The Experts below are selected from a list of 12858 Experts worldwide ranked by ideXlab platform
Simcha Pollack - One of the best experts on this subject based on the ideXlab platform.
-
social functioning in children with adhd treated with long term Methylphenidate and multimodal psychosocial treatment
Journal of the American Academy of Child and Adolescent Psychiatry, 2004Co-Authors: Howard Abikoff, Lily Hechtman, Rachel G. Klein, Richard Gallagher, Karen Fleiss, Joy Etcovitch, Lorne Cousins, Brian Greenfield, Diane Martin, Simcha PollackAbstract:ABSTRACT Objective To test that Methylphenidate combined with intensive multimodal psychosocial intervention, which includes social skills training, significantly enhances social functioning in children with attention-deficit/hyperactivity disorder (ADHD) compared with Methylphenidate alone and Methylphenidate plus nonspecific psychosocial treatment (attention control). Method One hundred three children with ADHD (ages 7–9), free of conduct and learning disorders, who responded to short-term Methylphenidate were randomized for 2 years to receive (1) Methylphenidate alone, (2) Methylphenidate plus multimodal psychosocial treatment that included social skills training, or (3) Methylphenidate plus attention control treatment. Assessments included parent, child, and teacher ratings of social function and direct school observations in gym. Results No advantage was found on any measure of social functioning for the combination treatment over Methylphenidate alone or Methylphenidate plus attention control. Significant improvement occurred across all treatments and continued over 2 years. Conclusions In young children with ADHD, there is no support for clinic-based social skills training as part of a long-term psychosocial intervention to improve social behavior. Significant benefits from Methylphenidate were stable over 2 years.
-
symptomatic improvement in children with adhd treated with long term Methylphenidate and multimodal psychosocial treatment
Journal of the American Academy of Child and Adolescent Psychiatry, 2004Co-Authors: Howard Abikoff, Lily Hechtman, Rachel G. Klein, Karen Fleiss, Joy Etcovitch, Lorne Cousins, Brian Greenfield, Diane Martin, Gabrielle Weiss, Simcha PollackAbstract:Objective: To test the hypotheses that in children with attention-deficit/hyperactivity disorder (ADHD) (1) symptoms of ADHD, oppositional defiant disorder, and overall functioning are significantly improved by Methylphenidate combined with intensive multimodal psychosocial treatment compared with Methylphenidate alone and with Methylphenidate plus attention control and (2) more children receiving combined treatment can be taken off Methylphenidate. Method: One hundred three children with ADHD (ages 7–9), free of conduct and learning disorders, who responded to short-term Methylphenidate were randomized for 2 years to (1) Methylphenidate alone; (2) Methylphenidate plus psychosocial treatment that included parent training and counseling, social skills training, psychotherapy, and academic assistance, or (3) Methylphenidate plus attention psychosocial control treatment. Assessments included parent, teacher, and psychiatrist ratings, and observations in academic and gym classes. Results: Combination treatment did not lead to superior functioning and did not facilitate Methylphenidate discontinuation. Significant improvement occurred across all treatments and continued over 2 years. Conclusions: In stimulant-responsive children with ADHD, there is no support for adding ambitious long-term psychosocial intervention to improve ADHD and oppositional defiant disorder symptoms. Significant benefits from Methylphenidate were stable over 2 years. J. Am. Acad. Child Adolesc. Psychiatry,
-
clinical efficacy of Methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder
Archives of General Psychiatry, 1997Co-Authors: Rachel G. Klein, Howard Abikoff, E Klass, David Ganeles, Laura M Seese, Simcha PollackAbstract:Background: Stimulants are not considered appropriate for the treatment of children with conduct disorders (CDs). The postulated differences in stimulant effect between children with attention deficit hyperactivity disorder (ADHD) and CD led to the hypothesis that Methylphenidate hydrochloride, which is effective in ADHD, would not significantly improve symptoms of CD. Methods: We randomly assigned 84 children with CD, between the ages of 6 and 15 years, to receive Methylphenidate hydrochloride (up to 60 mg/d) or placebo for 5 weeks. Behavior was evaluated by parent, teacher, and clinician reports and by direct classroom observations. Two thirds of the children also met criteria for ADHD. Results: Contrary to prediction, ratings of antisocial behaviors specific to CD were significantly reduced by Methylphenidate treatment. The magnitude of Methylphenidate effect indicated meaningful clinical benefit. Partialling out severity of ADHD did not alter the significant superiority of Methylphenidate on CD ratings specifically (P Conclusions: Methylphenidate has short-term positive effects on children and adolescents with CD. Key aspects of antisocial adjustment appear to be treatment responsive. This effect was independent of severity of the children's initial ADHD symptoms.
