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PubMed2000

Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate.

In children with attention-deficit hyperactivity disorder (ADHD), motoric hyperactivity is one of the striking abnormalities. Because this symptom might be due to an insufficient motor control, motor system excitability in 18 drug-naive ADHD-children aged 8-12 years was compared to 18 age-matched healthy children using the technique of transcranial magnetic stimulation (TMS). Whereas motor thresholds, cortical silent period, and intracortical facilitation did not differ between the two groups, ADHD-children had significantly reduced intracortical inhibition compared to healthy controls. In all ADHD-children, a second TMS could be started after their first intake of 10 mg methylphenidate. Under this medication, a significant enhancement in intracortical inhibition could be stated. This study provides the first evidence for inhibitory deficits within the motor cortex in ADHD-children and for an enhancement of inhibitory mechanisms in this brain region by methylphenidate.

Attention Deficit Disorder with Hyperactivity↗
PubMed2000

Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography.

Ten previously untreated adults with attention deficit hyperactivity disorder (ADHD) were investigated before and after 4 weeks of treatment with a dose of 3x5 mg methylphenidate/d by single photon emission computed tomography (SPECT) with [Tc-99m]TRODAT-1, the first Tc-99m labelled SPECT ligand specifically binding to the dopamine transporter (DAT). For semiquantitative evaluation of the DAT, specific binding ([STR-BKG]/BKG) was calculated in the striatum (STR) with the cerebellum used as background (BKG). The patients with ADHD presented with increased specific binding of Tc-99m-TRODAT-1 to the DAT as compared with age and sex matched controls ([STR-BKG]/BKG 1.43+/-0.18 vs. 1.22+/-0.05, P<0.001). After treatment with methylphenidate specific binding decreased in all patients ([STR-BKG]/BKG 1.02+/-0.23, P<0.001). Thus, for the first time it could be demonstrated using SPECT that methylphenidate lowers increased striatal DAT availability in adults suffering from ADHD.

Adult↗
PubMed1976

Abscess formation as a complication of parenteral methylphenidate abuse.

Case reports of five patients suffering from either skin abscesses or cellulitis following parenteral methylphenidate abuse are presented. Four patients had similar lesions consisting of abscesses or cellulitis which demonstrated typical signs and symptoms of an infective process and were treated with local symptomatic therapy, incision and drainage if indicated, and systemic antibiotics. The fifth patient suffered from a circular, necrotic, nonpurulent ulcer on the dorsum of the right foot which produced no local or systemic toxic effects. Attempts to culture a responsible organism yielded Streptococcus viridans, an organism which is normal flora of the skin and, although opportunistic, is generally considered nonpathogenic. These cases further substantiate the belief that local vasospasm, chemical irritation, or both, produced by the methylphenidate solution may primarily cause a necrotic ulcer susceptibble to secondary bacterial infection.

Abscess↗
PubMed2001

alpha(2C)-Adrenoceptors modulate the effect of methylphenidate on response rate and discrimination accuracy in an operant test.

The present study investigated the role of alpha(2C)-adrenoceptors in the regulation of activity and discrimination accuracy in an operant chamber test. We trained food deprived control and alpha(2C)-adrenoceptor knockout mice to collect liquid food rewards in an operant chamber during the light (20 s) period. No food reward was delivered during the dark period (40 s). The alpha(2C)-adrenoceptor knockout mice tended to make fewer total responses and collect less rewards than their controls after saline treatment. However, only response accuracy of alpha(2C)-adrenoceptor knockout mice was significantly lower than that of the control mice. Methylphenidate, a drug blocking dopamine re-uptake and increasing dopamine release, dose-dependently decreased the number of total responses and collected food rewards in control mice but increased those measures in alpha(2C)-adrenoceptor knockout mice. In addition, the effect of methylphenidate on discrimination accuracy differed between knockout and control mice. Our results indicate that alpha(2C)-adrenoceptors may regulate dopamine-mediated functions.

Animals↗
PubMed1984

[Frontal evoked potentials and sensitivity to methylphenidate. Individual differences].

