the cure for all diseases(Ritalin or Methylphenidate)

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    Charles Darwin

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    Methylphenidate

    (trade names Concerta, Methylin, Ritalin, Equasym XL) is a
    and
    approved for
    of
    (ADHD),
    and
    . The original patent was owned by
    , now
    . It was first licensed by the U.S.
    (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.

    ADHD and other similar conditions are believed to be linked to sub-performance of the
    and
    functions in the brain, primarily in the
    , responsible for
    functions of
    ,
    ,
    , and the concentration/
    of
    ,
    ,
    , and
    . Methylphenidate's pharmacological profile involves
    , similar to other sympathomimetics of the
    . In particular, methylphenidate is a
    and also a much weaker
    , which increases the levels of these
    in the brain.

    Medical

    MPH is a commonly prescribed
    and works by increasing the activity of the
    . It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention. The short-term benefits and cost effectiveness of methylphenidate are well established, although long-term effects are unknown. The long term effects of methylphenidate on the developing brain are unknown. Methylphenidate is not approved for children under six years of age. Methylphenidate may also be prescribed for
    in treatment-resistant cases of
    ,
    ,
    , and
    .

    Attention deficit hyperactivity disorder

    Methylphenidate is approved by the U.S.
    (FDA) for the treatment of
    . The addition of
    (e.g.
    (CBT)) has additional benefits on treatment outcome. People with ADHD have an increased risk of
    , and stimulant medications reduce this risk. A
    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.

    Methylphenidate's long-term efficacy in ADHD treatment has been questioned because of a lack of long-term studies. A 2010 study suggested that, "there is increasing evidence...[stimulant drugs such as methylphenidate] do not promote learning and academic achievement".

    Some research suggests that methylphenidate treatment need not be indefinite. Weaning off periods to assess symptoms and allay tolerance periodically are sometimes recommended.

    The dosage used can vary quite significantly among individuals with some people responding to quite low doses, whereas others require a higher dose range; consequently, dosage should be titrated to an optimal level that achieves therapeutic benefit and minimal side-effects. This can range from anywhere between 5–30 mg twice daily or up to 60 mg a day.

    Mechanisms of ADHD

    Main article:

    The means by which methylphenidate affects people diagnosed with ADHD are not well understood. Some researchers have theorized that ADHD is caused by a
    imbalance in the
    of those affected. Methylphenidate is a norepinephrine and
    , which means that it increases the level of the dopamine
    in the brain by partially blocking the dopamine transporter (DAT) that removes dopamine from the
    . This inhibition of DAT blocks the reuptake of dopamine and norepinephrine into the presynaptic neuron, increasing the amount of dopamine in the synapse, while decreasing the amount of dopamine in the presynaptic neuron. As a result, it decreases the magnitude of phasic dopamine release from the presynaptic neuron into the synapse upon exposure to a stimulus, decreasing the effective salience of the stimulus. An alternate explanation that has been explored is that the methylphenidate affects the action of
    in the brain. However, benefits with other stimulants that have a different mechanism of action indicates that support for a deficit in specific
    is unsupported and unproven by the evidence and remains a speculative
    .

    Studies confirm that biological and genetic differences of the kinds predicted by
    are clearly visible in ADHD individuals, and have been confirmed both genetically and by in vivo scans of ADHD affected brains.
    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. Methylphenidate's cognitive enhancement effects have been investigated using
    scans even in non-ADHD brains, which revealed modulation of brain activity in ways that enhance mental focus. Methylphenidate increases activity in the
    and attention-related areas of the
    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
    regions during the task.

    Aggression and criminality

    Two studies state that methylphenidate is
    for the treatment of ADHD in adults with a history of aggressive and
    . 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. Some of these clinical outcomes have been confirmed in similar studies with children and adolescents.

    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. Methylphenidate improves measures of
    on standardized tests, such as the
    , but performance does not improve to levels comparable to healthy controls.

    Other

    Use of stimulants such as methylphenidate in cases of treatment resistant depression is controversial. 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. Methylphenidate may be used in addition to an antidepressant for refractory
    . It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. However, benefits tend to be only partial with stimulants. Stimulants may, however, have fewer side-effects than
    in the elderly and medically ill.