Nora D Volkow - One of the best experts on this subject based on the ideXlab platform.
-
Dopamine Transporter Occupancies in the Human Brain Induced by Therapeutic Doses of Oral Methylphenidate
2016Co-Authors: Nora D Volkow, Genejack Wang, Joanna S Fowler, Ph. D, Robert HitzemannAbstract:Objective: The therapeutic effects of Methylphenidate in the treatment of attention defi-cit disorder have been attributed to its ability to increase the synaptic concentration of dopamine by blocking the dopamine transporters. However, the levels of dopamine trans-porter blockade achieved by therapeutic doses of Methylphenidate are not known. This study measured, for the first time, dopamine transporter occupancy by orally administered Methylphenidate in the human brain and its rate of uptake in the brain. Method: Positron emission tomography (PET) and [11C]cocaine were used to estimate dopamine transporter occupancies after different doses of oral Methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral Methylphenidate were measured in the baboon brain through use of PET and [11C]Methylphenidate administered through an orogastric tube. Results: At 120 minutes after administration, oral methylpheni-date produced a dose-dependent blockade of dopamine transporter; means=12 % (SD
-
Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers.
Molecular Psychiatry, 2014Co-Authors: Nora D Volkow, Genejack Wang, Joanna S Fowler, Jean Logan, Christopher Wong, Dardo Tomasi, D. Alexoff, Millard Jayne, Yin P, Congwu DuAbstract:increases induced by intravenous Methylphenidate and in 24 of the cocaine abusers, we also compared dopamine increases when Methylphenidate was administered concomitantly with a cocaine cue-video versus a neutral-video. In controls, Methylphenidate increased dopamine in dorsal (effect size 1.4; Po0.001) and ventral striatum (location of accumbens) (effect size 0.89; Po0.001), but in cocaine abusers Methylphenidate’s effects did not differ from placebo and were similar whether cocaine-cues were present or not. In cocaine abusers despite the markedly attenuated dopaminergic effects, the Methylphenidate-induced changes in ventral striatum were associated with intense drug craving. Our findings are consistent with markedly reduced signaling through D2 receptors during intoxication in active cocaine abusers regardless of cues exposure, which might contribute to compulsive drug use.
-
Methylphenidate elicited dopamine increases in ventral striatum are associated with long term symptom improvement in adults with attention deficit hyperactivity disorder
The Journal of Neuroscience, 2012Co-Authors: Nora D Volkow, Genejack Wang, Joanna S Fowler, Frank Telang, Jean Logan, Jeffrey H Newcorn, Dardo Tomasi, Scott H Kollins, Tim Wigal, Christopher WongAbstract:Stimulant medications, such as Methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by Methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral Methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term Methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous Methylphenidate significantly increased dopamine in striatum (assessed as decreases in D2/D3 receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous Methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to Methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that Methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.