Auditory evoked potentials (AEPs) were recorded from 2 sites (Cz and Fz) on 17 subjects while awake. Five sound intensities were used (40-50-60-70-80 dB). Regression slopes relating AEP amplitude (N1-P2 component) to stimulus intensity were used to describe augmentation or reduction (A/R) of amplitude with increasing intensity. The individual differences thereby obtained have been related with the individual responsiveness to methylphenidate (MPD) measured by the modifications of polygraphic sleep parameters after absorption of this substance. The sleep parameters were recorded under 3 conditions: N1, night of habituation; N2, reference night (placebo); N3, night after 20 mg of methylphenidate (MPD); nights 2 and 3 consisted of a double blind cross-over. For the placebo condition, the lower the A/R slope while awake (and particularly the Fz slope), the higher the sleep efficiency, with scarcity of nocturnal awakening and precocity of the morning awakening. Individual differences concerning MPD responsiveness measured with sleep parameter modifications are significantly correlated with the frontal A/R slopes: the wakefulness effect of MPD increases as the frontal A/R slope weakens while a paradoxal drowsiness effect is observed at the other extreme (frontal augmenters). Moreover, sleep modifications due to the first night effect show similarities with those due to MPD and are correlated in the same way with frontal A/R slopes.

Adult↗
PubMed2002

Isolated orofacial dyskinesia: a methylphenidate-induced movement disorder.

We report a case of orofacial dyskinesia in a 6-year-old female with attention-deficit-hyperactivity disorder who received a low dose of methylphenidate. The orofacial dyskinesia appeared immediately and subsided rapidly on the same day in an "on-off" fashion and on 3 separate days when methylphenidate was taken. To our knowledge this particular side effect has not been described previously and might represent an unusual type of brain response or sensitivity.

Attention Deficit Disorder with Hyperactivity↗
PubMedDate not supplied

In utero alcohol and postnatal methylphenidate: locomotion and dopamine receptors.

Prenatal alcohol exposure can cause central nervous system abnormalities and dysfunction referred to as Alcohol-Related Neurodevelopmental Disorder (ARND). Repeated intermittent methylphenidate (Ritalin) was used as a psychopharmacological challenge to reveal functional alterations in dopamine binding sites in rats exposed prenatally to alcohol. Pregnant Long-Evans dams were intubated with 0, 3, or 5 g/kg/day of alcohol from gestational day (GD) 8 to GD20. Adult offspring received repeated intraperitoneal injections of 0, 4, or 8 mg/kg of methylphenidate (MET), and were tested periodically for locomotor activity. Autoradiographic assessment of dopamine D1 and D2 receptors binding were visualized using [3H]SCH 23390 and [3H]raclopride, respectively. Prenatal alcohol did not produce significant dose-dependent effects on adult locomotor activity. Repeated MET injections produced dose-dependent sensitization of locomotor activity in all groups. The 3-g/kg prenatal alcohol group had a significantly decreased number of dopamine D2 binding sites within the dorsal and ventral striatum. This effect was reversed by MET. The neural changes detected in the lower alcohol group may indicate persistent changes within the dopaminergic system due to prenatal alcohol exposure.

Animals↗
PubMed2003

D-Methylphenidate is non-genotoxic in in vitro and in vivo assays.

D-Methylphenidate (dexmethylphenidate; D-MPH) and its racemate D,L-methylphenidate (D,L-MPH) are currently prescribed for the chronic treatment of attention deficit hyperactivity disorder (ADHD) in children. Studies have shown that D-MPH is the pharmacologically active enantiomer for ADHD and is therefore the preferred drug for the treatment of ADHD symptoms. Although studies on the mutagenicity of D,L-MPH have been conducted, similar data for D-MPH are lacking. Therefore, D-MPH was evaluated in the bacterial reverse mutation and mouse lymphoma assays with and without S9 and in a bone marrow micronucleus test in male and female CD-1 mice. As a comparison, the L-enantiomer and racemate were also included in the assessments. While MPH-associated toxicity was observed in the mammalian tests, none of the three compounds tested induced mutagenic or clastogenic effects. Our present results along with published epidemiological data from patient populations are consistent with the conclusion that D-MPH and D,L-MPH do not present a carcinogenic risk to humans.

Adrenergic Uptake Inhibitors↗
PubMed2006

Fine motor skills and effects of methylphenidate in children with attention-deficit-hyperactivity disorder and developmental coordination disorder.

The aims of this study were to investigate fine motor skills of children with both attention-deficit-hyperactivity disorder (ADHD) and developmental coordination disorder (DCD) and those of a control group, and to examine the effects of methylphenidate on these skills. A group of 12 children with ADHD-DCD (11 males, one female; mean age 9y 8mo [SD 1y 7mo]) and 12 age- and sex-matched controls (mean age 9y 7mo [SD 1y 2 mo]) participated. The manual dexterity subtests of the Movement Assessment Battery for Children, the concise assessment method for children's handwriting, and a computerized graphomotor task were used. Results demonstrated that children with ADHD-DCD performed more poorly on the manual dexterity subtests, had poorer quality of handwriting, and drew more rapidly, more fluently, but less accurately than controls on the graphomotor task. On methylphenidate, manual dexterity and quality of handwriting improved, and strokes on the graphomotor task became less fluent but more accurate. ADHD is characterized by persistent symptoms of inattention, impulsivity, and hyperactivity, affecting 3 to 5% of school-age children. Up to 50% of children with ADHD also have motor coordination problems that are severe enough to meet criteria for DCD. In DCD, children demonstrate functional motor performance deficits not explained by the child's (chronological) age or intellect, or by other neurological or psychiatric disorders.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

Correlations between motor persistence and plasma levels in methylphenidate-treated boys with ADHD.

