<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Methadone and can you explain it in depth? [/INST] Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid agonist used for chronic pain and also for opioid dependence. It is used to treat chronic pain, and it is also used to treat addiction to heroin or other opioids.  Prescribed for daily use, the medicine relieves cravings and removes withdrawal symptoms. Detoxification using methadone can be accomplished in less than a month, or it may be done gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take up to five days of use. The pain-relieving effects last about six hours after a single dose. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.Side effects are similar to those of other opioids. These frequently include dizziness, sleepiness, vomiting, and sweating. Serious risks include opioid abuse and  respiratory depression. Abnormal heart rhythms may also occur due to a prolonged QT interval. The number of deaths in the United States involving methadone poisoning declined from 4,418 in 2011 to 3,300 in 2015. Risks are greater with higher doses. Methadone is made by chemical synthesis and acts on opioid receptors.Methadone was developed in Germany around 1937 to 1939 by Gustav Ehrhart and Max Bockmühl. It was approved for use as an analgesic in the United States in 1947, and has been used in the treatment of addiction since the 1960s. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Opioid addiction
Methadone is used for the treatment of opioid use disorder.
It may be used as maintenance therapy or in shorter periods for detoxification to manage opioid withdrawal symptoms. Its use for the treatment of addiction is usually strictly regulated. In the US, outpatient treatment programs must be certified by the federal Substance Abuse and Mental Health Services Administration (SAMHSA) and registered by the Drug Enforcement Administration (DEA) in order to prescribe methadone for opioid addiction.
A 2009 Cochrane review found methadone was effective in retaining people in treatment and in the reduction or cessation of heroin use as measured by self-report and urine/hair analysis but did not affect criminal activity or risk of death.Treatment of opioid-dependent persons with methadone follows one of two routes: maintenance or detoxification. Methadone maintenance therapy (MMT) usually takes place in outpatient settings. It is usually prescribed as a single daily dose medication for those who wish to abstain from illicit opioid use. Treatment models for MMT differ. It is not uncommon for treatment recipients to be administered methadone in a specialist clinic, where they are observed for around 15–20 minutes post-dosing, to reduce the risk of diversion of medication.The duration of methadone treatment programs range from a few months to years. Given opioid dependence is characteristically a chronic relapsing/remitting disorder, MMT may be lifelong. The length of time a person remains in treatment depends on a number of factors. While starting doses may be adjusted based on the amount of opioids reportedly used, most clinical guidelines suggest doses start low (e.g. at doses not exceeding 40 mg daily) and are incremented gradually. It has been found that doses of 40 mg per day were sufficient to help control the withdrawal symptoms but not enough to curb the cravings for the drug. Doses of 80 to 100 mg per day have shown higher rates of success in patients and less illicit heroin use during the maintenance therapy. However, higher doses do put a patient more at risk for overdose than a moderately low dose (e.g. 20 mg/day). Methadone maintenance has been shown to reduce the transmission of bloodborne viruses associated with opioid injection, such as hepatitis B and C, and/or HIV. The principal goals of methadone maintenance are to relieve opioid cravings, suppress the abstinence syndrome, and block the euphoric effects associated with opioids.
Chronic methadone dosing will eventually lead to neuroadaptation, characterised by a syndrome of tolerance and withdrawal (dependence). However, when used correctly in treatment, maintenance therapy has been found to be medically safe, non-sedating, and can provide a slow recovery from opioid addiction. Methadone has been widely used for pregnant women addicted to opioids.

Pain
Methadone is used as an analgesic in chronic pain, often in rotation with other opioids. Due to its activity at the NMDA receptor, it may be more effective against neuropathic pain; for the same reason, tolerance to the analgesic effects may be less than that of other opioids.

Adverse effects
Adverse effects of methadone include:
Sedation
Constipation
Flushing
Perspiration
Heat intolerance
Dizziness or fainting
Weakness
Chronic fatigue, sleepiness and exhaustion
Sleep problems such as drowsiness,
Insomnia
Constricted pupils
Dry mouth
Nausea and vomiting
Low blood pressure
Headache
Heart problems such as chest pain or fast/pounding heartbeat
Abnormal heart rhythms
Respiratory problems such as trouble breathing, slow or shallow breathing (hypoventilation), light-headedness, or fainting
weight gain
Memory loss
Itching
Difficulty urinating
Swelling of the hands, arms, feet, and legs
Mood changes, euphoria, disorientation
Blurred vision
Decreased libido, difficulty in reaching orgasm, or impotence
Missed menstrual periods,
Skin rash
Central sleep apnea

Withdrawal symptoms
Physical symptoms

Lightheadedness
Tearing of the eyes
Mydriasis (dilated pupils)
Photophobia (sensitivity to light)
Hyperventilation syndrome (breathing that is too fast/deep)
Runny nose
Yawning
Sneezing
Nausea, vomiting, and diarrhea
Fever
Sweating
Chills
Tremors
Akathisia (restlessness)
Tachycardia (fast heartbeat)
Aches and pains, often in the joints or legs
Elevated pain sensitivity
Blood pressure that is too high (hypertension, may cause a stroke)Cognitive symptoms

Suicidal ideation
Susceptibility to cravings
Depression
Spontaneous orgasm
Prolonged insomnia
Delirium
Auditory hallucinations
Visual hallucinations
Increased perception of odors (olfaction), real or imagined
Marked increase in sex drive
Agitation
Anxiety
Panic disorder
Nervousness
Paranoia
Delusions
Apathy
Anorexia (symptom)Methadone withdrawal symptoms are reported as being significantly more protracted than withdrawal from opioids with shorter half-lives.
When used for opioid maintenance therapy, Methadone is generally administered as an oral liquid. Methadone has been implicated in contributing to significant tooth decay. Methadone causes dry mouth, reducing the protective role of saliva in preventing decay. Other putative mechanisms of methadone-related tooth decay include craving for carbohydrates related to opioids, poor dental care, and general decrease in personal hygiene. These factors, combined with sedation, have been linked to the causation of extensive dental damage.

Black box warning
Methadone has the following US FDA black box warning:
Risk of addiction and abuse
Potentially fatal respiratory depression
Lethal overdose in accidental ingestion
QT prolongation
Neonatal opioid withdrawal syndrome in children of pregnant women
CYP450 drug interactions
Risks when used with benzodiazepines and other CNS depressants, including alcohol.
A certified opioid treatment program is required under federal law (42 CFR 8.12) when dispensing methadone for the treatment of opioid addiction or detoxification.

Overdose
Most people who overdose on methadone show some of the following symptoms:

Miosis (constricted pupils)
Vomiting
Spasms of the stomach and intestines
Hypoventilation (breathing that is too slow/shallow)
Drowsiness, sleepiness, disorientation, sedation, unresponsiveness
Skin that is cool, clammy (damp), and pale
Blue fingernails and lips
Limp muscles, trouble staying awake, nausea
Unconsciousness and comaThe respiratory depression of an overdose can be treated with naloxone. Naloxone is preferred to the newer, longer-acting antagonist naltrexone. Despite methadones much longer duration of action compared to either heroin and other shorter-acting agonists and the need for repeat doses of the antagonist naloxone, it is still used for overdose therapy. As naltrexone has a longer half-life, it is more difficult to titrate. If too large a dose of the opioid antagonist is given to a dependent person, it will result in withdrawal symptoms (possibly severe). When using naloxone, the naloxone will be quickly eliminated and the withdrawal will be short-lived. Doses of naltrexone take longer to be eliminated from the persons system. A common problem in treating methadone overdoses is that, given the short action of naloxone (versus the extremely longer-acting methadone), a dosage of naloxone given to a methadone-overdosed person will initially work to bring the person out of overdose, but once the naloxone wears off, if no further naloxone is administered, the person can go right back into overdose (based upon time and dosage of the methadone ingested).

Tolerance and dependence
As with other opioid medications, tolerance and dependence usually develop with repeated doses. There is some clinical evidence that tolerance to analgesia is less with methadone compared to other opioids; this may be due to its activity at the NMDA receptor. Tolerance to the different physiological effects of methadone varies; tolerance to analgesic properties may or may not develop quickly, but tolerance to euphoria usually develops rapidly, whereas tolerance to constipation, sedation, and respiratory depression develops slowly (if ever). Methadone fills the same opioid receptors in the brain as heroin and other prescription painkillers making it a suitable substitute.

Driving
Methadone treatment may impair driving ability. Drug abusers had significantly more involvement in serious crashes than non-abusers in a study by the University of Queensland. In the study of a group of 220 drug abusers, most of them poly-drug abusers, 17 were involved in crashes killing people, compared with a control group of other people randomly selected having no involvement in fatal crashes. However, there have been multiple studies verifying the ability of methadone maintenance patients to drive. In the UK, persons who are prescribed oral methadone can continue to drive after they have satisfactorily completed an independent medical examination which will include a urine screen for drugs. The license will be issued for 12 months at a time and even then, only following a favourable assessment from their own doctor. Individuals who are prescribed methadone for either IV or IM administration cannot drive in the UK, mainly due to the increased sedation effects that this route of use can cause.

