LEVODOPA PHARMACOKINETICS & PHARMACODYNAMICS

帕金森病患者对左旋多巴的波动运动反应（“开-关”）

The fluctuating motor response to levodopa in Parkinson's disease ("on-off" phenomenon) is a common, disabling problem that occurs during chronic levodopa therapy and is resistant to current modes of therapeutic manipulation. In addition to fluctuations in motor function, fluctuations in mood, sensory symptoms and autonomic function are also common and can be incapacitating. Our goal is to understand how the fluctuating response develops and what factors determine motor function and mood at any point in time. This understanding is the foundation on which to design improved therapeutic strategies to reduce fluctuations or prevent their development. The aims of this clinical study are: 1. Investigate "off" periods that occur during constant rate levodopa infusions to determine if a. they are dose responsive, that is, occur at lower but not higher infusion rates, b. their frequency is altered by the length of infusion, c. they occur during elevations of plasma large neutral amino acids or 3-O-methyldopa which could block levodopa's entry into brain. 2. Define temporal relation between mood and plasma levodopa and motor function and determine if levodopa-induced fluctuations in mood are a trait or state marker for depression. 3. Explore possibility that "off" periods represent a negative levodopa effect rather than absence of positive or beneficial levodopa effect by a. examining response to stepwise subtherapeutic infusions to look for a biphasic response to levodopa and b. examining "off" periods after short and long infusions for evidence of withdrawal phenomena. 4. Examine the "long duration" response to levodopa by a. determining the rate of decline in motor function when levodopa is withheld for 2 to 3 days and correlating the rate of decline with disease severity, duration of levodopa therapy and concurrent medications and b. examining the recovery of the "long duration" response after the mini-holiday with diurnal and nocturnal levodopa infusions and apomorphine infusions. 5. Follow a small cohort of parkinsonian patients from the initiation of levodopa therapy to study the emergence of the "short" and "long" duration responses to levodopa as well as dyskinesia and "negative" levodopa actions.