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PubMed1994

Effect of dextroamphetamine and methylphenidate on calcium and magnesium concentration in hyperactive boys.

Levels of calcium in plasma, red blood cells, and mononuclear blood cells, levels of calcium in plasma, and the plasma calcium-to-magnesium ratio were measured at baseline and after 3 weeks of each drug phase of a double-blind, placebo-controlled study of methylphenidate and dextroamphetamine in hyperactive boys. Levels of magnesium in plasma were significantly higher after 3 weeks of dextroamphetamine treatment, and the calcium-to-magnesium ratio was significantly lower after 3 weeks of either drug compared with the baseline or placebo condition. There was no change in magnesium levels in red blood cells or mononuclear blood cells. These measures were obtained 30 minutes before the morning dose and at 9 a.m., 9:30 a.m., 10:30 a.m., 11:00 a.m., and noon on the last day of each 3-week phase. Analysis of variance revealed a drug effect on plasma magnesium and on the calcium-to-magnesium ratio but no drug x time interaction. Although these changes were not correlated with the time course of acute symptomatic response to stimulant therapy, the decrease in the ratio may be relevant to side effects and treatment resistance associated with stimulant use.

Attention Deficit Disorder with Hyperactivity↗
PubMed1984

Side effects of dextroamphetamine and methylphenidate in hyperactive children--a brief review.

Four of the most commonly reported side effects of dextroamphetamine ( Dexedrine ) and methylphenidate (Ritalin), viz., anorexia, insomnia, stomach pains, and weight loss, were reviewed, with special attention to growth suppression accompanying weight loss. The available evidence indicates that the effects of insomnia, anorexia, and stomach pains are transient and diminish as treatment continues and as medication is properly managed. There is evidence for growth suppression accomapnying weight loss, and possibly some suppression of stature, but these effects are not long-lasting and, from existing evidence, seem to have little effect on adult height or weight.

Anorexia↗
PubMed1991

Extensive and enantioselective presystemic metabolism of dl-threo-methylphenidate in humans.

1. Two pilot studies were carried out to investigate the enantioselective pharmacokinetics of methylphenidate (MPH) in children with attention deficit-hyperactivity disorder (ADHD). A more definitive study, which included administration of an intravenous dose, was carried out in healthy young men. 2. Serial plasma samples were harvested from predose to 8 hours in the first pilot study, predose to 12 hours in the second pilot study and predose to 16 hours in the definitive study. Plasma levels of the separate isomers d-MPH and 1-MPH were determined by an enantioselective gas chromatographic method. 3. In the first pilot study, 6 boys with ADHD each received his regular dose of MPH (10mg n = 5, 5mg n = 1), which contained equal proportions of d-MPH and 1-MPH in an immediate release formulation (MPH-IR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 4 to 10 fold higher than those of 1-MPH. Plasma levels of 1-MPH were so low that it was not possible to monitor them beyond 4 hours in some children. 4. In the second pilot study, 5 boys and 1 girl with ADHD each received their regular dose (20mg) of a slow release formulation (MPH-SR). No MPH was detectable in the predose plasma. Thereafter, plasma levels of the more active d-MPH were 5 to 10 fold higher than those of 1-MPH. It was possible to monitor plasma levels of 1-MPH over the full 12 hour period of study in 5 of the 6 children.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Locomotor rhythms induced by methylphenidate in suprachiasmatic nuclei-lesioned rats.

A robust locomotor activity rhythm with a circadian period appeared by chronic treatment with methylphenidate or methamphetamine in the suprachiasmatic nuclei (SCN)-lesioned rats whose circadian rhythms had been abolished. The appearance of the rhythmicity was accompanied by an increase in the activity level. However, significant circadian periods were detected only in rats whose locomotor activity increased more than 200% of the pretreatment levels. An increase in the activity level is necessary to generate and/or express the circadian locomotor rhythm in SCN-lesioned rats and there seems to be a threshold.

Animals↗
PubMed1992

The use of methylphenidate in patients with incident cancer pain receiving regular opiates. A preliminary report.