Mortality
In the United States, deaths linked to methadone more than quadrupled in the five-year period between 1999 and 2004. According to the U.S. National Center for Health Statistics, as well as a 2006 series in the Charleston Gazette (West Virginia), medical examiners listed methadone as contributing to 3,849 deaths in 2004. That number was up from 790 in 1999. Approximately 82 percent of those deaths were listed as accidental, and most deaths involved combinations of methadone with other drugs (especially benzodiazepines).
Although deaths from methadone are on the rise, methadone-associated deaths are not being caused primarily by methadone intended for methadone treatment programs, according to a panel of experts convened by the Substance Abuse and Mental Health Services Administration, which released a report titled "Methadone-Associated Mortality, Report of a National Assessment". The consensus report concludes that "although the data remains incomplete, National Assessment meeting participants concurred that methadone tablets or Diskets® distributed through channels other than opioid treatment programs most likely are the central factors in methadone-associated mortality."In 2006, the U.S. Food and Drug Administration issued a caution about methadone, titled "Methadone Use for Pain Control May Result in Death." The FDA also revised the drugs package insert. The change deleted previous information about the usual adult dosage. The Charleston Gazette reported, "The old language about the usual adult dose was potentially deadly, according to pain specialists."

Pharmacology
Methadone acts by binding to the µ-opioid receptor, but also has some affinity for the NMDA receptor, an ionotropic glutamate receptor. Methadone is metabolized by CYP3A4, CYP2B6, CYP2D6, and is a substrate, or in this case target, for the P-glycoprotein efflux protein, a protein which helps pump foreign substances out of cells, in the intestines and brain. The bioavailability and elimination half-life of methadone are subject to substantial interindividual variability. Its main route of administration is oral. Adverse effects include sedation, hypoventilation, constipation and miosis, in addition to tolerance, dependence and withdrawal difficulties. The withdrawal period can be much more prolonged than with other opioids, spanning anywhere from two weeks to several months.
The metabolic half-life of methadone differs from its duration of action. The metabolic half-life is 8 to 59 hours (approximately 24 hours for opioid-tolerant people, and 55 hours in opioid-naive people), as opposed to a half-life of 1 to 5 hours for morphine. The length of the half-life of methadone allows for exhibition of respiratory depressant effects for an extended duration of time in opioid-naive people.

Mechanism of action
Levomethadone (the L enantiomer) is a μ-opioid receptor agonist with higher intrinsic activity than morphine, but lower affinity. Dextromethadone (the S enantiomer) does not affect opioid receptors but binds to the glutamatergic NMDA (N-methyl-D-aspartate) receptor, and acts as an antagonist against glutamate. Methadone has been shown to reduce neuropathic pain in rat models, primarily through NMDA receptor antagonism. Glutamate is the primary excitatory neurotransmitter in the central nervous system. NMDA receptors have a very important role in modulating long-term excitation and memory formation. NMDA antagonists such as dextromethorphan (DXM, a cough suppressant), ketamine (a dissociative anaesthetic), tiletamine (a veterinary anaesthetic) and ibogaine (from the African tree Tabernanthe iboga) are being studied for their role in decreasing the development of tolerance to opioids and as possible for eliminating addiction/tolerance/withdrawal, possibly by disrupting memory circuitry. Acting as an NMDA antagonist may be one mechanism by which methadone decreases craving for opioids and tolerance, and has been proposed as a possible mechanism for its distinguished efficacy regarding the treatment of neuropathic pain. The dextrorotary form (dextromethadone), which acts as an NMDA receptor antagonist and is devoid of opioid activity, has been shown to produce analgesia in experimental models of chronic pain. Methadone also acted as a potent, noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist in rat receptors, expressed in human embryonic kidney cell lines.

Metabolism
Methadone has a slow metabolism and very high fat solubility, making it longer lasting than morphine-based drugs. Methadone has a typical elimination half-life of 15 to 60 hours with a mean of around 22. However, metabolism rates vary greatly between individuals, up to a factor of 100, ranging from as few as 4 hours to as many as 130 hours, or even 190 hours. This variability is apparently due to genetic variability in the production of the associated cytochrome enzymes CYP3A4, CYP2B6 and CYP2D6. Many substances can also induce, inhibit or compete with these enzymes further affecting (sometimes dangerously) methadone half-life. A longer half-life frequently allows for administration only once a day in opioid detoxification and maintenance programs. People who metabolize methadone rapidly, on the other hand, may require twice daily dosing to obtain sufficient symptom alleviation while avoiding excessive peaks and troughs in their blood concentrations and associated effects. This can also allow lower total doses in some such people. The analgesic activity is shorter than the pharmacological half-life; dosing for pain control usually requires multiple doses per day normally dividing daily dosage for administration at 8 hour intervals.The main metabolic pathway involves N-demethylation by CYP3A4 in the liver and intestine to give 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). This inactive product, as well as the inactive 2-ethyl-5-methyl-3,3-
diphenyl-1-pyrroline (EMDP), produced by a second N-demethylation, are detectable in the urine of those taking methadone.

Methadone and its two main metabolites

Route of administration
The most common route of administration at a methadone clinic is in a racemic oral solution, though in Germany, only the R enantiomer (the L optical isomer) has traditionally been used, as it is responsible for most of the desired opioid effects. The single-isomer form is becoming less common due to the higher production costs.
Methadone is available in traditional pill, sublingual tablet, and two different formulations designed for the person to drink. Drinkable forms include ready-to-dispense liquid (sold in the United States as Methadose), and Diskets® (known on the street as "wafers" or "biscuits") tablets which are dispersible in water for oral administration, used in a similar fashion to Alka-Seltzer. The liquid form is the most common as it allows for smaller dose changes. Methadone is almost as effective when administered orally as by injection. Oral medication is usually preferable because it offers safety, simplicity and represents a step away from injection-based drug abuse in those recovering from addiction. U.S. federal regulations require the oral form in addiction treatment programs. Injecting methadone pills can cause collapsed veins, bruising, swelling, and possibly other harmful effects. Methadone pills often contain talc that, when injected, produces a swarm of tiny solid particles in the blood, causing numerous minor blood clots. These particles cannot be filtered out before injection, and will accumulate in the body over time, especially in the lungs and eyes, producing various complications such as pulmonary hypertension, an irreversible and progressive disease. The formulation sold under the brand name Methadose (flavored liquid suspension for oral dosing, commonly used for maintenance purposes) should not be injected either.Information leaflets included in packs of UK methadone tablets state that the tablets are for oral use only and that use by any other route can cause serious harm. In addition to this warning, additives have now been included in the tablet formulation to make the use of them by the IV route more difficult.

Chemistry
Detection in biological fluids
Methadone and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), are often measured in urine as part of a drug abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Methadone usage history is considered in interpreting the results as a chronic user can develop tolerance to doses that would incapacitate an opioid-naïve individual. Chronic users often have high methadone and EDDP baseline values.

Conformation
The protonated form of methadone takes on an extended conformation, while the free base is more compact.  In particular, it was found that there is an interaction between the tertiary amine and the carbonyl carbon of the ketone function (R3N ••• >C=O) that limits the molecules conformation freedom, though the distance (291 pm by X-ray) is far too long to represent a true chemical bond.  However, it does represent the initial trajectory of attack of an amine on a carbonyl group and was an important piece of experimental evidence for the proposal of the Bürgi–Dunitz angle for carbonyl addition reactions.

