左旋多巴与阿扑吗啡联用对出现剂末运动波动的帕金森病患者的药效学研究

Pharmacodynamics of levodopa coadministered with apomorphine in parkinsonian patients with end-of-dose motor fluctuations.

作者信息

Baas H, Harder S, Bürklin F, Demisch L, Fischer P A

机构信息

Department of Neurology, University Hospital Frankfurt/Main, Germany.

出版信息

Clin Neuropharmacol. 1998 Mar-Apr;21(2):86-92.

PMID:9579293

Abstract

The modification of the pharmacodynamic response to a single oral dose of levodopa/benserazide by the coadministration of the dopamine agonist apomorphine was investigated in parkinsonian patients with end-of-dose motor fluctuations. The relation between levodopa plasma concentrations and motor response was examined in a double-blind, randomized, crossover design in 10 patients with idiopathic Parkinson's disease with end-of-dose motor fluctuations. Oral single-dose challenges with 100 mg of levodopa/25 mg of benserazide were carried out twice in each patient, under coadministration with apomorphine (1 mg/h) or 0.9% saline (placebo) subcutaneously. The sum scores (sigma score) of the Columbia University Rating Scale (CURS) were used as effect parameters for pharmacodynamic assessment. A sigmoidal Emax model was fitted to the data using a semiparametric pharmacokinetic-pharmacodynamic approach. Levodopa pharmacokinetics were not significantly modified by the coadministration of apomorphine. The area under the curve was 1599 +/- 615 ng.ml-1 h. (levodopa + saline) and 1821 +/- 625 ng.ml-1.h (levodopa + apomorphine). Cmax was 1094 +/- 476 ng.ml-1 (levodopa + saline) and 1129 +/- 435 ng.ml-1 (levodopa + apomorphine). Under both experimental regimens, the maximum clinical response to levodopa (Emax) yielded a decrease in the CURS sigma rating of about 20 score points. Estimates of the EC50 of levodopa decreased significantly from 430 +/- 163 ng.ml-1 (levodopa + saline) to 315 +/- 123 ng+ml-1 (levodopa + apomorphine) (95% confidence interval [CI] 0.51 -0.98, point estimator 0.75). The mean duration of the motor response rose from 1.9 +/- 0.5 h (levodopa + saline) to 3.0 +/- 0.9 h (levodopa + apomorphine (95% CI 1.23 to 2.06, point estimator 1.60). Thus, a reduction of the threshold levels for levodopa (EC50) was accompanied by approximately 50% gain in on-phase duration, but not in an increased magnitude of the motor response (Emax).

摘要

在出现剂末运动波动的帕金森病患者中，研究了多巴胺激动剂阿扑吗啡与左旋多巴/苄丝肼单剂量口服联合用药时对药效学反应的影响。采用双盲、随机、交叉设计，对10例出现剂末运动波动的特发性帕金森病患者，研究左旋多巴血药浓度与运动反应之间的关系。每位患者均接受两次口服100mg左旋多巴/25mg苄丝肼的单剂量激发试验，同时皮下注射阿扑吗啡（1mg/h）或0.9%生理盐水（安慰剂）。哥伦比亚大学评定量表（CURS）的总分（sigma评分）用作药效学评估的效应参数。采用半参数药代动力学-药效学方法，对数据拟合S形Emax模型。阿扑吗啡与左旋多巴联合用药时，左旋多巴的药代动力学未发生显著改变。曲线下面积分别为（左旋多巴+生理盐水）1599±615ng·ml⁻¹·h和（左旋多巴+阿扑吗啡）1821±625ng·ml⁻¹·h。Cmax分别为（左旋多巴+生理盐水）1094±476ng·ml⁻¹和（左旋多巴+阿扑吗啡）1129±435ng·ml⁻¹。在两种试验方案下，左旋多巴的最大临床反应（Emax）使CURS sigma评分降低约20分。左旋多巴的EC50估计值从（左旋多巴+生理盐水）430±163ng·ml⁻¹显著降至（左旋多巴+阿扑吗啡）315±123ng·ml⁻¹（95%置信区间[CI]0.51 - 0.98，点估计值0.75）。运动反应的平均持续时间从（左旋多巴+生理盐水）1.9±0.5h增加至（左旋多巴+阿扑吗啡）3.0±0.9h（95%CI 1.23至2.06，点估计值1.60）。因此，左旋多巴阈值水平（EC50）降低的同时，开期持续时间增加了约50%，但运动反应幅度（Emax）并未增加。