среда, 16 октября 2013 г.

Methylphenidate


 

"Concerta" redirects here. For the musical composition, see Concerto. For the implantable defibrillator named Medtronic Concerto, see defibrillator.
Methylphenidate
Systematic (IUPAC) name
methyl phenyl(piperidin-2-yl)acetate
Clinical data
Trade namesConcerta, Methylin, Ritalin, Equasym XL
AHFS/Drugs.commonograph
MedlinePlusa682188
Licence dataUS FDA:link
Pregnancy cat.C
Legal statusControlled (S8) (AU)Schedule III (CA) Class B(UK) Schedule II (US)
Dependence liabilityModerate
RoutesOral, Transdermal
Pharmacokinetic data
Bioavailability11–52%
Protein binding30%
MetabolismLiver (80%)
Half-lifeImmediate release tablets: 2 1/2 hours from oral take (2 hours from effect start);[1]extended-release capsules: 6 1/2 hours from oral take, 6 hours from effect start or additional hour for some release systems[citation needed]
ExcretionUrine
Identifiers
CAS number113-45-1 Yes
ATC codeN06BA04
PubChemCID 4158
DrugBankDB00422
ChemSpider4015 Yes
UNII207ZZ9QZ49 Yes
KEGGD04999 Yes
ChEBICHEBI:6887 Yes
ChEMBLCHEMBL796 Yes
Chemical data
FormulaC14H19NO2 
Mol. mass233.30 g/mol
Physical data
Melt. point214 °C (417 °F)
 Yes (what is this?)  (verify)
Methylphenidate is a psychostimulant drug and substituted phenethylamine approved for treatment of attention-deficit hyperactivity disorder (ADHD), postural orthostatic tachycardia syndrome and narcolepsy. The original patent was owned by CIBA, now Novartis Corporation. It was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as hyperactivity. Prescribed to patients beginning in 1960, the drug became heavily prescribed in the 1990s, when the diagnosis of ADHD itself became more widely accepted.[2]
ADHD and other similar conditions are believed to be linked to sub-performance of the dopamine and norepinephrine functions in the brain, primarily in the prefrontal cortex, responsible for self-regulation functions of inhibition, motivation, memory, and the concentration/executive functions of reasoning, organizing, solving, and planning.[3][4] Methylphenidate's pharmacological profile involves catecholamines, similar to other sympathomimetics of the phenethylamine class. In particular, methylphenidate is adopamine reuptake inhibitor and also a much weaker norepinephrine reuptake inhibitor, which increases the levels of theseneurotransmitters in the brain.

Medical uses[edit]

MPH is the most commonly prescribed psychostimulant and works by increasing the activity of the central nervous system.[5] It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention.[6] The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown.[7][8] The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age.[9][10]Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of lethargy, bipolar disorder, major depressive disorder, and obesity.[citation needed]

Attention deficit hyperactivity disorder[edit]

Methylphenidate is approved by the U.S. Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder.[11] The addition of behavioural modification therapy (e.g. cognitive behavioral therapy (CBT)) has additional benefits on treatment outcome.[12][13] People with ADHD have an increased risk of substance abuse, and stimulant medications reduce this risk.[14][15] 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.[citation needed]
Methylphenidate's long-term efficacy in ADHD treatment has been questioned because of a lack of long-term studies and possiblepublication bias.[16] A 2010 study suggested that, "there is increasing evidence...[stimulant drugs such as methylphenidate] do not promote learning and academic achievement".[17]
Some research suggests that methylphenidate treatment should not be indefinite. Weaning off periods to assess symptoms and allay tolerance are recommended.[18]
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.[19] This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day.

Mechanisms of ADHD[edit]

Main article: ADHD#Cause
The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a dopamineimbalance in the brains of those affected. Methylphenidate is a norepinephrine and dopamine reuptake inhibitor, which means that it increases the level of the dopamineneurotransmitter in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the synapses.[20] 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.[21][22] 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.[23]

Narcolepsy[edit]

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.[24] 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.[25]

Aggression and criminality[edit]

Newer studies indicate methylphenidate 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.[26] Some of these clinical outcomes have been confirmed in similar studies with children and adolescents.[27]

Adjunctive[edit]

Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial.[28] 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.[29] 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.[30]However, benefits tend to be only partial with stimulants. Stimulants may however, have fewer side-effects than tricyclic antidepressants in the elderly and medically ill.[31]

Substance dependence[edit]

Although possible, substance dependence is rare with Methylphenidate.[32] Methylphenidate has shown some benefits as a replacement therapy for individuals dependent onmethamphetamine.[33] Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine dependence[34][35][36][37] in the same way that methadone is used as a replacement for heroin. Its effectiveness in treatment of cocaine or psychostimulant dependence has not been proven and further research is needed.[38]
Early research began in 2007–2008 by Pharmacokinetics and Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, in University of Maryland, Baltimore, Maryland, first published, 19 September 2007 in the United States[39] on the effectiveness of methylphenidate as a substitute agent in refractory cases of cocaine dependence.[40][41]

Investigational[edit]

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.[42] However, long lasting benefits of stimulant drugs have not been found in humans.[43]

Adverse effects[edit]

Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended.[44] 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.[45][46] The most common side effects of methylphenidate are nervousness, drowsiness and insomnia.[citation needed] Other adverse reactions include:[47]
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."[50] Previously, 19 possible cases had been reported of cardiac arrest linked to children taking methylphenidate[51] 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.[52]
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[edit]

Main article: Stimulant 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.[53] In the majority of unremarkable isolated cases methylphenidate overdose is asymptomatic or only incurs minor symptoms even in children under six years of age.[54][55][56] Normally any reaction will show within three hours.[56] However, injection (particularly arterial) has sometimes led to toxic necrosis and amputation at the point of injection.[57] Emergency treatment is recommended beyond certain overdose levels, in cases of attempted suicide, and in those using monoamine oxidase inhibitors (MAOIs).[56]

Long-term effects[edit]

In 2000, by Zito et al.[58] documented "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.[59][60] 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.[61] There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks.[62] Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%.[63] 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.[64] The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown.[65] Concerns have been raised that long-term therapy might cause drug dependence, paranoia, schizophrenia and behavioral sensitisation, similar to other stimulants.[66] Psychotic symptoms from methylphenidate can include hearing voices[citation needed], visual hallucinations[citation needed], urges to harm oneself[citation needed], severe anxiety[citation needed], euphoria[citation needed], grandiosity[citation needed], paranoid delusions[citation needed], confusion[citation needed], increasedaggression[citation needed] and irritability[citation needed]. 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[citation needed]. High rates of childhood stimulant use is found in patients with a diagnosis of schizophrenia and bipolar disorder independent of ADHD[citation needed]. 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.[dubious – discuss][67][68][69]
Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects.[70] 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.[71]Measures tested included D2-like dopamine receptor density, dopamine transporter density, amphetamine-induced dopamine release responsiveness, cognitive performance, and growth.[71]

Precautions[edit]

Interactions[edit]

Intake of adrenergic agonist drugs or pemoline with methylphenidate increases the risk of liver toxicity.[72][73] When methylphenidate is coingested with ethanol, a metabolite calledethylphenidate is formed via hepatic transesterification,[74][75] 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.[5][76] Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.[77] Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[78] but has significantly less activity on the norepinephrine transporter(NET).[79]

Contraindications[edit]

Methylphenidate should not be prescribed concomitantly with tricyclic antidepressants, such as desipramine, or monoamine oxidase inhibitors, such as phenelzine ortranylcypromine, as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly, cardiovasculareffects).[medical 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.[18] Care should be taken while prescribing methylphenidate to children with a family history of Paroxysmal Supraventricular Tachycardia (PSVT).

