<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cromoglicic acid and explain in detail? [/INST] Cromoglicic acid (INN)—also referred to as cromolyn (USAN), cromoglycate (former BAN), or cromoglicate—is traditionally described as a mast cell stabilizer, and is commonly marketed as the sodium salt sodium cromoglicate or cromolyn sodium.  This drug prevents the release of inflammatory chemicals such as histamine from mast cells.
Cromoglicic acid has been the non-corticosteroid treatment of choice in the treatment of asthma, for which it has largely been replaced by leukotriene receptor antagonists because of their convenience (and perceived safety). Cromoglicic acid requires administration four times daily, and does not provide additive benefit in combination with inhaled corticosteroids.

History
Cromolyn sodium was discovered in 1965 by Roger Altounyan, a pharmacologist who had asthma. It is considered a breakthrough drug in management of asthma, as the patients can be freed from steroids in many cases; however, it is mainly effective as a prophylaxis for allergic and exercise-induced asthma, not as a treatment for acute attacks.  Altounyan was investigating certain plants and herbs which have bronchodilating properties. One such plant was khella (Ammi visnaga) which had been used as a muscle relaxant since ancient times in Egypt. Altounyan deliberately inhaled derivatives of the active ingredient khellin to determine if they could block his asthma attacks. After several years of trial he isolated an effective and safe asthma-preventing compound called cromolyn sodium.

Preparations
Cromoglicic acid is available in multiple forms:

as a nasal spray (Rynacrom (UK), Lomusol (France), Nasalcrom (the only over-the-counter form, US), Prevalin (non-direct version, NL)) to treat allergic rhinitis.
in a nebulizer solution for aerosol administration to treat asthma.
as an inhaler (Intal, Fisons Pharmaceuticals, UK) for preventive management of asthma </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ospemifene and explain in detail? [/INST] Ospemifene (brand names Osphena and Senshio produced by Shionogi) is an oral medication indicated for the treatment of dyspareunia – pain during sexual intercourse – encountered by some women, more often in those who are post-menopausal. Ospemifene is a selective estrogen receptor modulator (SERM) acting similarly to an estrogen on the vaginal epithelium, building vaginal wall thickness which in turn reduces the pain associated with dyspareunia. Dyspareunia is most commonly caused by "vulvar and vaginal atrophy."The medication was approved by the FDA in February 2013 and by the European Commission for marketing in the EU in January 2015.

Medical uses
Ospemifene is used to treat dyspareunia. In the US it is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due to menopause. In the EU it is indicated for the treatment of moderate to severe symptomatic VVA in post-menopausal women who are not candidates for local vaginal oestrogen therapy.

Contraindications
Women with "undiagnosed abnormal genital bleeding; known or suspected estrogen-dependent neoplasia; active or history of deep vein thrombosis; pulmonary embolism; arterial thromboembolic disease; and are or may become pregnant" or "with known or suspected breast cancer or those with extreme hepatic impairment" should not take ospemifene. This is not a full list of contraindications.

Side effects
Side effects associated with ospemifene include vaginal discharge, hot flashes, and diaphoresis. More serious adverse effects are similar to those of estrogens and estrogen receptor modulators. These include, but are not limited to, thromboembolism, allergic reactions, fatigue, and headache, and others could occur. There are other additional adverse effects.
Ospemifene is a selective estrogen receptor modulator. As such, many of the effects produced by estrogens are produced by ospemifene. The boxed warning of the medication indicates ospemifene may thicken the endometrium, which could lead to unusual bleeding and endometrial cancer. For women taking estrogens, concurrently taking a type of drug called a progestin has been shown to decrease the occurrence of endometrial hyperplasia. In theory, progestins may be expected to attenuate ospemifenes effects on endometrial thickening. However clinical trials confirming this have not been conducted. Like estrogens, ospemifene also may increase the risk for cardiovascular events, including "stroke, coronary heart disease, venous thromboembolism," and others. The risk of thrombotic and hemorrhagic strokes is given as 0.72 and 1.45 per 1,000 women, while that of deep vein thrombosis is estimated to be 1.45 per 1,000 women. The risks of these adverse events in women taking ospemifene are lower than those in women taking estrogen alone in the form of oral conjugated estrogens. Studies have not documented the relative risk compared with women taking estrogen/progestin therapy.

Pharmacology
Pharmacodynamics
Ospemifene is "an estrogen agonist/antagonist that makes vaginal tissue thicker and less fragile resulting in a reduction in the amount of pain women experience with sexual intercourse." This medication should be used for the shortest amount of time possible due to associated adverse effects. Ospemifene might not have an adverse influence on coagulation, in contrast to estrogens and other SERMs like tamoxifen and raloxifene.A binding assay was also performed to measure the affinity of ospemifene for the estrogen receptor (ERα and ERβ). The study showed that ospemifene bound ERα and ERβ with similar affinity. Ospemifene bound the estrogen receptors with a lower affinity than estradiol. Ospemifene was shown to be an antagonist of "ERE-mediated transactivation on MCF-7 cells," which the authors concluded indicates "anti-estrogenic activity in breast cancer cells."

Pharmacokinetics
The pharmacokinetics of ospemifene were dose-dependent over a dose range of 10 to 800 mg/day.

History
Approval process
Hormos Medical Ltd., which is a part of QuatRx Pharmaceuticals, filed a patent on January 19, 2005, for a solid dosage form of ospemifene. In March 2010, QuatRX Pharmaceuticals licensed ospemifene to Shionogi & Co., Ltd. for clinical development and marketing. A New Drug Application (NDA) was submitted to the FDA on April 26, 2012. Amendments to the NDA were submitted in June, July, August, October, and November 2012, and January and February 2013. It was ultimately approved by the FDA on February 26, 2013. Ospemifene (under the brand name Senshio) was subsequently approved by the European Commission for marketing in the EU in January 2015.

Preclinial and clinical trials
Preclinical trials were performed in ovariectomized rats to model menopause. Oral ospemifene was compared with raloxifene (another SERM), its metabolites 4-hydroxy ospemifene and 4-hydroxy ospemifene, estradiol, and ospemifene administered as an intravaginal suppository. Estradiol was used as a positive control and raloxifene was used because it is in the same drug class as ospemifene. Multiple doses of oral ospemifene were tested. 10 mg/kg/day of Ospemifene was found to cause a greater increase in vaginal weight and vaginal epithelial height than 10 mg/kg/day of raloxifene. Vaginal weight had a 1.46x increase after a two-week treatment of 10 mg/kg/day of ospemifene. The number of progesterone receptors was increased in the vaginal stroma and epithelium, which indicates that ospemifene has "estrogenic activity."Two 12-week phase 3 clinical trials were performed for ospemifene. One evaluated the effects of Ospemifene on vaginal tissue thickness, composition and vaginal pH. The other evaluated the effects of Ospemifene on vaginal tissue and on symptoms of dyspareunia. Between the two trials, 4 signs and symptoms were measured. These included three tissue-related signs, two of which represented histological changes in the vaginal tissue (change in percent parabasal cells and change in percent superficial cells) and the third was "change in vaginal pH". Dyspareunia was evaluated in one of the trials. It was defined as "change in most bothersome symptom" of discomfort during sexual activity and further limited to symptoms of either vaginal dryness or vaginal pain." Ospemifene produced more changes in vaginal tissue and greater reduction in dyspareunia symptoms than placebo. A dose-response also was observed in the trial; ospemifene 60 mg had greater efficacy than ospemifene 30 mg. Safety was also evaluated in these phase 3 trials </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Repaglinide and explain in detail? [/INST] Repaglinide is an antidiabetic drug in the class of medications known as meglitinides, and was invented in 1983. Repaglinide is an oral medication used in addition to diet and exercise for blood sugar control in type 2 diabetes mellitus. The mechanism of action of repaglinide involves promoting insulin release from β-islet cells of the pancreas; like other antidiabetic drugs, a main side effect concern is hypoglycemia. It is sold by Novo Nordisk under the name of Prandin in the United States, GlucoNorm in Canada, Surepost in Japan, Repaglinide in Egypt by EIPICO, and NovoNorm elsewhere.  In Japan it is produced by Dainippon Sumitomo Pharma.

Medical uses
Repaglinide is an oral medication used in addition to diet and exercise for blood sugar control in type 2 diabetes mellitus.

Contraindications
Repaglinide is contraindicated in people with:

Diabetic ketoacidosis, with or without coma
Type 1 diabetes
Co-administration with gemfibrozil
Known hypersensitivity to drug or inactive ingredients

Adverse events
Common adverse events include:Metabolic

Hypoglycemia (31%)Respiratory

Upper respiratory infection (16%)
Sinusitis (6%)
Rhinitis (3%)Gastrointestinal

Nausea (5%)
Diarrhea (5%)
Constipation (3%)
Vomiting (3%)Musculoskeletal

Arthralgia (6%)
Back Pain (5%)Other

Headache (11%)
Paresthesia (3%)Serious adverse events include:
Cardiac ischemia (2%)
Angina (1.8%)
Deaths due to cardiovascular events (0.5%)

Special populations
Pregnancy category C: safety in pregnant women has not been established. Data is limited, and there is only one case report that notes no complications with the use of repaglinide during pregnancy.Caution should be taken in people with liver disease and decreased kidney function when using this medication.

