WordNet
- central nervous system stimulant (trade name Ritalin) used in the treatment of narcolepsy in adults and attention deficit disorder in children (同)Ritalin
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/11 13:50:21」(JST)
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"Concerta" redirects here. For the musical composition, see Concerto. For the implantable defibrillator named Medtronic Concerto, see defibrillator.
| Systematic (IUPAC) name | |
|---|---|
| methyl phenyl(piperidin-2-yl)acetate | |
| Clinical data | |
| Trade names | Concerta, Methylin, Ritalin |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682188 |
| Licence data | US FDA:link |
| Pregnancy cat. | C |
| Legal status | Controlled (S8) (AU) Schedule III (CA) Class B (UK) Schedule II (US) ℞ Prescription only |
| Dependence liability | Moderate |
| Routes | Oral, Transdermal |
| Pharmacokinetic data | |
| Bioavailability | 11–52% |
| Protein binding | 30% |
| Metabolism | Liver (80%) |
| Half-life | Immediate release tablets = 4 hours; extended-release capsules = 7–12 hours |
| Excretion | Urine |
| Identifiers | |
| CAS number | 113-45-1 Y |
| ATC code | N06BA04 |
| PubChem | CID 4158 |
| DrugBank | DB00422 |
| ChemSpider | 4015 Y |
| UNII | 207ZZ9QZ49 Y |
| KEGG | D04999 Y |
| ChEBI | CHEBI:6887 Y |
| ChEMBL | CHEMBL796 Y |
| Chemical data | |
| Formula | C14H19NO2 |
| Mol. mass | 233.30 g/mol |
|
SMILES
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InChI
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| Physical data | |
| Melt. point | 214 °C (417 °F) |
| Y (what is this?) (verify) |
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Methylphenidate (Ritalin) is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. The original patent was owned by CIBA, now Novartis Corporation. It was first licensed by the FDA in 1955 for treating ADHD, prescribed from 1960, and became heavily prescribed in the 1990s, when the diagnosis of ADHD itself became more widely accepted.[1]
ADHD and some other conditions are believed to be linked to sub-performance of the dopamine, norepinephrine, and glutamate processes in the brain, primarily in the pre-frontal cortex and peripheral cortex, responsible for self-regulation functions, leading to self-regulation disorders compromising the sufferer's attention, self-control, behaviour, motivation, and executive function; methylphenidate primarily works by reducing the reuptake of dopamine and norepinephrine which improves the levels and utility of these neurotransmitters in the brain. Methylphenidate possesses some structural and pharmacological similarities to cocaine, though methylphenidate is less potent and longer in duration.[2][3][4]
Contents
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Production and brand-names
Methylphenidate is produced in the United States, Mexico, Spain and Pakistan. Ritalin is also sold in Canada, Australia, the United Kingdom, Spain, Germany and other European countries (although in much lower volumes than in the United States). Other brands include Concerta, Methylin, and Daytrana, and generic forms, including Methylin, Metadate and Attenta are produced by numerous pharmaceutical companies throughout the world. In Belgium the product is sold under the name Rilatine and in Brazil, Portugal and Argentina as Ritalina. In Thailand, it is found under the name Hynidate.
The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade.
History
Methylphenidate was first synthesized in 1944,[5] and was identified as a stimulant in 1954.[6]
Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. His wife, Marguerite, had low blood pressure and would take the drug as a stimulant before playing tennis. He named the substance Ritaline, after his wife's nickname, Rita.[7]
Originally it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer.[8][9][10]
Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD). Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.[11]
In 2000 Janssen received U.S. Food and Drug Administration (FDA) approval to market "Concerta", an extended-release form of Ritalin.[12] See the "Extended-release" section of this article, below, for more information about Concerta.
Pharmacology
3D space-filling model methylphenidate molecule
Methylphenidate is a benzylpiperidine derivative. It also shares part of its basic structure with catecholamines and phenethylamines.
Methylphenidate primarily acts as a norepinephrine-dopamine reuptake inhibitor. Methylphenidate is most active at modulating levels of dopamine and to a lesser extent norepinephrine.[13] Similar to cocaine, methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.[14]
While both amphetamine and methylphenidate are dopaminergic, it should be noted that their methods of action are distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is a dopamine releasing agent. Each of these drugs has a corresponding effect on norepinephrine which is weaker than its effect on dopamine. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from phenethylamine derivatives, as methylphenidate is thought to increase general firing rate, whereas amphetamine reverses the flow of the monoamine transporters.[15][16][17][18] Moreover, MPH is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine, though to a much lesser extent than amphetamine.[19]
Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed.[20]
Methylphenidate may also exert a neuroprotective action against the neurotoxic effects of Parkinson's disease and methamphetamine abuse.[21]
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[citation needed]
ADHD and stimulant dynamics in general
Main article: Attention deficit hyperactivity disorder#Pathophysiology
Studies confirm that biological and genetic differences of the kinds predicted by low arousal theory are clearly visible in ADHD sufferers, and have been confirmed both genetically and by in vivo scans of ADHD sufferer brains. MRI scans have revealed that people with ADHD show differences from non-ADHD individuals in brain regions important for attention regulation and control of impulsive behavior.[22] Methylphenidate's cognitive enhancement effects have been investigated using fMRI scans even in non-ADHD brains, which revealed modulation of brain activity in ways that enhance mental focus. Methylphenidate increases activity in the prefrontal cortex and attention-related areas of the parietal cortex during challenging mental tasks; these are the same areas that the above study demonstrated to be shrunken in ADHD brains. Methylphenidate also increased deactivation of default network regions during the task.[citation needed]
Pharmacokinetics
Methylphenidate taken orally has a bioavailability of 11-52% with a duration of action around 3–6 hours for instant release, 3–8 hours for sustained release, and 8–12 hours for extended release (Concerta). The half-life of methylphenidate is between 4–12 hours depending on the individual and the form of methylphenidate taken. The peak plasma time is achieved in 6–8 hours with peak plasma concentration averaging 3.7 ng/mL.[23]
Detection in biological fluids
The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.[24]
Medical uses
MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the central nervous system.[25] It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention.[26] The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown.[27][28] The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.[29][30]
Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of lethargy, Bipolar depression, Major Depressive Disorder, and obesity.