Following a 0.9 mg/kg methylphenidate loading dose, serial plasma level determinations, self-scored mood ratings, and measures of motor persistence were gathered on eight previously unmedicated boys with attention deficit disorder with hyperactivity (ADHD) during a 9-h period. The measures were repeated using the same loading dose after 6 months of maintenance treatment with methylphenidate (1.3 mg/kg x d). Kinetic-dynamic modelling suggests inverse correlative relationships between motor performance errors and plasma levels. Pharmacokinetic parameters did not change between acute and maintenance drug treatment phases, and there was no evidence of long-term tolerance.

Adolescent↗
PubMed2000

Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder.

Thirteen children (ages 5.6 to 11.2 years) with autism and symptoms of attention-deficit hyperactivity disorder (ADHD) participated in a double-blind, placebo-controlled crossover study of methylphenidate (0.3 and 0.6 mg/kg per dose). Eight subjects responded positively, based upon a minimum 50% decrease on the Conners Hyperactivity Index. Ratings of stereotypy and inappropriate speech, which are often associated with autistic core features, also decreased. However, no changes were found on the Child Autism Rating Scale, a global assessment of autistic symptomotology. Significant adverse side effects occurred in some children including social withdrawal and irritability, especially at the 0.6 mg/kg dose. Results suggest that methylphenidate can be efficacious for children with autism and ADHD symptoms. However, this group of children seems to be particularly susceptible to adverse side effects.

Attention Deficit Disorder with Hyperactivity↗
PubMed2000

Bioequivalence of methylphenidate immediate-release tablets using a replicated study design to characterize intrasubject variability.

PURPOSE: To determine the relative bioavailability of two marketed, immediate-release methylphenidate tablets. The study used a replicated study design to characterize intrasubject variability, and determine bioequivalence using both average and individual bioequivalence criteria. METHODS: A replicated crossover design was employed using 20 subjects. Each subject received a single 20 mg dose of the reference tablet on two occasions and two doses of the test tablet on two occasions. Blood samples were obtained for 10 hr after dosing, and plasma was assayed for methylphenidate by GC/MS. RESULTS: The test product was more rapidly dissolved in vitro and more rapidly absorbed in vivo than the reference product. The mean Cmax and AUC(0-infinity) differed by 11% and 9%, respectively. Using an average bioequivalence criterion, the 90% confidence limits for the Ln-transformed Cmax and AUC(0-infinity), comparing the two replicates of the test to the reference product, fell within the acceptable range of 80-125%. Using an individual bioequivalence criterion the test product failed to demonstrate equivalence in Cmax to the reference product. CONCLUSIONS: The test and reference tablets were bioequivalent using an average bioequivalence criterion. The intrasubject variability of the generic product was greater and the subject-by-formulation interaction variance was borderline high. For these reasons, the test tablets were not individually bioequivalent to the reference tablets.

Adult↗
PubMed1990

Optical purity determination of threo-methylphenidate hydrochloride using a chiral europium nuclear magnetic resonance (NMR) shift reagent.

A 1H-NMR spectroscopic method for the determination of the optical purity of threo-methylphenidate hydrochloride is presented. Complexation of the free-base form of the substrate with a chiral Eu(III) shift reagent resulted in two distinct enantiomeric ester methyl proton signals of utility for quantitative work. The accuracy of the method was validated by analyzing six synthetic mixtures of various proportions of (+)- and (-)-threo-methylphenidate. In addition to yielding assay results that were in close agreement with the known weights of each enantiomer in the mixture, and a mean recovery of the (-)-threo-enantiomer of better than 99.0%, the proposed method was capable of accurately measuring as little as 2% of one enantiomer in the presence of the other.

Europium↗
PubMed1995

Conformational analysis of methylphenidate and its structural relationship to other dopamine reuptake blockers such as CFT.