In this open, uncontrolled trial, 15 patients with severe incident cancer pain receiving regular opiates were administered 10 mg oral methylphenidate (MP) at 08.00 h and 15 mg at 12.00 h in order to antagonize opiate-induced sedation. The daily dose of opiate was increased by 30% 24 h after starting MP, followed by a 10% increase twice a day until maximal tolerated dose. In 14 evaluable patients, pain (VAS 0-100 mm), sedation (VAS), and mean equivalent daily dose (MEDD) of morphine were 55 +/- 17, 65 +/- 18 and 248 +/- 150 48 h before MP, versus 38 +/- 12 (P less than 0.01), 42 +/- 12 (P less than 0.01), and 405 +/- 130 (P less than 0.01) 48 h after MP, respectively. After 48 h of treatment, 12 of 14 patients felt better on MP, 2 of 12 patients felt no difference, and no patients felt worse (P less than 0.05). We conclude that the addition of MP allowed for an increase in the MEDD of morphine and increased pain control. Controlled double-blind trials should be performed.

Humans↗
PubMed1984

Methylphenidate (Ritalin) treatment of cocaine dependence--a preliminary report.

The authors report on three cases of cocaine dependence treated with methylphenidate. All patients treated showed marked to dramatic improvement with regard to toxic/abstinence signs and symptoms, craving behavior and other behavioral disturbances associated with heavy and chronic cocaine abuse. The authors explore the possibility that cocaine dependence is associated with pre-existing or resulting psychopathology, particularly mood disturbances. Emphasis is also placed on a predisposing or de novo attention deficit disorder (ADD) as possibly contributing to heavy or continued reliance on cocaine.

Adult↗
PubMed1995

Methylphenidate for the management of somatization in terminal cancer patients.

We report a case that illustrates methylphenidate's (MP) usefulness in the management of psychological distress and associated somatization in the palliative-care setting. A 60-year-old man affected by terminal cancer of the prostate had been complaining of increasing physical pain, without any evidence of significant disease progression, opioid toxicity, or previous history of drug addiction. Because of patient's denial, the team had been unsuccessful in identifying any potential emotional factors affecting his physical suffering. MP could both counteract opioid-induced sedation and improve pain control through a positive action on patient's mood. In spite of a rapid development of tolerance, which required a subsequent escalation in MP daily doses, the drug was well tolerated and the patient could die in good physical comfort 2 weeks later.

Humans↗
PubMed1994

Dextroamphetamine or methylphenidate as adjuvants to opioid analgesia for adolescents with cancer.

The doses of opioid analgesics required to control pain in patients with cancer may result in somnolence and reduced interaction with family members. Psychostimulants such as dextroamphetamine (DA, Dexedrine) or methylphenidate (MP, Ritalin) have been used in adults to counteract the sedation of opioid analgesia. We retrospectively reviewed our experience using these agents at Children's Hospital. Eleven patients (age 12-20 years) received DA or MP, and decreased somnolence or improved interaction was noted in five patients. Adverse effects potentially related to DA or MP were noted in two patients, none of which resulted in discontinuance of the stimulant. Further prospective, controlled studies are needed to assess the safety and efficacy of DA and MP in counteracting the sedation of opioid analgesia in children and adolescents.

Adjuvants, Pharmaceutic↗
PubMedDate not supplied

Differential effects of methylphenidate on the growth of neonatal and adolescent rats.

Methylphenidate (MPH), the drug of choice in the treatment of Attention Deficit Disorders with Hyperactivity (ADD/H), has raised concern regarding its suspected potential for reducing body stature in growing patients. In a previous study we demonstrated that neonatal rats treated with MPH (35 mg/kg, SC, twice daily) showed an acute growth impairment followed by a rapid growth-rebound phenomenon. This report confirms our earlier findings in neonatal rats and extends the investigation of the growth suppressing effects of MPH to the periadolescent period of development in rats. Specifically, neonatal groups of male and female rats treated with higher and lower doses of MPH than in the original study confirmed the growth impairment and growth rebound phenomena reported earlier. Unlike neonatal rats, rats treated during the periadolescent period of development failed to show any growth impairment. These data suggest that the growth suppressing effects of MPH are the result of an acute toxicity which is readily reversible on discontinuation of the drug. Further, it is concluded that there is a low probability of long term effects on human body stature when the minimal therapeutic dose is used in clinical practice.