History
Methadone was developed in 1937 in Germany by scientists working for I.G. Farbenindustrie AG at the Farbwerke Hoechst who were looking for a synthetic opioid that could be created with readily available precursors, to solve Germanys opium and morphine shortage problem. On 11 September 1941 Bockmühl and Ehrhart filed an application for a patent for a synthetic substance they called Hoechst 10820 or Polamidon (a name still in regular use in Germany) and whose structure had little relation to morphine or other "true opiates” such as diamorphine (HeroinTM), desomorphine (PermonidTM), nicomorphine (VilanTM), codeine, dihydrocodeine, oxymorphone (OpanaTM), hydromorphone (DilaudidTM), oxycodone (OxyContinTM), hydrocodone (DicodidTM), and other closely related opium alkaloid derivatives and analogues. It was brought to market in 1943 and was widely used by the German army during WWII as a substitute for morphine.In the 1930s, pethidine (meperidine) went into production in Germany; however, production of methadone, then being developed under the designation Hoechst 10820, was not carried forward because of side effects discovered in the early research. After the war, all German patents, trade names and research records were requisitioned and expropriated by the Allies. The records on the research work of the I.G. Farbenkonzern at the Farbwerke Hoechst were confiscated by the U.S. Department of Commerce Intelligence, investigated by a Technical Industrial Committee of the U.S. Department of State and then brought to the US. The report published by the committee noted that while methadone itself was potentially addictive, it produced “considerably” less euphoria, sedation, and respiratory depression than morphine at equianalgesic doses and was thus interesting as a commercial drug. The same report also compared methadone to pethidine. German researchers reported that methadone was capable of producing strong morphine-like physical dependence, which is characterized by opioid withdrawal symptoms which are lesser in severity and intensity compared to morphine, but methadone was associated with a considerably prolonged or protracted withdrawal syndrome when compared to morphine. Morphine produced higher rates of self-administration and reinforcing behaviour in both human and animal subjects when compared to both methadone and pethidine. In comparison to equianalgesic doses of pethidine (DemerolTM), methadone was shown to produce less euphoria, but higher rates of constipation, and roughly equal levels of respiratory depression and sedation.In the early 1950s, methadone (most times the racemic HCl salts mixture) was also investigated for use as an antitussive.Isomethadone, noracymethadol, LAAM, and normethadone were first developed in Germany, United Kingdom, Belgium, Austria, Canada, and the United States in the thirty or so years after the 1937 discovery of pethidine, the first synthetic opioid used in medicine. These synthetic opioids have increased length and depth of satiating any opiate cravings and generate very strong analgesic effects due to their long metabolic half-life and strong receptor affinity at the mu-opioid receptor sites. Therefore, they impart much of the satiating and anti-addictive effects of methadone by means of suppressing drug cravings.It was only in 1947 that the drug was given the generic name “methadone” by the Council on Pharmacy and Chemistry of the American Medical Association. Since the patent rights of the I.G. Farbenkonzern and Farbwerke Hoechst were no longer protected, each pharmaceutical company interested in the formula could buy the rights for the commercial production of methadone for just one dollar (MOLL 1990).
Methadone was introduced into the United States in 1947 by Eli Lilly and Company as an analgesic under the trade name Dolophine.  An urban myth later arose that Nazi leader Adolf Hitler ordered the manufacture of methadone or that the brand name Dolophine was named after him, probably based on the similarity of “doloph” with “Adolph”. (The pejorative term “adolphine” would appear in the early 1970s.) However, the name “Dolophine” was a contraction of "Dolo” from the Latin word dolor (pain), and finis, the Latin word for “end”. Therefore, Dolophine literally means “pain end”.Methadone was studied as a treatment for opioid addiction at the Addiction Research Center of the Narcotics Farm in Lexington, Kentucky in the 1950s, and by Rockefeller University physicians Robert Dole and Marie Nyswander in the 1960s in New York City.  By 1976, methadone clinics had opened in cities including Chicago, New York, and New Haven, with some 38,000 patients treated in New York City alone.

Society and culture
Brand names
Brand names include Dolophine, Symoron, Amidone, Methadose, Physeptone, Metadon, Metadol, Metadol-D, Heptanon and Heptadon among others.

Cost
In the US, generic methadone tablets are inexpensive, with retail prices ranging from $0.25 to $2.50 per defined daily dose. Brand-name methadone tablets may cost much more.
Methadone maintenance clinics in the US may be covered by private insurances, Medicaid, or Medicare. Medicare covers methadone under the prescription drug benefit, Medicare Part D, when it is prescribed for pain, but not when it is used for opioid dependence treatment because it cannot be dispensed in a retail pharmacy for this purpose. In California methadone maintenance treatment is covered under the medical benefit. Patients eligibility for methadone maintenance treatment is most often contingent on them being enrolled in substance abuse counseling. People on methadone maintenance in the US either have to pay cash or if covered by insurance must complete a pre-determined number of hours per month in therapeutic groups or counseling. The United States Department of Veterans Affairs (VA) Alcohol and Drug Dependence Rehabilitation Program offers methadone services to eligible veterans enrolled in the VA health care system.Methadone maintenance treatment (MMT) cost analyses often compare the cost of clinic visits versus the overall societal costs of illicit opioid use. A preliminary cost analysis conducted in 2016 by the US Department of Defense determined that methadone treatment, which includes psychosocial and support services, may cost an average of $126.00 per week or $6,552.00 per year. The average cost for one full year of methadone maintenance treatment is approximately $4,700 per patient, whereas one full year of imprisonment costs approximately $24,000 per person.

Controversy
Methadone substitution as a treatment of opioid addiction has been criticized in the social sciences for its role in the social control of addicts.  Such critique centers on the notion that substance addiction is reframed with a disease model. Thus methadone, which mimics the effects of opioids and renders the addict compliant, is labeled as a "treatment" and so achieves the disciplinary objectives of managing the "undesirables". It is suggested that methadone does not function as much to curb addiction as to redirect it and maintain dependency on authorised channels. Several authors apply a Foucauldian analysis to the widespread prescription of the drug and use in institutions such as prisons, hospitals, and rehabilitation centres.

Regulation
United States and Canada
Methadone is a Schedule I controlled substance in Canada and Schedule II in the United States, with an ACSCN of 9250 and a 2014 annual aggregate manufacturing quota of 31,875 kilos for sale. Methadone intermediate is also controlled, under ACSCN 9226 also under Schedule II, with a quota of 38,875 kilos. In most countries of the world, methadone is similarly restricted. The salts of methadone in use are the hydrobromide (free base conversion ratio 0.793), hydrochloride (0.894), and HCl monohydrate (0.850). Methadone is also regulated internationally as a Schedule I controlled substance under the United Nations Single Convention on Narcotic Drugs of 1961.

Methadone clinics
In the United States, prescription of methadone requires intensive monitoring and must be obtained in-person from an opioid treatment program—colloquially known as a methadone clinic—when prescribed for opioid use disorder (OUD). According to federal laws, methadone cannot be prescribed by a doctor and obtained from a pharmacy in order to treat addiction. Because of its long half-life, methadone is almost invariably prescribed to be taken in a single daily dose. At nearly all methadone clinics in the US, patients must visit a clinic to receive and take their dose under the supervision of a nurse. Both patients who are new to methadone treatment and high-risk patients—such as those who are using drugs and alcohol, including cannabis—must visit the clinic daily.  However, some clinics close on national holidays and provide doses to patients to take home.

Take-home or take-away methadone
After 90 days to six months (depending on the clinic), if patients have met the clinics criteria, they are typically eligible for take-home doses of methadone. Therefore, they may be allowed to take anywhere from one to six days to visit the clinic once or twice weekly instead of every day. In accordance with DEA and SAMHSA regulations, patients who use other drugs (including legally obtained cannabis) are not eligible for take-home methadone.In recent years, patients, doctors, nurses, those working in the addiction field, and advocates of many kinds have heavily criticized the extremely tight regulations regarding take-home methadone </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Crizanlizumab and can you explain it in depth? [/INST] Crizanlizumab, sold under the brand name Adakveo & Ryverna both by Novartis, is a monoclonal antibody medication that binds to P-selectin </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Phentermine/topiramate and can you explain it in depth? [/INST] Phentermine/topiramate, sold under the brand name Qsymia, is a combination drug of phentermine and topiramate used to treat obesity. It is used together with dietary changes and exercise. If less than 3% weight loss is seen after 3 months it is recommended the medication be stopped. The weight loss is modest. Effects on heart related health problems or death is unclear.Common side effects include tingling, dizziness, trouble sleeping, and constipation. Serious side effects may include suicide, abuse. Use is not recommended during pregnancy. Phentermine is a stimulant and appetite suppressant. Topiramate is an anticonvulsant that has weight loss side effects. The exact mechanism of action for both drugs is unknown.Phentermine/topiramate was approved for medical use in the United States in 2012. Approval was denied in Europe, due to concerns regarding safety.

Medical uses
In clinical trials, people treated with the highest dose of phentermine/topiramate ER in combination with a program of diet and exercise lost 10% to 11% of their body weight compared to 1% to 2% for those who received placebo. In addition, 62% to 70% of subjects receiving the recommended dose or top dose of phentermine/topiramate ER achieved ≥5% weight reduction by week 56 (ITT-LOCF) compared to 17% to 21% of those receiving a placebo.A Cochrane review on the long-term effects of weight-reducing drugs on people with hypertension found that phentermine/topiramate reduced body weight (when compared to orlistat, and naltrexone/bupropion) and also reduced blood pressure.

