title: Effects of methylphenidate hydrochloride on the cardiovascular system in vivo and in vitro: a safety pharmacology study.
abstract: BACKGROUND
  : We examined the effects of methylphenidate hydrochloride (MPH) on the cardiovascular system using in vivo and in vitro study methods in accordance with the ICH-S7B guideline.
  
  
  METHODS
  MPH was orally administered at doses of 3, 10 and 30 mg/kg to unrestrained conscious dogs implanted with a telemetry transmitter and attached with body surface electrodes, and electrocardiogram (ECG) leads. The QTcF interval was determined while heart rate (HR), and blood pressure (BP) were measured. Action potentials in isolated guinea-pig papillary muscle and the rapid component of the delayed rectifier potassium current (I(Kr)) in HEK-293 cells stably transfected with hERG were also investigated at concentrations of 0.1, 0.3 and 1 microg/mL (0.37, 1.1 and 3.7 micromol/L) of MPH.
  
  
  RESULTS
  No ECG changes were observed except for a shortening of the QT interval due to a shortening of the RR interval at the maximum dose tested, 30 mg/kg. The only observed change was an elevation of BP in dogs at the dose of 30 mg/kg, which is approximately 10 times higher than the maximum therapeutic dose for use in children with attention deficit hyperactivity disorder (ADHD). Neither APD prolongation nor I(Kr) inhibition was observed by MPH in the in vitro studies up to the maximum concentration tested, 1 microg/mL (3.7 micromol/L), which is approximately 34 times higher than the clinically attainable unbound plasma MPH concentrations in children with ADHD.
  
  
  CONCLUSIONS
  These results suggest that it is unlikely that MPH affects ventricular repolarization processes at the therapeutically recommended dose levels in patients with ADHD.
authors.affiliation: Janssen Pharmaceutical KK, Pre-clinical Department, Chiyoda-ku, Tokyo, Japan. awakamat@its.jnj.com
authors.forename: Akihide
authors.initials: A
authors.lastname: Wakamatsu
authors.forename: Shunji
authors.initials: S
authors.lastname: Nomura
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tate
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Shimizu
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Harada
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008774:Methylphenidate / Q000009:adverse effects / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D013686:Telemetry
chemical_list: D000697:Central Nervous System Stimulants; D051668:Delayed Rectifier Potassium Channels; D051638:Ether-A-Go-Go Potassium Channels; D008774:Methylphenidate