Pharmacokinetic and pharmacodynamic properties of stimulants: implications for the design of new treatments for ADHD
Behavioural Brain ResearchPublished 1 March 2002
James M. Swanson, Nora D. Volkow
Citations170
SJR quartileQ2
SJR score0.92
SNIP0.77
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TL;DR
Information from drug development programs and studies based on positron emission tomograpy in adult volunteers have provided new knowledge about the PK properties of MPH at the primary site of action in the brain, and this work will review these two topics.
Abstract
In the USA, the stimulant drug methylphenidate (MPH) is used to treat a large number (2 million or more per year) of children with Attention Deficit Hyperactivity Disorder (ADHD). Although the US FDA approved MPH in the 1960s, the pharmacokinetic (PK) properties of serum concentrations of MPH in children with ADHD were not described until the 1980s, and then in only a few cases. Recently, information from drug development programs have increased our knowledge about the serum PK and some pharmacodynamic (PD) characteristics of MPH in ADHD children, and studies based on positron emission tomograpy (PET) in adult volunteers have provided new knowledge about the PK properties of MPH at the primary site of action in the brain. We will review these two topics and use this new information to evaluate the mechanisms of action of MPH.
Keywords
MedicineNeuroscience
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To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder.
PEDIATRICSTime-Response Analysis of the Effect of Stimulant Medication on the Learning Ability of Children Referred for Hyperactivity
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A laboratory learning task is used to document that between one and two hours after the administration of a single dose of methylphenidate, the drug exerts its maximum effect on performance in a learning task in the laboratory.
Journal of Pharmacology and Experimental TherapeuticsPharmacology of the enantiomers of threo-methylphenidate.
197 Citations1987Kennerly S. Patrick, Robert W. Caldwell +2 more
Results suggest that synaptic inhibition of catecholaminergic uptake by d-threo-MPH may be involved fundamentally in behavioral and pressor effects of the racemic drug.
PEDIATRICSSustained Release and Standard Methylphenidate Effects on Cognitive and Social Behavior in Children With Attention Deficit Disorder
170 Citations1987William E. Pelham, James W. Sturges +5 more
Although group analyses of the data showed that both drugs were effective and there were few differences between them, standard methylphenidate was superior to SR-20 on several important measures of disruptive behavior and analyses of individual responsivity showed clearly that most boys responded more positively to standardethylphenidate than toSR-20.
Zhonghua wai ke za zhi [Chinese journal of surgery]Ritalin: Theory and Patient Management
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Journal of Pharmacology and Experimental TherapeuticsMETABOLISM AND DISPOSITION OF METHYLPHENIDATE-14C: STUDIES IN MAN AND ANIMALS
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PsychopharmacologyChiral drugs: comparison of the pharmacokinetics of [ 11 C] d-threo and l-threo -methylphenidate in the human and baboon brain
158 Citations1997Yu‐Shin Ding, Joanna S. Fowler +6 more
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Proceedings of the National Academy of SciencesRelationship between psychostimulant-induced "high" and dopamine transporter occupancy.
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It is indicated that DAT occupancy is not sufficient to account for the high, and that for DAT inhibitors to be therapeutically effective, occupancies > 80% may be required.
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Journal of the American Academy of Child PsychiatryClinical Studies of Methylphenidate Serum Levels in Children and Adults
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New England Journal of MedicineMore Frequent Diagnosis of Attention Deficit–Hyperactivity Disorder
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PubMedReliability and validity of the SKAMP rating scale in a laboratory school setting.
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Clinical Pharmacology & TherapeuticsEnantioselective pharmacokinetics and pharmacodynamics of dl-thero-mcthylphenidate in children with attention deficit hyperactivity disorder
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The computer tests revealed a drug‐induced improvement in sustained attention that was entirely attributable to the d‐enantiomer, and there was no evidence to suggest that the effectiveness of d‐methylphenidate was in any way compromised by the presence of its antipode.
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PEDIATRICSPsychopharmacology of Attention Deficit Disorder: Pharmacokinetic, Neuroendocrine, and Behavioral Measures Following Acute and Chronic Treatment with Methylphenidate
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Journal of Pharmacology and Experimental TherapeuticsStereoselective disposition of methylphenidate in children with attention-deficit disorder.
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No significant associations were found between blood levels and clinical response in behavioral measures or laboratory tests of attention or activity, and it is unlikely that routine methylphenidate blood level determinations will become a part of the routine clinical management of hyperactive children.
Clinical BiochemistryGas chromatographic/mass spectrometric analysis of methylphenidate (Ritalin) in serum
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The assay has been used to investigate the pharmacokinetics of methylphenidate administered to 6 children for treatment of hyperkinesis and yielded ranges for volume of distribution, elimination half-life, and total body clearance of 5.0-6.8 L/kg, 1.6-2.7 hours, and 1.4-3.5 hours respectively.
Journal of Mass SpectrometryA reproducible gas chromatographic mass spectrometric assay for low levels of methylphenidate and ritalinic acid in blood and urine
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PubMedEvaluation of individual subjects in the analog classroom setting: II. Effects of dose of amphetamine (Adderall).
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