Special precautions[edit]

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.[80] 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.[80] A number of small trials suggest that it is safe for use in children with epilepsy. Further randomised control trials are needed.

Pregnancy[edit]

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.[81] 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.[82] One of these studies (N = 11) demonstrated no significant increases in malformations.[83] 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.[84] 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[edit]

In the majority of unremarkable isolated cases MPH overdose is asymptomatic (symptomless) or only incurs minor symptoms even in children under age 6.[54][55][56] In cases that manifest symptoms, these can typically include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia.[85] LD50 in mice is 190 mg/kg.[86]
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,[54] 0.9% in the 2004 US national analysis with n=8336,[87] and 0.2% in the same analysis for 2010 with n=6503[55]).
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[56]).
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.[88] 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.[57]

Medical and emergency handling[edit]

Key recommendations in US guidelines for overdose handling include:[56]
  • 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[edit]

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).[54] 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:[54]
  • "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,[56][87] 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.[89] The 2010 report[55] 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)[87]
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.[57]

Tolerance[edit]

Tolerance and behavioural sensitisation may occur with long-term use of methylphenidate.[77] There is also cross tolerance with other stimulants, such as amphetamine.[90]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.[91][92][93]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.[94] 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.[18][95][96] Up to a third of children with ADHD experience arebound effect when methylphenidate dose wears off.[97]
However, there have also been studies that show that chronic administration of methylphenidate increases sensitivity.[98] This phenomenon, known as sensitization, is known to occur with chronic administration of amphetamine.[99]

Abuse potential[edit]

Legal warning printed on Ritalin packaging
Methylphenidate has some potential for abuse due to its action on dopamine transporters. 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.[100] The abuse and addiction potential of methylphenidate is therefore significantly lower than other dopaminergic stimulants.[100][101] The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or injected.[102] However, the dose that produces euphoric effects varies among individuals. 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.[85] IV users tend to be adults whose use may cause panlobular pulmonary emphysema.[89]
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.[103]
Patients who have been prescribed Ritalin have been known to sell their tablets to others who wish to take the drug recreationally[citation needed]. In the USA it is one of the top ten stolen prescription drugs.[medical 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[citation needed]. 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.[104]
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.[105] 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.[106][107] 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.[108]

Legal status[edit]

  • Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.[109]
  • 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.[110]
  • 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.
  • In Australia, methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a lockable safe before being handed out and possession without prescription carries hefty fines and even imprisonment.

Available forms[edit]

Clockwise from top: Concerta 18 mg (OROS), Medikinet 10 mg, Methylphenidat TAD 10 mg, Ritalin 10 mg (immediate release tablets), Medikinet XL 30 mg (CRcapsule).
The dosage forms of methylphenidate are tablets, capsules, patches, and liquid.

Immediate-release[edit]

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[edit]

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.[111]
  • 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).[112][113][114]Each pill is effective for 5–8 hours.[111]
A newer way of taking methylphenidate is by using a transdermal patch (under the brand name Daytrana), similar to those used fornicotine 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,[115] 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.[116]
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[117] 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.[118]

Controversy[edit]

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.[119] The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources,[120] 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".[121]
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.[122]
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.[123] In the U.S. and the United Kingdom, it is approved for use in children and adolescents. In the U.S., theFood and Drug Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD.[124] Methylphenidate has been approved for adult use in the treatment ofnarcolepsy.[125]
The pharmacological effects of methylphenidate resemble those of the class of DNRIs,[126] which is useful in the treatment of ADHD.[127]
Shortages of Ritalin in 2011[128] have been blamed on overmedication, itself ironically due to inattention to alternative therapies or measurement of long-term efficacy.[129]Attempts have been made to rebut these charges, primarily by questioning the assumptions of studies conducted long after the treatment period has ended.[130]

Chemistry[edit]

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.[131][132] 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 toepimerize 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.[133]
Methylphenidate preparation according to Jeffrey M. Axten et al. (1998)[134]
Methylphenidate production[135]

Production and brand-names[edit]

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,Metadateand 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[edit]

Methylphenidate was first synthesized in 1944,[136] and was identified as a stimulant in 1954.[137]
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.[138]
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.[139][140][141]
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.[142]
In 2000 Janssen received U.S. Food and Drug Administration (FDA) approval to market "Concerta", an extended-release form of Ritalin.[143] See the "Extended-release" section of this article, below, for more information about Concerta.

Pharmacology[edit]

3D space-filling modelmethylphenidatemolecule
Methylphenidate primarily acts as a dopamine-norepinephrine reuptake inhibitor. It is a benzylpiperidine and phenethylaminederivative which also shares part of its basic structure with catecholamines.
Methylphenidate is most active at modulating levels of dopamine and to a lesser extent norepinephrine.[131] Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.[144]
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 both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. 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 most other phenethylamine derivatives, as methylphenidate is thought to increase general firing rate, whereasamphetamine reverses the flow of the monoamine transporters via TAAR1.[21][145][146][147][148] 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.[149]
Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidateenantiomers 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.[150]
Methylphenidate may also exert a neuroprotective action against the neurotoxic effects of Parkinson's disease and methamphetamine abuse.[151]
The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.[131]

ADHD and stimulant dynamics in general[edit]

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 affected 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.[152] 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.[153]

Pharmacokinetics[edit]

Methylphenidate taken orally has a bioavailability of 11-52% with a duration of peak action around 2–4 hours for instant release, 3–8 hours for sustained release, and 8–12 hours for extended release (Concerta). The half-life of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours.[154] Contrary to the expectation, taking methylphenidate with a meal speeds absorption.[155]

Detection in biological fluids[edit]

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.[156]

References[edit]