Drug interactions
Repaglinide is a major substrate of CYP3A4 and should not be administered concomitantly with gemfibrozil, clarithromycin or azole antifungals such as itraconazole or ketoconazole. Administration of both repaglinide and one or more of these drugs results in an increase in plasma concentration of repaglinide and may lead to hypoglycemia. Co-administration of repaglinide and clopidogrel (a CYP2C8 inhibitor) may lead to a significant decrease in blood glucose levels due to a drug-drug interaction. In fact, using these drugs together for even one day can cause repaglinide levels to increase over 5-fold...and may lead to significant hypoglycemia.
Repaglinide should not be combined with sulfonylurea, because they have the same mechanism of action.

Pharmacology
Mechanism of action
Repaglinide lowers blood glucose by stimulating the release of insulin from the beta islet cells of the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells calcium channels, and the resulting calcium influx induces insulin secretion.

Pharmacokinetics
Absorption: repaglinide has a 56% bioavailability when absorbed from the gastrointestinal tract. Bioavailability is reduced when taken with food; the maximum concentration decreases by 20%.
Distribution: The protein binding of repalglinide to albumin is greater than 98%.
Metabolism: repaglinide is primarily metabolized by the liver - specifically CYP450 2C8 and 3A4 - and to a lesser extent via glucuronidation. Metabolites of repaglinide are inactive and do not display glucose-lowering effects.
Excretion: repaglinide is 90% excreted in the feces and 8% in the urine. 0.1% is cleared unchanged in the urine. Less than 2% is unchanged in the feces.

History
Precursor drugs to repaglinide were invented in late 1983 by scientists at Dr Karl Thomae GmbH, a German drug manufacturer located at Biberach an der Riß in southern Germany which was acquired by Boehringer Ingelheim in 1990. The drug that became repaglinide was later licensed by Boehringer to Novo Nordisk, which filed an Investigational New Drug application for the compound with the Food and Drug Administration (FDA) in April 1992. Novo Nordisk filed its New Drug Application (NDA) for Prandin in July 1997 and it was quickly approved, gaining FDA approval in December 1997. The drug was the first of the meglitinide class. It was branded Prandin because its quick onset and short duration of action concentrates its effect around meal time (the prandium was the Roman meal which is comparable to the modern lunch).

Intellectual property
After several attempts to file for U.S. patent protection, a filing was made in March 1990 which eventually became U.S. Patents 5,216,167 (June 1993), 5,312,924 (May 1994) and 6,143,769 (November 2000). After filing its NDA for repaglinide in 1997, Novo Nordisk applied for patent extension under the Hatch-Waxman Act. This process, called patent term restoration, allows drug patents to be extended based on the time that a drug spent in clinical trials and in the approval process. Previously it had been decided by the U.S </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Remifentanil and explain in detail? [/INST] Remifentanil  is a potent, short-acting synthetic opioid analgesic drug.  It is given to patients during surgery to relieve pain and as an adjunct to an anaesthetic.  Remifentanil is used for sedation as well as combined with other medications for use in general anesthesia. The use of remifentanil has made possible the use of high-dose opioid and low-dose hypnotic anesthesia, due to synergism between remifentanil and various hypnotic drugs and volatile anesthetics.

Clinical use
Remifentanil is used as an opioid analgesic that has a rapid onset and rapid recovery time. It has been used effectively during craniotomies, spinal surgery, cardiac surgery, and gastric bypass surgery. While opiates function similarly, with respect to analgesia, the pharmacokinetics of remifentanil allows for quicker post-operative recovery.

Administration
It is administered in the form remifentanil hydrochloride and in adults is given as an intravenous infusion in doses ranging from 0.1 microgram per kilogram per minute to 0.5 (µg/kg)/min. Children may require higher infusion rates (up to 1.0 (µg/kg)/min). The clinically useful infusion rates are 0.025–0.1 (µg/kg)/min for sedation (rates adjusted to age of patient, severity of their illness and invasiveness of surgical procedure). Small amounts of other sedative medications are usually co-administered with remifentanil to produce sedation. Clinically useful infusion rates in general anesthesia vary but are usually 0.1–1 (µg/kg)/min.Remifentanil can be administered as part of an anesthesia technique called TIVA (total intravenous anesthesia) using computer controlled infusion pumps in a process called target controlled infusion (TCI). A target plasma concentration is entered as ng/ml into the pump, which calculates its infusion rate according to patient factors like age and weight. Induction levels of 40 ng/ml are commonly used, but it generally varies between 3–8 ng/ml. For certain surgical procedures that produce particularly strong stimuli a level of up to 15 ng/ml might be needed. The relatively short context-sensitive half-life of remifentanil allows the desired blood plasma level to be achieved quickly, and also for the same reason, recovery occurs quickly. This allows remifentanil to be used in unique circumstances such as cesarean section.Remifentanils short context-sensitive half-life makes it ideal for intense pain of short duration. As such, it has been used for analgesia in labor successfully; however, it is not as effective as epidural analgesia.In combination with propofol, remifentanil is used for anesthesia of patients undergoing electroconvulsive therapy.

Metabolism
Remifentanil is considered a metabolic soft drug, one that is rapidly metabolized to an inactive form.  Unlike other synthetic opioids which are hepatically metabolized, remifentanil has an ester linkage which undergoes rapid hydrolysis by non-specific tissue and plasma esterases.  This means that accumulation does not occur with remifentanil and its context-sensitive half-life remains at 4 minutes after a 4-hour infusion.
Remifentanil is metabolized to a compound (remifentanil acid) which has 1/4600th the potency of the parent compound.Due to its quick metabolism and short effects, remifentanil has opened up new possibilities in anesthesia. When remifentanil is used together with a hypnotic (i.e. one that produces sleep) it can be used in relative high doses.  This is because remifentanil will be rapidly eliminated from the blood plasma on termination of the remifentanil infusion, hence the effects of the drug will quickly dissipate even after very long infusions. Owing to synergism between remifentanil and hypnotic drugs (such as propofol) the dose of the hypnotic can be substantially reduced. This leads often to more hemodynamic stability during surgery and a quicker post-operative recovery time.

Side-effects
Remifentanil is a specific μ-receptor agonist.   Hence, it causes a reduction in sympathetic nervous system tone, respiratory depression and analgesia. The drugs effects include a dose-dependent decrease in heart rate and arterial pressure and respiratory rate and tidal volume. Muscle rigidity is sometimes noted.
The most common side effects reported by patients receiving this medication are a sense of extreme "dizziness" (often short lived, a common side effect of other fast-acting synthetic phenylpiperidine narcotics such as fentanyl and alfentanil) and intense itching (pruritus), often around the face.  These side effects are often controlled by either altering the administered dose  (decreasing or in some cases, increasing the dose) or by administering other sedatives that allow the patient to tolerate or lose awareness of the side effect.
Because pruritus is due to excessive serum histamine levels, antihistamines such as diphenhydramine (Benadryl) are often co-administered. This is done with care, however, as excessive sedation may occur.
Nausea can occur as a side effect of remifentanil, however, it is usually transient in nature due to the drugs short half-life which rapidly removes it from the patients circulation once the infusion is terminated.

Potency
Comparing its analgesia-sedation effect in ventilated patients, remifentanil may be superior to morphine but not to fentanyl.

Circumventing naltrexone
Remifentanil has been used with some success to circumvent naltrexone in patients who are in need of pain management.

Abuse potential
Remifentanil, being a μ-receptor agonist, functions like other μ-receptor agonists, such as morphine and codeine; it can cause euphoria and has the potential for abuse. However, due to its rapid metabolism and short-acting half-life the likelihood of abuse is quite low. Nevertheless, there have been some documentations of remifentanil abuse.

Development and marketing
Prior to the development of remifentanil, most short-acting hypnotics and amnestics faced issues with prolonged use, where accumulation would result in unfavorable lingering effects during post-operative recovery. Remifentanil was designed to serve as a strong anesthetic with an ultra-short and predictable duration that would not have accumulation issues.Remifentanil was patented by Glaxo Wellcome Inc. and was FDA approved on July 12, 1996. Its patent ended on the 10th of September 2017.

Pricing for Ultiva
1 mg vial - US$30.19
2 mg vial - US$57.20
5 mg vial - US$118.15

Regulation
In Hong Kong, remifentanil is regulated under Schedule 1 of Hong Kongs Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals and for university research purposes </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Oxycodone and explain in detail? [/INST] Oxycodone, sold under the brand names Roxicodone and OxyContin (which is the extended release form) among others, is a semi-synthetic  opioid medication used for treatment of moderate to severe pain. It is highly addictive and a common drug of abuse. It is usually taken by mouth, and is available in immediate-release and controlled-release formulations. Onset of pain relief typically begins within fifteen minutes and lasts for up to six hours with the immediate-release formulation. In the United Kingdom, it is available by injection. Combination products are also available with paracetamol (acetaminophen), ibuprofen, naloxone, naltrexone, and aspirin.Common side effects include euphoria, constipation, nausea, vomiting, loss of appetite, drowsiness, dizziness, itching, dry mouth, and sweating. Severe side effects may include addiction and dependence, substance abuse, irritability, depression or mania, delirium, hallucinations, hypoventilation, gastroparesis, bradycardia, and hypotension. Those allergic to codeine may also be allergic to oxycodone. Use of oxycodone in early pregnancy appears relatively safe. Opioid withdrawal may occur if rapidly stopped. Oxycodone acts by activating the μ-opioid receptor. When taken by mouth, it has roughly 1.5 times the effect of the equivalent amount of morphine.Oxycodone was first made in Germany in 1916 from thebaine. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 54th most commonly prescribed medication in the United States, with more than 12 million prescriptions. A number of abuse-deterrent formulations are available, such as in combination with naloxone or naltrexone.

