帕金森病不同阶段患者左旋多巴的浓度-反应关系。

Concentration-response relationship of levodopa in patients at different stages of Parkinson's disease.

作者信息

Harder S, Baas H

机构信息

Institute for Clinical Pharmacology and the Clinic for Neurology, University Hospital Frankfurt am Main, Frankfurt, Germany.

出版信息

Clin Pharmacol Ther. 1998 Aug;64(2):183-91. doi: 10.1016/S0009-9236(98)90152-7.

DOI:10.1016/S0009-9236(98)90152-7

PMID:9728899

Abstract

OBJECTIVE

To assess differences in the pharmacokinetic and pharmacodynamic relations of levodopa in clinically defined groups and to prove that pharmacokinetic and pharmacodynamic parameters are associated with duration of disease and length of treatment.

METHODS

We studied the pharmacokinetic and pharmacodynamic relations of levodopa after a single dose (100 mg levodopa with 25 mg benserazide) among four groups of patients with Parkinson's disease. Group 1 was levodopa-naive patients (n = 8); group 2 was patients in stable condition taking levodopa (n = 10); group 3 was patients with on-and-off fluctuations (n = 11); and group 4 was patients with on-and-off fluctuations and peak-dose dyskinesia (n = 8). The Columbia University Rating Scale was used for clinical assessment. The pharmacokinetic-pharmacodynamic analysis was based on an estimate of the maximal response model with a semiparametric approach to effect-site equilibrium (equilibration half-life).

RESULTS

The mean concentration at half-maximal effect estimated for the different groups was as follows (mean value +/- SD): group 1, 389 +/- 138 ng x ml(-1); group 2, 346 +/- 203 ng x ml(-1); group 3, 543 +/- 245 ng x ml(-1); group 4, 711 +/- 215 ng x ml(-1). Estimate of the maximal response was determined to be the following: group 1, 10 +/- 3; group 2, 12 +/- 5; group 3, 24 +/- 13; group 4, 18 +/- 7. A significant correlation was observed between duration of Parkinson's disease and mean concentration at half-maximal effect (p < 0.001), estimate of maximal response (p < 0.05), and, inversely, equilibration half-life (p < 0.05).

CONCLUSIONS

The data suggested that levodopa-naive patients and patients in stable condition taking levodopa do not differ in pharmacokinetic-pharmacodynamic relations, whereas patients with fluctuations, especially patients with peak-dose dyskinesia, exhibit a larger threshold level (mean concentration at half-maximal effect). It was concluded that progression of the disease (loss of endogenous dopamine synthesis and reduced dopamine storage) is reflected by pharmacokinetic and pharmacodynamic parameters that characterize the demand for exogenous dopamine provided by levodopa.

摘要

目的

评估左旋多巴在临床定义组中的药代动力学和药效学关系差异，并证明药代动力学和药效学参数与疾病持续时间和治疗时长相关。

方法

我们研究了四组帕金森病患者单次服用一剂（100 mg左旋多巴加25 mg苄丝肼）后左旋多巴的药代动力学和药效学关系。第1组为未服用过左旋多巴的患者（n = 8）；第2组为服用左旋多巴病情稳定的患者（n = 10）；第3组为有开关现象波动的患者（n = 11）；第4组为有开关现象波动且有剂峰异动症的患者（n = 8）。采用哥伦比亚大学评定量表进行临床评估。药代动力学-药效学分析基于最大反应模型的估计，采用半参数方法计算效应室平衡（平衡半衰期）。

结果

不同组估计的半数最大效应时的平均浓度如下（平均值±标准差）：第1组，389±138 ng·ml⁻¹；第2组，346±203 ng·ml⁻¹；第3组，543±245 ng·ml⁻¹；第4组，711±215 ng·ml⁻¹。最大反应的估计值如下：第1组，10±3；第2组，12±5；第3组，24±13；第4组，18±7。观察到帕金森病持续时间与半数最大效应时的平均浓度（p < 0.001）、最大反应估计值（p < 0.05）呈显著正相关，与平衡半衰期呈显著负相关（p < 0.05）。

结论

数据表明，未服用过左旋多巴的患者和服用左旋多巴病情稳定的患者在药代动力学-药效学关系上无差异，而有波动的患者，尤其是有剂峰异动症的患者，表现出更高的阈值水平（半数最大效应时的平均浓度）。得出结论：疾病进展（内源性多巴胺合成减少和多巴胺储存降低）通过药代动力学和药效学参数反映出来，这些参数表征了左旋多巴提供外源性多巴胺的需求。