  1. Jump up^ Kimko, H. C.; Cross, J. T.; Abernethy, D. R. (1999). "Pharmacokinetics and clinical effectiveness of methylphenidate". Clinical pharmacokinetics 37 (6): 457–470.doi:10.2165/00003088-199937060-00002. PMID 10628897. edit
  2. Jump up^ www.ehow.com/about_5374709_ritalin-invented.html When Was Ritalin Invented?, citing Lawrence Diller: "Running on Ritalin", 1999
  3. Jump up^ "Functional Roles of Norepinephrine and Dopamine in ADHD: Dopamine in ADHD".Medscape. 2006. Retrieved 2013-10-08. "Catecholamines not only facilitate attention, they are essential to executive function. The prefrontal cortex directs behaviors, thoughts, and feelings represented in working memory. This representational knowledge is essential to fundamental cognitive abilities that compromise executive functions. These encompass the ability to (1) inhibit inappropriate behaviors and thoughts, (2) regulate our attention, (3) monitor our actions, and (4) plan and organize for the future. Difficulties with these prefrontal cortex functions are evident in neuropsychological and imaging studies of ADHD patients and account for many of the common behavioral symptoms. Measures of prefrontal cortical functioning in animals indicate that these functions are sensitive to small changes in catecholamine modulation of prefrontal cortex cells that can produce profound effects on the ability of the prefrontal cortex to guide behavior. Optimal levels of NE acting at postsynaptic alpha2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine alpha2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of ADHD, including impulsivity and locomotor hyperactivity. Conversely, stimulation of prefrontal cortical alpha2-adrenoceptors strengthens prefrontal cortex regulation of behavior and reduces distractibility. Thus, effective treatments for ADHD facilitate catecholamine transmission and apparently have their therapeutic actions by optimizing catecholamine actions in the prefrontal cortex"
  4. Jump up^ Arnsten, A. F. T.; Li, B. M. (2005). "Neurobiology of Executive Functions: Catecholamine Influences on Prefrontal Cortical Functions". Biological Psychiatry 57(11): 1377–1384. doi:10.1016/j.biopsych.2004.08.019. PMID 15950011. edit
  5. ^ Jump up to:a b Markowitz JS, Logan BK, Diamond F, Patrick KS (1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion".Journal of Clinical Psychopharmacology 19 (4): 362–6. doi:10.1097/00004714-199908000-00013. PMID 10440465.
  6. Jump up^ Steele M, Weiss M, Swanson J, Wang J, Prinzo RS, Binder CE (2006). "A randomized, controlled effectiveness trial of OROS-methylphenidate compared to usual care with immediate-release methylphenidate in attention deficit-hyperactivity disorder" (PDF).Can J Clin Pharmacol 13 (1): e50–62. PMID 16456216.
  7. Jump up^ Gilmore A, Milne R (2001). "Methylphenidate in children with hyperactivity: review and cost-utility analysis". Pharmacoepidemiol Drug Saf 10 (2): 85–94.doi:10.1002/pds.564. PMID 11499858.
  8. Jump up^ Mott TF, Leach L, Johnson L (2004). "Clinical inquiries. Is methylphenidate useful for treating adolescents with ADHD?". The Journal of Family Practice 53 (8): 659–61.PMID 15298843.
  9. Jump up^ Vitiello B (2001). "Psychopharmacology for young children: clinical needs and research opportunities". Pediatrics 108 (4): 983–9. doi:10.1542/peds.108.4.983.PMID 11581454.
  10. Jump up^ Hermens DF, Rowe DL, Gordon E, Williams LM (2006). "Integrative neuroscience approach to predict ADHD stimulant response". Expert Review of Neurotherapeutics 6(5): 753–63. doi:10.1586/14737175.6.5.753. PMID 16734523.
  11. Jump up^ Fone KC, Nutt DJ (2005). "Stimulants: use and abuse in the treatment of ADD". Current Opinion in Pharmacology 5 (1): 87–93. doi:10.1016/j.coph.2004.10.001.PMID 15661631.
  12. Jump up^ Capp PK, Pearl PL, Conlon C (2005). "Methylphenidate HCl: therapy for attention deficit hyperactivity disorder". Expert Rev Neurother 5 (3): 325–31.doi:10.1586/14737175.5.3.325. PMID 15938665.
  13. Jump up^ Greenfield B, Hechman L (2005). "Treatment of attention deficit hyperactivity disorder in adults". Expert Rev Neurother 5 (1): 107–21. doi:10.1586/14737175.5.1.107.PMID 15853481.
  14. Jump up^ Faraone SV, Wilens TE (2007). "Effect of stimulant medications for attention-deficit/hyperactivity disorder on later substance use and the potential for stimulant misuse, abuse, and diversion". J Clin Psychiatry. 68 Suppl 11: 15–22.PMID 18307377.
  15. Jump up^ Wilens TE, Faraone SV, Biederman J, Gunawardene S (January 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.
  16. Jump up^ Schachter HM, Pham B, King J, Langford S, Moher D (2001). "How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis". CMAJ 165 (11): 1475–88. PMC 81663.PMID 11762571.
  17. Jump up^ Advokat C (July 2010). "What are the cognitive effects of stimulant medications? Emphasis on adults with attention-deficit/hyperactivity disorder (ADHD)". Neurosci Biobehav Rev 34 (8): 1256–66. doi:10.1016/j.neubiorev.2010.03.006.PMID 20381522.
  18. ^ Jump up to:a b c Kidd PM (2000). "Attention deficit/hyperactivity disorder (ADHD) in children: rationale for its integrative management" (PDF). Altern Med Rev 5 (5): 402–28.PMID 11056411.
  19. Jump up^ Stevenson RD, Wolraich ML (1989). "Stimulant medication therapy in the treatment of children with attention deficit hyperactivity disorder". Pediatr. Clin. North Am. 36 (5): 1183–97. PMID 2677938.
  20. Jump up^ Volkow ND, Wang GJ, Fowler JS, et al. (1998). "Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate". The American Journal of Psychiatry 155 (10): 1325–31. PMID 9766762.
  21. ^ Jump up to:a b Viggiano D, Vallone D, Sadile A (2004). "Dysfunctions in dopamine systems and ADHD: evidence from animals and modeling". Neural Plasticity 11 (1–2): 102, 106–107.doi:10.1155/NP.2004.97. PMC 2565441. PMID 15303308.Full-text [1]
  22. Jump up^ Gainetdinov RR, Caron MG (2001). "Genetics of childhood disorders: XXIV. ADHD, part 8: hyperdopaminergic mice as an animal model of ADHD". Journal of the American Academy of Child and Adolescent Psychiatry 40 (3): 380–2. doi:10.1097/00004583-200103000-00020. PMID 11288782.
  23. Jump up^ Koelega HS (1993). "Stimulant drugs and vigilance performance: a review".Psychopharmacology (Berl.) 111 (1): 1–16. doi:10.1007/BF02257400.PMID 7870923.
  24. Jump up^ Fry JM (1998). "Treatment modalities for narcolepsy". Neurology 50 (2 Suppl 1): S43–8. PMID 9484423.
  25. Jump up^ Mitler MM (1994). "Evaluation of treatment with stimulants in narcolepsy". Sleep 17 (8 Suppl): S103–6. PMID 7701190.
  26. Jump up^ P. Lichtenstein et al. (2012). "Medication for Attention Deficit–Hyperactivity Disorder and Criminality." N Engl J Med 367:2006-2014. DOI: 10.1056/NEJMoa1203241
  27. Jump up^ E. Pappadopulos et al. (2006)."Pharmacotherapy of aggression in children and adolescents: efficacy and effect size." J Can Acad Child Adolesc Psychiatry. 15(1):27-39.PMID 18392193