Attention deficit hyperactivity disorder
Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder.[31] The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome.[32][33] While stimulants such as methylphenidate increase attention and concentration, they do not improve learning and academic performance.[34] People with ADHD have an increased risk of substance abuse, and stimulant medications reduce this risk.[35][36] A meta analysis of the literature concluded that methylphenidate quickly and effectively reduces the signs and symptoms of ADHD in children under the age of 18 in the short term but found that this conclusion may be biased due to the high number of low quality clinical trials in the literature.
There have been no placebo controlled trials investigating the long term effectiveness of methylphenidate beyond 4 weeks thus the long term effectiveness of methylphenidate has not been scientifically demonstrated. Serious concerns of publication bias regarding the use of methylphenidate for ADHD have also been noted.[37] A diagnosis of ADHD must be confirmed and the benefits and risks and proper use of stimulants as well as alternative treatments should be discussed with the parent before stimulants are prescribed.[38] The dosage used can vary quite significantly from individual child to individual child with some children responding to quite low doses whereas other children require the higher dose range. The dose, therefore, should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects.[39] This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day. Therapy with methylphenidate should not be indefinite. Weaning off periods to assess symptoms are recommended.[40]
Mechanisms of ADHD
The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamine imbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamine neurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses.[41] This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse. It also stimulates the release of dopamine and norepinephrine into the synapse. Finally, it increases the magnitude of dopamine release after a stimulus, increasing the salience of stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of serotonin in the brain.[15][42] However, benefits with other stimulants that have a different mechanism of action indicates that support for a deficit in specific neurotransmitters is unsupported and unproven by the evidence and remains a speculative hypothesis.[43]
Narcolepsy
Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance.[44] Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test, but performance does not improve to levels comparable to healthy controls.[45]
Aggression and criminality in Adult ADHD
While side-effects and misuse of methylphenidate have been associated with an increased risk of aggression and psychosis, newer studies indicate that it could be useful in the treatment of ADHD in adults with a history of aggressive and criminal behavior. A large clinical study conducted in Sweden found a significant reduction of the criminality rate in males (32%) and females (42%) as compared with the rate for the same patients while not receiving medication.[46] Some of these clinical outcomes have been confirmed in similar studies with children and adolescents.[47]
Adjunctive
Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial.[48] In individuals with cancer, methylphenidate is commonly used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.[49] Methylphenidate may be used in addition to an antidepressant for refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients.[50] However, benefits tend to be only partial with stimulants being, in general, less effective than traditional antidepressants and there is some suggestive evidence of a risk of habituation. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill.[51]
Substance dependence
Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on methamphetamine.[52] Cocaine and methamphetamine block the protein DAT, over time causing DAT upregulation and lower cytoplasmic dopamine levels in their absence. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence[53][54][55][56] in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or other psychostimulant dependence has not been proven and further research is needed.[57]
Early research began in 2007–2008[citation needed] in some countries[which?] on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence, owing to methylphenidate's longer half life, and reduced vasoconstrictive effects.[58][59] This replacement therapy is used in other classes of drugs such as opiates for maintenance and gradual withdrawal such as methadone, suboxone, etc.
Investigational
Animal studies using rats with ADHD-like behaviours were used to assess the safety of methylphenidate on the developing brain and found that psychomotor impairments, structural and functional parameters of the dopaminergic system were improved with treatment. This animal data suggests that methylphenidate supports brain development and hyperactivity in children diagnosed with ADHD. However, in normal control animals methylphenidate caused long lasting changes to the dopaminergic system suggesting that if a child is misdiagnosed with ADHD they may be at risk of long lasting adverse effects to brain development. Animal tests found that rats given methylphenidate grew up to be more stressed and emotional. It is unclear due to lack of follow-up study whether this occurs in ADHD like animals and whether it occurs in humans.[60] However, long lasting benefits of stimulant drugs have not been found in humans.[61]
Side effects
Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended.[62] Some adverse effects of stimulant therapy may emerge during long-term therapy, but there is very little research of the long-term effects of stimulants.[63][64] The most common side effects of methylphenidate are nervousness, drowsiness and insomnia. Other adverse reactions include:[65]
- Abdominal pain
- Akathisia (restlessness)
- Alopecia (loss of hair)
- Anger
- Angina (chest pain)
- Appetite loss
- Anxiety
- Blood pressure and pulse changes (both up and down)
- Cardiac arrhythmia
- Depression
- Diaphoresis (sweating)
- Dizziness
- Dyskinesia
- Euphoria or dysphoria
- Headache
- Hypersensitivity (including skin rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiforme, necrotizing vasculitis, and thrombocytopenic purpura)
- Lethargy
- Libido increased or decreased
- Mania or hypomania
- Nausea
- Palpitations
- Pupil dilation[66]
- Psychosis and psychiatric disorders - stimulants above the recommended dose level are associated with higher levels of psychosis, substance misuse and psychiatric admissions.[67]
- Short-term weight loss
- Somnolence
- Stunted growth
- Suicidal ideation
- Tachycardia (rapid resting heart rate)
- Xerostomia (dry mouth)
On March 22, 2006, the FDA Pediatric Advisory Committee decided that medications using methylphenidate ingredients do not need black box warnings about their risks, noting that "for normal children, these drugs do not appear to pose an obvious cardiovascular risk."[68] Previously, 19 possible cases had been reported of cardiac arrest linked to children taking methylphenidate[69] and the Drug Safety and Risk Management Advisory Committee to the FDA recommend a "black-box" warning in 2006 for stimulant drugs used to treat attention deficit/hyperactivity disorder.[70]
Historical concerns related to child growth and cancer risk have existed, and these are still monitored and studied, however current scientific consensus is that the evidence of studies suggests these are either dubious or low-significance risks. (See : Previous health concerns now considered doubtful or largely minor)
Treatment emergent psychosis
On occasion, treatment emergent psychosis can occur during long-term therapy with methylphenidate. Regular psychiatric monitoring of people who are taking methylphenidate for adverse effects such as psychotic symptomatology has been recommended.[71] In the majority of unremarkable isolated cases methylphenidate overdose is asymptomatic or only incurs minor symptoms even in children under age 6.[72][73][74] Normally any abreaction will show within 3 hours.[74] However, injection (particularly arterial) has sometimes led to toxic necrosis and amputation at the point of injection,.[75] Emergency treatment is recommended beyond certain overdose levels, in cases of attempted suicide, and in those using monoamine oxidase inhibitors (MAOIs).[74]
Long-term effects
It was documented in 2000, by Zito et al.[76] "that at least 1.5% of children between the ages of two and four are medicated with stimulants, anti-depressants and anti-psychotic drugs, despite the paucity of controlled scientific trials confirming safety and long-term effects with preschool children."
