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PubMed2006

An open-label trial of OROS methylphenidate in adults with late-onset ADHD.

INTRODUCTION: Many adults with current impairing symptoms of attention-deficit/hyperactivity disorder (ADHD) do not report an age at onset before 7 years of age and cannot, therefore, be assigned the full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnosis of ADHD. We hypothesized that treatment with oral release osmotic system (OROS) methylphenidate (MPH) will be safe and efficacious for the treatment of adults with late-onset ADHD. METHOD: This was a 6-week, open-label, prospective treatment study of OROS MPH monotherapy in 36 adult patients with late-onset ADHD (onset later than the required 7 years of age) using standardized instruments for diagnosis and a robust oral daily dose of up to 1.3 mg/kg/day. Symptom severity was assessed with the Adult ADHD Investigator Symptom Report Scale (AISRS) and the Clinical Global Impression (CGI) scale. RESULTS: Subjects reported robust current symptoms of ADHD at pre-treatment baseline (11.1+/-2.8 DSM-IV symptoms), but had an atypical mean age at onset of 14.2+/-8.6 years. Treatment with OROS MPH at an average daily dose of 78.2+/-29.4 mg was associated with a statistically and clinically significant reduction in ADHD symptoms relative to baseline as assessed through the AISRS (-16.4+/-10.5; P<.001). Using a categorical definition of response (CGI-I much or very much improved), a majority (n = 26; 72%) of subjects were rated as improved at endpoint. CONCLUSION: These results extend previous findings in adults with full ADHD to adults meeting criteria for late-onset ADHD and support the need for further controlled clinical trials in this population.

Adolescent↗
PubMed2002

Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a drug-placebo and drug-drug response curve analysis of a naturalistic study.

Stimulant medication has, for many years, been the pharmacological treatment of choice for children and adults with attention deficit hyperactivity disorder (ADHD). Recently, several studies have documented the efficacy of a new stimulant, Adderall. Although these initial studies provide useful information for clinicians treating ADHD children, their method of data presentation has provided limited information about the clinical significance of drug effects. Thus, to address the issue of clinical significance, we completed drug-placebo response curve analyses of a blinded, placebo-controlled study of Adderall and methylphenidate (MPH). Our results show that the efficacy of Adderall and MPH to improve functioning is seen throughout the full range of improvement scores. Both drugs prevent worsening and, for a majority of patients, lead to improvements that are well into the normal range. The analyses also highlight an important subgroup of placebo responders, which suggests that future research should focus on how to predict robust placebo response in ADHD patients.

Amphetamines↗
PubMed1981

Synthesis and pharmacology of hydroxylated metabolites of methylphenidate.

threo-dl-p-Hydroxymethylphenidate and erythro-dl-p-hydroxymethylphenidate (5a and 5b) and the deesterified products, threo-dl- and erythro-dl-p-hydroxyritalinic acid (6a and 6b), were synthesized. The effects of the intracerebroventricular administration of these compounds on the locomotor activity of rats was determined and compared to that of the respective racemates of methylphenidate (1a and 1b) and ritalinic acid (2a and 2b) as a relative index of in vivo dopaminergic activity. The maximal locomotor response was significantly greater for 5a than for 5b, 1a, or 1b. These findings suggest that metabolite 5a may play a role in the pharmacology of 1a. The intracerebroventricular administration of acids 2a, 2b, 6a, and 6b all produced a small increase in locomotor activity relative to their methyl esters which was not appreciably affected by stereochemistry or para-hydroxylation.

Amphetamine↗
PubMed2005

Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol.

Ethanol elevates methylphenidate (1) plasma concentrations and yields the metabolite ethylphenidate (2). The therapeutic implications are under investigation. The IC(50) for dopamine reuptake inhibition by (+)-2 was 27 nM compared to 367 nM for cocaine and 1730 nM for (-)-2. Binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-2 than for cocaine. Intraperitoneal (+)-2 was approximately half as active as (+)-1 in stimulating mouse motor activity at 5 mg/kg, but (+)-2 was as active as (+)-1 at 10 mg/kg.

