胶质细胞源性神经营养因子（GDNF）治疗帕金森病的随机双盲试验。

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.

作者信息

Nutt J G, Burchiel K J, Comella C L, Jankovic J, Lang A E, Laws E R, Lozano A M, Penn R D, Simpson R K, Stacy M, Wooten G F

机构信息

Oregon Health & Science University, Portland 97201-3098, USA.

出版信息

Neurology. 2003 Jan 14;60(1):69-73. doi: 10.1212/wnl.60.1.69.

DOI:10.1212/wnl.60.1.69

PMID:12525720

Abstract

OBJECTIVE

To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD.

BACKGROUND

GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys.

METHODS

A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies.

RESULTS

Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy.

CONCLUSIONS

GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

摘要

目的

评估通过植入式脑室内（ICV）导管和接入端口给予晚期帕金森病（PD）患者胶质细胞源性神经营养因子（GDNF）的安全性、耐受性和生物学活性。

背景

GDNF是一种促进多巴胺能神经元存活的肽。它改善了啮齿动物和猴子中6-羟基多巴胺（6-OHDA）或1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的行为缺陷。

方法

一项多中心、随机、双盲、安慰剂对照、序贯队列研究比较了50例PD患者每月ICV给予安慰剂以及25、75、150、300和500至4000微克GDNF的效果，为期8个月。一项开放标签研究将16例患者的暴露时间延长至另外20个月，最大单剂量增至4000微克。在整个研究过程中，每隔1至4周进行实验室检测、不良事件（AE）评估和统一帕金森病评定量表（UPDRS）评分。

结果

12例患者接受安慰剂，其他每个GDNF剂量组分配7或8例患者。任何剂量的GDNF均未改善“开”和“关”状态下的UPDRS总分及运动评分。恶心、厌食和呕吐在注射GDNF后的数小时至数天内很常见。大多数接受75微克或更大剂量GDNF的患者出现体重减轻。感觉异常，常被描述为电击样（莱尔米特征），在接受GDNF治疗的患者中很常见，与剂量无关，在停用GDNF后缓解。超过一半接受75微克或更大剂量GDNF的患者出现无症状性低钠血症；部分患者出现症状。开放标签扩展研究有类似的不良事件且缺乏治疗效果。