Adverse effects
In clinical trials, the most common adverse events which occurred at a rate ≥5% and ≥1.5 times placebo included paraesthesia (tingling in fingers/toes), dizziness, altered taste, insomnia, constipation, and dry mouth.In the U.S., the drug label contains warnings for increased heart rate, suicidal behavior and ideation, glaucoma, mood and sleep disorders, creatine elevation, and metabolic acidosis.  Some of these warnings are based on historical observations in epilepsy patients taking topiramate.  The FDA is requiring the company to perform a post-approval cardiovascular outcomes trial, due in part to the observation of increased heart rate in some people taking the drug in clinical trials.

Pregnancy
Phentermine and topiramate can cause fetal harm. Data from pregnancy registries and epidemiology studies indicate that a fetus exposed to topiramate in the first trimester of pregnancy has an increased risk of oral clefts (cleft lip with or without cleft palate). If a patient becomes pregnant while taking phentermine/topiramate ER, treatment should be discontinued immediately, and the patient should be apprised of the potential hazard to a fetus </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Mometasone and can you explain it in depth? [/INST] Mometasone, also known as mometasone y 3 s, is a steroid medication used to treat certain skin conditions, hay fever, and asthma. Specifically it is used to prevent rather than treat asthma attacks. It can be applied to the skin, inhaled, or used in the nose. Mometasone furoate, not mometasone, is used in medical products.Common side effects when used for asthma includes asthma and thrush. It is therefore recommended to rinse the mouth after use. Long term use may increase the risk for glaucoma and cataracts. Common side effects when used in the nose includes upper respiratory tract infections and nose bleeds. Common side effects when applied on the skin include acne, skin atrophy, and itchiness. It works by decreasing inflammation.Mometasone furoate was patented in 1981 and came into medical use in 1987. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2017, it was the 197th most commonly prescribed medication in the United States, with more than two million prescriptions.

Medical uses
Mometasone furoate is used in the treatment of inflammatory skin disorders (such as eczema and psoriasis) (topical form), allergic rhinitis (such as hay fever) (topical form), asthma (inhalation form) for patients unresponsive to less potent corticosteroids, and penile phimosis. In terms of steroid strength, it is more potent than hydrocortisone, and less potent than dexamethasone.Some low-quality evidence suggests the use of mometasone for symptomatic improvement in children with adenoid hypertrophy.Mometasone is used to alleviate inflammation and itchiness in skin conditions that respond to treatment with glucocorticoids such as psoriasis and atopic dermatitis.Nasal mometasone is used in adults (including the elderly) and children over two years of age, to diminish the symptoms of hay fever (seasonal allergic rhinitis) and other allergies (perennial rhinitis), including nasal congestion, discharge, pruritus, and sneezing and to treat nasal polyps.It is not useful for the common cold.

Asthma
Mometasone furoate can be used with formoterol for the treatment of asthma, due to its anti-inflammatory properties.

Contraindications
People should not use inhaled mometasone or mometasone nasal spray if:

glaucoma or cataracts
hypersensitivity or allergic to any ingredient in mometasoneThose who are using mometasone nasal or inhaled for a long period of time (e.g. more than three months) should get regular eye exams to check for glaucoma and cataracts and should take precautions to avoid infections such as taking a vitamin D supplement, staying away from those with an infection (chickenpox, measles, colds or flu, COVID-19), washing foods, hand washing and calling a family doctor at the first sign of a severe infection.
People should not use mometasone topical (skin cream) if:

hypersensitive or allergic to any ingredient in the skin creamMometasone furoate is in class C in terms of safety while use during pregnancy. Therefore, its risks to the baby cannot be ruled out. Therefore, the use in pregnancy is not recommended.

Side effects
The nasal spray form of mometasone may cause the following side effects:

headache
Viral upper respiratory infections
sore throat
nose bleeds
cough
muscle and joint painSerious side effects include: Thrush (fungal infection in the nose or throat), slow wound healing, eye problems such as glaucoma or cataracts, weakened immune system (immunodeficiency) which causes an increased susceptibility to infections and adrenal insufficiency.
The inhaled form of mometasone for asthma may cause the following side effects

headache
stuffy or runny nose
dry throat
swelling of nose, throat and sinuses
flu like symptoms
painful menstrual periodsSerious side effects may include: allergic reactions (anaphylaxis), increased risk of osteoporosis, glaucoma and cataracts, thrush in the mouth or throat, growth retardation in children, bronchospasms, adrenal insufficiency and weakened immune system which causes an increased susceptibility to infections.
The topical (skin cream) version may cause:

burning and itching at the application site
acne
changes in skin color
dryness at application site
skin soresThe only serious side effect that is known with mometasone topical is adrenal insufficiency.

Pharmacology
Pharmacodynamics
Mometasone furoate reduces inflammation by causing several effects:
Reversing the activation of inflammatory proteins
Activating the secretion of anti-inflammatory proteins
Stabilizing cell membranes
Decreasing the influx of inflammatory cellsIn addition to the glucocorticoid properties of mometasone furoate, it is a very potent agonist of the progesterone receptor as well as a partial agonist of the mineralocorticoid receptor.

Mechanism of action
Mometasone, like other corticosteroids, possesses anti-inflammatory, antipruritic, and vasoconstrictive properties. For allergies, corticosteroids reduce the allergic reactions in various types of cells (mastocytes and eosinophils) that are responsible for allergic reactions. Mometasone and other corticosteroids circulate in the blood easily, crossing cellular membranes and binding with cytoplasmic receptors, resulting in the transcription and synthesis of proteins. It also inhibits the actions of the enzyme cytochrome P450 2C8 which participates in the activity of monooxygenase.The inflammation is reduced in decreasing the liberation of hydrolase acids of leukocytes, the prevention of the accumulation macrophages in the sites of inflammation, the interference with adhesion of leukocytes to capillary walls, the reduction of the permeability of the capillary membranes and consequently edema, the reduction of complementary components, inhibition of histamine and kinin liberation, and interference with scar tissue formation. The proliferation of fibroblasts and collagen deposits is also reduced. It is believed that the action of corticosteroid anti-inflammatory agents is bound to inhibitive proteins of phospholipase A2, collectively called lipocortins. The lipocortins, in turn, control the biosynthesis of potent mediators of inflammation as the prostaglandins and leukotrienes, inhibiting the liberation of the molecular precursors of arachidonic acid. Intranasal mometasone alleviates symptoms such as rhinorrhea aquosa, nasal congestion, nasal drip, sneezing, and pharyngeal itching. Topical administration applied to skin reduces the inflammation associated with chronic or acute dermatosis.
Although mometasone furoate does not have significant systemic immunomodulatory effects, it can be considered a local immunosuppressive drug because clinical studies have shown reductions (vs. baseline ) in neutrophils (a white blood cell) in the nasal mucosa. It could be also considered an antihistamine along with its glucocorticoid effects because it significantly reduces histamine and eosinophil cationic protein levels.

Pharmacokinetics
Metabolism
Extensive metabolic hepatic metabolism of mometasone furoate to multiple metabolites occurs </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ciclosporin and can you explain it in depth? [/INST] Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is a natural product. It is taken orally or  intravenously for rheumatoid arthritis, psoriasis, Crohns disease, nephrotic syndrome, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).Common side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting. Other severe side effects include an increased risk of infection, liver problems, and an increased risk of lymphoma. Blood levels of the medication should be checked to decrease the risk of side effects. Use during pregnancy may result in preterm birth; however, ciclosporin does not appear to cause birth defects.Ciclosporin is believed to work by decreasing the function of lymphocytes. It does this by forming a complex with cyclophilin to block the phosphatase activity of calcineurin, which in turn decreases the production of inflammatory cytokines by T-lymphocytes.Ciclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983. It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 195th most commonly prescribed medication in the United States, with more than 2 million prescriptions that year. It is available as a generic medication.

Medical uses
Ciclosporin is indicated to treat and prevent graft-versus-host disease in bone marrow transplantation and to prevent rejection of kidney, heart, and liver transplants. It is also approved in the US for treating of rheumatoid arthritis and psoriasis, persistent nummular keratitis following adenoviral keratoconjunctivitis, and as eye drops for treating dry eyes caused by Sjögrens syndrome and meibomian gland dysfunction.In addition to these indications, ciclosporin is also used in severe atopic dermatitis, Kimura disease, pyoderma gangrenosum, chronic hives, acute systemic mastocytosis, and posterior or intermediate uveitis with noninfective cause. It is also used, albeit infrequently, in severe rheumatoid arthritis and related diseases.Ciclosporin has also been used in people with acute severe ulcerative colitis and hives that do not respond to treatment with steroids.