The effects of long-term methylphenidate treatment on the developing brains of children with ADHD is the subject of study and debate.[77][78] Although the safety profile of short-term methylphenidate therapy in clinical trials has been well established, repeated use of psychostimulants such as methylphenidate is less clear. There are no well defined withdrawal schedules for discontinuing long-term use of stimulants.[79] There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks.[80] Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%.[81] A small study of just under 100 children that assessed long-term outcome of stimulant use found that 6% of children became psychotic after months or years of stimulant therapy. Typically, psychosis would abate soon after stopping stimulant therapy. As the study size was small, larger studies have been recommended.[82] The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.[83] Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants.[84] Psychotic symptoms from methylphenidate can include hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, euphoria, grandiosity, paranoid delusions, confusion, increased aggression and irritability. Methylphenidate psychosis is unpredictable in whom it will occur. Family history of mental illness does not predict the incidence of stimulant toxicosis in children with ADHD. High rates of childhood stimulant use is found in patients with a diagnosis of schizophrenia and bipolar disorder independent of ADHD. Individuals with a diagnosis of bipolar or schizophrenia who were prescribed stimulants during childhood typically have a significantly earlier onset of the psychotic disorder and suffer a more severe clinical course of psychotic disorder.[85][86][87] Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects.[88]
Juvenile rhesus monkeys chronically administered twice daily methylphenidate doses that cause plasma levels similar to those of higher pharmalogical doses in humans show no apparent lasting effects.[89] Measures tested included D2-like dopamine receptor density, dopamine transporter density, amphetamine-induced dopamine release responsiveness, cognitive performance, and growth.[89]
Precautions
Interactions
Intake of adrenergic agonist drugs or pemoline with methylphenidate increases the risk of liver toxicity.[90][91] When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification,[92][93] not unlike the hepatic formation of cocaethylene from cocaine and alcohol. The reduced potency of ethylyphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.[25][94] Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[95] Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[96] but has significantly less activity on the norepinephrine transporter (NET).[97]
Contraindications
Methylphenidate should not be prescribed concomitantly with tricyclic antidepressants, such as desipramine, or monoamine oxidase inhibitors, such as phenelzine or tranylcypromine, as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly, cardiovascular effects).[citation needed][vague] Methylphenidate should not be prescribed to patients who suffer from severe arrhythmia, hypertension or liver damage. It should not be prescribed to patients who demonstrate drug-seeking behaviour, pronounced agitation or nervousness.[40] Care should be taken while prescribing methylphenidate to children with a family history of Paroxysmal Supraventricular Tachycardia (PSVT).
Special precautions
Special precaution is recommended in individuals with epilepsy with additional caution in individuals with uncontrolled epilepsy due to the potential for methylphenidate to lower the seizure threshold.[98] There is no published evidence to suggest that either the short or long term treatment with methylphenidate increases the risk of developing seizures in children with ADHD.[98] A number of small trials suggest that it is safe for use in children with epilepsy. Further randomised control trials are needed.
Pregnancy
The U.S. FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks.[99] Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies.[100] One of these studies (N = 11) demonstrated no significant increases in malformations.[101] A second (N = 13) demonstrated one major malformation in newborns with early exposure to methylphenidate, which was in the expected range of malformations. However, this was a cardiac malformation, which was not within the statistically expected range.[102] Finally, in a retrospective analysis of patients' medical charts (N = 38), researchers examined the relationship between abuse of intravenous methylphenidate and pentazocine in pregnant women. Twenty-one percent of these children were born prematurely, and several had stunted growth and withdrawal symptoms (31% and 28%, respectively). Intravenous methylphenidate abuse was confounded with the concurrent use of other substances (e.g., cigarettes, alcohol) during pregnancy.
Overdose and toxicology
In the majority of unremarkable isolated cases MPH overdose is asymptomatic (symptomless) or only incurs minor symptoms even in children under age 6.[72][73][74] In cases that manifest symptoms, these can typically include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia.[103] LD50 in mice is 190 mg/kg.[104]
Studies of reported incidents tend to show that most overdoses are unintentional and generally conclude that severe or major toxicity are comparatively rare events (none in the Michigan study of 289 incidents,[72] 0.9% in the 2004 US national analysis with n=8336,[105] and 0.2% in the same analysis for 2010 with n=6503[73]).
Death rates are also comparatively low (none in the Michigan study, 0.36 per 1000 with n=3 for the 2004 US national analysis, 0.15 per 1000 with n=1 for the 2010 analysis; the US national guideline approved 2007 also notes only 2 deaths reported as primarily to MPH overdose from 2000-05[74]).
A 2008 review generally agreed these findings but noted recreation or study use was "fairly common" in US university studies and that the risk could only be said to be low "in the short term" since there was little certainty about long term effects of overdose and abuse.[106] A 2011 Swiss study also agreed the general findings, adding a cautionary note that serious or severe outcomes such as necrosis, abscess and amputation had occurred as a result of severe toxicity at the injection site in 3 cases of abuse via injection, especially when arterial.[75]
Medical and emergency handling
Key recommendations in US guidelines for overdose handling include:[74]
- Well evidenced findings (evidence standard "A"): 0–6 years: <2 mg/kg rarely causes serious toxicity, 0–5 years: up to 40 mg well tolerated, 6–12 years: up to 80 mg well tolerated;
- Evidence grade "B" and "C": If <6 years and >2 mg/kg, or <60 kg and >1 mg/kg, or ≥60 kg and >60 mg: refer to emergency help;
- Tentative only (D): 4 mg/kg or 120 mg of intact modified (slow) release version: refer to emergency help.