  28. Jump up^ Kraus MF, Burch EA (1992). "Methylphenidate hydrochloride as an antidepressant: controversy, case studies, and review". South. Med. J. 85 (10): 985–91.doi:10.1097/00007611-199210000-00012. PMID 1411740.
  29. Jump up^ Rozans M, Dreisbach A, Lertora JJ, Kahn MJ (2002). "Palliative uses of methylphenidate in patients with cancer: a review". J. Clin. Oncol. 20 (1): 335–9.doi:10.1200/JCO.20.1.335. PMID 11773187.
  30. Jump up^ Leonard BE, McCartan D, White J, King DJ (2004). "Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects". Hum Psychopharmacol 19 (3): 151–80. doi:10.1002/hup.579. PMID 15079851.
  31. Jump up^ Satel SL, Nelson JC (1989). "Stimulants in the treatment of depression: a critical overview". J Clin Psychiatry 50 (7): 241–9. PMID 2567730.
  32. Jump up^ [2]
  33. Jump up^ Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J (2008). "Pharmacotherapy of methamphetamine addiction: an update". Substance Abuse 29 (3): 31–49. doi:10.1080/08897070802218554. PMC 2597382. PMID 19042205.
  34. Jump up^ Grabowski J, Roache JD, Schmitz JM, Rhoades H, Creson D, Korszun A (1997). "Replacement medication for cocaine dependence: methylphenidate". J Clin Psychopharmacol 17 (6): 485–8. doi:10.1097/00004714-199712000-00008.PMID 9408812.
  35. Jump up^ Gorelick DA, Gardner EL, Xi ZX (2004). "Agents in development for the management of cocaine abuse". Drugs 64 (14): 1547–73. doi:10.2165/00003495-200464140-00004.PMID 15233592.
  36. Jump up^ Karila L, Gorelick D, Weinstein A, et al. (2008). "New treatments for cocaine dependence: a focused review". Int. J. Neuropsychopharmacol. 11 (3): 425–38.doi:10.1017/S1461145707008097. PMID 17927843.
  37. Jump up^ "NIDA InfoFacts: Understanding Drug Abuse and Addiction". 2008.
  38. Jump up^ Shearer J (2008). "The principles of agonist pharmacotherapy for psychostimulant dependence". Drug Alcohol Rev 27 (3): 301–8. doi:10.1080/09595230801927372.PMID 18368612.
  39. Jump up^ Journal of Pharmaceutical Sciences, Volume 97, Issue 5, pages 1993–2007, May 2008
  40. Jump up^ Kaufman, Marc J.; et al., Cocaine-Induced Cerebral Vasoconstriction Detected in Humans With Magnetic Resonance Angiography
  41. Jump up^ Russo KE, Hall W, Chi OZ, Sinha AK, Weiss HR (1991). "Effect of amphetamine on cerebral blood flow and capillary perfusion". Brain Res 542 (1): 43–8. doi:10.1016/0006-8993(91)90995-8. PMID 1905179.
  42. Jump up^ Grund T, Lehmann K, Bock N, Rothenberger A, Teuchert-Noodt G (2006). "Influence of methylphenidate on brain development—an update of recent animal experiments".Behav Brain Funct 2: 2. doi:10.1186/1744-9081-2-2. PMC 1363724.PMID 16403217.
  43. Jump up^ Sagvolden T, Sergeant JA (1998). "Attention deficit/hyperactivity disorder—from brain dysfunctions to behaviour". Behav. Brain Res. 94 (1): 1–10. doi:10.1016/S0166-4328(97)00164-2. PMID 9708834.
  44. Jump up^ Gordon N (1999). "Attention deficit hyperactivity disorder: possible causes and treatment". Int. J. Clin. Pract. 53 (7): 524–8. PMID 10692738.
  45. Jump up^ King S, Griffin S, Hodges Z, et al. (2006). "A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents". Health Technol Assess 10 (23): iii–iv, xiii–146. PMID 16796929.
  46. Jump up^ Gonzalez de Dios J, Cardó E, Servera M (2006). "[Methylphenidate in the treatment of attention-deficit/hyperactivity disorder: are we achieving an adequate clinical practice?]".Rev Neurol (in Spanish; Castilian) 43 (12): 705–14. PMID 17160919.
  47. Jump up^ – Ritalin Side Effects. Drugs.com. Retrieved on 2011-10-16.
  48. Jump up^ Jaanus SD (1992). "Ocular side-effects of selected systemic drugs". Optom Clin 2 (4): 73–96. PMID 1363080.
  49. Jump up^ Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, Slocumb NL (2005). "Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study". Sleep 28 (6): 667–72. PMID 16477952.
  50. Jump up^ Minutes of the FDA Pediatric Advisory Committee. March 22, 2006.
  51. Jump up^ "FDA may reject safety warning for ADHD drugs". New Scientist. 18 February 2006
  52. Jump up^ Minutes of the FDA Pediatric Advisory Committee, March 22, 2006
  53. Jump up^ Kraemer M, Uekermann J, Wiltfang J, Kis B (July 2010). "Methylphenidate-induced psychosis in adult attention-deficit/hyperactivity disorder: report of 3 new cases and review of the literature". Clin Neuropharmacol 33 (4): 204–6.doi:10.1097/WNF.0b013e3181e29174. PMID 20571380.
  54. ^ Jump up to:a b c d e Characterization of Methylphenidate Exposures Reported to a Regional Poison Control Center - 2000, White & Yadao: Paediatrics & Adolescent Medicine
  55. ^ Jump up to:a b c d [www.poison.org/stats/2010%20NPDS%20Annual%20Report.pdf Annual report 2010, American Association of Poison Control Centers Toxic Exposure Surveillance System] - Bronstein et al, Table 22B p.136
  56. ^ Jump up to:a b c d e f g Scharman EJ, Erdman AR, Cobaugh DJ, et al. (2007). "Methylphenidate poisoning: an evidence-based consensus guideline for out-of-hospital management".Clinical Toxicology 45 (7): 737–52. doi:10.1080/15563650701665175.PMID 18058301. [3]
  57. ^ Jump up to:a b c Severe toxicity due to injected but not oral or nasal abuse of methylphenidate tablets - Bruggisser et al 2011
  58. Jump up^ Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, Lynch F (2000). "Trends in the prescribing of psychotropic medications to preschoolers". JAMA 283 (8): 1025–30.doi:10.1001/jama.283.8.1025. PMID 10697062.
  59. Jump up^ ADHD & Women's Health – Attention-deficit hyperactivity disorder National Women's Health Report. 2003. Retrieved 2007-11-03. "Although methylphenidate is perhaps one of the best-studied drugs available, with thousands of studies attesting to its long-term that finds the numbers of children taking the drug skyrocketing in recent years."
  60. Jump up^ Edmund J. S. Sonuga-Barke, Margaret Thompson, Howard Abikoff, Rachel Klein, Laurie Miller Brotman. "Nonpharmacological Interventions for Preschoolers With ADHD: The Case for Specialized Parent Training" (PDF). Infants & Young Children 19 (2): 142–153. Retrieved 2008-12-30. "While most recent studies suggest that methylphenidate is relatively well tolerated by young children, some suggest that side-effects might be more marked in preschoolers than in school-aged children (Firestone, Musten, Pisterman, Mercer, & Bennett, 1998). Furthermore, some researchers have argued that there is the potential for negative long-term effects on the developing brains of young children chronically medicated (Moll, Rothenberger, Ruther, & Huther, 2002)."
  61. Jump up^ Ashton H, Gallagher P, Moore B (2006). "The adult psychiatrist's dilemma: psychostimulant use in attention deficit/hyperactivity disorder". J. Psychopharmacol. (Oxford) 20 (5): 602–10. doi:10.1177/0269881106061710. PMID 16478756.