Medical uses
Oxycodone is used for managing moderate to severe acute or chronic pain when other treatments are not sufficient. It may improve quality of life in certain types of pain. It is unclear if use in chronic pain results in improved quality of life or ongoing pain relief.Oxycodone is available as a controlled-release tablet, intended to be taken every 12 hours. A July 1996 study independent of Purdue Pharma, the drugs originator, found the controlled-release formulation had a variable duration of action ranging from 10 to 12 hours. A 2006 review found that controlled-release oxycodone is comparable to immediate-release oxycodone, morphine, and hydromorphone in management of moderate to severe cancer pain, with fewer side effects than morphine. The author concluded that the controlled-release form is a valid alternative to morphine and a first-line treatment for cancer pain. In 2014, the European Association for Palliative Care recommended oxycodone by mouth as a second-line alternative to morphine by mouth for cancer pain.In the U.S., extended-release oxycodone is approved for use in children as young as eleven years old. The approved uses are for the relief of cancer pain, trauma pain, or pain due to major surgery, in children already treated with opioids, who can tolerate at least 20 mg per day of oxycodone; this provides an alternative to Duragesic (fentanyl), the only other extended-release opioid analgesic approved for children.

Available forms
Oxycodone is available in a variety of formulations for by mouth or under the tongue:
Immediate-release oxycodone (OxyFast, OxyIR, OxyNorm, Roxicodone)
Controlled-release oxycodone (OxyContin, Xtampza ER) – 10-12 hour duration
Oxycodone tamper-resistant (OxyContin OTR)
Immediate-release oxycodone with paracetamol (acetaminophen) (Percocet, Endocet, Roxicet, Tylox)
Immediate-release oxycodone with aspirin (Endodan, Oxycodan, Percodan, Roxiprin)
Immediate-release oxycodone with ibuprofen (Combunox)
Controlled-release oxycodone with naloxone (Targin, Targiniq, Targinact) – 10-12 hour duration
Controlled-release oxycodone with naltrexone (Troxyca) – 10-12 hour duration
In the US, oxycodone is only approved for use by mouth, available as tablets and oral solutions. Parenteral formulations of oxycodone (brand name OxyNorm) are also available in other parts of the world, however, and are widely used in the European Union. In Spain, the Netherlands and the United Kingdom, oxycodone is approved for intravenous (IV) and intramuscular (IM) use. When first introduced in Germany during World War I, both IV and IM administrations of oxycodone were commonly used for postoperative pain management of Central Powers soldiers.

Side effects
Most common side effects of oxycodone include reduced sensitivity to pain, delayed gastric emptying, euphoria, anxiolysis, feelings of relaxation, and respiratory depression. Common side effects of oxycodone include constipation (23%), nausea (23%), vomiting (12%), somnolence (23%), dizziness (13%), itching (13%), dry mouth (6%), and sweating (5%). Less common side effects (experienced by less than 5% of patients) include loss of appetite, nervousness, abdominal pain, diarrhea, urinary retention, dyspnea, and hiccups. Most side effects generally become less intense over time, although issues related to constipation are likely to continue for the duration of use. Oxycodone in combination with naloxone in managed-release tablets, has been formulated to both deter abuse and reduce "opioid-induced constipation".

Dependence and withdrawal
The risk of experiencing severe withdrawal symptoms is high if a patient has become physically dependent and discontinues oxycodone abruptly. Medically, when the drug has been taken regularly over an extended period, it is withdrawn gradually rather than abruptly. People who regularly use oxycodone recreationally or at higher than prescribed doses are at even higher risk of severe withdrawal symptoms. The symptoms of oxycodone withdrawal, as with other opioids, may include "anxiety, panic attack, nausea, insomnia, muscle pain, muscle weakness, fevers, and other flu-like symptoms".Withdrawal symptoms have also been reported in newborns whose mothers had been either injecting or orally taking oxycodone during pregnancy.

Hormone levels
As with other opioids, chronic use of oxycodone (particularly with higher doses) often causes concurrent hypogonadism (low sex hormone levels).

Overdose
In high doses, overdoses, or in some persons not tolerant to opioids, oxycodone can cause shallow breathing, slowed heart rate, cold/clammy skin, pauses in breathing, low blood pressure, constricted pupils, circulatory collapse, respiratory arrest, and death.In 2011, it was the leading cause of drug-related deaths in the U.S. However, from 2012 onwards, heroin and fentanyl have become more common causes of drug-related deaths.Oxycodone overdose has also been described to cause spinal cord infarction in high doses and ischemic damage to the brain, due to prolonged hypoxia from suppressed breathing.

Interactions
Oxycodone is metabolized by the enzymes CYP3A4 and CYP2D6. Therefore, its clearance can be altered by inhibitors and inducers of these enzymes, increasing and decreasing half-life, respectively. (For lists of CYP3A4 and CYP2D6 inhibitors and inducers, see here and here, respectively.) Natural genetic variation in these enzymes can also influence the clearance of oxycodone, which may be related to the wide inter-individual variability in its half-life and potency.Ritonavir or lopinavir/ritonavir greatly increase plasma concentrations of oxycodone in healthy human volunteers due to inhibition of CYP3A4 and CYP2D6. Rifampicin greatly reduces plasma concentrations of oxycodone due to strong induction of CYP3A4. There is also a case report of fosphenytoin, a CYP3A4 inducer, dramatically reducing the analgesic effects of oxycodone in a chronic pain patient. Dosage or medication adjustments may be necessary in each case.

Pharmacology
Pharmacodynamics
Oxycodone, a semi-synthetic opioid, is a highly selective full agonist of the μ-opioid receptor (MOR). This is the main biological target of the endogenous opioid neuropeptide β-endorphin. Oxycodone has low affinity for the δ-opioid receptor (DOR) and the κ-opioid receptor (KOR), where it is an agonist similarly. After oxycodone binds to the MOR, a G protein-complex is released, which inhibits the release of neurotransmitters by the cell by decreasing the amount of cAMP produced, closing calcium channels, and opening potassium channels. Opioids like oxycodone are thought to produce their analgesic effects via activation of the MOR in the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Conversely, they are thought to produce reward and addiction via activation of the MOR in the mesolimbic reward pathway, including in the ventral tegmental area, nucleus accumbens, and ventral pallidum. Tolerance to the analgesic and rewarding effects of opioids is complex and occurs due to receptor-level tolerance (e.g., MOR downregulation), cellular-level tolerance (e.g., cAMP upregulation), and system-level tolerance (e.g., neural adaptation due to induction of ΔFosB expression).Taken orally, 20 mg of immediate-release oxycodone is considered to be equivalent in analgesic effect to 30 mg of morphine, while extended release oxycodone is considered to be twice as potent as oral morphine.Similarly to most other opioids, oxycodone increases prolactin secretion, but its influence on testosterone levels is unknown. Unlike morphine, oxycodone lacks immunosuppressive activity (measured by natural killer cell activity and interleukin 2 production in vitro); the clinical relevance of this has not been clarified.

Active metabolites
A few of the metabolites of oxycodone have also been found to be active as MOR agonists, some of which notably have much higher affinity for (as well as higher efficacy at) the MOR in comparison. Oxymorphone possesses 3- to 5-fold higher affinity for the MOR than does oxycodone, while noroxycodone and noroxymorphone possess one-third of and 3-fold higher affinity for the MOR, respectively, and MOR activation is 5- to 10-fold less with noroxycodone but 2-fold higher with noroxymorphone relative to oxycodone. Noroxycodone, noroxymorphone, and oxymorphone also have longer biological half-lives than oxycodone.
However, despite the greater in vitro activity of some of its metabolites, it has been determined that oxycodone itself is responsible for 83.0% and 94.8% of its analgesic effect following oral and intravenous administration, respectively. Oxymorphone plays only a minor role, being responsible for 15.8% and 4.5% of the analgesic effect of oxycodone after oral and intravenous administration, respectively. Although the CYP2D6 genotype and the route of administration result in differential rates of oxymorphone formation, the unchanged parent compound remains the major contributor to the overall analgesic effect of oxycodone. In contrast to oxycodone and oxymorphone, noroxycodone and noroxymorphone, while also potent MOR agonists, poorly cross the blood–brain barrier into the central nervous system, and for this reason are only minimally analgesic in comparison.

κ-opioid receptor
In 1997, a group of Australian researchers proposed (based on a study in rats) that oxycodone acts on KORs, unlike morphine, which acts upon MORs. Further research by this group indicated the drug appears to be a high-affinity κ2b-opioid receptor agonist. However, this conclusion has been disputed, primarily on the basis that oxycodone produces effects that are typical of MOR agonists. In 2006, research by a Japanese group suggested the effect of oxycodone is mediated by different receptors in different situations. Specifically in diabetic mice, the KOR appears to be involved in the antinociceptive effects of oxycodone, while in nondiabetic mice, the μ1-opioid receptor seems to be primarily responsible for these effects.

