Levodopa Pharmacokinetics and Pharmacodynamics

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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.