LEVODOPA PHARMACOKINETICS & PHARMACODYNAMICS

帕金森病患者对左旋多巴的波动反应 OFF(关闭)现象)是一种常见的禁用问题 在慢性左旋多巴治疗期间，对当前模式具有抵抗力 治疗手法。我们的目标是了解为什么会这样 波动的响应会发展起来，是什么决定了分钟到 微小运动功能。这一认识是建立在 以设计改进的治疗策略来治疗 反复无常或阻碍其发展。 这项提案将1)探讨大容量等离子体的重要性 中性氨基酸(LNAA)浓度对反应的影响 左旋多巴在帕金森病患者中的应用 血浆氨基酸在一天中变化，无论比率 血浆左旋多巴至LNAA浓度是更好的预测 反应和空腹LNAA浓度是否与 最低疗效血浆左旋多巴 浓度；2)调查两相的可能性 对左旋多巴的反应(抑制和兴奋作用) 比较安慰剂、亚阈值、阈值和 阈值以上输液率和耐受性的可能性 十二指肠内持续滴注5次的疗效观察 对阿朴吗啡敏感的天数；3)检查中枢 左旋多巴在稳定和波动患者体内的药代动力学 左旋多巴和阿朴吗啡的量效曲线建立 判断效应器对药物动力学是否敏感 稳定期和波动性患者的隔室不同 和；4)作为中枢药代动力学的另一个指标；研究 犬血浆和脑脊液左旋多巴与脑脊液的关系 神经外科患者和随后的脑脊液左旋多巴和 帕金森病患者的反应。 这些实验将有助于确定修改 对左旋多巴的反应以及潜在的现象 波动反应的发展。

The fluctuating 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. Our goal is to understand why this fluctuating response develops and what determines the minute-to- minute motor function. This understanding is to foundation on which to design improved therapeutic strategies to treat the fluctuating response or prevent its development. This proposal will 1) explore the importance of plasma large neutral amino acid (LNAA) concentrations on response to levodopa in parkinsonian patients by determining how much plasma amino acids vary during the day, whether the ratio of plasma levodopa to LNAA concentrations is a better predictor of response and whether fasting LNAA concentrations correlate with minimum therapeutically effective plasma levodopa concentrations; 2) to investigate the possibility of a biphasic response to levodopa (both inhibitory and excitatory actions) by comparing responses to placebo, subthreshold, threshold, and suprathreshold infusion rates and the possibility of tolerance by determining the effect of constant intraduodenal infusions for 5 days on sensitivity to apomorphine and; 3) examine central pharmacokinetics of levodopa in stable and fluctuating patients by establishing dose response curves for levodopa and apomorphine to judge whether sensitivity to drug kinetics in the effector compartment is different between stable and fluctuating patients and; 4) as another index of central pharmacokinetics; study the relationship between plasma and CSF levodopa in dogs and neurosurgical patients and subsequently CSF levodopa and response in parkinsonian patients. These experiments will help define factors which modify the response to levodopa as well as the phenomenon which underlie the development of the fluctuating response.