    Performance-enhancing

    Therapeutic doses of methylphenidate and
    improve performance on
    tests both in normal functioning individuals and those with ADHD. Moreover, these stimulants also increase arousal and, within the
    , improve task
    . Thus, stimulants improve performance on effortful and tedious tasks as well. Based upon studies of self-reported illicit stimulant use among college students, performance-enhancing use, as opposed to
    as a recreational drug, is the primary reason that students use stimulants. In contrast, at doses much higher than those medically prescribed, methylphenidate can interfere with working memory and cognitive control. Like
    and
    , methylphenidate increases stamina and endurance in humans primarily through
    of dopamine in the central nervous system. Similar to cognition enhancement, very high doses of methylphenidate can induce side effects that impair athletic performance, such as
    and
    .

    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. However, long lasting benefits of stimulant drugs have not been found in humans.

    Adverse effects

    Some adverse effects may emerge during chronic use of methylphenidate so a constant watch for adverse effects is recommended. 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. The most common side effects of methylphenidate are nervousness, drowsiness and
    . Other adverse reactions include:

    Recent large-scale studies by the US FDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (
    ,
    , and
    ) and the medical use of Амф, methylphenidate, or other commonly prescribed ADHD stimulants.

    Substance dependence

    Although possible, substance dependence is rare with methylphenidate. Methylphenidate has shown some benefits as a replacement therapy for individuals dependent on
    . Methylphenidate and
    have been investigated as a chemical replacement for the treatment of Кока dependence in the same way that
    is used as a replacement for
    . Its effectiveness in treatment of Кока or psychostimulant dependence has not been proven and further research is needed.

    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 on the effectiveness of methylphenidate as a substitute agent in refractory cases of Кока dependence.

    Treatment emergent psychosis

    Main article:

    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. In the majority of unremarkable isolated cases methylphenidate overdose is asymptomatic or only incurs minor symptoms even in children under six years of age. Normally any reaction will show within three hours. However, injection (particularly arterial) has sometimes led to toxic
    and
    at the point of injection. Emergency treatment is recommended beyond certain overdose levels, in cases of attempted suicide, and in those using
    (MAOIs).

    Long-term effects

    In 2000, by Zito et al. 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. 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. There is limited data that suggests there are benefits to long-term treatment in correctly diagnosed children with ADHD, with overall modest risks. Short-term clinical trials lasting a few weeks show an incidence of psychosis of about 0.1%. 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. The long-term effects on mental health disorders in later life of chronic use of methylphenidate is unknown. Concerns have been raised that long-term therapy might cause
    ,
    ,
    and behavioral sensitisation, similar to other stimulants. Psychotic symptoms from methylphenidate can include
    ,
    , urges to harm oneself, severe
    ,
    ,
    ,
    ,
    , and
    .
    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
    and
    independent of ADHD.

    Knowledge of the effects of chronic use of methylphenidate is poorly understood with regard to persisting behavioral and neuroadaptational effects. 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. Measures tested included
    density,
    density, Амф-induced dopamine release responsiveness, cognitive performance, and growth.

    Precautions

    Interactions

    Intake of
    drugs or
    with methylphenidate increases the risk of
    .

    When methylphenidate is coingested with
    , a metabolite called
    is formed via hepatic transesterification, not unlike the hepatic formation of
    from
    . 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.

    Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.

    Contraindications

    Methylphenidate should not be prescribed concomitantly with
    , such as
    , or
    , such as
    or
    , as methylphenidate may dangerously increase plasma concentrations, leading to potential toxic reactions (mainly,
    effects). Methylphenidate should not be prescribed to patients who suffer from severe
    ,
    or
    . It should not be prescribed to patients who demonstrate
    , pronounced agitation or nervousness. Care should be taken while prescribing methylphenidate to children with a family history of
    .