Pharmacokinetics
Instant-release absorption profile
Oxycodone can be administered orally, intranasally, via intravenous, intramuscular, or subcutaneous injection, or rectally. The bioavailability of oral administration of oxycodone averages within a range of 60 to 87%, with rectal administration yielding the same results; intranasal varies between individuals with a mean of 46%.After a dose of conventional (immediate-release) oral oxycodone, the onset of action is 10 to 30 minutes, and peak plasma levels of the drug are attained within roughly 30 to 60 minutes; in contrast, after a dose of OxyContin (an oral controlled-release formulation), peak plasma levels of oxycodone occur in about three hours. The duration of instant-release oxycodone is 3 to 6 hours, although this can be variable depending on the individual.

Distribution
Oxycodone has a volume of distribution of 2.6L/kg, in the blood it is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. At equilibrium the unbound concentration in the brain is threefold higher than the unbound concentration in blood Conventional oral preparations start to reduce pain within 10 to 15 minutes on an empty stomach; in contrast, OxyContin starts to reduce pain within one hour.

Metabolism
The metabolism of oxycodone in humans occurs in the liver mainly via the cytochrome P450 system and is extensive (about 95%) and complex, with many minor pathways and resulting metabolites. Around 10% (range 8–14%) of a dose of oxycodone is excreted essentially unchanged (unconjugated or conjugated) in the urine. The major metabolites of oxycodone are noroxycodone (70%), noroxymorphone ("relatively high concentrations"), and oxymorphone (5%). The immediate metabolism of oxycodone in humans is as follows:
N-Demethylation to noroxycodone predominantly via CYP3A4
O-Demethylation to oxymorphone predominantly via CYP2D6
6-Ketoreduction to 6α- and 6β-oxycodol
N-Oxidation to oxycodone-N-oxideIn humans, N-demethylation of oxycodone to noroxycodone by CYP3A4 is the major metabolic pathway, accounting for 45% ± 21% of a dose of oxycodone, while O-demethylation of oxycodone into oxymorphone by CYP2D6 and 6-ketoreduction of oxycodone into 6-oxycodols represent relatively minor metabolic pathways, accounting for 11% ± 6% and 8% ± 6% of a dose of oxycodone, respectively.Several of the immediate metabolites of oxycodone are subsequently conjugated with glucuronic acid and excreted in the urine. 6α-Oxycodol and 6β-oxycodol are further metabolized by N-demethylation to nor-6α-oxycodol and nor-6β-oxycodol, respectively, and by N-oxidation to 6α-oxycodol-N-oxide and 6β-oxycodol-N-oxide (which can subsequently be glucuronidated as well). Oxymorphone is also further metabolized, as follows:
3-Glucuronidation to oxymorphone-3-glucuronide predominantly via UGT2B7
6-Ketoreduction to 6α-oxymorphol and 6β-oxymorphol
N-Demethylation to noroxymorphoneThe first pathway of the above three accounts for 40% of the metabolism of oxymorphone, making oxymorphone-3-glucuronide the main metabolite of oxymorphone, while the latter two pathways account for less than 10% of the metabolism of oxymorphone. After N-demethylation of oxymorphone, noroxymorphone is further glucuronidated to noroxymorphone-3-glucuronide.Because oxycodone is metabolized by the cytochrome P450 system in the liver, its pharmacokinetics can be influenced by genetic polymorphisms and drug interactions concerning this system, as well as by liver function. Some people are fast metabolizers of oxycodone, while others are slow metabolizers, resulting in polymorphism-dependent alterations in relative analgesia and toxicity. While higher CYP2D6 activity increases the effects of oxycodone (owing to increased conversion into oxymorphone), higher CYP3A4 activity has the opposite effect and decreases the effects of oxycodone (owing to increased metabolism into noroxycodone and noroxymorphone). The dose of oxycodone must be reduced in patients with reduced liver function.

Elimination
The clearance of oxycodone is 0.8 L/min. Oxycodone and its metabolites are mainly excreted in urine. Therefore, oxycodone accumulates in patients with kidney impairment. Oxycodone is eliminated in the urine 10% as unchanged oxycodone, 45% ± 21% as N-demethylated metabolites (noroxycodone, noroxymorphone, noroxycodols), 11 ± 6% as O-demethylated metabolites (oxymorphone, oxymorphols), and 8% ± 6% as 6-keto-reduced metabolites (oxycodols).

Duration of action
Oxycodone has a half-life of 4.5 hours. It is available as a generic medication. The manufacturer of OxyContin, a controlled-release preparation of oxycodone, Purdue Pharma, claimed in their 1992 patent application that the duration of action of OxyContin is 12 hours in "90% of patients". It has never performed any clinical studies in which OxyContin was given at more frequent intervals. In a separate filing, Purdue claims that controlled-release oxycodone "provides pain relief in said patient for at least 12 hours after administration". However, in 2016 an investigation by the Los Angeles Times found that "the drug weans off hours early in many people", inducing symptoms of opiate withdrawal and intense cravings for OxyContin. One doctor, Lawrence Robbins, told journalists that over 70% of his patients would report that OxyContin would only provide 4–7 hours of relief. Doctors in the 1990s often would switch their patients to a dosing schedule of once every eight hours when they complained that the duration of action for OxyContin was too short to be taken only twice a day.Purdue strongly discouraged the practice: Purdues medical director Robert Reder wrote to one doctor in 1995 that "OxyContin has been developed for [12-hour] dosing...I request that you not use a [8-hourly] dosing regimen." Purdue repeatedly released memos to its sales representatives ordering them to remind doctors not to deviate from a 12-hour dosing schedule. One such memo read, "There is no Q8 dosing with OxyContin... [8-hour dosing] needs to be nipped in the bud. NOW!!" The journalists who covered the investigation argued that Purdue Pharma has insisted on a 12-hour duration of action for nearly all patients, despite evidence to the contrary, to protect the reputation of OxyContin as a 12-hour drug and the willingness of health insurance and managed care companies to cover OxyContin despite its high cost relative to generic opiates such as morphine.Purdue sales representatives were instructed to encourage doctors to write prescriptions for larger 12-hour doses instead of more frequent dosing. An August 1996 memo to Purdue sales representatives in Tennessee entitled "$$$$$$$$$$$$$ Its Bonus Time in the Neighborhood!" reminded the representatives that their commissions would dramatically increase if they were successful in convincing doctors to prescribe larger doses. Los Angeles Times journalists argue using interviews from opioid addiction experts that such high doses of OxyContin spaced 12 hours apart create a combination of agony during opiate withdrawal (lower lows) and a schedule of reinforcement that relieves this agony, fostering addiction.

Chemistry
Oxycodones chemical name is derived from codeine. The chemical structures are very similar, differing only in that

Oxycodone has a hydroxy group at carbon-14 (codeine has just a hydrogen in its place)
Oxycodone has a 7,8-dihydro feature. Codeine has a double bond between those two carbons; and
Oxycodone has a carbonyl group (as in ketones) in place of the hydroxyl group of codeine.It is also similar to hydrocodone, differing only in that it has a hydroxyl group at carbon-14.

Biosynthesis
In terms of biosynthesis, oxycodone has been found naturally in nectar extracts from the orchid family Epipactis helleborine; together along with another opioid: 3-{2-{3-{3-benzyloxypropyl}-3-indol, 7,8-didehydro- 4,5-epoxy-3,6-d-morphinan.Thodey et al., 2014 introduces a microbial compound manufacturing system for compounds including oxycodone. The Thodey platform produces both natural and semisynthetic opioids including this one. This system uses Saccharomyces cerevisiae with transgenes from Papaver somniferum (the opium poppy) and Pseudomonas putida to turn a thebaine input into other opiates and opioids.

Detection in biological fluids
Oxycodone and/or its major metabolites may be measured in blood or urine to monitor for clearance, non-medical use, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial opiate screening tests cross-react appreciably with oxycodone and its metabolites, but chromatographic techniques can easily distinguish oxycodone from other opiates.

History
Martin Freund and (Jakob) Edmund Speyer of the University of Frankfurt in Germany published the first synthesis of oxycodone from thebaine in 1916. When Freund died, in 1920, Speyer wrote his obituary. Speyer, born to a Jewish family in Frankfurt am Main in 1878, became a victim of the Holocaust. He died on 5 May 1942, the second day of deportations from the Lodz Ghetto; his death was noted in the ghettos chronicle.The first clinical use of the drug was documented in 1917, the year after it was first developed. It was first introduced to the U.S. market in May 1939. In early 1928, Merck introduced a combination product containing scopolamine, oxycodone, and ephedrine under the German initials for the ingredients SEE, which was later renamed Scophedal (SCOpolamine, ePHEDrine, and eukodAL) in 1942. It was last manufactured in 1987, but can be compounded. This combination is essentially an oxycodone analogue of the morphine-based "twilight sleep", with ephedrine added to reduce circulatory and respiratory effects. The drug became known as the "Miracle Drug of the 1930s" in Continental Europe and elsewhere and it was the Wehrmachts choice for a battlefield analgesic for a time. The drug was expressly designed to provide what the patent application and package insert referred to as "very deep analgesia and profound and intense euphoria" as well as tranquillisation and anterograde amnesia useful for surgery and battlefield wounding cases. Oxycodone was allegedly chosen over other common opiates for this product because it had been shown to produce less sedation at equianalgesic doses compared to morphine, hydromorphone (Dilaudid), and hydrocodone (Dicodid).During Operation Himmler, Skophedal was also reportedly injected in massive overdose into the prisoners dressed in Polish Army uniforms in the staged incident on 1 September 1939 which opened the Second World War.The personal notes of Adolf Hitlers physician, Theodor Morell, indicate Hitler received repeated injections of "Eukodal" (oxycodone) and Scophedal, as well as Dolantin (pethidine) codeine, and morphine less frequently; oxycodone could not be obtained after late January 1945.In the early 1970s, the U.S. government classified oxycodone as a schedule II drug.Purdue Pharma, a privately held company based in Stamford, Connecticut, developed the prescription painkiller OxyContin. Upon its release in 1995, OxyContin was hailed as a medical breakthrough, a long-lasting narcotic that could help patients with moderate to severe pain. The drug became a blockbuster, and has reportedly generated some US$35 billion in revenue for Purdue.