Age Factors↗
PubMed2006

[Benefit of the extended-release methylphenidate formulations: a comparative study in childhood].

UNLABELLED: Methylphenidate (MPH) is a potential therapeutic tool for Attention Deficit with Hyperactivity Disorders (ADHD). In addition to the immediate-release formulation, Ritalin, two extended-release formulations, Ritalin LA and Concerta are available and allow a once-daily administration. We compared the respective benefits of both formulations for the patients and their family in terms of efficacy, handling and tolerance. PATIENTS AND METHODS: This prospective study was based on 30 children aged 6 to 15 years. All patients had a confirmed ADHD and were efficiently treated with Ritalin. The children were consecutively treated with Ritalin LA and Concerta, with a comparable MPH daily dosage, during 2 months for each molecule. The 3 drugs were evaluated individually and comparatively through a battery of questionnaires submitted to the parents and the teachers of each child. RESULTS: Extended-release MPH efficacy was comparable to the immediate-release formulation, Ritalin. For both of them, the once-daily administration appeared beneficial. Concerta was finally prescribed in 18 children, Ritalin LA in 8 cases and Ritalin in 4 cases. In each case the medical choice was consistent with the parents preference. Concerta was appreciated for its persisting efficacy in late afternoon during homework. Concerta and Ritalin LA did not induce significant adverse effects, especially regarding alimentation and sleep. CONCLUSIONS: MPH therapy in ADHD carries an excellent risk/benefit ratio without addictive induced behaviours. The extended-release MPH formulations provide an improvement for the patients in keeping with Ritalin efficacy through a once-daily administration. Regardless of its formulation, MPH indications and guidelines must be respected.

Adolescent↗
PubMed2005

An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate.

The causes of nigrostriatal neuron degeneration in Parkinson's disease (PD) are not known, but it has been suggested that exogenous or endogenous factors or neurotoxins may play a role. The degree of vulnerability to neurotoxins or other potential mediators of nigral dopamine cell death is thought to be important in understanding Parkinson's disease. In most animal models, the rate of terminal degeneration and corresponding functional impairment is too rapid to investigate effectively either cell vulnerability or the potential benefits of some neuroprotective treatments. In the present study, a new model of Parkinson's disease is described that might help in addressing the issue of nigral cell vulnerability and to evaluate interventions with clinical potential. 6-Hydroxydopamine (6-OHDA) was infused in escalating, intrastriatal doses over several weeks. Control animals received multiple infusions of vehicle at the same volume. Behavioral testing was carried out between each infusion, including forelimb-use and somatosensory function. A symptomatic threshold was established for each animal, indicating the amount of neurotoxin required to induce a stable deficit. Oral administration of L-DOPA (Sinemet) ameliorated limb-use asymmetries acutely. An immunocytochemical assay for tyrosine hydroxylase, a dopamine cell marker, revealed a partial loss of immunoreactive cells in the substantia nigra. Animals that were co-administered methylphenidate (MPH), a dopamine transport inhibitor, along with the 6-OHDA were spared from the behavioral and neurochemical effects of 6-OHDA, despite receiving more than twice as much neurotoxin as controls. These data suggest that establishing a symptomatic threshold preclinically may help researchers evaluate potential treatments and model individual and group resistance to nigrostriatal insults.

Animals↗
PubMed2003

Enduring behavioral effects of early exposure to methylphenidate in rats.

BACKGROUND: Methylphenidate (MPH) is a stimulant prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulant drugs can cause enduring behavioral adaptations, including altered drug sensitivity, in laboratory animals. We examined how early developmental exposure to stimulants affects behavior in several rodent models. METHODS: Rats received MPH or cocaine during preadolescence (P20-35). Behavioral studies began during adulthood (P60). We compared how early exposure to MPH and cocaine affects sensitivity to the rewarding and aversive properties of cocaine using place conditioning. We also examined the effects of early exposure to MPH on depressive-like signs using the forced swim test, and habituation of spontaneous locomotion, within activity chambers. RESULTS: In place-conditioning tests, early exposure to MPH or cocaine each made moderate doses of cocaine aversive and high doses less rewarding. Early MPH exposure also caused depressive-like effects in the forced swim test, and it attenuated habituation to the activity chambers. CONCLUSIONS: Early exposure to MPH causes behavioral changes in rats that endure into adulthood. Some changes (reduced sensitivity to cocaine reward) may be beneficial, whereas others (increases in depressive-like signs, reduced habituation) may be detrimental. The effects of MPH on cocaine-related behaviors may be a general consequence of early stimulant exposure.