PURPOSE: This work was performed 1) to determine the conformational preferences of the threo and erythro isomers of the dopamine reuptake blocker methylphenidate, 2) to determine the crystal conformation of the threo isomer, 3) to confirm the absolute configuration of the more active threo enantiomer, and 4) to incorporate the compound into a previously determined pharmacophore for dopamine reuptake blockers. METHODS: A conformational analysis was performed with the MM2-87 program, a crystal of the (-)-threo HCl salt was analyzed by x-ray crystallography, and the global minima of the (+)-threo isomer and the potent dopamine reuptake blocker CFT were superimposed. RESULTS: In the global minimum of the threo isomer, the carbonyl oxygen of the ester group is oriented toward the ammonium group as was also found in the crystal state. In the erythro isomer, the ester group prefers an extended conformation relative to the piperidine group. The absolute configuration of the biologically active (+)-threo enantiomer was confirmed to be R,R. The atomic sequence from the amine group through the ester group is identical in the active enantiomers of methylphenidate and CFT. CONCLUSIONS: The dopamine reuptake protein requires a precise orientation of the ammonium and ester groups but allows considerable leeway in the position of the phenyl ring. The pKa of the threo isomer is predicted to be higher than that of the erythro isomer.

Cocaine↗
PubMed2003

Neurofeedback treatment for attention-deficit/hyperactivity disorder in children: a comparison with methylphenidate.

Clinical trials have suggested that neurofeedback may be efficient in treating attention-deficit/hyperactivity disorder (ADHD). We compared the effects of a 3-month electroencephalographic feedback program providing reinforcement contingent on the production of cortical sensorimotor rhythm (12-15 Hz) and betal activity (15-18 Hz) with stimulant medication. Participants were N = 34 children aged 8-12 years, 22 of which were assigned to the neurofeedback group and 12 to the methylphenidate group according to their parents' preference. Both neurofeedback and methylphenidate were associated with improvements on all subscales of the Test of Variables of Attention, and on the speed and accuracy measures of the d2 Attention Endurance Test. Furthermore, behaviors related to the disorder were rated as significantly reduced in both groups by both teachers and parents on the IOWA-Conners Behavior Rating Scale. These findings suggest that neurofeedback was efficient in improving some of the behavioral concomitants of ADHD in children whose parents favored a nonpharmacological treatment.

Attention Deficit Disorder with Hyperactivity↗
PubMed2005

Delta plots in the study of individual differences: new tools reveal response inhibition deficits in AD/Hd that are eliminated by methylphenidate treatment.

The authors highlight the utility of distribution-analytical techniques in the study of individual differences and clinical disorders. Cognitive deficits associated with attention-deficit/hyperactivity disorder (AD/HD) were examined by using delta-plot analyses of performance data (reaction time and accuracy) obtained through the use of a prototypical conflict task, the Eriksen flanker task. In 20 children with AD/HD (compared with matched control participants), overall performance measures indicated a marginal performance deficit. Delta-plot analyses indicated that performance deficits associated with AD/HD involve response inhibition but not automatic response activation. In a within-subjects titration study, the response inhibition deficit was eliminated by methylphenidate treatment, but these effects were highly dose specific. The beneficial effect of methylphenidate was clarified further after correcting for inter-individual variation in sensitivity to medicine dosage.

Attention↗
PubMed1990

Methylphenidate and baseball playing in ADHD children: who's on first?

The effects of 0.3 and 0.6 mg/kg methylphenidate were analyzed in a double-blind, placebo-controlled, cross-over study in which 17 boys (ages 7.8-9.9 years) with attention deficit hyperactivity disorder (ADHD) played in baseball games. Drug effects were evaluated on children's attention during the game, as indicated by their on-task behavior on the field and their ability to answer questions about the status of the game at all times. Judgment during batting, batting skill during the game, and performance on skill drills prior to the game were also assessed as a function of medication. Results revealed that methylphenidate had a beneficial effect on attending during the game.

Attention Deficit Disorder with Hyperactivity↗
PubMed1992

Covert antisocial behavior in boys with attention-deficit hyperactivity disorder: external validation and effects of methylphenidate.

Covert antisocial behaviors such as stealing, destroying property, and cheating carry high risk for delinquency. An individual laboratory setting was devised in which youngsters could take desired objects and use answer keys to assist with worksheets. Twenty-two boys with attention-deficit hyperactivity disorder (ADHD) and 22 comparison boys were observed on two occasions, with the ADHD Ss receiving a methylphenidate-placebo crossover. Laboratory stealing and property destruction were positively correlated with maternal and staff ratings of parallel behaviors. Methylphenidate resulted in significant reductions of these acts, but it also effected an increase in cheating, presumably because of its enhancement of task involvement. The generalizability of the laboratory findings, actions of stimulants in this domain, and the ethics of experimental investigations of covert antisocial behavior are discussed.

Antisocial Personality Disorder↗