Opioid epidemic
Oxycodone, like other opioid analgesics, tends to induce feelings of euphoria, relaxation and reduced anxiety in those who are occasional users. These effects make it one of the most commonly abused pharmaceutical drugs in the United States. Diverted oxycodone may be taken orally or ingested through insufflation; used intravenously, or the heated vapors inhaled.

United States
Oxycodone is the most widely recreationally used opioid in America. In the United States, more than 12 million people use opioid drugs recreationally. The U.S. Department of Health and Human Services estimates that about 11 million people in the U.S. consume oxycodone in a non-medical way annually.Opioids were responsible for 49,000 of the 72,000 drug overdose deaths in the U.S. in 2017. In 2007, about 42,800 emergency room visits occurred due to "episodes" involving oxycodone.  In 2008, recreational use of oxycodone and hydrocodone was involved in 14,800 deaths. Some of the cases were due to overdoses of the acetaminophen component, resulting in fatal liver damage.In September 2013, the FDA released new labeling guidelines for long acting and extended release opioids requiring manufacturers to remove moderate pain as indication for use, instead stating the drug is for "pain severe enough to require daily, around-the-clock, long term opioid treatment". The updated labeling will not restrict physicians from prescribing opioids for moderate, as needed use.Reformulated OxyContin is causing some recreational users to change to heroin, which is cheaper and easier to obtain.

Lawsuits
In October 2017, The New Yorker published a story on Mortimer Sackler and Purdue Pharma regarding their ties to the production and manipulation of the oxycodone markets. The article links Raymond and Arthur Sacklers business practices with the rise of direct pharmaceutical marketing and eventually to the rise of addiction to oxycodone in the United States. The article implies that the Sackler family bears some responsibility for the opioid epidemic in the United States. In 2019, The New York Times ran a piece confirming that Richard Sackler, the son of Raymond Sackler, told company officials in 2008 to "measure our performance by Rxs by strength, giving higher measures to higher strengths". This was verified with documents tied to a lawsuit – which was filed by the Massachusetts attorney general, Maura Healey – claiming that Purdue Pharma and members of the Sackler family knew that high doses of OxyContin over long periods would increase the risk of serious side effects, including addiction. Despite Purdue Pharmas proposal for a US$12 billion settlement of the lawsuit, the attorneys general of 23 states, including Massachusetts, rejected the settlement offer in September 2019.

Australia
The non-medical use of oxycodone existed from the early 1970s, but by 2015, 91% of a national sample of injecting drug users in Australia had reported using oxycodone, and 27% had injected it in the last six months.

Canada
Opioid-related deaths in Ontario had increased by 242% from 1969 to 2014. By 2009 in Ontario there were more deaths from oxycodone overdose than from cocaine overdose. Deaths from opioid pain relievers had increased from 13.7 deaths per million residents in 1991 to 27.2 deaths per million residents in 2004. The non-medical use of oxycodone in Canada became a problem. Areas where oxycodone is most problematic are Atlantic Canada and Ontario, where its non-medical use is prevalent in rural towns, and in many smaller to medium-sized cities. Oxycodone is also widely available across Western Canada, but methamphetamine and heroin are more serious problems in the larger cities, while oxycodone is more common in rural towns. Oxycodone is diverted through doctor shopping, prescription forgery, pharmacy theft, and overprescribing.The recent formulations of oxycodone, particularly Purdue Pharmas crush-, chew-, injection- and dissolve-resistant OxyNEO which replaced the banned OxyContin product in Canada in early 2012, have led to a decline in the recreational use of this opiate but have increased the recreational use of the more potent drug fentanyl. According to a Canadian Centre on Substance Abuse study quoted in Macleans magazine, there were at least 655 fentanyl-related deaths in Canada in a five-year period.In Alberta, the Blood Tribe police claimed that from the fall of 2014 through January 2015, oxycodone pills or a lethal fake variation referred to as Oxy 80s containing fentanyl made in illegal labs by members of organized crime were responsible for ten deaths on the Blood Reserve, which is located southwest of Lethbridge, Alberta. Province-wide, approximately 120 Albertans died from fentanyl-related overdoses in 2014.

United Kingdom
Prescriptions of Oxycodone rose in Scotland by 430% between 2002 and 2008, prompting fears of usage problems that would mirror those of the United States. The first known death due to overdose in the UK occurred in 2002.

Preventive measures
In August 2010, Purdue Pharma reformulated their long-acting oxycodone line, marketed as OxyContin, using a polymer, Intac, to make the pills more difficult to crush or dissolve in water to reduce non-medical use of OxyContin. The FDA approved relabeling the reformulated version as abuse-resistant in April 2013.Pfizer manufactures a preparation of short-acting oxycodone, marketed as Oxecta, which contains inactive ingredients, referred to as tamper-resistant Aversion Technology. It does not deter oral recreational use. Approved by the FDA in the U.S. in June 2011, the new formulation makes crushing, chewing, snorting, or injecting the opioid impractical because of a change in its chemical properties.

Legal status
Oxycodone is subject to international conventions on narcotic drugs. In addition, oxycodone is subject to national laws that differ by country. The 1931 Convention for Limiting the Manufacture and Regulating the Distribution of Narcotic Drugs of the League of Nations included oxycodone. The 1961 Single Convention on Narcotic Drugs of the United Nations, which replaced the 1931 convention, categorized oxycodone in Schedule I. Global restrictions on Schedule I drugs include "limit[ing] exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, use and possession of" these drugs; "requir[ing] medical prescriptions for the supply or dispensation of [these] drugs to individuals"; and "prevent[ing] the accumulation" of quantities of these drugs "in excess of those required for the normal conduct of business".

Australia
Oxycodone is in Schedule I (derived from the Single Convention on Narcotic Drugs) of the Commonwealths Narcotic Drugs Act 1967. In addition, it is in Schedule 8 of the Australian Standard for the Uniform Scheduling of Drugs and Poisons ("Poisons Standard"), meaning it is a "controlled drug... which should be available for use but require[s] restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence".

Canada
Oxycodone is a controlled substance under Schedule I of the Controlled Drugs and Substances Act (CDSA).

Canadian legislative changes
In February 2012, Ontario passed legislation to allow the expansion of an already existing drug-tracking system for publicly funded drugs to include those that are privately insured. This database will function to identify and monitor patients attempts to seek prescriptions from multiple doctors or retrieve them from multiple pharmacies. Other provinces have proposed similar legislation, while some, such as Nova Scotia, have legislation already in effect for monitoring prescription drug use. These changes have coincided with other changes in Ontarios legislation to target the misuse of painkillers and high addiction rates to drugs such as oxycodone. As of 29 February 2012, Ontario passed legislation delisting oxycodone from the provinces public drug benefit program. This was a first for any province to delist a drug based on addictive properties. The new law prohibits prescriptions for OxyNeo except to certain patients under the Exceptional Access Program including palliative care and in other extenuating circumstances. Patients already prescribed oxycodone will receive coverage for an additional year for OxyNeo, and after that, it will be disallowed unless designated under the exceptional access program.Much of the legislative activity has stemmed from Purdue Pharmas decision in 2011 to begin a modification of Oxycontins composition to make it more difficult to crush for snorting or injecting. The new formulation, OxyNeo, is intended to be preventive in this regard and retain its effectiveness as a painkiller. Since introducing its Narcotics Safety and Awareness Act, Ontario has committed to focusing on drug addiction, particularly in the monitoring and identification of problem opioid prescriptions, as well as the education of patients, doctors, and pharmacists. This Act, introduced in 2010, commits to the establishment of a unified database to fulfil this intention. Both the public and medical community have received the legislation positively, though concerns about the ramifications of legal changes have been expressed. Because laws are largely provincially regulated, many speculate a national strategy is needed to prevent smuggling across provincial borders from jurisdictions with looser restrictions.In 2015, Purdue Pharmas abuse-resistant OxyNEO and six generic versions of OxyContin had been on the Canada-wide approved list for prescriptions since 2012. In June 2015, then federal Minister of Health Rona Ambrose announced that within three years all oxycodone products sold in Canada would need to be tamper-resistant. Some experts warned that the generic product manufacturers may not have the technology to achieve that goal, possibly giving Purdue Pharma a monopoly on this opiate.

Canadian lawsuits
Several class-action suits across Canada have been launched against the Purdue group of companies and affiliates. Claimants argue the pharmaceutical manufacturers did not meet a standard of care and were negligent in doing so. These lawsuits reference earlier judgments in the United States, which held that Purdue was liable for wrongful marketing practices and misbranding. Since 2007, the Purdue companies have paid over CAN$650 million in settling litigation or facing criminal fines.

Germany
The drug is in Appendix III of the Narcotics Act (Betäubungsmittelgesetz or BtMG). The law allows only physicians, dentists, and veterinarians to prescribe oxycodone and the federal government to regulate the prescriptions (e.g., by requiring reporting).