- Symptoms (D): "Patients experiencing any changes in behavior other than mild stimulation or agitation should be referred to an emergency department. Examples of moderate to severe symptoms that warrant referral include moderate-to-severe agitation, hallucinations, abnormal muscle movements, headache, chest pain, loss of consciousness, or convulsions".
- Other factors: Cases of intent, malicious administration (by another), as well as monoamine oxidase inhibitor (MAOI) users should always be referred to emergency help;
- Passage of time/delay: Patients where more than 3 hours have passed without symptoms do not usually need referral to emergency help.
- Benzodiazepines may be used as treatment if agitation, dystonia, or convulsions are present.
Poison control centre analyses and study findings
A study in 2000 looked in detail at all 289 overdoses of MPH reported to the Children's Hospital of Michigan regional poison control center during 1993 and 1994 (excluded: 105 extended-release formulations or co-ingestants, to ensure MPH overdose effects were not confounded by other effects).[72] The case histories were: Age: 251 aged under 18, 38 adult; Reason: 68 (23%) intentional/unknown/error. In 163 cases (56%) the dose was known and in 41% the patient's own MPH was involved. Variation in overdose ranged from <1 mg/kg (30%) to >3 mg/kg (7.5%) mean 1.7 mg/kg. Findings:
- Although no patient developed "severe" symptoms, but "less favourable" symptoms were seen with intentional overdoses. In overdoses below 2 mg/kg the majority (63-75%) suffered no effect and a minority (9-16%) suffered a moderate effect. Above 3 mg/kg around 27% suffered a moderate effect. Overall symptoms occurred in 31% of all overdoses. In paediatric exposures 29% developed symptoms but 66% suffered no clinical effects (mild/moderate effects: 34%). Symptomatic findings were:[72]
- "Intentional ingestion of MPH was most commonly associated with isolated symptoms of tachycardia, agitation, lethargy, vomiting, dizziness, mydriasis, and tremor. Of the 8 patients in this group who manifested multiple symptoms, erythema, diaphoresis, hypertension, emesis, chest pain, tremor, fever, and insomnia"
- Symptoms were common (33%) in the 0-5 age group: "Isolated lethargy, agitation, headache, and vomiting were most commonly seen. One patient in this group developed dystonia, and two developed agitation in combination with hypertension or tachycardia."
In 2004, the American Association of Poison Control Centers Toxic Exposure Surveillance System annual report showed about 8300 methylphenidate ingestions reported in US poison center data,[74][105] of which 72% were accidental or unintended, and 19% involved children age 0-6. The most common reasons for intentional exposure were drug abuse and suicide attempts.[107] The 2010 report[73] showed 6500 single reported exposures in the US for the year. 2010 incidents:
- By age: 0-5: 24%, 6-12: 38%, 13-19:21%, 20+: 16%, other adult: 1%.
- By cause: accident/error: 79%, intended: 18%, other: 3%.
- By outcome: moderate: 624, major:13, death:1, others were no outcome, minor, or unknown. (2004 outcomes: moderate: 940, major: 73, death: 3)[105]
A Swiss study in 2011 also concurred, noting similar findings in several studies and national analyses in that country, but noted that these findings were potentially inapplicable to the few cases of abuse via crushed MPH injection, which was the sole situation where "serious" or "severe" local toxicity was observed, leading in their study to pain, necrosis and partial limb or digit amputation in two of 14 adult cases over 8 years (14%) who mistakenly injected arterially, and inguinal abscess and fever in one who injected intravenously.[75]
Tolerance
Tolerance and behavioural sensitisation may occur with long-term use of methylphenidate.[95] There is also cross tolerance with other stimulants such as amphetamine and cocaine.[108] Stimulant withdrawal or rebound reactions can occur and should be minimised in intensity, e.g. via a gradual tapering off of medication over a period of weeks or months.[109][110][111] A very small study of abrupt withdrawal of stimulants did suggest that withdrawal reactions are not typical. Nonetheless, withdrawal reactions may still occur in susceptible individuals.[112] The withdrawal or rebound symptoms of methylphenidate can include psychosis, depression, irritability and a temporary worsening of the original ADHD symptoms. Methylphenidate, due to its very short elimination half life, may be more prone to rebound effects than d-amphetamine.[40][113][114] Up to a third of children with ADHD experience a rebound effect when methylphenidate dose wears off.[115]
However, there have also been studies that show that chronic administration of methylphenidate increases sensitivity.[116] This phenomenon, known as sensitization, is known to occur with chronic administration of amphetamine.[117]
Abuse potential
Legal warning printed on Ritalin packaging
Methylphenidate has some potential for abuse due to its action on dopamine transporters, which is the same as that of cocaine.[40][118] Methylphenidate, like other stimulants, increases dopamine levels in the brain, but at therapeutic doses this increase is slow, and thus euphoria only rarely occurs even when it is administered intravenously.[119] The abuse and addiction potential of methylphenidate is therefore significantly lower than that of cocaine.[119] The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or when it is injected, producing effects somewhat similar to cocaine.[citation needed] Cocaine-like effects can also occur with very large doses taken orally.[citation needed] However, the dose that produces euphoric effects varies among individuals. Methylphenidate has less abuse potential than cocaine and amphetamine.[120]
The primary source of methylphenidate for abuse is diversion from legitimate prescriptions, rather than illicit synthesis. Those who use methylphenidate medicinally generally take it orally, while intranasal and intravenous are the preferred means for recreational use.[103] IV users tend to be adults whose use may cause panlobular pulmonary emphysema.[107]
Abuse of prescription stimulants is higher amongst college students than non-college attending young adults. College students use methylphenidate either as a study aid or to stay awake longer. Increased alcohol consumption due to stimulant misuse has additional negative effects on health.[121]
Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally. In the USA it is one of the top ten stolen prescription drugs.[citation needed] Recreational users may crush the tablets and either snort the powder, or dissolve the powder in water, filter it through cotton wool into a syringe to remove the inactive ingredients and other particles and inject the drug intravenously. Both of these methods increase bioavailability and produce a much more rapid onset of effects than when taken orally (within c. 5–10 minutes through insufflation and within just 10–15 seconds through intravenous injection); however the overall duration of action tends to be decreased by any non-oral use of drug preparations made for oral use.[122]
Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study. Professor John Harris, an expert in bioethics, has said that it would be unethical to stop healthy people taking the drug. He also argues that it would be "not rational" and against human enhancement to not use the drug to improve people's cognitive abilities.[123] Professor Anjan Chatterjee however has warned that there is a high potential for abuse and may cause serious adverse effects on the heart, meaning that only people with an illness should take the drug. In the British Medical Journal he wrote that it was premature to endorse the use of Ritalin in this way as the effects of the drug on healthy people have not been studied.[124][125] Professor Barbara Sahakian has argued that the use of Ritalin in this way may give students an unfair advantage in examinations and that as a result universities may want to discuss making students give urine samples to be tested for the drug.[126]
Legal status
- Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[127]
- In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for abuse.
