LEVODOPA PHARMACOKINETICS AND PHARMACODYNAMICS

帕金森病（PD）患者对左旋多巴的初始反应通常是 一种运动功能显著持续的改善 与长期 左旋多巴治疗后，这种反应被波动反应所取代 这可能是非常失能的并且对治疗操作有抵抗力。 我们假设左旋多巴治疗的帕金森病患者的运动功能是一种产物， 短期反应（SDR）的左旋多巴，半衰期为 小时;对左旋多巴的长期反应（LDR），半衰期为 天;和内源性多巴胺产生。 最初的良好反应是 左旋多巴主要由LDR控制。 波动的发展 反映了LDR和内源性多巴胺合成的减少， 疾病进展和可能的左旋多巴治疗。 我们还 我假设，记录为早晨改善的昼夜运动变化 PD患者运动功能的夜间恶化可能是 内源性多巴胺合成受损。 这一提议改变了 特别提款权的强调，这主导了对电机的思考 左旋多巴对LDR的反应在很大程度上被忽视了。 目标 本临床研究的目的是：1.） 研究SDR和LDR的变化 在左旋多巴治疗的前4年中， 出现临床上明显的运动波动，以确定 特别提款权和最不发达国家债务对波动的相对影响。 2.）的情况。 审查 多巴胺反应性肌张力障碍（DRD）中SDR和LDR，DRD是一种帕金森病 其中多巴胺合成受损但多巴胺储存完好， 以确定多巴胺储存对SDR和LDR的重要性。 3.）第三章 确定阿扑吗啡，一种多巴胺激动剂，是否会维持LDR， 确定LDR是突触前还是突触后作用。 4.） 检查 PD、DRD和正常对照的昼夜运动变化，以确定 昼夜运动变化是多巴胺受损的标志 神经传递 还确定运动活动是否影响 PD的昼夜模式表明多巴胺的消耗可能是PD的基础， 现象。 我们的总体目标是了解 对左旋多巴的反应 本资助期的主要目的是 确定LDR对左旋多巴获益的贡献 治疗，并建议选择性诱导或增加LDR的方法。

The initial response to levodopa in Parkinson's disease (PD) is generally one of marked, sustained improvement in motor function. With long-term levodopa treatment, this response is replaced by fluctuating response which may be very disabling and is resistant to therapeutic manipulations. We hypothesize that the motor function in levodopa-treated PD is a product of the short-duration response (SDR) to levodopa, with a half-life of hours; the long-duration response (LDR) to levodopa, with a half-life of days; and endogenous dopamine production. The initial, good response to levodopa is dominated by the LDR. The development of fluctuations reflects reduction of the LDR and endogenous dopamine synthesis caused by disease progression and, possible, levodopa treatment. Further, we hypothesize that the diurnal motor variation noted as morning improvement and evening deterioration in motor function in PD may be a marker of impaired endogenous dopamine synthesis. This proposal switches the emphasis from the SDR which has dominated the thinking about the motor response to levodopa to the LDR which has been largely ignored. The aims of this clinical study are: 1.) Examine the changes in the SDR and LDR during the first 4 years of levodopa treatment and correlate them with the emergence of clinically apparent motor fluctuations to determine the relative contribution of the SDR and LDR to fluctuations. 2.) Examine the SDR and LDR in dopa-responsive dystonia (DRD), a form of parkinsonism in which dopamine synthesis is impaired but dopamine storage is intact, to determine the importance of dopamine storage to the SDR and LDR. 3.) Determine if apomorphine, a dopamine agonist, will sustain the LDR to establish if the LDR is a pre- or a postsynaptic action. 4.) Examine the diurnal motor variation in PD, DRD and normal controls to determine if diurnal motor variation is a marker for impaired dopamine neurotransmission. Also determine is motor activity influences the diurnal pattern in PD to suggest that depletion of dopamine could underlie the phenomenon. Our overall goal is to understand the fluctuating response to levodopa. The major thrust for this grant period is to determine the contribution of the LDR to the benefits of levodopa treatment and to suggest methods to selectively induce or augment the LDR.