Hong Kong
Oxycodone is regulated under Part I of Schedule 1 of Hong Kongs Chapter 134 Dangerous Drugs Ordinance.

Japan
Oxycodone is a restricted drug in Japan. Its import and export are strictly restricted to specially designated organizations having a prior permit to import it. In a high-profile case an American who was a top Toyota executive living in Tokyo, who claimed to be unaware of the law, was arrested for importing oxycodone into Japan.

Singapore
Oxycodone is listed as a Class A drug in the Misuse of Drugs Act of Singapore, which means offences concerning the drug attract the most severe level of punishment. A conviction for unauthorized manufacture of the drug attracts a minimum sentence of 10 years of imprisonment and corporal punishment of 5 strokes of the cane, and a maximum sentence of life imprisonment or 30 years of imprisonment and 15 strokes of the cane. The minimum and maximum penalties for unauthorized trafficking in the drug are respectively 5 years of imprisonment and 5 strokes of the cane, and 20 years of imprisonment and 15 strokes of the cane.

United Kingdom
Oxycodone is a Class A drug under the Misuse of Drugs Act 1971. For Class A drugs, which are "considered to be the most likely to cause harm", possession without a prescription is punishable by up to seven years in prison, an unlimited fine, or both. Dealing of the drug illegally is punishable by up to life imprisonment, an unlimited fine, or both. In addition, oxycodone is a Schedule 2 drug per the Misuse of Drugs Regulations 2001 which "provide certain exemptions from the provisions of the Misuse of Drugs Act 1971".

United States
Under the Controlled Substances Act, oxycodone is a Schedule II controlled substance whether by itself or part of a multi-ingredient medication. The DEA lists oxycodone both for sale and for use in manufacturing other opioids as ACSCN 9143 and in 2013 approved the following annual aggregate manufacturing quotas: 131.5 metric tons for sale, down from 153.75 in 2012, and 10.25 metric tons for conversion, unchanged from the previous year. In 2020, oxycodone possession was decriminalized in the U.S. state of Oregon.

Economics
The International Narcotics Control Board estimated 11.5 short tons (10.4 t) of oxycodone were manufactured worldwide in 1998; by 2007 this figure had grown to 75.2 short tons (68.2 t). United States accounted for 82% of consumption in 2007 at 51.6 short tons (46.8 t). Canada, Germany, Australia, and France combined accounted for 13% of consumption in 2007. In 2010, 1.3 short tons (1.2 t) of oxycodone were illegally manufactured using a fake pill imprint. This accounted for 0.8% of consumption. These illicit tablets were later seized by the U.S. Drug Enforcement Administration, according to the International Narcotics Control Board. The board also reported 122.5 short tons (111.1 t) manufactured in 2010. This number had decreased from a record high of 135.9 short tons (123.3 t) in 2009.

Names
Expanded expressions for the compound oxycodone in the academic literature include "dihydrohydroxycodeinone", "Eucodal", "Eukodal", "14-hydroxydihydrocodeinone", and "Nucodan". In a UNESCO convention, the translations of "oxycodone" are oxycodon (Dutch), oxycodone (French), oxicodona (Spanish), الأوكسيكودون (Arabic), 羟考酮 (Chinese), and оксикодон (Russian). The word "oxycodone" should not be confused with "oxandrolone", "oxazepam", "oxybutynin", "oxytocin", or "Roxanol".Other brand names include Longtec and Shortec.

See also
Sackler family
Medical-industrial complex

References
Further reading
Coluzzi F, Mattia C (July–August 2005). "Oxycodone. Pharmacological profile and clinical data in chronic pain management" (PDF) </s>


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<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Cefepime and explain in detail? [/INST] Cefepime is a fourth-generation cephalosporin antibiotic. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both types of organism than third-generation agents. A 2007 meta-analysis suggested when data of trials were combined, mortality was increased in people treated with cefepime compared with other β-lactam antibiotics. In response, the U.S. Food and Drug Administration (FDA) performed their own meta-analysis which found no mortality difference.Cefepime was patented in 1982 by Bristol-Myers Squibb and approved for medical use in 1994. It is available as a generic drug and sold under a variety of trade names worldwide.It was removed from the World Health Organizations List of Essential Medicines in 2019.

Medical use
Cefepime is usually reserved to treat moderate to severe nosocomial pneumonia, infections caused by multiple drug-resistant microorganisms (e.g </s>


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


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Levothyroxine and explain in detail? [/INST] Levothyroxine, also known as L-thyroxine, is a manufactured form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including and a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken by mouth or given by intravenous injection. Maximum effect from a specific dose can take up to six weeks to occur.Side effects from excessive doses include weight loss, trouble tolerating heat, sweating, anxiety, trouble sleeping, tremor, and fast heart rate. Use is not recommended in people who have had a recent heart attack. Use during pregnancy has been found to be safe. Dosing should be based on regular measurements of thyroid-stimulating hormone (TSH) and T4 levels in the blood. Much of the effect of levothyroxine is following its conversion to triiodothyronine (T3).Levothyroxine was first made in 1927. It is on the World Health Organizations List of Essential Medicines. Levothyroxine is available as a generic medication. In 2020, it was the second most commonly prescribed medication in the United States, with more than 98 million prescriptions.

Medical use
Levothyroxine is typically used to treat hypothyroidism, and is the treatment of choice for people with hypothyroidism who often require lifelong thyroid hormone therapy.It may also be used to treat goiter via its ability to lower thyroid-stimulating hormone (TSH), which is considered goiter-inducing. Levothyroxine is also used as interventional therapy in people with nodular thyroid disease or thyroid cancer to suppress TSH secretion. A subset of people with hypothyroidism treated with an appropriate dose of levothyroxine will describe continuing symptoms despite TSH levels in the normal range. In these people, further laboratory and clinical evaluation is warranted, as they may have another cause for their symptoms. Furthermore, reviewing their medications and possible dietary supplements is important, as several medications can affect thyroid hormone levels.Levothyroxine is also used to treat subclinical hypothyroidism, which is defined by an elevated TSH level and a normal-range free T4 level without symptoms. Such people may be asymptomatic and whether they should be treated is controversial. One benefit of treating this population with levothyroxine therapy is preventing development of hypothyroidism. As such, treatment should be taken into account for patients with initial TSH levels above 10 mIU/L, people with elevated thyroid peroxidase antibody titers, people with symptoms of hypothyroidism and TSH levels of 5–10 mIU/L, and women who are pregnant or want to become pregnant. Oral dosing for patients with subclinical hypothyroidism is 1 μg/kg/day.It is also used to treat myxedema coma, which is a severe form of hypothyroidism characterized by mental status changes and hypothermia. As it is a medical emergency with a high mortality rate, it should be treated in the intensive-care unit with thyroid hormone replacement and aggressive management of individual organ system complications.

Dosages vary according to the age groups and the individual condition of the person, body weight, and compliance to the medication and diet. Other predictors of the required dosage are sex, body mass index, deiodinase activity (SPINA-GD), and etiology of hypothyroidism. Annual or semiannual clinical evaluations and TSH monitoring are appropriate after dosing has been established. Levothyroxine is taken on an empty stomach about half an hour to an hour before meals. As such, thyroid replacement therapy is usually taken 30 minutes prior to eating in the morning. For patients with trouble taking levothyroxine in the morning, bedtime dosing is effective, as well. A study in 2015 showed greater efficacy of levothyroxine when taken at bedtime. Doses of levothyroxine that normalize serum TSH may not normalize abnormal levels of LDL cholesterol and total cholesterol.Poor compliance in taking the medicine is the most common cause of elevated TSH levels in people receiving appropriate doses of levothyroxine.

50 and older
For older people (over 50 years old) and people with known or suspected ischemic heart disease, levothyroxine therapy should not be initiated at the full replacement dose. Since thyroid hormone increases the hearts oxygen demand by increasing heart rate and contractility, starting at higher doses may cause an acute coronary syndrome or an abnormal heart rhythm.

Pregnancy and breastfeeding
Hypothyroidism is common among pregnant women. A nationwide cohort study showed that 1.39% of all pregnant women in 2010 in Denmark received a prescription of levothyroxine during pregnancy. According to the U.S. Food and Drug Administration pregnancy categories, levothyroxine has been assigned category A. Given that no increased risk of congenital abnormalities has been demonstrated in pregnant women taking levothyroxine, therapy should be continued during pregnancy. Furthermore, therapy should be immediately administered to women diagnosed with hypothyroidism during pregnancy, as hypothyroidism is associated with a higher rate of complications, such as spontaneous abortion, preeclampsia, and premature birth.Thyroid hormone requirements increase during and last throughout pregnancy. As such,  pregnant women are recommended to increase to nine doses of levothyroxine each week, rather than the usual seven, as soon as their pregnancy is confirmed. Repeat thyroid function tests should be done five weeks after the dosage is increased.While a minimal amount of thyroid hormones is found in breast milk, the amount does not influence infant plasma thyroid levels. Furthermore, levothyroxine was not found to cause any adverse events to the infant or mother during breastfeeding. As adequate concentrations of thyroid hormone are required to maintain normal lactation,  appropriate levothyroxine doses should be administered during breastfeeding.

Children
Levothyroxine is safe and effective for children with hypothyroidism; the goal of treatment for children with hypothyroidism is to reach and preserve normal intellectual and physical development.