  62. Jump up^ Kociancic T, Reed MD, Findling RL (2004). "Evaluation of risks associated with short- and long-term psychostimulant therapy for treatment of ADHD in children". Expert Opin Drug Saf 3 (2): 93–100. doi:10.1517/eods.3.2.93.27337. PMID 15006715.
  63. Jump up^ "Ritalin & Ritalin-SR Prescribing Information" (PDF). Novartis. 2007.
  64. Jump up^ Cherland E, Fitzpatrick R (1999). "Psychotic side effects of psychostimulants: a 5-year review" (PDF). Can J Psychiatry 44 (8): 811–3. PMID 10566114.
  65. Jump up^ Kimko HC, Cross JT, Abernethy DR (1999). "Pharmacokinetics and clinical effectiveness of methylphenidate". Clin Pharmacokinet 37 (6): 457–70.doi:10.2165/00003088-199937060-00002. PMID 10628897.
  66. Jump up^ Dafny, N.; Yang, P. (2006). "The role of age, genotype, sex, and route of acute and chronic administration of methylphenidate: a review of its locomotor effects". Brain Research Bulletin 68 (6): 393–405. doi:10.1016/j.brainresbull.2005.10.005.PMID 16459193. edit
  67. Jump up^ Ross RG (2006). "Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder". Am J Psychiatry 163 (7): 1149–52.doi:10.1176/appi.ajp.163.7.1149. PMID 16816217.
  68. Jump up^ DelBello MP, Soutullo CA, Hendricks W, Niemeier RT, McElroy SL, Strakowski SM (2001). "Prior stimulant treatment in adolescents with bipolar disorder: association with age at onset". Bipolar Disord 3 (2): 53–7. doi:10.1034/j.1399-5618.2001.030201.x.PMID 11333062.
  69. Jump up^ Soutullo CA, DelBello MP, Ochsner JE, et al. (2002). "Severity of bipolarity in hospitalized manic adolescents with history of stimulant or antidepressant treatment". J Affect Disord 70 (3): 323–7. doi:10.1016/S0165-0327(01)00336-6.PMID 12128245.
  70. Jump up^ Kuczenski R, Segal DS (2005). "Stimulant actions in rodents: implications for attention-deficit/hyperactivity disorder treatment and potential substance abuse". Biol. Psychiatry57 (11): 1391–6. doi:10.1016/j.biopsych.2004.12.036. PMID 15950013.
  71. ^ Jump up to:a b Soto, Paul L.; Kristin M Wilcox, Yun Zhou, Nancy A Ator, Mark A Riddle, Dean F Wong, Michael R Weed (18). "Long-Term Exposure to Oral Methylphenidate or dl-Amphetamine Mixture in Peri-Adolescent Rhesus Monkeys: Effects on Physiology, Behavior, and Dopamine System Development". Neuropsychopharmacology 37: 2566–2579. doi:10.1038/npp.2012.119. PMID 22805599. Retrieved 2 December 2012.
  72. Jump up^ Roberts SM, DeMott RP, James RC (1997). "Adrenergic modulation of hepatotoxicity".Drug Metab. Rev. 29 (1–2): 329–53. doi:10.3109/03602539709037587.PMID 9187524.
  73. Jump up^ Marotta PJ, Roberts EA (1998). "Pemoline hepatotoxicity in children". The Journal of Pediatrics 132 (5): 894–7. doi:10.1016/S0022-3476(98)70329-4. PMID 9602211.
  74. Jump up^ Patrick KS, González MA, Straughn AB, Markowitz JS (2005). "New methylphenidate formulations for the treatment of attention-deficit/hyperactivity disorder". Expert Opinion on Drug Delivery 2 (1): 121–43. doi:10.1517/17425247.2.1.121. PMID 16296740.
  75. Jump up^ Markowitz JS, DeVane CL, Boulton DW, et al. (2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug Metabolism and Disposition 28 (6): 620–4. PMID 10820132.
  76. Jump up^ Markowitz, J. S.; Devane, C. L.; Boulton, D. W.; Nahas, Z.; Risch, S. C.; Diamond, F.; Patrick, K. S. (2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug metabolism and disposition: the biological fate of chemicals 28 (6): 620–624. PMID 10820132. edit
  77. ^ Jump up to:a b Patrick KS, Straughn AB, Perkins JS, González MA (2009). "Evolution of stimulants to treat ADHD: transdermal methylphenidate". Human Psychopharmacology 24 (1): 1–17. doi:10.1002/hup.992. PMC 2629554. PMID 19051222.
  78. Jump up^ Patrick KS, Williard RL, VanWert AL, Dowd JJ, Oatis JE, Middaugh LD (2005). "Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol". Journal of Medicinal Chemistry 48 (8): 2876–81. doi:10.1021/jm0490989. PMID 15828826.
  79. Jump up^ Williard RL, Middaugh LD, Zhu HJ, Patrick KS (2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology 18 (1): 39–51.doi:10.1097/FBP.0b013e3280143226. PMID 17218796.
  80. ^ Jump up to:a b Tan M, Appleton R (2005). "Attention deficit and hyperactivity disorder, methylphenidate, and epilepsy". Archives of Disease in Childhood 90 (1): 57–9.doi:10.1136/adc.2003.048504. PMC 1720074. PMID 15613514.
  81. Jump up^ Methylphenidate Use During Pregnancy and Breastfeeding. Drugs.com. Retrieved on 2011-04-30.
  82. Jump up^ Humphreys C, Garcia-Bournissen F, Ito S, Koren G (2007). "Exposure to attention deficit hyperactivity disorder medications during pregnancy". Canadian Family Physician53 (7): 1153–5. PMC 1949295. PMID 17872810.
  83. Jump up^ Kaufman, David Myland; Heinonen, Olli P.; Slone, Dennis; Shapiro, Samuel (1977).Birth defects and drugs in pregnancy. Littleton, Mass: Publishing Sciences Group.ISBN 0-88416-034-3. OCLC 2387745.[page needed]
  84. Jump up^ Yaffe, Sumner J.; Briggs, Gerald G.; Freeman, Roger Anthony (2005). Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-5651-0.[page needed]
  85. ^ Jump up to:a b Klein-Schwartz W (2002). "Abuse and toxicity of methylphenidate". Current Opinion in Pediatrics 14 (2): 219–23. doi:10.1097/00008480-200204000-00013.PMID 11981294.
  86. Jump up^ https://www.erowid.org/pharms/methylphenidate/methylphenidate_info1.shtml
  87. ^ Jump up to:a b c 2004 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System - Table 22B p.652
  88. Jump up^ Safety of therapeutic methylphenidate in adults: a systematic review of the evidence- 2008, Godfrey
  89. ^ Jump up to: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.
  90. Jump up^ 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.
  91. Jump up^ 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.
  92. Jump up^ 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.
  93. Jump up^ 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.
  94. Jump up^ 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.
  95. Jump up^ Smucker WD, Hedayat M (2001). "Evaluation and treatment of ADHD". Am Fam Physician 64 (5): 817–29. PMID 11563573.
  96. Jump up^ Rosenfeld AA (1979). "Depression and psychotic regression following prolonged methylphenidate use and withdrawal: case report". Am J Psychiatry 136 (2): 226–8.PMID 760559.
  97. Jump up^ 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.
  98. Jump up^ Yang. "Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization". Retrieved 2 April 2013.
  99. Jump up^ 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
  100. ^ Jump up to:a b Volkow, N. D.; Wang, G. J.; Fowler, J. S.; Gatley, S. J.; Logan, J.; Ding, Y. S.; Dewey, S. L.; Hitzemann, R.; Gifford, A. N.; Pappas, N. R. (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. edit
  101. Jump up^ 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.
  102. Jump up^ Morton WA, Stockton GG (2000). "Methylphenidate Abuse and Psychiatric Side Effects". Primary Care Companion Journal of Clinical Psychiatry 2 (5): 159–64.