Side effects
Side effects of ciclosporin can include gum enlargement, increased hair growth, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, increased cholesterol, trouble breathing, numbness and tingling (particularly of the lips), itchiness, high blood pressure, potassium retention (possibly leading to hyperkalemia), kidney and liver dysfunction, burning sensations at finger tips, and an increased vulnerability to opportunistic fungal and viral infections. Ciclosporin causes hypertension by inducing vasoconstriction in the kidneys and increasing sodium reabsorption. The increase in blood pressure can cause cardiovascular events; it is thus recommended that the lowest effective dose for people requiring long-term treatment be used.Ciclosporin use after a kidney transplantation is associated with increased levels of uric acid in the blood and, in some cases, gout. This is due to the decrease in glomerular filtration rate, which leads to uric acid retention. Use of azathioprine as an alternative has shown to reduce the incidence of gouty arthritis.Ciclosporin is listed as an IARC Group 1 carcinogen (i.e. there is sufficient evidence of carcinogenicity in humans), specifically leading to squamous cell skin cancer and non-Hodgkin lymphoma.

Pharmacology
Mechanism of action
Ciclosporins main effect is to lower the activity of T-cells; it does so by inhibiting calcineurin in the calcineurin–phosphatase pathway and preventing the mitochondrial permeability transition pore from opening. Ciclosporin binds to the cytosolic protein cyclophilin (immunophilin) of lymphocytes, especially of T cells. This cyclosporin—cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of interleukin 2. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the T-cell nucleus and increases the transcription of genes for IL-2 and related cytokines. Ciclosporin, by preventing the dephosphorylation of NF-AT, leads to reduced effector T-cell function; it does not affect cytostatic activity.Ciclosporin also binds to the cyclophilin D protein that constitutes part of the mitochondrial permeability transition pore (MPTP), thus preventing MPTP opening. The MPTP is found in the mitochondrial membrane of cardiac muscle cells. MPTP opening signifies a sudden change in the inner mitochondrial membrane permeability, allowing protons and other ions and solutes of a size up to ~1.5 kDa to go through the inner membrane. This change of permeability is considered a cellular catastrophe, leading to cell death. However, brief mitochondrial permeability transition pore openings play an essential physiological role in maintaining healthy mitochondrial homeostasis.

Pharmacokinetics
Ciclosporin is a cyclic peptide of 11 amino acids; it contains a single D-amino acid, which is rarely encountered in nature. Unlike most peptides, ciclosporin is not synthesized by ribosomes.Ciclosporin is highly metabolized in humans and animals after ingestion. The metabolites, which include cyclosporin B, C, D, E, H, and L, have less than 10% of ciclosporins immunosuppressant activity and are associated with higher kidney toxicity. Individual ciclosporin metabolites have been isolated and characterized but do not appear to be extensively studied.

Biosynthesis
Cyclosporin is synthesized by a nonribosomal peptide synthetase, cyclosporin synthetase. The enzyme contains an adenylation domain, a thiolation domain, a condensation domain, and an N-methyltransferase domain. The adenylation domain is responsible for substrate recognition and activation, whereas the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine, and the condensation domain elongates the peptide chain. Cyclosporin synthetase substrates include L-valine, L-leucine, L-alanine, glycine, 2-aminobutyric acid, 4-methylthreonine, and D-alanine, which is the starting amino acid in the biosynthetic process. With the adenylation domain, cyclosporin synthetase generates the acyl-adenylated amino acids, then covalently binds the amino acid to phosphopantetheine through a thioester linkage. Some of the amino acid substrates become N-methylated by S-adenosyl methionine. The cyclization step releases cyclosporin from the enzyme. Amino acids such as D-Ala and butenyl-methyl-L-threonine (Bmt) indicate cyclosporin synthetase requires the action of other enzymes. The racemization of L-Ala to D-Ala by alanine racemase is pyridoxal phosphate-dependent. The formation of butenyl-methyl-L-threonine is performed by a Bmt polyketide synthase that uses acetate/malonate as its starting material.

Gene cluster
Tolypocladium inflatum, the species currently used for mass production of Cyclosporin, has the biosynthetic genes arranged into a 12-gene cluster. Of these 12 genes, SimA (Q09164) is the cyclosporin synthetase, SimB (CAA02484.1) is the alanine racemase, and SimG (similar to ATQ39432.1) is the polyketide synthase. These genes are associated with an active retrotransposon. Although these sequences are poorly-annotated on GenBank and other databases, 90% similar sequences can be found for the Cyclosporin-producing Beauveria felina (or Amphichorda ~). SimB has two paralogs in the same organism with different but overlapping functions thanks to their low speficity.

History
In 1970, new strains of fungi were isolated from soil samples taken from Norway and from Wisconsin in the US by employees of Sandoz (now Novartis) in Basel, Switzerland. Both strains produced a family of natural products called cyclosporins. Two related components that had antifungal activity were isolated from extracts from these fungi. The Norwegian strain, Tolypocladium inflatum Gams, was later used for the large scale fermentation of ciclosporin.The immunosuppressive effect of the natural product ciclosporin was discovered on January 31, 1972 in a screening test on immune suppression designed and implemented by Hartmann F. Stähelin at Sandoz. The chemical structure of cyclosporin was determined in 1976, also at Sandoz. The success of the drug candidate ciclosporin in preventing organ rejection was shown in kidney transplants by R.Y. Calne and colleagues at the University of Cambridge, and in liver transplants performed by Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on 9 March 1980, was a 28-year-old woman. In the United States, the Food and Drug Administration (FDA) approved ciclosporin for clinical use in 1983.

Society and culture
Name
The natural product was named cyclosporin by the German-speaking scientists who first isolated it and cyclosporine when translated into English. Per International Nonproprietary Name (INN) guidelines for drugs, the y was replaced with i so that the INN for the medication is spelled ciclosporin.Ciclosporin is the INN and the British Approved Name (BAN), while cyclosporine is the United States Adopted Name (USAN) and cyclosporin is a former BAN.

Available forms
Ciclosporin exhibits very poor solubility in water, and, as a consequence, suspension and emulsion forms of the medication have been developed for oral administration and for injection. Ciclosporin was originally brought to market by Sandoz (now Novartis), under the brand name Sandimmune, which is available as soft gelatin capsules, an oral solution, and a formulation for intravenous administration. These are all nonaqueous compositions. A newer microemulsion, orally-administered formulation, Neoral, is available as a solution and as soft gelatin capsules. The Neoral compositions are designed to form microemulsions in contact with water.Generic ciclosporin preparations have been marketed under various trade names, including Cicloral (Sandoz/Hexal), Gengraf (Abbott) and Deximune (Dexcel Pharma). Since 2002, a topical emulsion of ciclosporin for treating inflammation caused by keratoconjunctivitis sicca (dry eye syndrome) has been marketed under the trade name Restasis. Ikervis is a similar formulation with a concentration of 0.1%. Inhaled ciclosporin formulations are in clinical development, and include a solution in propylene glycol and liposome dispersions.

Research
Neuroprotection
Ciclosporin is currently in a phase II/III (adaptive) clinical study in Europe to determine its ability to ameliorate neuronal cellular damage and reperfusion injury (phase III) in traumatic brain injury. This multi-center study is being organized by NeuroVive Pharma and the European Brain Injury Consortium using NeuroVives formulation of ciclosporin called NeuroSTAT (also known by its cardioprotection trade name of CicloMulsion). This formulation uses a lipid emulsion base instead of cremophor and ethanol. NeuroSTAT was compared to Sandimmune in a phase I study and found to be bioequivalent. In this study, NeuroSTAT did not exhibit the anaphylactic and hypersensitivity reactions found in cremophor- and ethanol-based products.Ciclosporin has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury. Ciclosporin blocks the formation of the mitochondrial permeability transition pore, which has been found to cause much of the damage associated with head injury and neurodegenerative diseases. Ciclosporins neuroprotective properties were first discovered in the early 1990s when two researchers (Eskil Elmér and Hiroyuki Uchino) were conducting experiments in cell transplantation. An unintended finding was that cyclosporin A was strongly neuroprotective when it crossed the blood–brain barrier. This same process of mitochondrial destruction through the opening of the MPT pore is implicated in making traumatic brain injuries much worse.