-
evidence that Methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain
American Journal of Psychiatry, 2004Co-Authors: Nora D Volkow, Genejack Wang, Joanna S Fowler, Frank Telang, Laurence Maynard, Jean Logan, S J Gatley, Naomi Pappas, Christopher Wong, P VaskaAbstract:OBJECTIVE: Methylphenidate is the most commonly prescribed drug for attention deficit hyperactivity disorder (ADHD), yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if Methylphenidate, by increasing dopamine (neurotransmitter involved in motivation) in brain, would enhance the saliency of an academic task, making it more interesting. METHOD: Healthy subjects (N=16) underwent positron emission tomography with [11C]raclopride (dopamine D2 receptor radioligand that competes with endogenous dopamine for binding) to assess the effects of oral Methylphenidate (20 mg) on extracellular dopamine in the striatum. The authors compared the effects of Methylphenidate during an academic task (solving mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). In parallel, the effects of Methylphenidate on the interest that the academic task elicited were also evaluated. RESULTS: Methylphenidate, when coupled with t...
-
relationship between blockade of dopamine transporters by oral Methylphenidate and the increases in extracellular dopamine therapeutic implications
Synapse, 2002Co-Authors: Nora D Volkow, Genejack Wang, Joanna S Fowler, Laurence Maynard, Jean Logan, S J Gatley, Yushin Ding, Dinko Franceschi, Andrew N GiffordAbstract:Methylphenidate (Ritalin) is an effective drug in the treatment of attention deficit hyperactivity disorder. However, the doses required therapeutically vary significantly between subjects and it is not understood what determines these differences. Since Methylphenidate's therapeutic effects are in part due to increases in extracellular DA secondary to blockade of dopamine transporters (DAT), the variability could reflect differences in levels of DAT blockade. Here we used PET to assess if for a given dose of Methylphenidate the differences in DAT blockade account for the variability in Methylphenidate-induced increases in extracellular DA. Ten healthy adult subjects were tested before and 60 min after oral Methylphenidate (60 mg) with PET to estimate DAT occupancy (with [11C]cocaine as the radioligand) and levels of extracellular DA (with [11C]raclopride as the D2 receptor radioligand that competes with endogenous DA for binding to the receptor). Methylphenidate significantly blocked DAT (60 ± 11%) and increased extracellular DA in brain (16 ± 8% reduction in [11C]raclopride binding in striatum). However, the correlation between Methylphenidate-induced DAT blockade and DA increases was not significant. These results indicate that for a given dose of Methylphenidate, individual differences in DAT blockade are not the main source for the intersubject variability in MP-induced increases in DA. This finding suggests that individual differences in response to MP are due in part to individual differences in DA release, so that for an equivalent level of DAT blockade, MP would induce smaller DA changes in subjects with low than with high DA cell activity. Synapse 43:181–187, 2002. © 2002 Wiley-Liss, Inc.
Suneel K Gupta - One of the best experts on this subject based on the ideXlab platform.
-
development of a new once a day formulation of Methylphenidate for the treatment of attention deficit hyperactivity disorder proof of concept and proof of product studies
Archives of General Psychiatry, 2003Co-Authors: James M Swanson, Nishit B Modi, Suneel K Gupta, Ira Shoulson, Marc Lerner, Elizabeth Lindemulder, Sharon B WigalAbstract:Background The duration of action of the immediate-release formulation of Methylphenidate hydrochloride is short (3 to 4 hours), and 3 times daily dosing is thought to maximize effectiveness across a 12-hour day. The initial sustained-release formulations of Methylphenidate had reduced efficacy compared with immediate-release Methylphenidate and were not well accepted. Tachyphylaxis was hypothesized to account for the reduced effects, and an ascending drug delivery pattern was proposed to overcome this acute tolerance. Methods Children with attention-deficit/hyperactivity disorder were evaluated in a laboratory school to characterize onset and duration of the effect of a variety of Methylphenidate regimens. In a proof-of-concept study, an experimental ascending profile was established by an initial bolus followed by small increasing doses of immediate-release Methylphenidate in capsules administered every 30 minutes for 8 hours. Two proof-of-product studies of a new oral once-a-day formulation to deliver Methylphenidate by an osmotic pump process based on OROS (ALZA Corp, Mountain View, Calif) technology (hereafter referred to "OROS-Methylphenidate") were conducted: a pharmacokinetic study and a pharmacodynamic study. Results The experimental ascending profile matched the effect of the standard regimen of Methylphenidate, 3 times daily. In the pharmacokinetic study, OROS-Methylphenidate treatment produced a rapid rise followed by increasing plasma concentrations that peaked 7 to 9 hours after administration. In the pharmacodynamic study, OROS-Methylphenidate treatment matched the 3 times daily dosing of Methylphenidate for onset and duration of efficacy. Conclusions These studies demonstrate the translation of a basic science finding (acute tolerance to clinical doses of Methylphenidate) into clinical application (the selection of a new drug delivery pattern for Methylphenidate). This approach produced a new product (OROS-Methylphenidate or Concerta), which proved to have the predicted rapid onset (with 1-2 hours) and long duration of efficacy(10-12 hours) after a single administration in the morning.
