Psychobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd, Suite 200, Baltimore, MD, 21224, USA.
Psychopharmacology (Berl). 2014 Jan;231(1):191-8. doi: 10.1007/s00213-013-3220-8. Epub 2013 Aug 24.
Current formulations of methylphenidate (MPH) used in treatment of attention-deficit/hyperactivity disorder (ADHD) result in significantly different bioavailability of MPH enantiomers. Daytrana®, a dl-MPH transdermal patch system, produces higher levels of l-MPH than when dl-MPH is administered orally (e.g., Ritalin®). One potential limitation of increased l-MPH was indicated in a preclinical study showing l-MPH may attenuate effects of d-MPH.
The objective of the study was to investigate the interactive effects of MPH enantiomers by (1) assessing drug effects via a preclinical model of "impulsivity" and (2) performing a quantitative dose equivalence analysis of MPH enantiomer interactions.
Sprague-Dawley rats were trained to emit either of two responses, one producing an immediate food pellet, the other producing four pellets delivered at increasing delays (0, 8, and 32 s). The percent selection of the larger food amount was graphed as a function of delay with the area under the curve (AUC) assessed. Increases in AUC are consistent with decreases in "impulsivity" (i.e., selection of the smaller, immediate over the larger, delayed reinforcer).
Systemic administration of dl-MPH and d-MPH dose-dependently increased AUC, while l-MPH, morphine, and pentobarbital did not alter AUC. An analysis based upon dose equivalence indicated that dl-MPH produced additive effects that were not different from that predicted from effects of the enantiomers administered alone.
The present results indicate pharmacologically selective effects in that only drugs prescribed for the treatment of ADHD symptoms decreased a measure of "impulsivity" and that l-MPH likely does not attenuate or enhance the effects of d-MPH in the current delay-discounting task.
目前用于治疗注意力缺陷多动障碍（ADHD）的哌甲酯（MPH）制剂在 MPH 对映体的生物利用度上有显著差异。Daytrana®，一种 dl-MPH 透皮贴系统，产生的 l-MPH 水平高于 dl-MPH 口服给药（例如，利他林®）。一项临床前研究表明，l-MPH 可能会减弱 d-MPH 的作用，这表明增加 l-MPH 可能存在潜在的局限性。
该研究的目的是通过（1）评估“冲动”的临床前模型中的药物作用，以及（2）对 MPH 对映体相互作用进行定量剂量等效分析，来研究 MPH 对映体的相互作用。
Sprague-Dawley 大鼠接受训练，以发出两种反应之一，一种反应立即产生食物丸，另一种反应则在逐渐增加的延迟（0、8 和 32 秒）后产生四个食物丸。将较大食物量的选择百分比绘制为延迟的函数，并用曲线下面积（AUC）进行评估。AUC 的增加与“冲动”的降低一致（即选择较小的即时奖励而不是较大的延迟奖励）。
dl-MPH 和 d-MPH 的全身给药剂量依赖性地增加了 AUC，而 l-MPH、吗啡和戊巴比妥则没有改变 AUC。基于剂量等效性的分析表明，dl-MPH 产生了相加作用，与单独使用各对映体预测的效果没有差异。
目前的结果表明存在药理学选择性作用，只有用于治疗 ADHD 症状的药物可以降低“冲动”的一种测量指标，并且在当前的延迟折扣任务中，l-MPH 不太可能减弱或增强 d-MPH 的作用。