- In the United Kingdom, methylphenidate is a controlled 'Class B' substance. Possession without prescription carries with a sentence up to 5 years and/or an unlimited fine, and supplying it is 14 years and/or an unlimited fine.[128]
- In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act (along with LSD, psychedelic mushrooms, and mescaline, among others), and is illegal to possess without a prescription, pursuant to Part G (section G.01.002) of the Food and Drug Regulations under the Food and Drugs Act.
- In New Zealand, methylphenidate is a 'class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and distribution of it is punishable by a 14-year sentence.
Available forms
Clockwise from top: Concerta 18 mg (OROS), Medikinet 10 mg, Methylphenidat TAD 10 mg, Ritalin 10 mg (immediate release tablets), Medikinet XL 30 mg (CR capsule).
The dosage forms of methylphenidate are tablets, capsules, patches, and liquid.
Immediate-release
Ritalin 10 mg tablet
A formulation by the Novartis trademark name Ritalin, is an immediate-release racemic mixture, although a variety of formulations and generic brand names exist. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, and Rubifen. Focalin is a preparation containing only dextro-methylphenidate, rather than the usual racemic dextro- and levo-methylphenidate mixture of other formulations.
Extended-release
Extended-release tablets or capsules include:
- Concerta (brand-name); Watson methylphenidate ER (US generic); Teva-Methylphenidate ER‑C (Canadian generic). Each pill is effective for 12 hours.[129]
- Equasym XL; Medikinet XL; Metadate CD; Ritalin LA; Rubifen SR. Some of these work identically to each other; some do not.
- Ritalin‑SR (brand-name); Methylin ER (US generic); Metadate ER (US generic); methylphenidate SR (Canadian generic).[130][131][132] Each pill is effective for 5–8 hours.[129]
A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used for nicotine replacement therapy.
Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the dose is immediate release,[133] and the remaining 78% of the dose is released over 10–12 hours post ingestion, with an initial increase over the first 6 to 7 hours, and subsequent decline in released drug.[134]
Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. Both Ritalin LA[135] and Equasym XL provide two standard doses – half the total dose being released immediately and the other half released four hours later. In total, each capsule is effective for about eight hours.
Metadate CD capsules contain two types of beads; 30% of the beads are immediate release, and the other 70% of the beads are evenly sustained release.[136]
Controversy
Main article: Attention deficit hyperactivity disorder controversies
Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. One such criticism is prescribing psychostimulants medication to children to reduce ADHD symptoms.[137] The pharmacological effects of methylphenidate resemble closely those of cocaine and amphetamine,[138] which is the desired effect in the treatment of ADHD,[139] and how methylphenidate works.[140]
Shortages of Ritalin in 2011[141] have been blamed on overmedication, itself ironically due to inattention to alternative therapies or measurement of long-term efficacy.[142] Attempts have been made to rebut these charges, primarily by questioning the assumptions of studies conducted long after the treatment period has ended.[143]
A 2002 study showed that rats treated with methylphenidate are more receptive to the reinforcing effects of cocaine.[144] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[145][146][147] according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life".[148]
Another controversial idea surrounding ADHD is whether to call it a disorder when patients, in general, have healthy appearing brains with no gross neurological deficits.[149] However, this is generally accepted as fallacious reasoning because many individuals with mental retardation, schizophrenia, migraine headaches or epilepsy will have a normal brain MRI and neurologic exam.[citation needed]
Treatment of ADHD by way of Methylphenidate has led to legal actions including malpractice suits regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems.[150] In the U.S. and the United Kingdom, it is approved for use in children and adolescents. In the U.S., the Food and Drug Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD.[151] Methylphenidate has been approved for adult use in the treatment of narcolepsy.[152][153]
Neil Bush, in an interview with Connie Chung, has spoken of his opposition to the use of Ritalin as well as labeling children with ADHD.[154]
Chemistry
Four isomers of methylphenidate are known to exist. One pair of threo isomers and one pair of erythro are distinguished, from which only d-threo-methylphenidate exhibits the pharmacologically usually desired effects.[13][155] When the drug was first introduced it was sold as a 3:1 mixture of erythro:threo diastereomers. The erythro diastereomers are also pressor amines. "TMP" is referring only to the threo product that does not contain any erythro diastereomers. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotary methylphenidate is called d-TMP. A review on the synthesis of enantiomerically pure (2R,2'R)-(+)-threo-methylphenidate hydrochloride has been published.[156]
Methylphenidate preparation according to Jeffrey M. Axten et al. (1998)[157]
Methylphenidate production[158]
See also
- Pethidine
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- ^ Safety of therapeutic methylphenidate in adults: a systematic review of the evidence - 2008, Godfrey
- ^ a b Stern EJ, Frank MS, Schmutz JF, Glenny RW, Schmidt RA, Godwin JD (1994). "Panlobular pulmonary emphysema caused by i.v. injection of methylphenidate (Ritalin): findings on chest radiographs and CT scans". American Journal of Roentgenology 162 (3): 555–60. PMID 8109495.
