LEVODOPA PHARMACOKINETICS AND PHARMACODYNAMICS

帕金森病(PD)患者对左旋多巴的最初反应通常是 运动功能的显著、持续改善之一。与长期合作 左旋多巴治疗后，这种反应被波动反应所取代 这可能是非常无效的，并对治疗手法具有抵抗力。 我们假设左旋多巴治疗帕金森病的运动功能是一种产物 对左旋多巴的短期反应(SDR)，半衰期为 小时；对左旋多巴的长期反应(LDR)，半衰期为 天；以及内源性多巴胺的产生。最初，良好的反应 左旋多巴由LDR主导。涨落的发展 反映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。此外，我们 假设白天的运动变化记录为早晨的改善 帕金森病患者夜间运动功能的恶化可能是 内源性多巴胺合成受损。这项提议改变了 对特别提款权的强调一直主导着对电机的思考 左旋多巴对LDR的反应在很大程度上被忽视了。目标 这项临床研究的主要内容如下：1)考察SDR和LDR的变化 在左旋多巴治疗的前4年中，并将它们与 临床上出现明显的运动波动以确定 SDR和LDR对波动的相对贡献。2.)考查 帕金森病的一种形式--多巴反应性肌张力障碍的SDR和LDR 其中多巴胺合成受损，但多巴胺存储完好无损， 以确定多巴胺存储对SDR和LDR的重要性。3.) 确定多巴胺激动剂阿朴吗啡是否会维持LDR 确定LDR是突触前动作还是突触后动作。4.)请查看 PD、DRD和正常对照组的昼夜运动变化 昼夜运动变化是多巴胺受损的标志 神经传递。同样确定的是运动活动影响 帕金森病患者的昼夜模式提示多巴胺的耗竭可能是 这一现象。我们的总体目标是理解波动的 对左旋多巴的反应。这一批款期的主要目的是 确定LDR对左旋多巴益处的贡献 并提出有选择地诱导或增加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.