Contraindications
Levothyroxine is contraindicated in people with hypersensitivity to levothyroxine sodium or any component of the formulation, people with acute myocardial infarction, and people with thyrotoxicosis of any etiology. Levothyroxine is also contraindicated for people with uncorrected adrenal insufficiency, as thyroid hormones may cause an acute adrenal crisis by increasing the metabolic clearance of glucocorticoids. For oral tablets, the inability to swallow capsules is an additional contraindication.

Side effects
Adverse events are generally caused by incorrect dosing. Long-term suppression of TSH values below normal values frequently cause cardiac side effects and contribute to decreases in bone mineral density (low TSH levels are also well known to contribute to osteoporosis).Too high a dose of levothyroxine causes hyperthyroidism. Overdose can result in heart palpitations, abdominal pain, nausea, anxiousness, confusion, agitation, insomnia, weight loss, and increased appetite. Allergic reactions to the drug are characterized by symptoms such as difficulty breathing, shortness of breath, or swelling of the face and tongue. Acute overdose may cause fever, hypoglycemia, heart failure, coma, and unrecognized adrenal insufficiency.
Acute massive overdose may be life-threatening; treatment should be symptomatic and supportive. Massive overdose can be associated with increased sympathetic activity, thus may require treatment with beta-blockers.The effects of overdosing appear 6 hours to 11 days after ingestion.

Interactions
Many foods and other substances  can interfere with absorption of thyroxine. Substances that reduce absorption are aluminium- and magnesium-containing antacids, simethicone, sucralfate, cholestyramine, colestipol, and polystyrene sulfonate. Sevelamer with calcium carbonate may decrease the bioavailability of levothyroxine. Grapefruit juice may delay the absorption of levothyroxine, but based on a study of 10 healthy people aged 20–30 (eight men, two women), it may not have a significant effect on bioavailability in young adults. A study of eight women suggested that coffee may interfere with the intestinal absorption of levothyroxine, though at a level less than eating bran. Certain other substances can cause adverse effects that may be severe. Combination of levothyroxine with ketamine may cause hypertension and tachycardia; and tricyclic and tetracyclic antidepressants increase its toxicity.  Lithium, though, can cause hyperthyroidism (but most often hypothyroidism)  by affecting iodine metabolism of the thyroid itself, thus inhibiting synthetic levothyroxine, as well. Soy,  walnuts, fiber, calcium supplements, and iron supplements can also adversely affect absorption. A study found that cows milk reduces levothyroxine absorption.To minimize interactions, a manufacturer of levothyroxine recommends after taking it,  waiting 30 minutes to one hour before eating or drinking anything that is not water. They further recommend to take it in the morning on an empty stomach.

Mechanism of action
Levothyroxine is a synthetic form of thyroxine (T4), an endogenous hormone secreted by the thyroid gland, which is converted to its active metabolite, L-triiodothyronine (T3). T4 and T3 bind to thyroid receptor proteins in the cell nucleus and cause metabolic effects through the control of DNA transcription and protein synthesis. Like its naturally secreted counterpart, levothyroxine is a chiral compound in the L-form.

Pharmacokinetics
Absorption of orally administered levothyroxine from the gastrointestinal tract ranges from 40 to 80%, with the majority of the drug absorbed from the jejunum and upper ileum. Levothyroxine absorption is increased by fasting and decreased in certain malabsorption syndromes, by certain foods, and with age. The bioavailability of the drug is decreased by dietary fiber.Greater than 99% of circulating thyroid hormones are bound to plasma proteins including thyroxine-binding globulin, transthyretin (previously called thyroxine-binding prealbumin), and albumin. Only free hormone is metabolically active.The primary pathway of thyroid hormone metabolism is through sequential deiodination. The liver is the main site of T4 deiodination, and along with the kidneys, are responsible for about 80% of circulating T3. In addition to deiodination, thyroid hormones are also excreted through the kidneys and metabolized through conjugation and glucuronidation and excreted directly into the bile and the gut, where they undergo enterohepatic recirculation.Half-life elimination is 6–7 days for people with normal lab results; 9–10 days for people with hypothyroidism; 3–4 days for people with hyperthyroidism. Thyroid hormones are primarily eliminated by the kidneys (about 80%), with urinary excretion decreasing with age. The remaining 20% of T4 is eliminated in the stool.

History
Thyroxine was first isolated in pure form in 1914, at the Mayo Clinic by Edward Calvin Kendall from extracts of hog thyroid glands. The hormone was synthesized in 1927 by British chemists Charles Robert Harington and George Barger.

Society and culture
Economics
As of 2011, levothyroxine was the second-most commonly prescribed medication in the U.S., with 23.8 million prescriptions filled each year.In 2016, it became the most commonly prescribed medication in the U.S., with more than 114 million prescriptions.

Available forms
Levothyroxine for systemic administration is available as an oral tablet, an intramuscular injection, and as a solution for intravenous infusion. Furthermore, it is available as both brand-name and generic products. While the FDA approved the use of generic levothyroxine for brand-name levothyroxine in 2004, the decision was met with disagreement by several medical associations. The American Association of Clinical Endocrinologists (AACE), the Endocrine Society, and the American Thyroid Association did not agree with the FDA that brand-name and generic formulations of levothyroxine were bioequivalent. As such,  people were recommended to be started and kept on either brand-name or generic levothyroxine formulations and not changed back and forth from one to the other. For people who do switch products,  their TSH and free T4 levels should be tested after six weeks to check that they are within normal range.Common brand names include Eltroxin, Euthyrox, Eutirox, Letrox, Levaxin, Lévothyrox, Levoxyl, L-thyroxine, Thyrax, and Thyrax Duotab in Europe; Thyrox and Thyronorm in South Asia; Unithroid, Eutirox, Synthroid, and Tirosint in North and South America; and Thyrin and Thyrolar in Bangladesh. Numerous generic versions also are available.The related drug dextrothyroxine (D-thyroxine) was used in the past as a treatment for hypercholesterolemia (elevated cholesterol levels), but was withdrawn due to cardiac side effects. Once weekly thyroxine (OWT) preparations are also available for clinical use. A recent meta-analysis published by Dutta et al. involving data from 4 studies (294 patients) showed that OWT is associated with less efficient control of hypothyroidism, risks of supraphysiologic elevation of thyroid hormone levels along with transient echocardiographic changes in some patients following 2-4 h of thyroxine intake </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tazarotene and explain in detail? [/INST] Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid. It is primarily used for the treatment of plaque psoriasis and acne. Tazarotene is also used as a therapeutic for photoaged and photodamaged skin. Tazarotene is a member of the acetylenic class of retinoids.

Medical uses
Tazarotene is most commonly used topically to treat acne vulgaris and psoriasis. Like other topical retinoids, such as tretinoin and adapalene, tazarotene can be combined with benzoyl peroxide or an oral antibiotic, such as clindamycin or dapsone, for the treatment of acne. This results in increased efficacy compared to tazarotene monotherapy. For psoriasis, a combination therapy of tazarotene and a mid- to high-potency corticosteroid is more effective than either treatment alone.Tazarotene can also be used for the treatment of photodamaged skin. It can reduce the clinical and histological signs of photodamaged skin. The therapy is more effective when used with the daily application of sunscreen.

Pregnancy
Before 2015, tazarotene was considered a Category X drug (meaning its use was contraindicated during pregnancy) according to Food and Drug Administration (FDA) guidelines, despite demonstrating similar plasma retinoid levels as adapalene and tretinoin, which were classified as Category C drugs. Under the FDAs updated Pregnancy and Lactation Labeling Rule which eliminated the lettered pregnancy categories and came into effect in 2015, tazarotene was determined to be contraindicated in pregnancy. Because of the lack of pregnancy outcomes data for the drug, the determination was based on the teratogenic effects observed in rat and rabbit studies.

Contraindications
Tazarotene is contraindicated for use in patients who are known to be or suspected of being pregnant. Tazarotene is a known teratogen. It is also contraindicated in patients with a known hypersensitivity to any ingredient in the specific pharmaceutical formulation.

Adverse effects
Adverse effects for tazarotene include skin irritation, such as redness, itchiness, and burning. In patients with psoriasis, these adverse effects can be mitigated by a combined treatment with either mometasone furoate or fluocinonide. These effects tend to be mild to moderate, and increase in intensity as tazarotene concentration increases.

Pharmacology
Mechanism of action
Tazarotene is selective for two types of retinoic acid receptors, RAR-γ and RAR-β. Like all retinoids, it affects the ability of keratinocytes in the epidermis to proliferate and differentiate </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Clevidipine and explain in detail? [/INST] Clevidipine (INN, trade name Cleviprex) is a dihydropyridine calcium channel blocker indicated for the reduction of  blood pressure when oral therapy is not feasible or not desirable. Clevidipine is used IV only and practitioners titrate this drug to lower blood pressure. It has a half-life of approximately one minute. It is rapidly inactivated by esterases.
It was approved by the United States Food and Drug Administration on August 1, 2008.