- ^ Leith NJ, Barrett RJ (1981). "Self-stimulation and amphetamine: tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate". Psychopharmacology (Berl.) 74 (1): 23–8. doi:10.1007/BF00431751. PMID 6791199.
- ^ Cohen D, Leo J, Stanton T, et al. (2002). "A boy who stops taking stimulants for "ADHD": commentaries on a Pediatrics case study". Ethical Hum Sci Serv 4 (3): 189–209. PMID 15278983.
- ^ Schwartz RH, Rushton HG (2004). "Stuttering priapism associated with withdrawal from sustained-release methylphenidate". J. Pediatr. 144 (5): 675–6. doi:10.1016/j.jpeds.2003.12.039. PMID 15127013.
- ^ Garland EJ (1998). "Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats". J. Psychopharmacol. (Oxford) 12 (4): 385–95. doi:10.1177/026988119801200410. PMID 10065914.
- ^ Nolan EE, Gadow KD, Sprafkin J (1999). "Stimulant medication withdrawal during long-term therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder". Pediatrics 103 (4 Pt 1): 730–7. doi:10.1542/peds.103.4.730. PMID 10103294.
- ^ Smucker WD, Hedayat M (2001). "Evaluation and treatment of ADHD". Am Fam Physician 64 (5): 817–29. PMID 11563573.
- ^ Rosenfeld AA (1979). "Depression and psychotic regression following prolonged methylphenidate use and withdrawal: case report". Am J Psychiatry 136 (2): 226–8. PMID 760559.
- ^ Riccio CA, Waldrop JJ, Reynolds CR, Lowe P (2001). "Effects of stimulants on the continuous performance test (CPT): implications for CPT use and interpretation". J Neuropsychiatry Clin Neurosci 13 (3): 326–35. doi:10.1176/appi.neuropsych.13.3.326. PMID 11514638.
- ^ Yang. "Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization". Retrieved 2 April 2013.
- ^ Featherstone, R. E.; Kapur, S.; Fletcher, P. J. (2007). "The amphetamine-induced sensitized state as a model of schizophrenia". Progress in Neuro-Psychopharmacology and Biological Psychiatry 31 (8): 1556–1571. doi:10.1016/j.pnpbp.2007.08.025. PMID 17884274. edit
- ^ Zhu J, Reith ME (2008). "Role of the dopamine transporter in the action of psychostimulants, nicotine, and other drugs of abuse". CNS & Neurological Disorders Drug Targets 7 (5): 393–409. doi:10.2174/187152708786927877. PMC 3133725. PMID 19128199.
- ^ a b Volkow, N. D.; Wang, G. J.; Fowler, J. S.; Gatley, S. J.; Logan, J.; Ding, Y. S.; Dewey, S. L.; Hitzemann, R. et al. (1999). "Blockade of striatal dopamine transporters by intravenous methylphenidate is not sufficient to induce self-reports of "high"". The Journal of Pharmacology and Experimental Therapeutics 288 (1): 14–20. PMID 9862747.
|displayauthors=suggested (help) edit - ^ Volkow ND, Swanson JM (2003). "Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD". The American Journal of Psychiatry 160 (11): 1909–18. doi:10.1176/appi.ajp.160.11.1909. PMID 14594733.
- ^ Arria AM, Wish ED (2006). "Nonmedical use of prescription stimulants among students". Pediatric Annals 35 (8): 565–71. PMC 3168781. PMID 16986451.
- ^ Midgely, Carol (February 21, 2003). "Kiddie coke: A new peril in the playground". The Times (London). Retrieved 21 February 2010. [unreliable medical source?]
- ^ Harris J (2009). "Is it acceptable for people to take methylphenidate to enhance performance? Yes". BMJ 338: b1955. doi:10.1136/bmj.b1955. PMID 19541705.
- ^ Chatterjee A (2009). "Is it acceptable for people to take methylphenidate to enhance performance? No". BMJ 338: b1956. doi:10.1136/bmj.b1956. PMID 19541706.
- ^ "Ritalin backed as brain-booster". BBC News. 19 June 2009. Retrieved 21 February 2010.
- ^ Davies, Caroline (21 February 2010). "Universities told to consider dope tests as student use of 'smart drugs' soars". The Observer (London). Retrieved 21 February 2010.
- ^ Green List: Annex to the annual statistical report on psychotropic substances (form P) PDF (1.63 MB) 23rd edition. August 2003. International Narcotics Board, Vienna International Centre. Retrieved 2 March 2006.
- ^ http://webarchive.nationalarchives.gov.uk/+/http://www.homeoffice.gov.uk/drugs/drugs-law/Class-a-b-c/
- ^ a b Moses, Scott (2009-07-26). "Methylphenidate". Family Practice Notebook. Retrieved 2012-08-07. "Duration: 5-8 hours (gradual decrease after 3 hours)" .
- ^ "Education/Training » Clinical Resources". Illinois DocAssist website. University of Illinois at Chicago. Retrieved 2012-07-26. "Ritalin‑SR, methylphenidate SR, Methylin ER, and Metadate ER are the same formulation and have the same drug delivery system" .
- ^ "Apo‑Methylphenidate SR product monograph" (PDF). Apotex Inc. 2005-03-31. "Comparative Bioavailability" section. Retrieved 2012-07-26. If the monograph link doesn't work, visit Health Canada's Drug Product Database query form one time, then click the monograph link again.
- ^ "New product: Sandoz Methylphenidate SR 20 mg". Sandoz Canada Inc. 2009-05-05. Retrieved 2012-07-26. "An alternative to Ritalin‑SR from Novartis" .
- ^ Concerta for Kids with ADHD. Pediatrics.about.com (2003-04-01). Retrieved on 2011-04-30.