Animals↗
PubMed1998

Asymmetric synthesis and pharmacology of methylphenidate and its para-substituted derivatives.

We report the first asymmetric synthesis of the individual enantiomers of methylphenidate (1). From d-pipecolic acid, the (2R,2'R) and (2S,2'R) enantiomers of 1 were obtained in > 99% optical purity while the (2S,2'S) and (2R,2'S) enantiomers of 1 were derived from l-pipecolic acid in 96% optical purity. The versatility of this methodology is demonstrated with the synthesis of the (2R,2'R) and (2S,2'S) enantiomers of p-bromo and p-methoxy derivatives in similar yields and enantiomeric purities. Comparative neurochemical assessments of these synthesized enantiomers at purported dopamine, norepinephrine, and serotonin uptake sites along with locomotor activity studies in rats are also reported.

Animals↗
PubMed2001

Effects of food on the pharmacokinetics of methylphenidate.

PURPOSE: To test the hypothesis that the pharmacokinetics of d-methylphenidate (d-MPH) would be altered by food ingested before administration of an immediate release formulation (dl-MPH- IR) but not when food is ingested before a slow release formulation (dl-MPH-SR). METHODS: A randomized, four-phase, open label, crossover design was conducted in 24 healthy men who each received, on separate occasions, dl-MPH-IR and dl-MPH-SR taken after an overnight fast and 15 min after a standardized breakfast (20% protein, 21% fat, 59% carbohydrate). Plasma MPH levels were monitored by a validated, stereoselective. GLC-ECD method. RESULTS: For plasma d-MPH, there were significant differences (ANOVA) between dl-MPH-IR and dl-MPH-SR in tmax, Cmax (peak exposure), and Cmax/AUC (sensitive to rate of absorption). Dl-MPH-SR on average delayed tmax from 2.3 to 3.7 h and lowered Cmax 34%. There was no significant difference between the formulations in AUC (extent of absorption). For dl-MPH-IR, food significantly increased Cmax (23%) and AUC (15%) and for dl-MPH-SR the corresponding increases were Cmax (17%) and AUC (14%). After dl-MPH-IR, food delayed average tmax from 2.0 to 2.5 but had no effect on tmax after dl-MPH-SR. There was no effect of food on Cmax/AUC (rate of absorption). CONCLUSIONS: Food caused a significant increase in extent of absorption but had no effect on rate of absorption of d-MPH after either dl-MPHIR or dl-MPH-SR.

Adolescent↗
PubMed1997

Pharmacodynamic modeling for change of locomotor activity by methylphenidate in rats.

PURPOSE: The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. METHODS: MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. RESULTS: The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (Ki) of MPD for DA reuptake was estimated to be 41.3 +/- 73.8 nM (mean +/- SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. CONCLUSIONS: The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may by useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.

Animals↗
PubMed1994

Stereospecific distribution of methylphenidate enantiomers in rat brain: specific binding to dopamine reuptake sites.

To investigate the stereoselective distribution of methylphenidate (MPD) enantiomers in rats, the concentrations of each enantiomer were determined in plasma and brain regions (cerebellum, striatum, basal forebrain, brain stem, and cortex) after iv administration of racemic MPD and its individual enantiomers. The concentrations of MPD enantiomers in each brain region reached pseudo-steady state within 10 min after iv administration of racemic MPD (2 mg/kg dose). The influx clearances for MPD calculated from Kpapp values in each brain region were not significantly different between MPD enantiomers and between the five brain regions. The mean Kpapp values for (+)-MPD in the striatum at 120 and 240 min after administration of racemic MPD were 10.1 and 10.5, respectively, and these values at each time were significantly larger than the Kpapp values (7.5 and 7.0, respectively) for the (-)-isomer (P < 0.01). The Kpapp value for (+)-MPD in the striatum decreased by coadministration of mazindol as an inhibition of both dopamine and norepinephrine reuptake, but it was not changed by desipramine as a norepinephrine reuptake inhibitor. These results suggest that (+)-MPD was bound specifically to the dopamine reuptake site in the striatum.