  103. Jump up^ Arria AM, Wish ED (2006). "Nonmedical use of prescription stimulants among students". Pediatric Annals 35 (8): 565–71. PMC 3168781. PMID 16986451.
  104. Jump up^ Midgely, Carol (February 21, 2003). "Kiddie coke: A new peril in the playground".The Times (London). Retrieved 21 February 2010.[unreliable medical source?]
  105. Jump up^ 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.
  106. Jump up^ 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.
  107. Jump up^ "Ritalin backed as brain-booster". BBC News. 19 June 2009. Retrieved 21 February 2010.
  108. Jump up^ 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.
  109. Jump up^ 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.
  110. Jump up^ "Misuse of Drugs Act 1971 (c. 38): SCHEDULE 2: Controlled Drugs". Office of Public Sector Information. Retrieved 2009-06-15.
  111. ^ Jump up to:a b Moses, Scott (2009-07-26). "Methylphenidate". Family Practice Notebook. Retrieved 2012-08-07. "Duration: 5-8 hours (gradual decrease after 3 hours)".
  112. Jump up^ "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".
  113. Jump up^ "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.
  114. Jump up^ "New product: Sandoz Methylphenidate SR 20 mg". Sandoz Canada Inc. 2009-05-05. Retrieved 2012-07-26. "An alternative to Ritalin‑SR from Novartis".
  115. Jump up^ Concerta for Kids with ADHD. Pediatrics.about.com (2003-04-01). Retrieved on 2011-04-30.
  116. Jump up^ Concerta (Methylphenidate Extended-Release Tablets) Drug Information: User Reviews, Side Effects, Drug Interactions and Dosage at RxList. Rxlist.com. Retrieved on 2011-04-30.
  117. Jump up^ Ritalin LA® (methylphenidate hydrochloride) extended-release capsules, Novartis
  118. Jump up^ Metadate CD. Adhd.emedtv.com. Retrieved on 2011-04-30.
  119. Jump up^ 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.
  120. Jump up^ New Research Helps Explain Ritalin's Low Abuse Potential When Taken As Prescribed – 09/29/1998. Nih.gov. Retrieved on 2011-04-30.
  121. Jump up^ Stimulant ADHD Medications: Methylphenidate and Amphetamines – InfoFacts – NIDA. Drugabuse.gov. Retrieved on 2011-04-30.
  122. Jump up^ 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.
  123. Jump up^ 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.
  124. Jump up^ FDA OKs Concerta for Adult ADHD, webmd.com
  125. Jump up^ Ritalin for Adults. Adhd.emedtv.com (2007-03-06). Retrieved on 2011-04-30.
  126. Jump up^ Drug Enforcement Administration, Greene, S.H., Response to CHADD petition concerning Ritalin, 1995, August 7. Washington, DC: DEA, U.S. Department of Justice.
  127. Jump up^ The Neurobiology of ADHD, ADHD.org.nz
  128. Jump up^ 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 [4])"
  129. Jump up^ 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 [5])"
  130. Jump up^ 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.
  131. ^ Jump up to:a b c Heal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system".CNS Drugs 20 (9): 713–38. doi:10.2165/00023210-200620090-00002.PMID 16953648.
  132. Jump up^ 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.
  133. Jump up^ 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.
  134. Jump up^ 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
  135. Jump up^ 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.
  136. Jump up^ Panizzon, Leandro (1944). "La preparazione di piridil- e piperidil-arilacetonitrili e di alcuni prodotti di trasformazione (Parte Ia)". Helvetica Chimica Acta 27: 1748–56.doi:10.1002/hlca.194402701222.
  137. Jump up^ Meier, R; Gross, F; Tripod, J (1954). "Ritalin, a new synthetic compound with specific analeptic components". Klinische Wochenschrift 32 (19–20): 445–50.PMID 13164273.
  138. Jump up^ Myers, Richard L (2007-08). The 100 most important chemical compounds: a reference guide By Richard L. Myers. ISBN 978-0-313-33758-1. Retrieved 2010-09-10.
  139. Jump up^ Leandro Panizzon et al Pyridine and piperdjine compounds U.S. Patent 2,507,631Issue date: May 16, 1950
  140. Jump up^ Rudolf Rouietscji et al Process for the conversion of U.S. Patent 2,838,519 Issue date: Jun 10, 1958
  141. Jump up^ Rudolf Rouietscji et alProcess for the conversion of U.S. Patent 2,957,880 Issue date: Oct 25, 1960
  142. Jump up^ Terrance Woodworth (May 16, 2000). "DEA Congressional Testimony". Retrieved 2007-11-02.
  143. Jump up^ Approved Drug Therapies (637) Concerta, Alza. CenterWatch. Retrieved on 2011-04-30.
  144. Jump up^ Iversen L (2006). "Neurotransmitter transporters and their impact on the development of psychopharmacology". British Journal of Pharmacology 147 (Suppl 1): S82–8.doi:10.1038/sj.bjp.0706428. PMC 1760736. PMID 16402124.
  145. Jump up^ Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–76. doi:10.1111/j.1471-4159.2010.07109.x.PMC 3005101. PMID 21073468.
  146. Jump up^ Novartis:Focalin XR Overview
  147. Jump up^ Focalin XR – Full Prescribing Information. Novartis.
  148. Jump up^ Concerta XL 18 mg – 36 mg prolonged release tablets last updated on the eMC: 05/11/2010
  149. Jump up^ Sulzer D, Sonders MS, Poulsen NW, Galli A (2005). "Mechanisms of neurotransmitter release by amphetamines: a review" (PDF). Prog. Neurobiol. 75 (6): 406–33.doi:10.1016/j.pneurobio.2005.04.003. PMID 15955613.
  150. Jump up^ Markowitz JS, DeVane CL, Pestreich LK, Patrick KS, Muniz R (2006). "A comprehensive in vitro screening of d-, l-, and dl-threo-methylphenidate: an exploratory study". J Child Adolesc Psychopharmacol 16 (6): 687–98.doi:10.1089/cap.2006.16.687. PMID 17201613.
  151. Jump up^ T. J. Volz (2008). "Neuropharmacological Mechanisms Underlying the Neuroprotective Effects of Methylphenidate". Current Neuropharmacology.doi:10.2174/157015908787386041. PMC 2701286.
  152. Jump up^ Rosack Jim (2 January 2004). "Brain Scans Reveal Physiology of ADHD".Psychiatric News 39 (1): 26.
  153. Jump up^ Liddle, E. B.; Hollis, C.; Batty, M. J.; Groom, M. J.; Totman, J. J.; Liotti, M.; Scerif, G.; Liddle, P. F. (2011). "Task-related default mode network modulation and inhibitory control in ADHD: Effects of motivation and methylphenidate". Journal of Child Psychology and Psychiatry 52 (7): 761–771. doi:10.1111/j.1469-7610.2010.02333.x.PMID 21073458. edit
  154. Jump up^ Kimko, H. C.; Cross, J. T.; Abernethy, D. R. (1999). "Pharmacokinetics and Clinical Effectiveness of Methylphenidate". Clinical Pharmacokinetics 37 (6): 457.doi:10.2165/00003088-199937060-00002. PMID 10628897. edit
  155. Jump up^ Chan, Y. P.; Swanson, J. M.; Soldin, S. S.; Thiessen, J. J.; MacLeod, S. M.; Logan, W. (1983). "Methylphenidate hydrochloride given with or before breakfast: II. Effects on plasma concentration of methylphenidate and ritalinic acid". Pediatrics 72 (1): 56–59.PMID 6866592. edit
  156. Jump up^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp. 1091–93.
Автор: на 1 комментарий:

вторник, 15 октября 2013 г.

Контрацептивы тормозят рост мышечной массы.


 

По результатам недавних экспериментов, проводившихся американскими учеными, было установлено, что прием оральных контрацептивов негативно сказывается на росте мышечной массы, играющей основную роль в избавлении от жировой ткани. 

Американские ученые сообщают, что женщины, желающие иметь развитую мускулистую фигуру, должны избегать применения оральных контрацептивов. Женщины, не принимающие противозачаточные таблетки, уже после 10-недельной тренировки набирают на 60 процентов больше мышечной массы, чем женщины, употребляющие оральные контрацептивы. Результаты этого исследования, проведенного учеными Техасского (A&M University) и Питсбургского (University of Pittsburgh) университетов будут представлены в Новом Орлеане на предстоящей в конце апреля встрече Американского психологического общества. Для эксперимента были выбраны 73 здоровые женщины в возрасте от 18 до 31 года, которые должны были выполнить программу интенсивных тренировок, направленных на развитие всех групп мышц. Одна группа женщин принимала оральные контрацептивы, вторая – нет. Каждый день все женщины получали протеины – по 1 грамму белка на килограмм веса, для того, чтобы обеспечить достаточное его количество и усилить эффект упражнений. Обе группы тренировались три раза в неделю, делая с одинаковой интенсивностью одно и то же количество упражнений под руководством опытных тренеров. Через 10 недель женщины, не принимавшие оральные контрацептивы, обладали значительно большим количеством сухой мышечной массы. Кроме того, анализы крови, взятые до и после тренировок, показали, что у женщин, принимающих таблетки, уровень тестостерона (гормона, отвечающего за мышечную массу) был значительно снижен, а уровень кортизола, гормона, способствующего потере мышечной ткани, достаточно высок. В результате этих исследований, ученые сделали заключение, что оральные контрацептивы оказывают неблагоприятное воздействие на способность нарастить мышечную массу, но науке еще предстоит найти ответ на вопрос «почему?»
Автор: на Комментариев нет:

суббота, 12 октября 2013 г.

Обезжиренные продукты зачастую не приносят ни малейшей пользы.

  Давайте же узнаем всю правду про них.

Миф и реальность

Сегодня на полках магазинов можно найти продукты с нулевой жирностью (если задуматься над этим вопросом, то можно понять – 0 % жира содержит разве что вода). Американцы на собственном примере доказали – чем больше обезжиренных продуктов человек употребляет, тем толще становится. Объясняется все достаточно просто – жир хорошо насыщает и надолго отодвигает чувство голода. Ну а популярные ныне продукты с минимальной жирностью не насыщают вовсе – буквально через час возникает чувство голода и заставляет вновь обращаться к любимой обезжиренной пище. Благодаря этому калорийность рациона увеличивается в среднем на 250 ккал.

О пользе жиров

В продуктах с нормальным процентом жирности находятся кислоты, регулирующие обмен веществ. Употребляя одни лишь нежирные продукты можно внести дисбаланс в обменные процессы, что в конечном итоге практически неизбежно приведет к появлению лишней массы тела.

Жирные кислоты обеспечивают эластичность и прочность кровеносных сосудов.