- ^ Concerta (Methylphenidate Extended-Release Tablets) Drug Information: User Reviews, Side Effects, Drug Interactions and Dosage at RxList. Rxlist.com. Retrieved on 2011-04-30.
- ^ Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, Novartis
- ^ Metadate CD. Adhd.emedtv.com. Retrieved on 2011-04-30.
- ^ Lakhan SE, Hagger-Johnson GE (2007). "The impact of prescribed psychotropics on youth". Clin Pract Epidemol Ment Health 3 (1): 21. doi:10.1186/1745-0179-3-21. PMC 2100041. PMID 17949504.
- ^ Drug Enforcement Administration, Greene, S.H., Response to CHADD petition concerning Ritalin, 1995, August 7. Washington, DC: DEA, U.S. Department of Justice.
- ^ The Neurobiology of ADHD, ADHD.org.nz
- ^ Volkow ND et al. (2001). "Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain". The Journal of neuroscience : the official journal of the Society for Neuroscience 21 (2): RC121. PMID 11160455.
- ^ GARDINER HARRIS (2012-02-03). "F.D.A. Finds Short Supply of Attention Deficit Drugs". The New York Times. Archived from the original on 2012-02-03. Retrieved 2012-02-03. "(Archived by WebCite® at [3])"
- ^ L. ALAN SROUFE (2012-01-28). "Ritalin Gone Wrong - Opinion - Children\'s A.D.D.Drugs Don\'t Work Long-Term". The New York Times. Archived from the original on 2012-02-03. Retrieved 2012-02-03. "(Archived by WebCite® at [4])"
- ^ Presenters: Joan Hamburg and Dr. Harold Koplewicz (2012-02-03). "Are we over medicating our kids? Speaking with Dr. Harold Koplewicz of @ChildMindDotOrg". Joan Hamburg Show (Radio). 1:11 into the complete two part show - 2 minutes in. WOR Radio Network. WOR.
- ^ http://www.udel.edu/chemo/teaching/CHEM465/SitesF02/Prop26b/Rit%20Page4.html Pretreatment with methylphenidate sensitizes rats to the reinforcing effects of cocaine
- ^ New Research Helps Explain Ritalin's Low Abuse Potential When Taken As Prescribed – 09/29/1998. Nih.gov. Retrieved on 2011-04-30.
- ^ Wilens TE, Faraone SV, Biederman J, Gunawardene S (2003). "Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature". Pediatrics 111 (1): 179–85. doi:10.1542/peds.111.1.179. PMID 12509574.
- ^ Barkley RA, Fischer M, Smallish L, Fletcher K (2003). "Does the treatment of attention-deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study". Pediatrics 111 (1): 97–109. doi:10.1542/peds.111.1.97. PMID 12509561.
- ^ Stimulant ADHD Medications: Methylphenidate and Amphetamines – InfoFacts – NIDA. Drugabuse.gov. Retrieved on 2011-04-30.
- ^ Weinberg WA, Brumback RA (1992). "The myth of attention deficit-hyperactivity disorder: symptoms resulting from multiple causes". J. Child Neurol. 7 (4): 431–45; discussion 446–61. doi:10.1177/088307389200700420. PMID 1469255.
- ^ Ouellette EM (1991). "Legal issues in the treatment of children with attention deficit hyperactivity disorder". Journal of Child Neurology. 6 Suppl: S68–75. PMID 2002217.
- ^ FDA OKs Concerta for Adult ADHD, webmd.com
- ^ Ritalin for Adults. Adhd.emedtv.com (2007-03-06). Retrieved on 2011-04-30.
- ^ Attention Deficit Hyperactivity Disorder (ADHD) – Treatment – NHS Choices. Nhs.uk (2010-05-19). Retrieved on 2011-04-30.
- ^ Interview With Neil Bush; Interview With Magic Johnson. Transcripts.cnn.com. September 26, 2002. Retrieved on 2011-10-16.
- ^ Froimowitz M, Patrick KS, Cody V (1995). "Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT". Pharmaceutical Research 12 (10): 1430–4. doi:10.1023/A:1016262815984. PMID 8584475.
- ^ Prashad, M (2001). "Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride". Adv. Synth. Catal 343 (5): 379–92. doi:10.1002/1615-4169(200107)343:5<379::AID-ADSC379>3.0.CO;2-4.
- ^ Axten, J. M.; Krim, L.; Kung, H. F.; Winkler, J. D. (1998). "A Stereoselective Synthesis of dl-threo-Methylphenidate: Preparation and Biological Evaluation of Novel Analogues". The Journal of Organic Chemistry 63 (26): 9628. doi:10.1021/jo982214t. edit
- ^ Singh, Satendra (2000). "Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists". Chem. Rev. 100 (3): 925–1024 (1008). doi:10.1021/cr9700538. PMID 11749256.
External links
- Methylphenidate at the Open Directory Project
- Department of Energy September 29, 1998 press release on Ritalin at Brookhaven National Laboratory
- Erowid methylphenidate vault
- U.S. National Library of Medicine: Drug Information Portal – Methylphenidate
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UpToDate Contents
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
- 1. ドラッグを注射している患者における肺疾患の概要 overview of pulmonary disease in injection drug users
- 2. 緩和ケア：疲労、脱力および無力症の概要 palliative care overview of fatigue weakness and asthenia
- 3. Sleep in children and adolescents with attention deficit hyperactivity disorder
- 4. 小児や青年の注意欠陥多動性障害治療薬の薬理学 pharmacology of drugs used to treat attention deficit hyperactivity disorder in children and adolescents
- 5. 成人の精神刺激薬使用障害への薬物療法 pharmacotherapy for stimulant use disorders in adults
English Journal
- Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice.
