Levodopa Pharmacokinetics and Pharmacodynamics

描述(由申请人提供)：该项目的总体目标是利用在综合临床研究中心(GCRC)内进行的原则性临床试验来开发更好的帕金森氏病(PD)对症疗法。目的1：第一个目标将是对当前资助期的一项研究的后续研究，该研究发现，单剂量的多巴胺转运体(DAT)抑制剂哌醋甲酯(MPD)在不增加运动障碍严重程度的情况下，增强了两小时左旋多巴输注的效果。我们现在建议检查相对较高剂量的MPD每日三次对口服左旋多巴的反应的影响。在GCRC中接受MPD治疗的受试者接受为期4天的左旋多巴滴定，随后两天将进行MPD和安慰剂的随机双盲交叉临床评估。这项原则证明试验将评估DAT抑制剂作为左旋多巴治疗帕金森病患者的辅助治疗的耐受性和治疗潜力。 目的2：第二个目的是探索持续的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说。在一项随机双盲临床试验中，我们将比较6个月持续和搏动性多巴胺能刺激使用阿朴吗啡连续给药或由门诊泵团注给药的效果。将调查阿朴吗啡6个月前后对试验剂量左旋多巴的反应，以确定不同给药方式对左旋多巴的反应是否有变化。持续多巴胺能刺激改善运动障碍的另一种解释是长期服用左旋多巴治疗的运动并发症的发生和维持，并表明持续给予阿朴吗啡作为治疗这些复杂患者的一种方法的有效性。

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.