Animals↗
PubMed1993

Enantioselective pharmacokinetics of dl-threo-methylphenidate in humans.

A definitive enantioselective pharmacokinetic evaluation of dl-threo-methylphenidate (MPH) was carried out in 11 healthy volunteers, all of whom received, in a randomized crossover design, three oral administrations of MPH: immediate release (IR), slow release (SR), and SR chewed before swallowing (CH). In addition, all subjects received MPH intravenously (IV) on a separate occasion. Both plasma and urine samples were collected for up to 16 hr after each drug administration. Significant enantioselective differences were found in pharmacokinetic parameters such as CL, MRT, Vdss, AUC infinity 0, and t1/2. A profound distortion of the enantiomeric ratio for MPH (d >> 1) was evident in all plasma samples harvested after oral administration. After IV MPH, however, there was no significant distortion in the plasma d/l ratio until 1.5 hr after dosing, whereafter there was a divergence of the plasma levels of the enantiomers. After oral administration of dl-MPH, the absolute bioavailability (F) of d-MPH was 0.23 and that of l-MPH was 0.05. There were no significant differences in renal clearance for d- or l-MPH after oral or IV administration, although the fraction of the dose excreted unchanged in the urine was significantly greater after IV MPH. These data suggest that enantioselective differences in the pharmacokinetics of oral MPH are the result of enantioselectivity in presystemic metabolism rather than in renal excretion, such that l-MPH is preferentially converted into l-ritalinic acid. Finally, it was found that chewing the slow release formulation led to a pharmacokinetic profile very similar to that of MPH-IR, suggesting that MPH-SR should not be prescribed for children who chew tablets.

Administration, Oral↗
PubMed2003

The effect of methylphenidate on three forms of response inhibition in boys with AD/HD.

The current study was aimed at (a) investigating the effect of three doses methylphenidate (MPH) and placebo on inhibition of a prepotent response, inhibition of an ongoing response, and interference control in Attention Deficit/Hyperactivity Disorder (AD/HD), and (b) studying dose-response relations for the three forms of response inhibition. To meet these aims, the following tasks were selected: two versions of the Stop Paradigm for inhibition of a prepotent response, a Circle Tracing Task and a recently developed Follow Task for inhibition of an ongoing response, and the Stroop Color-Word Test and an Eriksen Flanker Task for interference control. These tasks were administered to 23 boys with AD/HD during four treatment conditions: 5 mg MPH, 10 mg MPH, 20 mg MPH, and placebo. A pseudorandomized, multiple-blind, placebo-controlled, within-subject design was used. As hypothesized, inhibitory control in children with AD/HD improved under MPH compared to placebo. However, this effect was only significant for inhibition of a prepotent response and inhibition of an ongoing response (as measured by the Follow Task), but not for interference control. The relation between treatment condition and response was linear. However, this linear relation was due to improved inhibitory control under MPH compared to placebo, because no effects of MPH dose were observed for any of the response inhibition measures.

Attention↗
PubMed2006

[Methylphenidate-induced cytogenetic alterations?].

OBJECTIVES: Due to concerns that methylphenidate (MPH) might induce cytogenetic alterations in children, treatment with this drug is a controversial issue. The controversy arose following a report by El-Zein et al. (2005) of increased chromosomal aberrations, sister chromatid exchanges, and micronuclei in twelve children after three months of MPH treatment. METHODS: The study by El-Zein is discussed with regard to current cytogenetic standards and earlier studies on the mutagenicity, clastogenicity, and carcinogenicity of MPH are reviewed. RESULTS: Conclusions from the El-Zein study are limited due to methodological shortcomings. Results of animal studies on the mutagenicity and clastogenicity of MPH are inconsistent. While there was no indication of mutagenic effects in bacteria or mammalian cells, MPH might have some potential to induce clastogenic damage in mammalian cells. There was no evidence of carcinogenic activity in rats, while in mice the occurrence of hepatic neoplasms increased. In an epidemiological study, the incidence of cancers following MPH treatment was lower than had been expected. CONCLUSIONS: Given the ambiguous findings of genetic toxicology studies in animals, the paucity of long-term toxicology data on MPH in humans is disquieting. Although it seems premature to conclude that MPH entails a mutagenic risk, the concern raised by El-Zein et al. warrants profound clarification.

