Lepeintre J-F, D'Arbigny P, Mathé J-F, Vigué B, Loubert G, Delcour J, Kempf C, Tadié M
Service de Neurochirurgie, CHU de Bicêtre, AP-HP, 78, rue du Général-Leclerc, 94275 Le Kremlin-Bicêtre Cedex, France.
Neurochirurgie. 2004 Jun;50(2-3 Pt 1):83-95.
The aim of this study was to assess the safety and efficacy of intravenous (IV) injections of gacyclidine, a novel NMDA receptor antagonist, for neurological and functional recovery following acute traumatic brain injury. This multicenter, prospective, randomized, placebo-controlled, double-blind study compared four parallel groups. Two IV doses were administrated (placebo, 2x0.005mg/kg, 2x0.001mg/kg, 2x0.02mg/kg): the first dose was given within 2 hours following the trauma, and the second dose 4 hours after the first. Fifty-one patients were enrolled and 48 studied between March 1995 and June 1997 in France. Evaluation criteria for safety were physical examination, cardiovascular parameters, blood chemistry, hematology, ECG, and neuropsychological changes monitored after medication. Primary evaluation criteria for efficacy was the Glasgow coma scale complemented by the initial CT-scan and Glasgow outcome scale, motor deficiencies, neuropsychological changes, and functional indenpendence at D90 and D365 or endpoint. Intracranial pressure (ICP) monitoring was not taken into account because all the clinical centers participating in this study did not use this technique in daily practice during the inclusion period. Twelve patients died during the follow-up period, none of these deaths being related to the drug. Serious adverse events (181) were reported by most of the patients with no significant differences between groups. Only 10 of these adverse events were considered to be drug-related. Safety-related laboratory tests did not show any relevant changes. Concerning efficacy, the predefined prognostic factors (initial CT-scan score, initial Glasgow Coma Scale and occurrence of low systolic blood pressure during the first 24 hours) largely determinated the patient's outcome. When the prognostic factors were taken into account together with the dose level in a logistic regression model, gacyclidine showed a beneficial long-term effect and a best dose-result in the 0.04mg/kg treated group. Data obtained in this clinical trial appeared sufficient to warrant a European multicenter study on gacyclidine using the same evaluation criteria and ICP monitoring.
本研究旨在评估新型N-甲基-D-天冬氨酸（NMDA）受体拮抗剂加环利定静脉注射对急性创伤性脑损伤后神经功能恢复的安全性和有效性。这项多中心、前瞻性、随机、安慰剂对照、双盲研究比较了四个平行组。给予两种静脉注射剂量（安慰剂、2×0.005mg/kg、2×0.001mg/kg、2×0.02mg/kg）：第一剂在创伤后2小时内给予，第二剂在第一剂后4小时给予。1995年3月至1997年6月期间，在法国招募了51名患者，其中48名进行了研究。安全性评估标准包括用药后监测的体格检查、心血管参数、血液化学、血液学、心电图和神经心理变化。疗效的主要评估标准是格拉斯哥昏迷量表，并辅以初始CT扫描和格拉斯哥预后量表、运动缺陷、神经心理变化以及第90天和第365天或终点时的功能独立性。由于参与本研究的所有临床中心在纳入期的日常实践中均未使用颅内压（ICP）监测技术，因此未考虑ICP监测。随访期间有12名患者死亡，这些死亡均与药物无关。大多数患者报告了严重不良事件（181例），各组之间无显著差异。这些不良事件中只有10例被认为与药物有关。与安全性相关的实验室检查未显示任何相关变化。关于疗效，预定义的预后因素（初始CT扫描评分、初始格拉斯哥昏迷量表以及最初24小时内出现的低收缩压）在很大程度上决定了患者的预后。当在逻辑回归模型中将预后因素与剂量水平一起考虑时，加环利定在0.04mg/kg治疗组中显示出有益的长期效果和最佳的剂量效果。该临床试验获得的数据似乎足以保证在欧洲进行一项使用相同评估标准和ICP监测的加环利定多中心研究。