-
single and multiple dose pharmacokinetics of an oral once a day osmotic controlled release oros Methylphenidate hc1 formulation
The Journal of Clinical Pharmacology, 2000Co-Authors: Nishit B Modi, Betsy Lindemulder, Suneel K GuptaAbstract:Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS (Methylphenidate HCl) is an osmotic controlled-release delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS (Methylphenidate HCl) 18 mg qd, sustained-release (SR) Methylphenidate 20 mg qd, and the immediate-release (IR) formulation given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single- and multiple-dose pharmacokinetics of the OROS formulation were studied. Following OROS (Methylphenidate HCl), there was a gradual increase in the mean Methylphenidate plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR formulation, peak plasma concentrations were noted at approximately 4 hours. Following the IR regimen, Methylphenidate plasma concentrations fluctuated in tandem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half-life of Methylphenidate was similar for the three formulations. The dose-normalized Methylphenidate Cmax for OROS (Methylphenidate HCl) was significantly lower than for IR and SR Methylphenidate. The bioavailability of Methylphenidate and PPA from OROS (Methylphenidate HCl) relative to the IR and SR formulations was complete. Mean Methylphenidate AUC and terminal half-life were similar after single (32.9 ng.h/mL and 3.9 hours) and multiple doses (35.2 ng.h/mL and 3.9 hours) of OROS (Methylphenidate HCl).
-
effect of food on the pharmacokinetics of osmotic controlled release Methylphenidate hcl in healthy subjects
Biopharmaceutics & Drug Disposition, 2000Co-Authors: Nishit B Modi, Bei Wang, Suneel K GuptaAbstract:The effect of a high-fat meal on the pharmacokinetics of OROS® (Methylphenidate HCl), an osmotic controlled-release formulation of Methylphenidate HCl, was investigated in healthy subjects. Mean peak Methylphenidate plasma concentrations occurred slightly later and peak Methylphenidate plasma concentrations and AUC values were slightly higher (∼10–30%) in the presence of food than in the absence of food. There was no difference in the plasma elimination half-life of Methylphenidate between the fed and fasted state. Similarly, peak concentrations and AUC values for α-phenyl-2-piperidine acetic acid (PPA; ritalinic acid), the major metabolite of Methylphenidate, were slightly higher in the presence of food than in its absence. The 90% confidence interval (CI) for the treatment ratio (fed/fasted) for Cmax was 120.6%–140.0% for the 18-mg dose and 105.4–119.3% for a 36-mg dose. The 90% CI for the treatment ratio for AUC∞ was 114.6–125.7% for the 18-mg dose and 115.1–124.6% for the 36-mg dose. PPA levels were measured following the 18-mg dose and the 90% CI of the treatment ratio was 106.8–115.4% for Cmax and 97.9–103.6% for AUC∞. These results indicate the absence of dose dumping from OROS® (Methylphenidate HCl) in the presence of food. Food does not impede drug absorption and OROS® (Methylphenidate HCl) may be administered in the fed or fasted state. There were no differences in the adverse event profile between the fed and fasted state. Copyright © 2000 John Wiley & Sons, Ltd.
Howard Abikoff - One of the best experts on this subject based on the ideXlab platform.
