AMPA拮抗剂ZK200775用于急性缺血性中风患者：通过监测血清S-100B水平检测到可能的胶质细胞毒性。

AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels.

作者信息

Elting Jan-Willem, Sulter Geert A, Kaste Markku, Lees Kennedy R, Diener Hans C, Hommel Marc, Versavel Mark, Teelken Albert W, De Keyser Jacques

机构信息

Department of Neurology, University Hospital Groningen, Groningen, Netherlands.

出版信息

Stroke. 2002 Dec;33(12):2813-8. doi: 10.1161/01.str.0000043823.37955.fb.

DOI:10.1161/01.str.0000043823.37955.fb

PMID:12468775

Abstract

BACKGROUND AND PURPOSE

S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients.

METHODS

In a multicenter, double-blind, randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were treated with either placebo or active drug in a dose-finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours (dose group 2). Eleven patients received a total dose of 105 mg over a period of 6 hours (dose group 3; reduction of total dose and infusion time because of adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed with the use of a monoclonal sandwich immunoluminometric assay. Neurological outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS).

RESULTS

In group 2 there was a significant transient worsening in the mean NIHSS score 48 hours after the start of treatment. The mean increase was 11 points. This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients. Neurological deterioration in group 2 was associated with a higher increase of S-100B concentrations, but not of NSE concentrations, than in the placebo group. The trial was stopped prematurely for safety reasons.

CONCLUSIONS

The AMPA antagonist ZK200775 transiently worsened the neurological condition in patients with acute ischemic stroke. Our results suggest that in addition to neuronal dysfunction, glial cell toxicity may have occurred. It may be useful to introduce monitoring of serum markers of brain damage in phase 2 trials with glutamate receptor antagonists.

摘要

背景与目的

S - 100B和神经元特异性烯醇化酶（NSE）的血清浓度可分别用作胶质细胞和神经元损伤的外周标志物。我们在一项针对急性缺血性中风患者使用α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸（AMPA）拮抗剂ZK200775的临床试验中对这些标志物进行了研究。

方法

在一项多中心、双盲、随机、安慰剂对照的2期试验中，61例缺血性中风患者采用剂量探索设计，分别接受安慰剂或活性药物治疗。25例患者接受安慰剂治疗，12例患者在48小时内接受总剂量262.5 mg（剂量组1），13例患者在48小时内接受总剂量525 mg（剂量组2）。11例患者在6小时内接受总剂量105 mg（剂量组3；因剂量组2出现不良事件而减少了总剂量和输注时间）。使用单克隆夹心免疫发光分析法分析S - 100B和NSE的血清浓度。用美国国立卫生研究院卒中量表（NIHSS）评估神经功能结局。