Cardiac disease
Ciclosporin has been used experimentally to treat cardiac hypertrophy (an increase in cell volume).
Inappropriate opening of the mitochondrial permeability transition pore (MPTP) manifests in ischemia (blood flow restriction to tissue) and reperfusion injury (damage occurring after ischemia when blood flow returns to tissue), after myocardial infarction (heart attack) and when mutations in mitochondrial DNA polymerase occur. The heart attempts to compensate for disease state by increasing the intracellular Ca2+ to increase the contractility cycling rates. Constitutively high levels of mitochondrial Ca2+ cause inappropriate MPTP opening leading to a decrease in the cardiac range of function, leading to cardiac hypertrophy as an attempt to compensate for the problem.Cyclosporin A has been shown to decrease cardiac hypertrophy by affecting cardiac myocytes in many ways. Cyclosporin A binds to cyclophilin D to block the opening of MPTP, and thus decreases the release of protein cytochrome C, which can cause programmed cell death. CypD is a protein within the MPTP that acts as a gate; binding by cyclosporin A decreases the amount of inappropriate opening of MPTP, which decreases the intramitochondrial Ca2+. Decreasing intramitochondrial Ca2+ allows for reversal of cardiac hypertrophy caused in the original cardiac response </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Methylprednisolone and can you explain it in depth? [/INST] Methylprednisolone (Depo-Medrol, Medrol, Solu-Medrol) is a synthetic glucocorticoid, primarily prescribed for its anti-inflammatory and immunosuppressive effects. It is either used at low doses for chronic illnesses or used concomitantly at high doses during acute flares. Methylprednisolone and its derivatives can be administered orally or parenterally.Regardless of route of administration, methylprednisolone integrates systemically as exhibited by its effectiveness to quickly reduce inflammation during acute flares. It is associated with many adverse reactions that require tapering off the drug as soon as the disease is under control. Serious side effects include iatrogenic Cushings Syndrome, hypertension, osteoporosis, diabetes, infection, and skin atrophy.Chemically, methylprednisolone is a synthetic pregnane steroid hormone derived from hydrocortisone and prednisolone. It belongs to a class of synthetic glucocorticoids and more generally, corticosteroids. It acts as a mineralocorticoid and glucocorticoid receptor agonist. In comparison to other exogenous glucocorticoids, methylprednisolone has a higher affinity to glucocorticoid receptors than to mineralocorticoid receptors.
Glucocorticoids name was derived after the discovery of their involvement in regulating carbohydrate metabolism. The cellular functions of glucocorticoids, such as methylprednisolone, are now understood to regulate homeostasis, metabolism, development, cognition, and inflammation. They play a critical role in adapting and responding to environmental, physical and emotional stress.Methylprednisolone was first synthesized and manufactured by The Upjohn Company (now Pfizer) and FDA approved in the United States in October 1957. In 2019, it was the 161st most commonly prescribed medication in the United States, with more than 3 million prescriptions. Methylprednisolone is also on the World Health Organizations List of Essential Medicines for its effects against lymphoid leukemia.

Pharmacodynamics
Methylprednisolone is a synthetic glucocorticoid (GCs) that exhibits pleiotropic effects on a variety of physiological mechanisms. However, they have been prescribed extensively for their effects on inflammation and immunity. The effects of synthetic glucocorticoids, such as methylprednisolone, is dependent on its association with intracellular glucocorticoid receptors (GRs), and to a lesser extent, mineralocorticoid receptors (MRs). GRs are widely distributed in contrast to MRs that show a restricted tissue distribution. By this mechanism, the ligand-bound receptor translocate to the nucleus and modulate gene expression.

Signal transduction
In the absence of endogenous or synthetic GCs, monomeric GRs are located in the cytoplasm and form multiprotein complexes with heat shock proteins (HSPs), immunophilins, and other chaperones such as src, and p23. The GR acts in a ligand-dependent manner, with the complex holding the GR in an inactive form with high specificity for the ligand. When methylprednisolone from the plasma or interstitial fluid diffuses passively across the cell membrane, it binds to the GR inducing a conformational change and GC-GR dimerization. It was previously thought that this conformational change was necessary to dissociate the multiprotein complex to allow the ligand bound receptor to translocate to the nucleus. However, recent studies have indicated that chaperones play a role in nuclear import. The now active methylprednisolone-GR complex can either transduce non-genomic changes in the cytoplasm or translocate to the nucleus and regulate transcriptional activity of target genes by direct, tethering or composite mechanisms.

Genomic signaling
Genomic mechanisms, regardless of which type, elicit responses with a slow onset and a slow dissipation. This is attributed to the duration of mRNA transcription and translation. Glucocorticoids have the ability to regulate roughly 100 to 1000 genes with specificity to cell-type.Three major mechanisms have described how the MP-GR complex alter gene expression by either binding to DNA or transcription modulators. One mechanism of genomic signaling occurs when the MP-GR complex directly binds to DNA sequences called glucocorticoid response elements (GREs). GREs are located in regulatory regions of target genes and mediate their transactivation or transrepression. For example, the activation of lipocortin 1 (ANAX1) negatively interferes with the production of prostaglandins and leukotrienes, known pro-inflammatory signals. Likewise, negative GREs (nGREs) are responsible for repressing genes involved in immune cell activation.

Post transcriptional  modifications
Post translational modifications (PTMs) also contribute to methylprednisolone signaling and can produce genomic and non-genomic effects. The GR has contains several sites for phosphorylation, sumoylation, ubiquitination, and acetylation that primarily occurs after intracellular methylprednisolone binding to the GR. PTMs modulate many functions including nuclear translocation, strength and duration of receptor signaling and cofactor interaction. A specific example is the deacetylation by histone deacetylase 2 (HDACe) was necessary for transrepression of  NF-κB.

Non-genomic signaling
The mechanisms of non-genomic signaling are distinct from genomic signaling, yet mediate similar pathways and provide therapeutic relevance. These mechanisms are characterized as having a rapid onset (less than 15 minutes), because they do not rely on time-consuming transcription or translation and are not modified by inhibitors of transcription.Methylprednisolone induced non-genomic signaling is classified by three mechanisms: (1) cytoplasmic glucocorticoid receptor (cGR)-mediated non-genomic effects, (2) membrane-bound glucocorticoid receptor (mGR) non-genomic effects, and (3) physiochemical interactions with cellular membranes (non-specific non-genomic effects).Proteins that dissociate from the activated GC-cGR complex, initiate intracellular transcription-independent mechanisms. It is evidence that dissociated SRC is responsible for inhibiting the release of arachidonic acid (AA) from cell membrane phospholipids. AA is required for the synthesis of inflammatory mediators (prostaglandins and leukotrienes) and thus AA inhibition mediates several important pathways such as cellular growth, metabolism and inflammation.Previous studies identified mGRs in lymphoma cells, but it wasnt until 2004 that mGRs were identified in human peripheral mononuclear cells. The prevalence of mGRs ranges per cell type, with the highest concentration in B lymphocytes at up to 12.3%, up to 9.2% in monocytes, and absent from T lymphocytes. Studies have shown a positive correlation between the mGR-positive cells and disease related activity. There are no proven signaling pathways associated with mGR at this time. Some researchers hypothesize that high disease activity activates mGR expression and upon administering methylprednisolone, creates a negative feedback loop by inducing apoptosis.High concentrations of methylprednisolone intercalate in plasma and mitochondrial cellular membranes. This association changes physiochemical properties of the membrane; activating membrane proteins, altering cellular functions and ultimately influencing cation transport through the plasma membrane and stimulating the proton leak across the inner mitochondrial membrane.  Hindered oxidative phosphorylation compromises ATP production, a major energy source for cellular energy metabolism and immune function. In vivo studies of Con-A stimulated thymocytes (in rats) and human immune cells that were administered high doses of methylprednisolone has been shown to inhibit respiration in a dose-dependent manner, inhibit plasma calcium and sodium uptake, and increase cytoplasmic calcium concentration. The summative process is as follows: Methylprednisolone intercalates in the plasma membrane, causes physiochemical changes, activates membrane proteins that inhibit plasma calcium and sodium uptake (mimicking an energy deficit state). ATP consumption drops (resembled by inhibited respiration), resulting in protein permeability at the inner mitochondrial membrane and uncoupling of oxidative phosphorylation. Of notable importance, DNA/RNA synthesis was not hindered. The dependency of house keeping cells and immune cells on ATP, results in immunosuppression during ATP deficit. Specific immune functions effected by this process are cytokinesis, migration, phagocytosis, antigen processing and presenting, antibody synthesis, cytotoxicity and regulation.

The HPA axis
The activation of the hypothalamic-pituitary axis (HPA axis) stimulates the production of endogenous glucocorticoids within the adrenal cortex. The HPA axis interprets stimuli (stress, inflammation and circadian cues) and transduces a corresponding physiochemical response. Glucocorticoids released in the blood, serve as a messenger by binding to glucocorticoid receptors in a wide distribution across the body, including the HPA axis itself. Thus, the physiological range of GCs is monitored by the  negative feedback loop GCs exert on any portion of the HPA axis. Methylprednisolone structurally and functionally mimics endogenous corticoids and will act upon the HPA axis in a similar fashion.