-
social functioning in children with adhd treated with long term Methylphenidate and multimodal psychosocial treatment
Journal of the American Academy of Child and Adolescent Psychiatry, 2004Co-Authors: Howard Abikoff, Lily Hechtman, Rachel G. Klein, Richard Gallagher, Karen Fleiss, Joy Etcovitch, Lorne Cousins, Brian Greenfield, Diane Martin, Simcha PollackAbstract:ABSTRACT Objective To test that Methylphenidate combined with intensive multimodal psychosocial intervention, which includes social skills training, significantly enhances social functioning in children with attention-deficit/hyperactivity disorder (ADHD) compared with Methylphenidate alone and Methylphenidate plus nonspecific psychosocial treatment (attention control). Method One hundred three children with ADHD (ages 7–9), free of conduct and learning disorders, who responded to short-term Methylphenidate were randomized for 2 years to receive (1) Methylphenidate alone, (2) Methylphenidate plus multimodal psychosocial treatment that included social skills training, or (3) Methylphenidate plus attention control treatment. Assessments included parent, child, and teacher ratings of social function and direct school observations in gym. Results No advantage was found on any measure of social functioning for the combination treatment over Methylphenidate alone or Methylphenidate plus attention control. Significant improvement occurred across all treatments and continued over 2 years. Conclusions In young children with ADHD, there is no support for clinic-based social skills training as part of a long-term psychosocial intervention to improve social behavior. Significant benefits from Methylphenidate were stable over 2 years.
-
symptomatic improvement in children with adhd treated with long term Methylphenidate and multimodal psychosocial treatment
Journal of the American Academy of Child and Adolescent Psychiatry, 2004Co-Authors: Howard Abikoff, Lily Hechtman, Rachel G. Klein, Karen Fleiss, Joy Etcovitch, Lorne Cousins, Brian Greenfield, Diane Martin, Gabrielle Weiss, Simcha PollackAbstract:Objective: To test the hypotheses that in children with attention-deficit/hyperactivity disorder (ADHD) (1) symptoms of ADHD, oppositional defiant disorder, and overall functioning are significantly improved by Methylphenidate combined with intensive multimodal psychosocial treatment compared with Methylphenidate alone and with Methylphenidate plus attention control and (2) more children receiving combined treatment can be taken off Methylphenidate. Method: One hundred three children with ADHD (ages 7–9), free of conduct and learning disorders, who responded to short-term Methylphenidate were randomized for 2 years to (1) Methylphenidate alone; (2) Methylphenidate plus psychosocial treatment that included parent training and counseling, social skills training, psychotherapy, and academic assistance, or (3) Methylphenidate plus attention psychosocial control treatment. Assessments included parent, teacher, and psychiatrist ratings, and observations in academic and gym classes. Results: Combination treatment did not lead to superior functioning and did not facilitate Methylphenidate discontinuation. Significant improvement occurred across all treatments and continued over 2 years. Conclusions: In stimulant-responsive children with ADHD, there is no support for adding ambitious long-term psychosocial intervention to improve ADHD and oppositional defiant disorder symptoms. Significant benefits from Methylphenidate were stable over 2 years. J. Am. Acad. Child Adolesc. Psychiatry,
-
academic achievement and emotional status of children with adhd treated with long term Methylphenidate and multimodal psychosocial treatment
Journal of the American Academy of Child and Adolescent Psychiatry, 2004Co-Authors: Lily Hechtman, Howard Abikoff, Rachel G. Klein, Joy Etcovitch, Brian Greenfield, Gabrielle Weiss, Chara Respitz, Joan Kouri, Carol Blum, Karen FleissAbstract:ABSTRACT Objective To test the hypothesis that intensive multimodal psychosocial intervention (that includes academic assistance and psychotherapy) combined with Methylphenidate significantly enhances the academic performance and emotional status of children with attention-deficit/hyperactivity disorder (ADHD) compared with Methylphenidate alone and with Methylphenidate combined with nonspecific psychosocial treatment (attention control). Method One hundred three children with ADHD (ages 7–9), free of conduct and learning disorders, who responded to short-term Methylphenidate were randomized for 2 years to receive one of three treatments: (1) Methylphenidate alone, (2) Methylphenidate plus psychosocial treatment that included academic remediation, organizational skills training, and psychotherapy as well as parent training and counseling and social skills training, or (3) Methylphenidate plus attention control treatment. Children's function was assessed through academic testing, parent ratings of homework problems, and self-ratings of depression and self-esteem. Results No advantage was found on any measure of academic performance or emotional status for the combination treatment over Methylphenidate alone and over Methylphenidate plus attention control. Significant improvement occurred across all treatments and was maintained over 2 years. Conclusions In stimulant-responsive young children with ADHD without learning and conduct disorders, there is no support for academic assistance and psychotherapy to enhance academic achievement or emotional adjustment. Significant short-term improvements were maintained over 2 years.