Basic chemical and pharmacological properties
Clevidipine is a dihydropyridine L-type calcium channel blocker, highly selective for vascular, as opposed to myocardial, smooth muscle and, therefore, has little or no effect on myocardial contractility or cardiac conduction. It reduces mean arterial blood pressure by decreasing systemic vascular resistance. Clevidipine does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels. No increase in myocardial lactate production in coronary sinus blood has been seen, confirming the absence of myocardial ischemia due to coronary steal.
Clevidipine is rapidly metabolized by esterases in the blood and extravascular tissues. Therefore, its elimination is unlikely to be affected by hepatic (liver) or renal (kidney) dysfunction. Clevidipine does not accumulate in the body, and its clearance is independent of body weight.
The initial phase half-life is approximately 1 minute and the terminal half-life is approximately 15 minutes. Clevidipine will still be rapidly metabolized in pseudocholinesterase-deficient patients.
Clevidipine is formulated as a lipid emulsion in 20% soybean oil (Intralipid) and contains approximately 0.2 g of fat per mL (2.0 kcal/ml). Clevidipine also contains glycerin (22.5 mg/mL), purified egg yolk phospholipids (12 mg/mL), and sodium hydroxide to adjust pH. Clevidipine has a pH of 6.0–8.0
In the perioperative patient population Clevidipine produces a 4–5% reduction in systolic blood pressure within 2–4 minutes after starting a 1–2 mg/hour IV infusion.
In studies up to 72 hours of continuous infusion, there was no evidence of tolerance.
In most patients, full recovery of blood pressure is achieved in 5–15 minutes after the infusion is stopped.

Stereochemistry
Clevidipine contains a stereocenter and consists of two enantiomers. This is a racemate, ie a 1: 1 mixture of ( R ) – and the ( S ) - form:

Dosage and administration
Aseptic technique should be used when handling Cleviprex since it contains phospholipids and can support microbial growth.
Cleviprex is administered intravenously and should be titrated to achieve the desired blood pressure reduction. Blood pressure and heart rate should be monitored continually during infusion.
Cleviprex is a single use product that should not be diluted and should not be administered in the same line as other medications. Once the stopper is punctured, Cleviprex should be used within 12 hours and any unused portion remaining in the vial should be discarded. Change IV lines in accordance with hospital protocol.
An IV infusion at 1–2 mg/hour is recommended for initiation and should be titrated by doubling the dose every 90 seconds. As the blood pressure approaches goal, the infusion rate should be increased in smaller increments and titrated less frequently. The maximum infusion rate for Cleviprex is 32 mg/hour. Most patients in clinical trials were treated with doses of 16 mg/hour or less.
Because of lipid load restrictions, no more than 1000 mL (or an average of 21 mg/hour) of Cleviprex infusion is recommended per 24 hours. In clinical studies, no significant changes occurred in serum triglyceride levels in the Cleviprex treated patients. There is little experience with infusion durations beyond 72 hours at any dose. The infusion can be reduced or discontinued to achieve desired blood pressure while appropriate oral therapy is established.

Safety information
Cleviprex is intended for intravenous use. Titrate drug depending on the response of the individual patient to achieve the desired blood pressure reduction. Monitor blood pressure and heart rate continually during infusion, and then until vital signs are stable. Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped.
In clinical trials, the safety profile of clevidipine was generally similar to sodium nitroprusside, nitroglycerin, or nicardipine in patients undergoing cardiac surgery.Cleviprex is contraindicated in patients with allergies to soybeans, soy products, eggs, or egg products; defective lipid metabolism such as pathologic hyperlipemia (rare genetic disorders characterized by abnormal triglyceride metabolism), lipoid nephrosis, or acute pancreatitis if it is accompanied by hyperlipidemia; and in patients with severe aortic stenosis.
Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. In clinical trials, a similar increase in heart rate was observed in both Cleviprex and comparator arms. Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Heart failure patients should be monitored carefully. Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal.
Most common adverse reactions (>2%) are headache, nausea, and vomiting.
Cleviprex should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Maintain aseptic technique while handling Cleviprex. Cleviprex contains phospholipids and can support microbial growth. Do not use if contamination is suspected. Once the stopper is punctured, use or discard within 12 hours.

Drug interactions
No clinical drug interaction studies were conducted. Cleviprex does not have the potential for blocking or inducing any CYP enzymes.

Storage
Cleviprex is available in ready-to-use 50- and 100-mL glass vials at a concentration of 0.5 mg/mL of clevidipine butyrate. Vials should be refrigerated at 2-8oC (36-46 °F). Cleviprex can be stored to controlled room temperature for up to 2 months.  Cleviprex is photosensitive and storage in cartons protects against photodegradation. Protection from light during administration is not required.

Phase III clinical trial results
Cleviprex has been evaluated in 6 Phase III clinical studies including the perioperative and emergency department/intensive care settings. These include ESCAPE-1, ESCAPE-2, ECLIPSE, and VELOCITY trials.
ESCAPE-1 was a double-blind, randomized, placebo-controlled efficacy trial of 105 cardiac surgery patients. In ESCAPE-1, Cleviprex had a significantly lower rate of treatment failure when compared with placebo (7.5% vs 82.7%) and a 92.5% rate of success in lowering systolic blood pressure (SBP) by ≥15% </s>


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


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


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Diltiazem and explain in detail? [/INST] Diltiazem, sold under the brand name Cardizem among others, is a calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias. It may also be used in hyperthyroidism if beta blockers cannot be used. It is taken by mouth or injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours.Common side effects include swelling, dizziness, headaches, and low blood pressure. Other severe side effects include an overly slow heart beat, heart failure, liver problems, and allergic reactions. Use is not recommended during pregnancy. It is unclear if use when breastfeeding is safe.Diltiazem works by relaxing the smooth muscle in the walls of arteries, resulting in them opening and allowing blood to flow more easily. Additionally, it acts on the heart to prolong the period until it can beat again. It does this by blocking the entry of calcium into the cells of the heart and blood vessels. It is a class IV antiarrhythmic.Diltiazem was approved for medical use in the United States in 1982. It is available as a generic medication. In 2019, it was the 72nd most commonly prescribed medication in the United States, with more than 10 million prescriptions. An extended release formulation is also available.

Medical uses
Diltiazem is indicated for:

Stable angina (exercise-induced) – diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.
Variant angina – it is effective owing to its direct effects on coronary dilation.
Unstable angina (preinfarction, crescendo) – diltiazem may be particularly effective if the underlying mechanism is vasospasm.
Myocardial bridge
DysmenorrheaFor supraventricular tachycardias (PSVT), diltiazem appears to be as effective as verapamil in treating re-entrant supraventricular tachycardia.Atrial fibrillation or atrial flutter  is another indication.  The initial bolus should be 0.25 mg/kg, intravenous (IV).
Because of its vasodilatory effects, diltiazem is useful for treating hypertension. Calcium channel blockers are well tolerated, and especially effective in treating low-renin hypertension.It is used as topical application for Anal Fissures as it promotes healing of fissures due to its vasodilatory property.

Contraindications and precautions
In congestive heart failure, patients with reduced ventricular function may not be able to counteract the inotropic and chronotropic effects of diltiazem, the result being an even higher compromise of function.
With SA node or AV conduction disturbances, the use of diltiazem should be avoided in patients with SA or AV nodal abnormalities, because of its negative chronotropic and dromotropic effects.
Low blood pressure patients, with systolic blood pressures below 90 mm Hg, should not be treated with diltiazem.
Diltiazem may paradoxically increase ventricular rate in patients with Wolff-Parkinson-White syndrome because of accessory conduction pathways.Diltiazem is relatively contraindicated in the presence of sick sinus syndrome, atrioventricular node conduction disturbances, bradycardia, impaired left ventricle function, peripheral artery occlusive disease, and chronic obstructive pulmonary disease.

Side effects
A reflex sympathetic response, caused by the peripheral dilation of vessels and the resulting drop in blood pressure, works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Undesirable effects include hypotension, bradycardia, dizziness, flushing, fatigue, headaches and edema. Rare side effects are congestive heart failure, myocardial infarction, and hepatotoxicity.Diltiazem is one of the most common drugs that cause drug-induced lupus, along with hydralazine, procainamide, isoniazid, minocycline.

Drug interactions
Because of its inhibition of hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, there are a number of drug interactions. Some of the more important interactions are listed below.

Beta-blockers
Intravenous diltiazem should be used with caution with beta-blockers because, while the combination is most potent at reducing heart rate, there are rare instances of dysrhythmia and AV node block.

Quinidine
Quinidine should not be used concurrently with calcium channel blockers because of reduced clearance of both drugs and potential pharmacodynamic effects at the SA and AV nodes.

Fentanyl
Concurrent use of fentanyl with diltiazem, or any other CYP3A4 inhibitors, as these medications decrease the breakdown of fentanyl and thus increase its effects.

Mechanism
Diltiazem, also known as (2S,3S)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochlorid has a vasodilating activity attributed to the (2S,3S)-isomer.
Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. It binds to the alpha-1 subunit of L-type calcium channels in a fashion somewhat similar to verapamil, another nondihydropyridine (non-DHP) calcium channel blocker. Chemically, it is based upon a 1,4-thiazepine ring, making it a benzothiazepine-type calcium channel blocker.It is a potent and mild vasodilator of coronary and peripheral vessels, respectively, which reduces peripheral resistance and afterload, though not as potent as the dihydropyridine (DHP) calcium channel blockers. This results in minimal reflexive sympathetic changes.Diltiazem has negative inotropic, chronotropic, and dromotropic effects. This means diltiazem causes a decrease in heart muscle contractility – how strong the beat is, lowering of heart rate – due to slowing of the sinoatrial node, and a slowing of conduction through the atrioventricular node – increasing the time needed for each beat. Each of these effects results in reduced oxygen consumption by the heart, reducing angina, typically unstable angina, symptoms. These effects also reduce blood pressure by causing less blood to be pumped out.

Research
Diltiazem is prescribed off-label by doctors in the US for prophylaxis of cluster headaches </s>


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