    Pregnancy

    The U.S. FDA gives methylphenidate a
    of C, and women are advised to only use the drug if the benefits outweigh the potential risks. 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. One of these studies (N = 11) demonstrated no significant increases in malformations. 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. 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.,
    ,
    ) 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. In cases that manifest symptoms, these can typically include agitation, hallucinations, psychosis, lethargy, seizures, tachycardia, dysrhythmias, hypertension, and hyperthermia. LD50 in mice is 190 mg/kg.

    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, 0.9% in the 2004 US national analysis with n=8336, and 0.2% in the same analysis for 2010 with n=6503).

    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 2000-2005).

    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. A 2011 Swiss study also agreed the general findings, adding a cautionary note that serious or severe outcomes such as
    ,
    and
    had occurred as a result of severe toxicity at the injection site in 3 cases of abuse via arterial injection.

    Medical and emergency handling

    Key recommendations in US guidelines for overdose handling include:

    • 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
      (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.
    • may be used as treatment if agitation, dystonia, or convulsions are present.
    Poison control center analyses and study findings

    A study in 2000 looked in detail at all 289 overdoses of MPH reported to the
    regional
    during 1993 and 1994 (excluded: 105 extended-release formulations or co-ingestants, to ensure MPH overdose effects were not confounded by other effects). 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:
    • "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, 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. The 2010 report 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)
    A
    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
    ,
    and partial limb or digit
    in two of 14 adult cases over 8 years (14%) who mistakenly injected
    , and
    and
    in one who injected
    .

    Abuse potential



    Legal warning printed on Ritalin packaging
    Methylphenidate has some potential for
    due to its action on dopamine transporters. Methylphenidate, like other
    , increases
    levels in the brain, but at therapeutic doses this increase is slow, and thus
    only rarely occurs even when it is administered
    . The abuse and addiction potential of methylphenidate is therefore significantly lower than that of other dopaminergic stimulants. The abuse potential is increased when methylphenidate is crushed and insufflated (snorted), or injected. 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. IV users tend to be adults whose use may cause panlobular
    .

    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.

    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. 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
    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.

    Methylphenidate is sometimes used by students to enhance their mental abilities, improving their concentration and helping them to study. Professor
    , 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. 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
    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. 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.

    Pharmacology





    Pharmacodynamics

    Methylphenidate primarily acts as a dopamine-norepinephrine reuptake inhibitor. It is a
    and
    which also shares part of its basic structure with
    .

    Methylphenidate is most active at modulating levels of
    and to a lesser extent
    . Methylphenidate binds to and blocks
    and
    .

    While both
    and methylphenidate are
    , it should be noted that their methods of action are distinct. Specifically, methylphenidate is a
    while Амф is both a
    and
    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
    derivatives, as methylphenidate is thought to increase general firing rate, whereas
    reduces firing rate and reverses the flow of the monoamines via
    activation.

    Methylphenidate has both
    and
    binding affinity, with the
    displaying a prominent affinity for the norepinephrine transporter. Both the
    and
    enantiomers displayed receptor affinity for the
    5HT1A and 5HT2B subtypes, though direct binding to the
    was not observed.

    Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine abuse.

    The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain
    .

    Methylphenidate has been identified as a
    agonist.

    Binding profile of methylphenidate

    Transporter Ki (nM)
    >10000
    345.1
    41

    Pharmacokinetics

    Methylphenidate taken orally has a
    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.

    d-methylphenidate is much more bioavailable than l-methylphenidate when administered orally, and is primarily responsible for the psychoactivity of
    methylphenidate.

    Contrary to the expectation, taking methylphenidate with a meal speeds absorption.

    Detection in biological fluids

    The concentration of methylphenidate or
    , 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.

    Chemistry

    Four isomers of methylphenidate are known to exist. One pair of
    isomers and one pair of erythro are distinguished, from which only
    exhibits the pharmacologically usually desired effects. When the drug was first introduced it was sold as a 3:1 mixture of erythro:threo
    . The erythro diastereomers are also
    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
    out any of the undesired erythro isomers. The drug that contains only
    methylphenidate is called d-TMP. A review on the synthesis of enantiomerically pure (2R,2'R)-(+)-threo-methylphenidate hydrochloride has been published
     
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    Charles Darwin, 13/5/14
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