Adolescent↗
PubMed2006

[Switching from a short-acting to a long-acting methylphenidate preparation: a multicentre, open study in children with ADHD].

OBJECTIVES: The objective was to evaluate the safety and efficacy of a switch in medication to a single daily dose of OROS-Methylphenidate (OROS-MPH, Concerta) in clinically stable children and adolescents with ADHD. METHODS: A prospective, multi-centre open-label study was carried out for a period of three weeks in 213 patients aged 6-16 years with ADHD who had previously been treated with IR-MPH. Their medication was switched to a single daily dose of OROS-MPH. Primary endpoints were changes in the IOWA Conners Inattention/Overactivity Subscale and the global assessment of efficacy as rated by parents and teachers. The safety of the medication was evaluated by means of recording adverse events. The development of weight, sleep quality, and appetite were also observed. RESULTS: Switching the medication from IR-MPH to OROS-MPH resulted in a significant positive effect as evidenced by caregivers' ratings of core symptoms. Corresponding ratings by teachers revealed no significant difference from baseline values. The global efficacy was rated by teachers as "good" or "excellent" for 55% of the cases, by caregivers for 79% thereof, and by investigators in 77% of the cases, respectively. The study medication was well tolerated. The most frequent adverse events were headache (8.9%) and rhinopharyngitis (7.0%). No unexpected adverse events occurred. CONCLUSIONS: Changing patients' medication from IR-MPH to a single daily dose of OROS-MPH resulted in a significant improvement of ADHD symptoms as rated by parents. In a school setting, the efficacy of OROS-MPH was comparable to that of IR-MPH.

Adolescent↗
PubMed2003

Methylphenidate and intracortical excitability: opposite effects in healthy subjects and attention-deficit hyperactivity disorder.

OBJECTIVE: To test the effects of a standard dosage of the psychostimulant methylphenidate (MPH) - which significantly enhances intracortical inhibition but had no effects on intracortical facilitation in children with attention-deficit hyperactivity disorder (ADHD) - on intracortical excitability in healthy subjects. METHOD: In 12 healthy subjects, aged 20-40 years, intracortical inhibition and facilitation were investigated before and 70 min after the intake of 10 mg MPH using the technique of transcranial magnetic stimulation (TMS) with the paired-stimulus paradigm. RESULTS: In comparison of the two TMS measurements, a significant enhancement in intracortical facilitation but no effects on intracortical inhibition could be stated under MPH administration. CONCLUSION: This study provides first evidence for opposite effects of MPH on intracortical excitability in healthy adult subjects showing enhanced intracortical facilitation in contrast to ADHD children in whom enhanced intracortical inhibition has recently been shown.

Adult↗
PubMed2002

Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence.

In this 12-week double-blind placebo-controlled trial of methylphenidate (MTP) versus placebo in 48 cocaine-dependent attention-deficit/hyperactivity disorder (ADHD) adults, the authors sought to determine whether MTP would be safe, control ADHD symptoms, and affect cocaine use. Efficacy indexes revealed significantly greater ADHD symptom relief in the MTP group. There were no group differences in self-reported cocaine use, urinalysis results, or cocaine craving. Because of the relatively small sample size, the results are preliminary. However, we found that MTP improved subjective reports of ADHD symptoms and did not worsen cocaine use while participants were in treatment.

Adolescent↗
PubMed1997

Alerting effects of methylphenidate under basal and sleep-deprived conditions.