- Mines MA, Jope RS.AbstractAcute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity. Here we tested if regulation of Akt and GSK3 was similarly affected by longer-term administration of amphetamine, as well as of methylphenidate, since each of these is administered chronically in patients with attention deficit hyperactivity disorder (ADHD). Akt is activated by post-translational phosphorylation on Thr308, and modulated by Ser473 phosphorylation, whereas phosphorylation on Ser21/9 inhibits the two GSK3 isoforms, GSK3α and GSK3β. After eight days of amphetamine or methylphenidate treatment, striatal Akt and GSK3 were dephosphorylated similar to reported changes after acute amphetamine treatment. Oppositely, in the cerebral cortex and hippocampus Akt and GSK3 phosphorylation increased after eight days of amphetamine or methylphenidate treatment. These opposite brain region changes in Akt and GSK3 phosphorylation matched opposite changes in the association of Akt with β-arrestin and GSK3, which after eight days of amphetamine treatment were increased in the striatum and decreased in the cerebral cortex. Thus, whereas the acute dephosphorylating effect of stimulants on Akt and GSK3 in the striatum was maintained, the response switched in the cerebral cortex after eight days of amphetamine or methylphenidate treatment to cause increased phosphorylation of Akt and GSK3. These results demonstrate that prolonged administration of stimulants causes brain region-selective differences in the regulation of Akt and GSK3.
- Cellular signalling.Cell Signal.2012 Jul;24(7):1398-405. Epub 2012 Mar 10.
- Acute amphetamine administration activates glycogen synthase kinase-3 (GSK3) by reducing its inhibitory serine-phosphorylation in mouse striatum and cerebral cortex. This results from Akt inactivation and is required for certain behavioral effects of amphetamine, such as increased locomotor activity
- PMID 22434044
- Dissociative Effects of Methylphenidate in Nonhuman Primates: Trade-offs between Cognitive and Behavioral Performance.
- Rajala AZ, Henriques JB, Populin LC.SourceUniversity of Wisconsin, Madison.
- Journal of cognitive neuroscience.J Cogn Neurosci.2012 Jun;24(6):1371-81. Epub 2012 Mar 8.
- Low doses of methylphenidate reduce hyperactivity and improve attention in individuals with attention deficit hyperactivity disorder (ADHD) as well as in healthy humans and animals. Despite its extensive use, relatively little is known about its mechanisms of action. This study investigated the effe
- PMID 22401288
Japanese Journal
- コンサータとADHD (特集 症例から学ぶ--新しい薬を使いこなすには)
- 星野 仁彦
- 精神科 18(2), 138-144, 2011-02
- NAID 40018703235
- 薬物乱用・依存の今日的状況 : 有機溶剤、覚せい剤から脱法ドラッグ、リタリン、大麻等、使用しても捕まらない薬物へのシフト
- 和田 清,尾崎 茂,嶋根 卓也
- 日本アルコール・薬物医学会雑誌 = Japanese journal of alcohol studies & drug dependence 44(4), 224-225, 2009-08-28
- NAID 10025108022
Related Links
- 日本ではリタリン® (Ritalin®、商標登録番号第439740号) とコンサータ® (Concerta® 、商標登録番号第4657942号) がメチルフェニデートを含む医薬品である。日本 におけるリタリンの適応症はナルコレプシー、コンサータの適応症は18歳未満のADHD である。
- Methylphenidate (Ritalin, MPH, MPD) is a psychostimulant drug approved for treatment of ADHD or attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in ...
Related Pictures
★リンクテーブル★
| リンク元 | 「薬物濫用」「メチルフェニデート」「リタリン」 |
「薬物濫用」
- 英
- drug abuse, substance abuse
- 同
- 薬物乱用
- 関
- 薬物依存、薬物嗜癖、物質乱用、物質依存症、薬物使用、接着剤吸引
薬物使用が身体に及ぼす効果
- 濫用 substance abuse：a pattern of abnormal substance use that leads to impairment of occupational, physical, or social functioning(BBS.73)
- 依存 substance dependence：ub stance abuse puls withdrawal symptoms, tolerance, or a pattern of repetitive use(BBS.73)
- 離脱 withdrawal：the development of physical or pschological symptoms after the reduction or cessation of intake of a substance(BBS.73)
- 耐性 tolerance：the need for increased amounts of the substance to achieve the same positive psychological effect(BBS.73)
- 交差耐性 cross-tolerance：the development of tolerance to one substance as the result of using another substance(BBS.73)
薬物
- 1. 中枢神経興奮薬(覚醒剤を含む) stimulants 身体依存はないとされている
- カフェイン caffeine
- ニコチン nicotine
- amphetamines 精神依存有り。身体依存無し
- アンフェタミン amphetamine 精神依存有り。身体依存無し。耐性は連用で出現
- デキストロアンフェタミン dextroamphetamine Dexedrine
- メタンフェタミン methamphetamine Desoxyn speed ice ヒロポン 精神依存有り。身体依存無し。耐性は連用で出現 ← 以前、日本で多く使われた
- メチルフェニデート methylphenidate Ritalin
- methylene dioxymethamphetamine MDMA ecstasy
- 2. sedatives
- alcohol 精神依存有り。身体依存有り。
- barbiturates
- benzodiazepines
- ⇔flumazenil Mazicon Romazicon
- 3. opioids
- 4. hallucinogens and related agents
- cannabis(marijuana(tetrahydrocannabinol THC,hashish) 精神依存有り。身体依存無し 精神依存軽度。耐性は長期使用で軽度出現 大麻草
- lysergic acid diethylamide LSD
- phencyclidine PCP angel dust
- psilocybin
- mescaline
精神依存、身体依存
| 精神依存 | 身体依存 | |
| コカイン、アンフェタミン類(アンフェタミン、メチルフェタミン)、大麻 | ○ | |
| 麻薬(モルヒネ、ヘロイン、コデイン)、バルビツール酸系(フェノバルビタール、チオペンタール)、アルコール | ○ | ○ |
「メチルフェニデート」
- 英
- methylphenidate
- 化
- 塩酸メチルフェニデート methylphenidate hydrochloride
- 商
- リタリン Ritalin, Methylin, Concerta,metadate ER, Flocalin、コンサータ
- 関
- 精神神経用剤
特徴
- 中程度の中枢神経興奮薬
- 運動系より知能面を刺激
構造
作用機序
- ドパミン遊離促進作用
薬理作用
動態
適応
- 小児の運動亢進症候群 hyperkinetic syndrome