Лецитин (жироподобное вещество) участвует в образовании клеточных мембран.

Жировая прослойка у женщин, находящаяся в области бедер и живота, способствует выработке определенных гормонов, отвечающих за сексуальность.

Как выбирать обезжиренные продукты?

Реклама просто обязана преподнести продукт в наилучшем свете, поэтому ей не стоит доверять. Единственный способ избежать ошибки – внимательное изучение этикетки на приобретаемом продукте. Зачастую минимальное количество жира соседствует с ароматизаторами, заменителями сахара, красителями и прочими небезопасными добавками. Чем меньше их там содержится, тем лучше.

Диетические хлебцы на самом деле не так уж полезны – в них действительно мало жиров, зато зачастую содержится сухое молоко и, а также достаточно большое количество углеводов и соли. Для диетического питания больше подходит хлеб из муки грубого помола.

Хлопья быстрого приготовления также сложно назвать по-настоящему диетическими – обычных жиров в них действительно нет, зато ароматизаторы, углеводы, а иногда и небезопасные транс-жиры присутствуют. Желая похудеть, стоит кушать обычные постные каши (гречку, неочищенный рис, овсянку и пр.).

Выбирая творог с минимальным количеством жира, обязательно сравните его калорийность с более жирным продуктом – часто она никак не меньше, а иногда и больше. Объясняется это наличием определенных добавок, призванных улучшить вкусовые качества нежирного продукта.

Молочные продукты стоит приобретать лишь те, которые имеют минимальный срок хранения. Также не мешает проверить калорийность – обезжиренные продукты очень мало отличаются по энергетической ценности от аналогов со средним уровнем жирности. Йогурты лучше выбирать несладкие и без фруктовых добавок – меньше шансов насытить организм всяческими «Е».

Постные мясные полуфабрикаты чаще всего содержат транс-жиры, которые способствуют увеличению уровня холестерина в крови. То же самое относится к маргарину и прочим масляным смесям (так называемым, спрэдам).

Полезные нежирные продукты

Нежирные продукты могут иметь и совершенно натуральное происхождение – это в первую очередь относится к нежирным сортам мяса, рыбы и птицы. Для диетического питания стоит использовать белое мясо птицы, телятину, говядину, крольчатину, треску, мерлузу и пр.

Стоит ли употреблять продукты с минимальной жирностью? Конечно же, да, но в разумных количествах. Они прекрасно подходят для разгрузочных дней, но вот длительное их присутствие в рационе питания может спровоцировать серьезные проблемы.
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Наркотизация под видом лечения


 

Психотропный препаратНо и без этой легализации, наркотики уже легальномассово употребляются в США и во всем мире. Психиатры и психологи массово выписывают лекарства, которые по сути являются наркотиками, значительной части населения.
Такие психотропные препараты прописываются по любому поводу, поскольку за выписывание такого рецепта врач имеет премию.
Психотропные препараты массировано рекламируются в СМИ. Как выяснилось, при современном своде психиатрических диагнозов, который пополняется ежегодно, не одну психическую проблему психологи легко найдут для любого здорового человека. И человек, которому выписали лекарства, обязан их принимать, поскольку отказ от их приема будет восприниматься как отказ от лечения и повлечет неприятные последствия для медицинской страховки и для репутации.
Так волны «МК-ультра» коснулись и малолетних, ведь психотропные теперь массово выписывают и им. Впоследствии потребители таких лекарств легко переходят на потребление других наркотиков.
Детский наркотик - Риталин
В документальном фильме «Психиатрия – индустрия смерти» я видел документальную скрытую съемку того, как журналист посещает разных психологов. У каждого из психологов журналист о своем состоянии говорил одно и то же, но они ставили ему разные диагнозы. Общее, что проявили все психологи – они с одинаковой уверенностью выписывали психотропные препараты. Конечно, препараты были разными, поскольку диагнозы были разными. Это означает, что психологи и психиатры лечат наугад. Глупо ожидать пользу от такого лечения.
Таков сегодня уровень психиатрии и такова сегодня этика психологов и психиатров. То, что прием психотропных препаратов ведет к реальным психическим проблемам, болезням, депрессиям, зависимости, наркомании, криминальному поведению и самоубийствам, не смущает ни психиатрическую верхушку, ни власти.
Когда специальные комиссии расследуют многочисленные случаи вреда от таких препаратов, экспертами оказываются психиатры, имеющие свой коммерческий интерес от их продажи. Поэтому не удается обосновать претензии к таким лекарствам. А ведь через такие лекарства на наркотики подсаживают весь мир!
Например, широко используемый препарат Риталин химически похож на кокаин. В 2000 году американское Агентство по Борьбе с наркотиками (АБН) обнародовало результаты исследования, в котором людям давали кокаин и риталин. Люди, на которых проводили испытания, не смогли определить разницу!
Риталин - антидепрессант
Риталин и подобные ему вызывают наркотическую зависимость и массу побочных эффектов, в том числе депрессию и склонность к самоубийству. То есть, эффект приёма этих продуктов практически идентичен. В общем, это наркотик без всяких скидок.
Детский риталин
Согласно исследованиям АБН 2005 года, у тех подростков, которые злоупотребляют предписанными психотропными препаратами, по сравнению с теми, кто не употребляет их, вероятность перехода на героин выше в 12 раз, на экстази – в 15 раз, и на кокаин – в 21 раз.
Все встанет на свои места, если вспомните, что в проекте «МК-ультра» активно участвовал Ивен Камерон, ставший главой Ассоциации американских психиатров и Всемирной ассоциации психиатров. Руководители меняются, а характер действий остается прежним. Размывание сознания с помощью наркотиков, запланированное в том проекте, теперь осуществляется совершенно открыто и легально.
А всего-то и нужно было – назвать наркотики лекарствами, транквилизаторами и антидепрессантами, и материально заинтересовать врачей выписывать их. Психиатрия стала инструментом подсаживания на наркотики.
Последствия приема антидепрессантов
А ведь вся мировая психиатрия ориентируется на опыт США.
Подобный кошмар уже давно творится и в России. С попустительства доверчивых родителей психологи ради своих премиальных подсаживают детей на наркотики, называемые лекарствами.
На этом фоне не выглядит странным, что в значительной части голливудских фильмов употребление легких наркотиков типа марихуаны преподносится как безобидное баловство, которое нормально испытать каждому человеку. Так дополнительно подталкивают людей к наркомании.
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Аминазин инструкция по применению

 

Примечание

Здесь представлены инструкции по применению препарата Аминазин различных форм выпуска и производителей.
Для того чтобы прочитать инструкцию Аминазин щелкните левой кнопкой мыши по изображению.
Источником информации является государственный реестр лекарственных средств (http://grls.rosminzdrav.ru/).

Важно!

Лекарства должны применяться только после консультации с врачом!

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