Aging↗
PubMed2004

Sources of auditory selective attention and the effects of methylphenidate in children with attention-deficit/hyperactivity disorder.

BACKGROUND: The aim of this study was to determine 1) whether abnormal auditory selective attention in children with attention-deficit/hyperactivity disorder (ADHD), as reflected in the processing negativity (PN) of the event-related potential, is related to impaired frontal functioning; and 2) how methylphenidate (MPh) affects attentional functioning in ADHD. METHODS: Sources of electrical brain activity were estimated in healthy control children, in ADHD children without medication, and in children with ADHD during a placebo-controlled medication trial involving MPh. RESULTS: The source models showed that the PN is generated in the auditory cortex. Children with ADHD showed less activity related to selective attention in this brain region. Administration of MPh resulted in more frontally located sources. CONCLUSIONS: The results showed no evidence for an important role of the frontal cortex in abnormalities in selective attention in children with ADHD. Also, the data did not indicate that MPh normalizes brain activity in these children.

Attention↗
PubMed2005

Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats.

BACKGROUND: Methylphenidate (MPH) is prescribed for the treatment of attention and hyperactivity disorders. We showed previously that early developmental exposure to MPH in rats causes behavioral alterations during adulthood, including reduced cocaine reward in place conditioning studies. Here we examined if early MPH exposure alters the ability of cocaine to potentiate the rewarding effects of electrical stimulation of the medial forebrain bundle (MFB) using intracranial self-stimulation (ICSS). METHODS: Rats received MPH or saline during pre-adolescence (P20-35) and were implanted with MFB stimulating electrodes at adulthood (P60). Rats then were tested with cocaine in the ICSS paradigm. RESULTS: Cocaine dose-dependently decreased ICSS thresholds in all rats, but the threshold-lowering effects of cocaine were smaller in rats exposed to MPH during pre-adolescence. There were no differences between groups in sensitivity to the rewarding effects of MFB stimulation itself. CONCLUSIONS: Early developmental exposure to MPH reduces the reward-related effects of cocaine in the ICSS paradigm. These results are consistent with previous studies in which early exposure to MPH reduced the ability of cocaine to establish conditioned place preferences, as well as the rewarding effects of sucrose and sexual behavior. Reduced sensitivity to these various types of reward may reflect general dysfunctions of brain reward systems.

Age Factors↗
PubMed2005

A large, double-blind, randomized clinical trial of methylphenidate in the treatment of adults with attention-deficit/hyperactivity disorder.

BACKGROUND: The few controlled studies of methylphenidate (MPH) in adults with attention deficit/hyperactivity disorder (ADHD) have reported equivocal results. A previous, pilot study by our group suggested that these results were due to inadequate dosing. METHOD: We conducted a randomized, 6-week, placebo-controlled, parallel study of MPH in 146 adult patients with DSM-IV ADHD using standardized instruments for diagnosis, separate assessments of ADHD, depressive and anxiety symptoms, and a robust average oral daily dose of 1.1 mg/kg/day. RESULTS: We found a marked therapeutic response for the MPH treatment of ADHD symptoms that exceeded the placebo response (76% vs. 19%). Treatment was safe and well tolerated. Response to MPH was independent of socioeconomic status, gender, and lifetime history of psychiatric comorbidity. CONCLUSIONS: These results confirm that robust doses of MPH are effective in the treatment of adult ADHD.

Adult↗
PubMed2005

Different adaptations in ventral tegmental area dopamine neurons in control and ethanol exposed rats after methylphenidate treatment.

