Sacco R L, DeRosa J T, Haley E C, Levin B, Ordronneau P, Phillips S J, Rundek T, Snipes R G, Thompson J L
The Neurological Institute, Columbia University, 710 W 168th St, Room 547, New York, NY 10032, USA.
JAMA. 2001 Apr 4;285(13):1719-28. doi: 10.1001/jama.285.13.1719.
Elucidation of the ischemic cascade has helped stimulate development of neuroprotective drugs aimed at limiting brain injury in the hours following an ischemic stroke. To date, none of these drugs has shown clinical efficacy.
To examine the efficacy of gavestinel (GV150526), an antagonist of the glycine site of the N-methyl-D-aspartate receptor, as a neuroprotective therapy for acute ischemic stroke when administered within 6 hours of symptom onset.
The Glycine Antagonist in Neuroprotection (GAIN) Americas trial, a randomized, double-blind placebo-controlled trial with enrollment from April 1998 to October 1999.
One hundred thirty-two hospital centers across the United States and Canada.
The primary efficacy population consisted of 1367 ischemic stroke patients with a predefined level of limb weakness and functional independence prior to stroke, stratified at randomization by age (</=75 vs >75 years) and initial stroke severity (National Institutes of Health [NIH] Stroke Scale scores of 2-5, 6-13, or >/=14).
Patients were randomly assigned to receive an intravenous loading dose (800 mg) plus 5 maintenance doses (200 mg every 12 hours) of gavestinel (n = 701) or placebo (n = 666) for 3 days.
Functional capability at 3 months, measured by the Barthel Index (BI), with scores trichotomized as dead/0-55, 60-90, and 95-100, compared between the gavestinel and placebo groups.
Treatment groups were well matched for baseline characteristics. For each group, median NIH Stroke Scale was 12, median age was 72 years, and median time to treatment was 5.2 hours. No statistically significant improvement on the 3-month BI trichotomy was demonstrated for gavestinel (P =.79). The proportion who were functionally independent (BI score = 95-100) was 39% in the gavestinel group and 37% in the placebo group. No statistically significant difference in 3-month survival was observed using Kaplan-Meier curves (P =.11). No other secondary end point suggested an advantage for gavestinel. Among the 333 patients (24%) who received recombinant tissue-type plasminogen activator, there was also no benefit for gavestinel (P =.53). There were no serious safety issues.
In this study, gavestinel administered up to 6 hours after an acute ischemic stroke did not improve functional outcome at 3 months.
对缺血级联反应的阐释有助于推动旨在限制缺血性卒中后数小时内脑损伤的神经保护药物的研发。迄今为止，这些药物均未显示出临床疗效。
研究甘氨酸位点N-甲基-D-天冬氨酸受体拮抗剂加维斯地尔（GV150526）在症状发作6小时内给药时作为急性缺血性卒中神经保护疗法的疗效。
神经保护中的甘氨酸拮抗剂（GAIN）美洲试验，这是一项1998年4月至1999年10月进行的随机、双盲、安慰剂对照试验。
美国和加拿大的132家医院中心。
主要疗效人群包括1367例缺血性卒中患者，这些患者在卒中前具有预先定义的肢体无力水平和功能独立性，随机分组时按年龄（≤75岁与＞75岁）和初始卒中严重程度（美国国立卫生研究院卒中量表评分为2 - 5、6 - 13或≥14）分层。
患者被随机分配接受静脉负荷剂量（800毫克）加5次维持剂量（每12小时200毫克）的加维斯地尔（n = 701）或安慰剂（n = 666），持续3天。
3个月时的功能能力，采用巴氏指数（BI）测量，得分分为三组：死亡/0 - 55、60 - 90和95 - 100，比较加维斯地尔组和安慰剂组。
治疗组的基线特征匹配良好。每组的美国国立卫生研究院卒中量表中位数为12，年龄中位数为72岁，治疗中位时间为5.2小时。加维斯地尔在3个月BI三分法上未显示出统计学上的显著改善（P = 0.79）。功能独立（BI评分 = 95 - 100）的比例在加维斯地尔组为39%，在安慰剂组为37%。使用Kaplan - Meier曲线观察到3个月生存率无统计学显著差异（P = 0.11）。没有其他次要终点显示加维斯地尔有优势。在接受重组组织型纤溶酶原激活剂的333例患者（24%）中，加维斯地尔也没有益处（P = 0.53）。没有严重的安全问题。
在本研究中，急性缺血性卒中后6小时内给予加维斯地尔未改善3个月时的功能结局。
