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

Greenhill, Laurence L.; Perel, James M.; Rudolph, George R.; Feldman, Bruce; Curran, Susan; Puig-Antich, Joaquim; Gardner, Richard A.

doi:10.1017/s1461145701002413

Cited by 24 publications

(10 citation statements)

References 25 publications

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“…The MPH administration was oral, further modeling the human exposure. In addition to the modeling parameters described above, the 3 mg/kg dose resulted in MPH serum levels similar to those described for the clinical range of children [Greenhill et al, 2001;Quinn et al, 2004;Teicher et al, 2006;Quinn et al, 2007] and adolescent rats using oral treatment (2-5 mg MPH/kg) [Wheeler et al, 2007]. MPH serum levels of female rats were higher than those of males, a sex effect previously described [Bakhtiar and Tse 2003].…”

Section: Discussionsupporting

confidence: 70%

Flow cytometric detection of Pig‐A mutant red blood cells using an erythroid‐specific antibody: Application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats

Dobrovolsky

Boctor

Twaddle

et al. 2009

Environ and Mol Mutagen

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A modified flow cytometry assay for Pig-A mutant rat red blood cells (RBCs) was developed using an antibody that positively identifies rat RBCs (monoclonal antibody HIS49). The assay was used in conjunction with a flow cytometric micronucleus (MN) assay to evaluate gene mutation and clastogenicity/aneugenicity in adolescent male and female rats treated with methylphenidate hydrochloride (MPH). Sprague-Dawley rats were treated orally with 3 mg/kg MPH (70/sex) or water (40/sex) 3 x /day on postnatal days (PNDs) 29-50. Eight additional rats (4/sex) were injected i.p. with N-ethyl-N-nitrosourea (ENU) on PND 28. Blood was collected on PNDs 29, 50, and 90, and used for determining serum MPH levels and/or conducting genotoxicity assays. On the first and last days of MPH treatment (PNDs 29 and 50), serum MPH levels averaged 21 pg/microl, well within the clinical treatment range. Relative to our previously published method (Miura et al. [2008]; Environ Mol Mutagen 49: 614-629), the HIS49 Pig-A mutation assay significantly reduced the background RBC mutant frequency; in the experiments with ENU-treated rats, the modification increased the overall sensitivity of the assay 2-3 fold. Even with the increased assay sensitivity, the 21 consecutive days of MPH treatment produced no evidence of Pig-A mutation induction (measured at PND 90); in addition, MPH treatment did not increase MN frequency (measured at PND 50). These results support the consensus view that the genotoxicity of MPH in pediatric patients reported earlier (El-Zein et al. [2005]: Cancer Lett 230: 284-291) cannot be reproduced in animal models, suggesting that MPH at clinically relevant levels may be nongenotoxic in humans.

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Section: Discussionsupporting

confidence: 70%

Flow cytometric detection of Pig‐A mutant red blood cells using an erythroid‐specific antibody: Application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats

Dobrovolsky

Boctor

Twaddle

et al. 2009

Environ and Mol Mutagen

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“…These doses were selected to ensure some clinical relevance. Doses of amphetamine that are used clinically range from 5 to 60 mg [45,46] and these are thought to result in blood plasma concentrations between 120 and 140 ng/ml in people receiving treatment for ADHD [47,48]. When administered orally to rats, a dose 0.067 mg/ml gives a peak plasma concentration of 4 ng/ml [49] and, therefore, assuming a linear scaling, a dose of 2 mg/Kg would amount to a blood plasma level of approximately 120 ng/ml.…”

Section: Chronic Drug Treatmentmentioning

confidence: 99%

Chronic amphetamine treatment affects collicular-dependent behaviour

Turner

Stramek

Kraev

et al. 2018

Behavioural Brain Research

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Distractibility can be defined as an attention deficit where orientation toward irrelevant targets cannot be inhibited. There is now mounting evidence that the superior colliculus is a key neural correlate of distractibility, with increased collicular-activity resulting in heightened distractibility. Heightened distractibility is reduced by amphetamine, which acutely suppresses collicular responsiveness. However, when amphetamine is used to treat distractibility, it is given chronically, yet no data exist on whether chronic amphetamine treatment affects the colliculus. Here, the effect of chronic amphetamine treatment was assessed in healthy hooded lister rats on two collicular dependent behaviours following a twenty-eight day treatment period: i) orienting to visual stimuli, and ii) height-dependent modulation of air-righting. We found no significant impact of amphetamine treatment on visual orienting despite showing dose-dependent decreases in orienting to repeated stimuli. However, we did find that treatment with amphetamine significantly reduced the ability to modulate righting according to the height the animal is dropped from - a function known to be dependent on the colliculus. We suggest that the results are in line with previous research showing acute amphetamine suppresses collicular activity and we speculate that the psychostimulant may increase receptive field size, altering time-to-impact calculations carried out by the colliculus during air-righting.