BACKGROUND: Methylphenidate (MPH) is a psychostimulant effective in treating attention-deficit/hyperactivity disorder (ADHD). Repeated MPH treatment may increase substance abuse risk because of adaptations in dopaminergic (DA) function associated with sensitization to subsequent stimulant exposure. However, this possibility is based on observations in normal animals and may not apply to animals with attention problems linked to compromised DA function such as prenatal ethanol exposed (PE) animals. METHODS: The electrical activity of ventral tegmental area (VTA) DA neurons was studied after the cessation of repeated MPH treatment at a threshold dose (1 mg/kg/day for 3 weeks) in PE and control rats. RESULTS: In control rats, there was a continuous increase in VTA DA neuron excitability post-MPH treatment, characterized by a transient increase in population activity (1 day posttreatment) followed by decreased population activity (30-60 days posttreatment) in most of the animals due to depolarization inactivation. In PE rats, MPH treatment decreased the excessive excitability of VTA DA neurons and resulted in prolonged normalization in the population activity (1-60 days posttreatment). These changes were not mediated by altered sensitivity of somatodendritic DA autoreceptors. CONCLUSIONS: Repeated MPH treatment produced distinctly different effects on VTA DA neuron activity in control and PE animals. These results suggest that repeated MPH treatment for ADHD may not lead to increased substance abuse risk in special populations such as individuals with fetal alcohol spectrum disorder.

Action Potentials↗
PubMed2005

A randomized, placebo-controlled trial of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder.

BACKGROUND: The objective of this study was to evaluate the safety and efficacy of once-daily OROS methylphenidate (MPH) in the treatment of adults with DSM-IV attention-deficit/hyperactivity disorder (ADHD). METHODS: We conducted a randomized, 6-week, placebo-controlled, parallel-design study of OROS MPH in 141 adult subjects with DSM-IV ADHD, using standardized instruments for diagnosis. OROS MPH or placebo was initiated at 36 mg/day and titrated to optimal response, depending on efficacy and tolerability, up to 1.3 mg/kg/day. RESULTS: Treatment with OROS MPH was associated with clinically and statistically significant reductions in DSM-IV symptoms of inattention and hyperactivity/impulsivity relative to subjects treated with placebo. At endpoint, 66% of subjects (n = 44) receiving OROS MPH and 39% of subjects (n = 29) [corrected] receiving placebo attained our a priori definition of response of much or very much improved on the Clinical Global Impression-Improvement scale plus a >30% reduction in Adult ADHD Investigator System Report Scale score. OROS MPH was associated with small but statistically significant increases in systolic blood pressure (3.5 +/- 11.8 mm Hg), diastolic blood pressure (4.0 +/- 8.5 mm Hg), and heart rate (4.5 +/- 10.5 bpm). CONCLUSIONS: These results show that treatment with OROS MPH in daily doses of up to 1.3 mg/kg/day was effective in the treatment of adults with ADHD. Because of the potential for increases in blood pressure and heart rate, subjects receiving treatment with MPH should be monitored for changes in blood pressure parameters during treatment.

Adult↗
PubMed2006

Preadolescent methylphenidate versus cocaine treatment differ in the expression of cocaine-induced locomotor sensitization during adolescence and adulthood.

BACKGROUND: Methylphenidate (MPH), the most commonly prescribed medication for childhood attention-deficit/hyperactivity disorder (ADHD), shares chemical and mechanistic similarities to cocaine which has stimulated research to address the addiction liability following treatment. METHODS: Utilizing locomotor sensitization we examined the consequences of recurrent MPH versus cocaine treatment during preadolescence in altering cocaine-induced locomotor behavior in adolescent and adult mice. Black Swiss Webster mice were treated with MPH, cocaine, or saline during preadolescence. To test whether MPH pretreatment during preadolescence contributed to an altered sensitivity to cocaine during adolescence, these mice were treated with recurrent cocaine or saline during adolescence. All mice were challenged with cocaine as adults. RESULTS: Recurrent MPH treatment, unlike cocaine treatment in preadolescent mice, had no effect on locomotor sensitization to cocaine during adolescence or adulthood, as compared with saline controls. Furthermore, unlike cocaine, administration of MPH in adolescence did not augment the response to cocaine challenge. CONCLUSIONS: MPH treatment during preadolescence does not increase subsequent sensitivity to cocaine, whereas cocaine treatment does. Thus, MPH treatment during preadolescence does not appear to persistently induce long-term adaptations, which may underlie an enhanced liability for subsequent drug abuse.

Age Factors↗