title: Comparative pharmacodynamics and plasma concentrations of d-threo-methylphenidate hydrochloride after single doses of d-threo-methylphenidate hydrochloride and d,l-threo-methylphenidate hydrochloride in a double-blind, placebo-controlled, crossover laboratory school study in children with attention-deficit/hyperactivity disorder.
abstract: OBJECTIVE
  Methylphenidate has four optical isomers due to two asymmetries (erythro-threo and dextro-levo). The initial commercial formulation eliminated the erythro isomer, but the dextro-levo asymmetry was racemic, with equal amounts of d and l-threo isomers (d,l-MPH). Previous work has suggested that the d-threo isomer methylphenidate (d-MPH) rather than the l-threo isomer (l-MPH) is responsible for the clinical effects in children with attention-deficit/hyperactivity disorder (ADHD). This study compared the efficacy of acute equimolar doses of d-MPH and dl-MPH in reducing ADHD symptoms over an 8-hour period in a laboratory school setting and investigated the relationship of efficacy to plasma levels of MPH.
  
  
  METHODS
  Thirty-two children with ADHD enrolled in this double-blind, placebo-controlled, crossover study, and 31 completed the study. On seven separate occasions separated by at least 6 days, the children received a single morning dose of d-MPH (2.5, 5, or 10 mg), d,l-MPH (5, 10, or 20 mg), or placebo and then were observed in a laboratory classroom setting for 8 hours. At specified intervals, blinded observers rated behavior, and the children performed a computerized math test. The plasma levels of MPH were related to the response to study medication. The safety profiles of the two formulations were compared.
  
  
  RESULTS
  For both formulations, the responses to both MPH preparations were dose related, the plasma concentrations of l-MPH were negligible and of d-MPH were indistinguishable, and clinical efficacy was highly correlated with plasma concentrations of d-MPH. The efficacy of the d-isomer was equivalent to the racemic preparation in reducing ADHD symptoms and increasing academic productivity.
  
  
  CONCLUSIONS
  The efficacy of MPH resides in the d-isomer. The elimination of the l-isomer does not diminish the efficacy of an acute dose of methylphenidate.
authors.affiliation: Division of Child Psychiatry, Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan Canada.
authors.forename: Declan
authors.initials: D
authors.lastname: Quinn
authors.forename: Sharon
authors.initials: S
authors.lastname: Wigal
authors.forename: James
authors.initials: J
authors.lastname: Swanson
authors.forename: Sharon
authors.initials: S
authors.lastname: Hirsch
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ottolini
authors.forename: Maghsoud
authors.initials: M
authors.lastname: Dariani
authors.forename: Mark
authors.initials: M
authors.lastname: Roffman
authors.forename: Jerome
authors.initials: J
authors.lastname: Zeldis
authors.forename: Thomas
authors.initials: T
authors.lastname: Cooper
mesh_terms: D000284:Administration, Oral; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002648:Child; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010919:Placebos; D013237:Stereoisomerism; D013334:Students; D016896:Treatment Outcome
chemical_list: D000697:Central Nervous System Stimulants; D010919:Placebos; D008774:Methylphenidate