Pharmacokinetics
Methylprednisolone is approved for oral and parenteral administration. Methylprednisolone (Medrol) for oral administration is available in a tablet formulation in 2 mg, 4 mg, 8 mg, 16 mg or 32 mg strengths. Both methylprednisolone acetate (Depo-Medrol) and methylprednisolone succinate (Solu-Medrol) are approved for intramuscular injection. Depo-Medrol is additionally approved for intralesional, intra-articular, and soft tissue injections. Depo-Medrol is available as sterile aqueous solution in 20 mg/mL, 40 mg/mL, or 80 mg/mL strengths. Solu-Medrol is the only derivative of methylprednisolone that is approved for intravenous infusion, as the sterile powder is soluble in water and can be mixed with a diluent. Strengths vary from 40 mg to 2g.Synthetic glucocorticoids are similar to endogenous steroids in metabolism, but differ in affinity for glucocorticoid and mineralocorticoid receptors, affinity for protein-binding, rate of elimination, and metabolic products.Oral methylprednisolone is readily absorbed from the gastrointestinal tract with a bioavailability of 89.9%. In contrast to endogenous GCs, methylprednisolone does not bind to the glycoprotein transcortin (corticosteroid binding globulin, CBG) but does have moderate protein binding to albumin. Thus, pharmacokinetics of methylprednisolone is linear and show no dose dependency. Patients exhibiting low albumin concentrations are at risk for adverse effects during glucocorticoid therapy. Oral methylprednisolone has a moderate distribution into tissue at 1.38L/kg.Methylprednisolone is primarily eliminated by hepatic metabolism and renal excretion of metabolites; with renal excretion of unchanged methylprednisolone at only 1.3–9.2%.  Methylprednisolone can be interconverted with methylprednisone. Hepatic metabolism is mediated by 11 beta-hydroxysteroid dehydrogenases (11[beta]-HSD) and 20-ketosteroid reductases. Methylprednisolone undergoes renal excretion of hydrophilic inactive metabolites, including 20-carboxymelthylprednisolone and 6[beta]-hydroxy-20[alpha]-hydroxymethylprednisolone.

Medical uses
As stated previously, the primary use of methylprednisolone is to suppress inflammatory and immune responses. Methylprednisolone achieves this primarily by regulating the number and function of leukocytes, cytokines and chemokines. Its widespread inflammatory control is conducive in use across multiple disorders regardless of pathology. Methylprednisolone is commonly prescribed as short-term therapy for acute flares, as seen with acute gouty arthritis. It can be prescribed during on-going therapy in lower doses contingent upon monitorization of adverse effects. Dosage strength and formulation are optimized per medical use.

Asthma
In 2001–2002, 11.4% of patients diagnosed with asthma and seen at an outpatient visit were prescribed oral corticosteroids as a long-term control therapy. The National Asthma Education and Prevention Program (NAEPP) indicates systemic methylprednisolone in both short and long term therapies to quickly control and to suppress persistent asthma, respectively. For exacerbations that result in a visit to the Emergency Department (ED), oral methylprednisolone is preferred over intravenous administration, unless there are issues with adherence or vomiting. Oral methylprednisolone is less invasive and studies have shown that equivalent efficacy compared to intravenous methylprednisolone.  Dosage above 60–80 mg/day or 2 mg/kg/day is not recommended as it has not been shown to alter pulmonary function, rate of admission, or length of stay in the hospital compared to lower doses. Following ED discharge, it is advised to prescribed a five-day course of methylprednisolone to decrease the probability of relapse or withdrawal symptoms.

Rheumatic diseases
Methylprednisolone is used to treat several rheumatic diseases, such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). Methylprednisolone dosage and administration for these diseases is highly variable due to varied pathophysiology between the diseases and within patients diagnosed with a given disease. In Lupus Nephritis, a common manifestation of SLE, patients are often prescribed methylprednisolone concomitantly with immunosuppressants. Severe manifestations are often treated with Cyclophosphamide or Rituximab and three doses of methylprednisolone IV-pulse treatment (as recommended by ACR guidelines) prior to switching to oral prednisolone and azathioprine for maintenance.Intra-articular corticosteroid injections (IACI) are a second line therapy to relieve joint pain resulting from  rheumatoid arthritis. It is most commonly injected into the joints of  the knees and shoulders. Although the injection is local, studies have shown systemic absorption as evidenced by beneficial effects on distant joints. In an attempt to minimize HPA suppression, FDA guidelines have restricted IACIs to three per year, with a minimum of 30 days in between injections.

Primary or secondary adrenocortical insufficiency
Methylprednisolone is not typically recommended for primary or secondary adrenocortical insufficiency compared to other corticosteroids which have a higher affinity for mineralocorticoid receptor and salt retaining properties.

Labeled indications
The labeled indications below are categorized by route of administration then by medical discipline.

Oral methylprednisolone
Allergy and Immunology: angioneurotic edema, asthma, urticaria, seasonal or perennial allergic rhinitis, drug hypersensitivity reactions, and serum sickness.
Dermatology:  toxic epidermal necrolysis, atopic dermatitis, contact dermatitis, pemphigus, erythema multiforme, Steven-Johnson syndrome, bullous dermatitis herpetiformis, severe seborrheic dermatitis, exfoliative dermatitis, mycosis fungoides, and severe psoriasis.
Endocrinology: congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis, and primary or secondary adrenocortical insufficiency.
Gastroenterology: inflammatory bowel disease and ulcerative colitis.
Hematology: acquired (autoimmune) hemolytic anemia, idiopathic thrombocytopenic purpura, secondary thrombocytopenia, erythroblastopenia, leukemia, lymphoma and congenital (erythroid) hypoplastic anemia.
Pulmonary: aspiration pneumonitis, chronic beryllium disease, eosinophilic pneumonia, symptomatic sarcoidosis, and pulmonary tuberculosis in conjunction with antituberculosis chemotherapy.
Nephrology: nephrotic syndrome, idiopathic type or secondary to lupus nephritis.
Neurology: multiple sclerosis.
Ophthalmology:  scleritis, retinal vasculitis, uveitis, choroiditis, iritis, iridocyclitis, keratitis, optic neuritis, allergic conjunctivitis, allergic corneal marginal ulcers, herpes zoster ophthalmicus, sympathetic ophthalmia, and chorioretinitis.
Rheumatology: rheumatoid arthritis, rheumatic carditis, acute gouty arthritis, ankylosing spondylitis, dermatomyositis and polymyositis, psoriatic arthritis, systemic lupus erythematosus, acute and subacute bursitis, synovitis of osteoarthritis, post-traumatic osteoarthritis, and epicondylitis.
Miscellaneous: trichinosis with neurologic or myocardial involvement.

Parenteral methylprednisolone
Intra-articular or soft tissue injections: acute gouty arthritis, acute and subacute bursitis, acute tenosynovitis, epicondylitis, and synovitis of osteoarthritis.
Intralesional injections: alopecia areata, discoid lupus erythematosus, keloids, granuloma annulare, lichen planus, lichen simplex chronicus, psoriatic plaques, necrobiosis lipoidica diabeticorum.
Intramuscular injections are prescribed treat many of the same conditions indicated for oral administration. Intramuscular injections are administered as an alternative to oral therapy.

Off-label indications
Some of the off-label indications of methylprednisolone include acute spinal cord injury, acute respiratory distress syndrome, alcoholic hepatitis, hormonal resuscitation in cadaveric organ recovery, and chronic obstructive pulmonary disease.

Available forms
Footnotes:
1Signifies varying strengths of available forms. Is not indicative of frequency nor daily cumulative dose; varies per patient and condition.
2Benzyl alcohol should not to be used on neonates
3Preservative free formulation

Contraindications
Methylprednisolone should not be taken orally by people who have systemic fungal infections, with the exception of Depo-Medrol when administered as an intra-articular injection for localized joint conditions. Methylprednisolone is contraindicated in those with known hypersensitivity to methylprednisolone or its components Steroids should be used with caution in patients with ulcerative colitis, heart disease or hypertension, peptic ulcer, renal insufficiency, osteoporosis, myasthenia gravis, glaucoma, and diabetes. Psychic manifestations may appear while taking methylprednisolone, ranging from euphoria, insomnia, personality changes to depression. Caution is required for patients with predisposed psychoses, as psychotic tendencies may be exacerbated while taking corticosteroids.Solu-Medrol 40 mg dosage contains lactose monohydrate produced from cows milk; It should not be taken by anyone with known hypersensitivity to dairy products or its components. Severe medical events have been associated with epidural administration of Solu-Medrol and Depo-Medrol, including spinal cord infarction, paraplegia, quadriplegia, cortical blindness and stroke. Intramuscular injections should not be administered to those with idiopathic thrombocytopenic purpura. Formulations of Solu-Medrol and Depo-Medrol containing benzyl alcohol are contraindicated for use in premature infants. Exposure of neural tissue to excessive amounts of benzyl alcohol has been associated with toxicity and in rare events has resulted in death.