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“…4,5 Due to these PK and PD properties, multiple doses of IR MPH are usually required to maintain effectiveness across the day. 6 The initial sustainedrelease (SR) formulations of MPH (eg, Ritalin SR), developed to overcome the need for multiple daily doses, were approved by the US Food and Drug Administration (FDA) for the treatment of ADHD decades ago, but they were not well accepted in clinical practice, apparently due to a perception of reduced clinical effectiveness, slower onset of action, and greater variability of response compared with IR MPH. 7 Recently, second-generation, once-daily, extended-release (ER) formulations of MPH were developed that were shown to be as effective as multiple doses of IR MPH.…”

Section: The a Priori Hypothesis Called For A Comparison Of Thementioning

confidence: 99%

A Comparison of Once-Daily Extended-Release Methylphenidate Formulations in Children With Attention-Deficit/Hyperactivity Disorder in the Laboratory School (The Comacs Study)

et al. 2004

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ABSTRACT. Objective. The objective of this study was to evaluate differences in the pharmacodynamic (PD) profile of 2 second-generation extended-release (ER) formulations of methylphenidate (MPH): Metadate CD (MCD; methylphenidate HCl, US Pharmacopeia) extended-release capsules, CII, and Concerta (CON; methylphenidate HCl) extended-release tablets, CII. Little empirical information exists to help the clinician compare the PD effects of the available ER formulations on attention and behavior. Previous studies have shown that the near-equal doses of MCD and CON provide equivalent, total exposure to MPH as measured by area under the plasma concentration time curve, yet their pharmacokinetic (PK) plasma concentration versus time profiles are different. We previously offered a theoretical PK/PD account of the similarities and differences among available ER formulations based on the hypothesis that all formulations produce effects related to MPH delivered by 2 processes: 1) an initial bolus dose of immediate-release (IR) MPH that is expected to achieve peak plasma concentration in the early morning and have rapid onset of efficacy within 2 hours of dosing, which for the MCD capsule is delivered by 30% of the total daily dose as uncoated beads and for the CON tablet is delivered by an overcoat of 22% of the total daily dose; and 2) an extended, controlled delivery of ER MPH that is expected to achieve peak plasma concentrations in the afternoon to maintain efficacy for a programmed period of time after the peak of the initial bolus, which for the MCD capsule is delivered by polymer-coated beads and for the CON tablet by an osmotic-release oral system. According to this PK/PD model, clinical superiority is expected at any point in time for the formulation with the highest MPH plasma concentration.Methods. This was a multisite, double-blind, doubledummy, 3-way crossover study of 2 active treatments (MCD and CON) and placebo (PLA). Children with confirmed diagnoses of attention-deficit/hyperactivity disorder were stratified to receive bioequivalent doses of MCD and CON that were considered to be low (20 mg of MCD and 18 mg of CON), medium (40 mg of MCD and 36 mg of CON), or high (60 mg of MCD and 54 mg of CON), and in a randomized order each of the study treatments was administered once daily in the morning for 1 week. On the seventh day of each treatment week, children attended a laboratory school, where surrogate measures of response were obtained by using teacher ratings of attention and deportment and a record of permanent product of performance on a 10-minute math test at each of the 7 classroom sessions spread across the day at 1.5-hour intervals. Safety was assessed by patient reports of adverse events, parent ratings on a stimulant side-effects scale, and measurement of vital signs.Results. The analyses of variance revealed large, statistically significant main effects for the within-subject factor of treatment for all 3 outcome measures (deportment, attention, and permanent product). The interactions of treatment...

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

Cited by 24 publications

References 25 publications

Flow cytometric detection of Pig‐A mutant red blood cells using an erythroid‐specific antibody: Application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats

Flow cytometric detection of Pig‐A mutant red blood cells using an erythroid‐specific antibody: Application of the method for evaluating the in vivo genotoxicity of methylphenidate in adolescent rats

Chronic amphetamine treatment affects collicular-dependent behaviour

A Comparison of Once-Daily Extended-Release Methylphenidate Formulations in Children With Attention-Deficit/Hyperactivity Disorder in the Laboratory School (The Comacs Study)

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