Levodopa Pharmacokinetics and Pharmacodynamics

描述（由申请人提供）： 该项目的总体目标是使用在一般临床研究中心（GCRC）内进行的原则性临床试验证明，开发更好的帕金森病（PD）对症治疗。目标1：第一个目标将跟踪当前资助期间的一项研究，该研究发现单剂量哌甲酯（MPD），多巴胺转运蛋白（DAT）的抑制剂，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的MPD每天给药三次对口服左旋多巴的反应的影响。当受试者在GCRC中接受MPD时，左旋多巴滴定4天，随后2天进行MPD和安慰剂的随机双盲交叉临床评价。这项原则性试验将评估DAT抑制剂作为左旋多巴治疗的PD患者的连续治疗的耐受性和治疗潜力。 目标二：第二个目标探讨了持续多巴胺能刺激将逆转长期左旋多巴治疗期间出现的运动波动和运动障碍的假设。我们将在一项随机双盲临床试验中比较连续和脉冲式多巴胺能刺激6个月的效果，其中使用阿扑吗啡连续或通过流动泵推注。将研究在阿扑吗啡6个月之前和之后对测试剂量的左旋多巴的反应，以确定是否存在由不同递送模式诱导的对左旋多巴的反应的变化。另一种解释是，持续多巴胺能刺激可改善运动障碍，导致长期左旋多巴治疗的运动并发症的发生和维持，并表明持续阿扑吗啡给药可作为管理这些复杂患者的方法。

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.