-
clinical efficacy of Methylphenidate in conduct disorder with and without attention deficit hyperactivity disorder
Archives of General Psychiatry, 1997Co-Authors: Rachel G. Klein, Howard Abikoff, E Klass, David Ganeles, Laura M Seese, Simcha PollackAbstract:Background: Stimulants are not considered appropriate for the treatment of children with conduct disorders (CDs). The postulated differences in stimulant effect between children with attention deficit hyperactivity disorder (ADHD) and CD led to the hypothesis that Methylphenidate hydrochloride, which is effective in ADHD, would not significantly improve symptoms of CD. Methods: We randomly assigned 84 children with CD, between the ages of 6 and 15 years, to receive Methylphenidate hydrochloride (up to 60 mg/d) or placebo for 5 weeks. Behavior was evaluated by parent, teacher, and clinician reports and by direct classroom observations. Two thirds of the children also met criteria for ADHD. Results: Contrary to prediction, ratings of antisocial behaviors specific to CD were significantly reduced by Methylphenidate treatment. The magnitude of Methylphenidate effect indicated meaningful clinical benefit. Partialling out severity of ADHD did not alter the significant superiority of Methylphenidate on CD ratings specifically (P Conclusions: Methylphenidate has short-term positive effects on children and adolescents with CD. Key aspects of antisocial adjustment appear to be treatment responsive. This effect was independent of severity of the children's initial ADHD symptoms.
Dolly A Parasrampuria - One of the best experts on this subject based on the ideXlab platform.
-
assessment of pharmacokinetics and pharmacodynamic effects related to abuse potential of a unique oral osmotic controlled extended release Methylphenidate formulation in humans
The Journal of Clinical Pharmacology, 2007Co-Authors: Dolly A Parasrampuria, Kerri A Schoedel, Reinhard Schuller, Patrick Ciccone, Steven A Silber, Edward M SellersAbstract:This was a double-blind, placebo-controlled, randomized, 5-period crossover study in 49 healthy subjects with a history of light (occasional) recreational stimulant use, to evaluate the abuse-related subjective effects of oral osmotic-controlled extended-release Methylphenidate with comparable doses of immediate-release Methylphenidate. Healthy subjects with a history of light recreational stimulant use were enrolled in the study if they demonstrated a positive response to a 20-mg dose of d-amphetamine and a negative placebo response. Enrolled subjects received single doses of placebo, 54 and 108 mg osmotic-controlled extended-release Methylphenidate, and 50 and 90 mg immediate-release Methylphenidate. For each treatment, pharmacokinetics, pharmacodynamics, and safety were assessed for 24 hours. Subjective data were collected through standard questionnaires and visual analog scales for positive, stimulant, negative, and other effects. Immediate-release and osmotic-controlled extended-release Methylphenidate produced expected plasma concentration-time profiles of d-Methylphenidate. Both doses of immediate-release Methylphenidate (50 and 90 mg) produced statistically significantly higher subjective effects (eg, positive, stimulant) with respect to placebo for all measures. The higher osmotic-controlled extended-release Methylphenidate dose of 108 mg also produced statistically significant differences from placebo for most measures. However, the most commonly prescribed therapeutic dose of osmotic-controlled extended-release Methylphenidate (54 mg) did not produce significant differences from placebo for most measures. In addition, for comparable dose levels, osmotic-controlled extended-release Methylphenidate produced lower positive and stimulant subjective effects than immediate-release Methylphenidate, and low-dose immediate-release Methylphenidate (50 mg) produced greater subjective effects than high-dose osmotic-controlled extended-release Methylphenidate, with many effects demonstrating statistically significant differences. These data support the hypothesis that a formulation can modulate abuse potential by controlling the rate and extent of drug delivery.