Six men and 3 women on each of 4 days received 10 mg of methylphenidate or placebo (2 times a day) at 0800 and 1200 after 8 hr or 0 hr of sleep. Sleep latency was measured by the Multiple Sleep Latency Test (MSLT) at 0930, 1130, 1330, 1530, and 1730. Participants also completed divided-attention and auditory vigilance tasks at 1000 and 1400 and the Profile of Mood States (POMS) and the Addiction Research Center Inventory (ARCI) after the 0930 and 1330 latency tests. The drug increased mean latency on the MSLT in both sleep conditions. Performance only showed drug effects after prior sleep deprivation. On the POMS, the drug increased Vigor and reduced Fatigue and Depression scale scores, primarily after sleep deprivation. The drug increased the ARCI Amphetamine and Morphine-Benzedrine scores only in the basal state. The ARCI Pentobarbital score was increased by sleep deprivation and decreased by the drug.

Adult↗
PubMed1998

Parkinsonian patients report blunted subjective effects of methylphenidate.

Mesolimbic-mesocortical dopamine brain circuits important for psychostimulant reward in animals are developed to greater extents in humans. Brains of patients with Parkinson's disease show depletion of ventral tegmental area mesolimbic-mesocortical neurons. The authors assessed psychostimulant responses in parkinsonian patients to test whether intact dopaminergic systems are required for subjective psychostimulant effects. Responses to placebo and 15, 20, 25, and 30 mg of methylphenidate were studied in 12 parkinsonian patients and 12 neurologically intact matched controls. Physiological and subjective mood responses were recorded using the Profile of Mood States, Addiction Research Center Inventory, and Visual Analog Scale. Drug-induced changes in "good" feelings and overall drug responses were attenuated in the parkinsonian patients. These results, in conjunction with animal data, provide support for dopamine hypotheses of psychostimulant reward in humans and suggest possible bases for some of the mood disturbances found in many parkinsonian patients.

Adult↗
PubMed1999

Sleepiness and the reinforcing and subjective effects of methylphenidate.

On 4 days, 6 volunteers received 10 mg methylphenidate or placebo at 0900 after 4 or 8 hr time in bed (TIB) and then on 4 days after 4 or 8 hr TIB chose their preferred capsule. On sampling days, 4 hr TIB increased multiple sleep latency test (MSLT) scores and Fatigue scale scores on the Profile of Mood States (POMS). In both TIBs, the drug increased the MSLT and POMS Vigor and Tension scale scores. It reduced POMS Fatigue scores and improved divided attention performance to a greater extent after 4 versus 8 hr. Drug was chosen on 88% of days after 4 hr, but only 29% of days after 8 hr. Preference for the drug depends on sleepiness and is mediated by performance-enhancing and fatigue-altering effects.

Adult↗
PubMed1999

Effects of repeated methylphenidate treatment in the young rat: sensitization of both locomotor activity and stereotyped sniffing.

The behavioral effects of repeated methylphenidate (MPH) treatment were assessed in young rats. In 4 experiments, rats (starting at Postnatal Day 10 or 16) were pretreated on 5 consecutive days with saline or MPH (2.5-20.0 mg/kg i.p.). Sensitization was assessed after 1 or 7 abstinence days, with rats receiving a test day challenge injection of either a low dose of MPH (2.5 mg/kg) or the same dose of MPH as given during pretreatment. Results show that a test day injection of 2.5 mg/kg MPH produced a sensitized locomotor response in rats pretreated with 2.5-20.0 mg/kg MPH. This MPH-induced locomotor sensitization was evident only after 1 abstinence day. Various pretreatment doses of MPH (5, 10, 15, or 20 mg/kg) were capable of sensitizing the stereotyped sniffing of young rats, but only rats pretreated and tested with the highest dose (20 mg/kg) of MPH showed an augmented stereotyped sniffing response that was still robust after 7 abstinence days. Results indicate that young rats are capable of exhibiting sensitization after an extended abstinence period, which contrasts with previous research suggesting that psychostimulant treatment does not produce long-term sensitization in young rats.

Aging↗