Levodopa Pharmacokinetics and Pharmacodynamics

描述（由申请人提供）：该项目的总体目标是通过在普通临床研究中心（GCRC）进行的原理临床试验来开发更好的帕金森病（PD）症状治疗方法。目标1：第一个目标将跟踪当前资助期的一项研究，该研究发现单剂量哌醋甲酯（MPD），一种多巴胺转运体（DAT）抑制剂，增强了两小时左旋多巴输注的效果，而不会增加运动障碍的严重程度。我们现在建议检查相对高剂量每日三次的MPD对口服左旋多巴反应的影响。受试者在GCRC中接受MPD时，将进行为期4天的左旋多巴滴定，随后两天进行MPD和安慰剂的随机双盲交叉临床评估。这项原理验证试验将评估DAT抑制剂作为左旋多巴治疗的PD患者的辅助治疗的耐受性和治疗潜力。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop better symptomatic therapies for Parkinson's disease (PD) using proof of principle clinical trials conducted within the General Clinical Research Center (GCRC. Aim 1: The first aim will follow up a study from the current funding period that found that single doses of methylphenidate (MPD), an inhibitor of the dopamine transporter (DAT), augmented the effects of two-hour levodopa infusions without increasing severity of dyskinesia. We now propose to examine the effects of relatively high doses of MPD administered three times daily on the response to oral levodopa. A 4-day titration of levodopa while the subjects are receiving MPD in the GCRC will be followed by two days for a randomized double-blinded crossover clinical evaluation of MPD and placebo. This proof of principle trial will assess the tolerability and therapeutic potential of DAT inhibitors as adjunctive therapy in levodopa-treated PD patients. Aim 2: The second aim explores the hypothesis that continuous dopaminergic stimulation will reverse motor fluctuations and dyskinesia that have emerged during long-term levodopa therapy. We will compare the effects of 6 months of continuous and pulsatile dopaminergic stimulation using apomorphine delivered continuously or in boluses by ambulatory pumps in a randomized double blind clinical trial. The response to test doses of levodopa before and after the 6 months of apomorphine will be investigated to determine if there is a change in the response to levodopa induced by the different modes of delivery. Another explanation for improvements in dyskinesia with continuous dopaminergic stimulation to the genesis and maintenance of motor complications of long-term levodopa therapy and indicate the utility of continuous apomorphine administration as a method to manage these complicated patients.