-
do formulation differences alter abuse liability of Methylphenidate a placebo controlled randomized double blind crossover study in recreational drug users
Journal of Clinical Psychopharmacology, 2007Co-Authors: Dolly A Parasrampuria, Patrick E Ciccone, Kerri A Schoedel, Reinhard Schuller, Steven A Silber, Edward M SellersAbstract:The primary objective of this study was to determine if the abuse liability of Methylphenidate is governed by formulation differences that affect rates of drug delivery. In this double-blind, placebo-controlled, randomized, crossover study, subjects with a history of recreational drug use received single oral doses of placebo, 60 mg of immediate-release Methylphenidate (IR) and 108 mg of extended-release Methylphenidate (osmotic release oral system [OROS]). Over 24 hours after dosing, blood was collected to determine plasma concentrations of Methylphenidate, and subjects completed subjective assessments of abuse liability (Addiction Research Center Inventory, Drug Rating Questionnaire-Subject, and Subjective Drug Value). The abuse-related subjective effects of IR and OROS Methylphenidate were statistically significantly different from placebo, confirming the overall validity of the study. Although a higher dose of OROS Methylphenidate was used compared with IR Methylphenidate (108 mg vs 60 mg), subjective effects were consistently lower for OROS compared with IR Methylphenidate (statistically significant for 3 of 6 measures of positive effects), particularly at early time points. In general, pharmacokinetic-pharmacodynamic parameters were correlated from a poor to modest degree, with greater correlations observed for IR Methylphenidate. In addition, a post hoc "qualification" method was developed, which demonstrated that pharmacological qualification might improve the assessment of subjective effects. Although requiring epidemiological confirmation, the results suggest that OROS Methylphenidate, with its characteristic slow ascending plasma concentration profile, may have lower abuse potential. This conclusion is reflected by lower subjective responses during early hours as compared with the IR formulation with its rapid drug delivery and accompanying greater subjective effects.
-
pet study examining pharmacokinetics detection and likeability and dopamine transporter receptor occupancy of short and long acting oral Methylphenidate
American Journal of Psychiatry, 2006Co-Authors: Thomas J Spencer, Ali A Bonab, Darin D Dougherty, Bertha K. Madras, Joseph Biederman, E Livni, Patrick E Ciccone, Dolly A Parasrampuria, Alan J FischmanAbstract:Objective: The abuse potential of Methylphenidate has been related to the drug’s capacity to produce a rapid onset of blockade of the presynaptic dopamine transporter in the brain. An oral once-aday osmotic controlled-release formulation of Methylphenidate produces a more gradual rise in plasma Methylphenidate concentration, compared with immediate-release Methylphenidate. The authors hypothesized that osmotic-release Methylphenidate would also produce a slower onset of blockade of the presynaptic dopamine transporter and would be associated with a lower risk for detection and likeability, compared to immediaterelease Methylphenidate. Method: Twelve healthy adults were randomly assigned to receive single doses of immediate-release Methylphenidate or osmotic-release Methylphenidate. Doses predicted to produce equivalent maximum concentration (Cmax) values were selected (40 mg of immediate-release Methylphenidate and 90 mg of osmoticrelease Methylphenidate). Plasma dMethylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of Methylphenidate on two separate occasions for each subject. Dopamine transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. Results: Despite similar Cmax values for both formulations, osmotic-release Methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS dopamine transporter occupancy, and no detection/likeability, compared with immediate-release Methylphenidate. Conclusions: The findings suggest that the abuse potential of oral Methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain transporter occupancy. These results advance understanding of the underlying central effects of Methylphenidate in humans and identify a potentially less abusable Methylphenidate formulation.
