases, rashes and itchy skin, hair loss, blood and protein in urine, flu-like symptoms, and edema.Common adverse effects (occurring in 1–10% of users) include fever, loss of appetite, headache, difficulty sleeping, tiredness, cough, runny nose, diarrhea, mouth and lip sores, sweating, back pain, and muscle pain.Thrombotic thrombocytopenic purpura (TTP) is a rare but serious side effect that been associated with particular chemotherapy medications including gemcitabine. TTP is a blood disorder and can lead to microangipathic hemolytic anemia (MAHA), neurologic abnormalities, fever, and renal disease.

Pharmacology
Gemcitabine is hydrophilic and must be transported into cells via molecular transporters for nucleosides (the most common transporters for gemcitabine are SLC29A1 SLC28A1, and SLC28A3). After entering the cell, gemcitabine is first modified by attaching a phosphate to it, and so it becomes gemcitabine monophosphate (dFdCMP).  This is the rate-determining step that is catalyzed by the enzyme deoxycytidine kinase (DCK).  Two more phosphates are added by other enzymes. After the attachment of the three phosphates gemcitabine is finally pharmacologically active as gemcitabine triphosphate (dFdCTP). After being thrice phosphorylated, gemcitabine can masquerade as deoxycytidine triphosphate and is incorporated into new DNA strands being synthesized as the cell replicates.When gemcitabine is incorporated into DNA it allows a native, or normal, nucleoside base to be added next to it. This leads to "masked chain termination" because gemcitabine is a "faulty" base, but due to its neighboring native nucleoside it eludes the cells normal repair system (base-excision repair). Thus, incorporation of gemcitabine into the cells DNA creates an irreparable error that leads to inhibition of further DNA synthesis, and thereby leading to cell death.The form of gemcitabine with two phosphates attached (dFdCDP) also has activity; it inhibits the enzyme ribonucleotide reductase (RNR), which is needed to create new DNA nucleotides.  The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which also increases uptake of gemcitabine.

Chemistry
Gemcitabine is a synthetic pyrimidine nucleoside prodrug—a nucleoside analog in which the hydrogen atoms on the 2 carbon of deoxycytidine are replaced by fluorine atoms.The synthesis described and pictured below is the original synthesis done in the Eli Lilly Company labs. Synthesis begins with enantiopure D-glyceraldehyde (R)-2 as the starting material which can made from D-mannitol in 2–7 steps. Then fluorine is introduced by a "building block" approach using ethyl bromodifluroacetate. Then, Reformatsky reaction under standard conditions will yield a 3:1 anti/syn diastereomeric mixture, with one major product. Separation of the diastereomers is carried out via HPLC, thus yielding the anti-3 gemcitabine in a 65% yield. At least two other full synthesis methods have also been developed by different groups.

History
Gemcitabine was first synthesized in Larry Hertels lab at Eli Lilly and Company during the early 1980s.  It was intended as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.During the early 1990s gemcitabine was studied in clinical trials. The pancreatic cancer trials found that gemcitabine increased one-year survival time significantly, and it was approved in the UK in 1995 and approved by the FDA in 1996 for pancreatic cancers. In 1998, gemcitabine received FDA approval for treating non-small cell lung cancer and in 2004, it was approved for metastatic breast cancer.European labels were harmonized by the EMA in 2008.By 2008, Lillys worldwide sales of gemcitabine were about $1.7 billion; at that time its US patents were set to expire in 2013 and its European patents in 2009 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tagraxofusp and can you explain it in depth? [/INST] Tagraxofusp, sold under the brand name Elzonris, is an anti-cancer medication for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).  It was approved for use in the United States in 2018, and after a second review, in the EU in January 2021.  The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.Tagraxofusp is a fusion protein consisting of interleukin 3 (IL-3) fused to diphtheria toxin. The fusion protein readily kills cultured pDC by binding to their IL-3 receptors to thereby gain entrance to the cells and then blocking these cells protein synthesis (due to its diphtheria toxin portion inhibiting eukaryotic elongation factor 2).

Society and culture
Legal status
In July 2020, the European Medicines Agency (EMA) recommended the refusal of the marketing authorization for tagraxofusp </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Tepotinib and can you explain it in depth? [/INST] Tepotinib, sold under the brand name Tepmetko, is a medication used for the treatment of adults with non-small cell lung cancer (NSCLC).Tepotinib first received marketing approval in Japan, in March 2020, as a "line-agnostic" drug, meaning it is approved both for treatment-naive patients and for those in whom previous attempts at treatment have failed. U.S. approval followed in February 2021. It is the second therapy approved by the U.S. Food and Drug Administration (FDA) to treat non-small cell lung cancer with these particular mutations, after capmatinib.

Medical uses
Tepotinib is indicated for the treatment of adults with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping.

Adverse effects
The most common side effects seen in clinical trials were edema, fatigue, nausea, diarrhea, muscle aches, and shortness of breath. Like capmatinib, tepotinib can also cause interstitial lung disease and liver damage, and is toxic to a developing fetus.  The most common treatment-related adverse effect in a 2021 study were peripheral edema (54.1%), nausea (20.0%), diarrhea (19.6%), blood creatinine increased (17.6%), and hypoalbuminemia (14.5%), which were mostly mild or moderate.

Society and culture
Legal status
On 16 December 2021, the Committee for Medicinal Products for Human Use (CHMP)  of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tepmetko, intended for the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping. The applicant for this medicinal product is Merck Europe B.V. Tepotinib (Tepmetko) was approved for medical use in the European Union in February 2022.

References
Further reading
Paik PK, Felip E, Veillon R, Sakai H, Cortot AB, Garassino MC,  et al. (September 2020). "Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations". N Engl J Med. 383 (10): 931–43. doi:10.1056/NEJMoa2004407 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Prednicarbate and can you explain it in depth? [/INST]  </s>