Adverse reactions
Adverse reactions may overshadow the therapeutic effects of methylprednisolone.

Central nervous system
There is minimal clinical diagnostic criteria to define the psychic adverse effects (PAE) associated with methylprednisolone use in patients with systemic lupus erythematosus (SLE). The  prevalence varies from 1.3 to 62% of adult treated patients. The type and severity of neuropsychiatric symptoms also varies significantly between patients, with 33% of patients reporting mild to moderate PAE and 5-10% reporting severe PAE. Methylprednisolone dose and duration have been implicated in PAE development. 20 mg/day of prednisone (16 mg/day of methylprednisolone) is the threshold dosage for PAE development agreed upon by many studies. Short-term pulse IV therapy at high doses is associated with rapid onset of manic and hypomanic symptoms, whereas long term therapy gives rise to depressive symptoms (suicide attempts infrequent). PAE are reversible with treatment reduction or discontinuation.

Metabolic and endocrine
Iatrogenic Cushings Syndrome is a direct complication of glucocorticoid therapy, and the most common cause of exogenous Cushings Syndrome. Clinical features of Cushings Syndrome is inclusive of many adverse effects in glucocorticoid therapy. Traditional symptoms include weight gain, myopathy, osteoporosis, increased risk of infection, hypertension and psychological effect. Fat deposition is centralized on the trunk, in between shoulders ("buffalo hump"), and on the face ("moon face"). Patient education and provider monitoring is the first step in recognizing and diagnosing Iatrogenic Cushings Syndrome. Exogenous glucocorticoids suppress adrenocorticotropic hormone (ATCH) production, which can be verified by AM biochemical analysis. The onset of side effects varies; neuropsychiatric symptoms can arise within a few hours, while osteoporosis would take months to develop.The metabolic effects of taking methylprednisolone involve the continuous breakdown of proteins for gluconeogenesis increase necessity for insulin. This results in hyperlipidemia, weight gain, myopathy that may prompt a patient to cease treatment.

Infections
See: Glucocorticoids § ImmunodeficiencyThe Immunodeficiency section tabulates known pathogens of concern in glucocorticoid induced immunodeficiency.

Musculoskeletal
Osteoporosis is a type of bone disease characterized by a loss of bone density, mass and architecture that leaves a patient susceptible to fractures. The World Health Organization (WHO) defines osteoporosis in caucasian postmenopausal women as a bone mineral density (BMD) and a T-score of -2.5 or less. The prevalence of osteoporosis in patients with SLE varies geographically and some attribute it to BMD and T-score diagnostic appropriateness. British 10.3%, Chinese 21.7%The Canadian Clinical Practice Guidelines and The American College of Rheumatology have switched to using a Z-score as a diagnostic marker for osteoporosis but have failed to find a clinical diagnostic threshold. Additionally, a UK-based study showed that BMD may underrepresent a patient with SLE, as their risk for fractures is 22% higher than the healthy individual.Exogenous corticosteroids induce osteoporosis by increasing bone resorption and reducing bone formation. Bone loss can be pronounced within the first few months of initiating methylprednisolone with a steady decrease with chronic use. Trabecular bone loss in the lumbar spine precedes cortical bone loss in the femoral neck.

Exhaustive list
Allergic: allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, and urticaria.Cardiovascular: hypertension, congestive heart failure in susceptible patients, premature atherosclerotic disease, arrhythmias, and possible hyperlipidemia.Dermatologic: impaired wound healing, petechiae and ecchymoses, thinning of the skin, facial erythema, and increased sweating.Endocrine: Cushingoid features, growth suppression in children, secondary adrenocortical and pituitary unresponsiveness, menstrual irregularities, decreased carbohydrate intolerance, and latent diabetes mellitus. In patients with diabetes, increased requirements of insulin or oral hypoglycemic agents.Fluid and electrolyte disturbances: sodium retention, fluid retention, potassium loss, hypokalemic alkalosis, or congestive heart failure in susceptible patients.Gastrointestinal: peptic ulcer, pancreatitis, abdominal distention, and ulcerative esophagitis.Metabolic: protein catabolism which causes negative nitrogen balance.Musculoskeletal: muscle weakness, loss of muscle mass, steroid myopathy, osteoporosis, tendon rupture (especially Achilles), vertebral compression fractures, aseptic necrosis of femoral and humeral heads, and pathologic fracture of long bones.Neurological: increased intracranial pressure with papilledema, convulsions, vertigo, and headache.Ophthalmic: posterior sub-capsular cataracts, increased intraocular pressure, glaucoma, and exophthalmos.

Withdrawal
Feedback of the exogenous glucocorticoids at the hypothalamic–pituitary–adrenal (HPA) axis inhibits the secretion of the corticotropin-releasing hormone (CRH) and the adrenocorticotropic hormone (ATCH) at the hypothalamus and pituitary glands, respectively. Prolonged suppression leads to inadequate responses to physical and emotional stresses, such as illness and trauma. Suppression of ATCH may result in adrenal hypoplasia or secondary adrenal gland atrophy within 6 weeks of methylprednisolone therapy, leaving a patient at risk for developing life-threatening adrenal insufficiency crisis. Factors that contribute to the extent of HPA axis suppression include steroid hormone potency (type of compound and route of administration), cumulative dose, duration of treatment and concomitant drug use. Any individual who has taken steroid hormones for 2+ weeks is at risk for developing HPA axis suppression. t Systemic methylprednisolone risk has been marked as moderate within the class of synthetic glucocorticoids.Consult with your physician prior to discontinuing methylprednisolone for any reason. Abrupt termination of the drug commonly causes transient non-specific symptoms such as loss of appetite, upset stomach, vomiting, drowsiness, confusion, headache, fever, joint and muscle pain, peeling skin, and weight loss. These symptoms can be attributed to steroid withdrawal syndrome, adrenal insufficiency or disease relapse. Those who have been taking methylprednisolone as a long-term treatment may be gradually be tapered off to minimize withdrawal symptoms and potential for relapse. If symptoms are exacerbated, temporarily increasing methylprednisolone dosage has shown clinical relevancy. Studies retesting patients upon methylprednisolone withdrawal, showed persistent adrenal insufficiency, with one study showing 15% after 3 years. However, there was a wide range of prevalence and lack of uniformity in the follow-up timeline.

Drug interactions
Caution is advised when taking methylprednisolone concurrently with the medications described below.
Enzyme inducers
All drugs that fall within the class of enzyme inducers increase the clearance and decrease the half-life of methylprednisolone when co-administered. Phenobarbital, phenytoin, rifampin, carbamazepine and barbiturates, increase hepatic enzymes and rate of elimination, thus reducing the immunosuppressive effect of methylprednisolone. Increased dosages may be required to achieve desired effect of methylprednisolone.Cytochrome P450 (CYP) 3A4 inhibitors
Troleandomycin, ketoconazole, and Clarithromycin inhibit metabolism; and may decrease rate of elimination and increase half-life of methylprednisolone. Dosages should be decreased accordingly to avoid side effects. Another CYP 3A4 inhibitor, grapefruit juice, prolongs half-life of oral methylprednisolone.Oral contraceptives
Oral contraceptives inhibit oxidative processes, as highlighted by its ability to decrease methylprednisolone clearance.P-glycoprotein inhibitors
Methylprednisolone is shown to be a substrate of P-glycoprotein; its inhibition is thought to increase methylprednisone absorption and distribution. No clinical relevance has been linked.Ciclosporin, tacrolimus, sirolimus (Rapamycin)
Methylprednisolone and cyclosporin inhibit metabolism and therefore increase the likelihood of experiencing side effects associated with either of the individual drugs. In addition to known individual side effects, convulsions have been reported.Cox1 inhibitors
Methylprednisolone may increase rate of elimination with chronic high dose aspirin. Patients are susceptible to increased salicylate serum levels or salicylate toxicity upon termination of methylprednisolone. Excessive caution should be taken when prescribing methylprednisolone and aspirin to patients with hypoprothrombinemia.Anticoagulants

Anticoagulants exhibit variable interactions; monitoring coagulation indices is recommended to achieve the desired effect.

Physical properties
Oral methylprednisolone (Medrol) and its derivatives are a white, odorless crystalline powder. Its solubility ranges from practically insoluble in water, very slightly soluble in ether, sightly soluble in acetone and chloroform to sparingly soluble in alcohol, dioxane and methanol. Methylprednisolone acetate suspension (Depo-Medrol) is a 6-methyl derivative of prednisolone that melts at 215 degrees Celsius with some decomposition. Methylprednisolone sodium succinate (Solu-Medrol) is the sodium succinate ester of methylprednisolone </s>