Stroke. 2000 Feb;31(2):358-65. doi: 10.1161/01.str.31.2.358.
GV150526, a selective glycine site antagonist, reduces infarct volume in rats with focal cerebral ischemia. Safety and efficacy in humans with acute stroke are being investigated. We sought to further explore the safety, pharmacokinetics, and preliminary outcome of GV150526 treatment in patients with a clinical diagnosis of acute stroke.
Two trials were conducted in North America. The North American Glycine Antagonist in Neuroprotection trial (GAIN 1) (GLYA2001; United States only) was designed as a sequential dose escalation study. GAIN 2 (GLYA2005; United States and Canada) was designed to further assess the safety of the highest dose tolerated in GAIN 1. Both trials were randomized (2:1), double-blind, and placebo controlled. Treatment was started within 12 hours of symptom onset; patients with both ischemic stroke and primary intracerebral hemorrhage were included in both trials.
The dose escalation study (GAIN 1) completed 3 dosing tiers. Enrollment was suspended before escalation to the fourth tier because of laboratory reports of transiently elevated bilirubin levels in a concurrent European study that employed the dose targeted for this tier. After review by an independent safety committee of the worldwide safety data, the second study (GAIN 2) commenced. One hundred nine patients were randomized and dosed with study drug, either an 800-mg loading dose followed by 200 mg every 12 hours for 3 days of GV150526 or placebo. The incidence of serious adverse events was similar in the drug and placebo groups. Mild irritation at the infusion site and symptoms suggestive of mild and reversible altered mentation were reported more frequently in the GV150526 group than in the placebo group. Hyperbilirubinemia was reported in 6% of GV150526-treated patients compared with 3% of placebo-treated patients. Outcome at 4 weeks after stroke was better in GV150526-treated patients, but the studies were not powered to show statistical significance, and the baseline neurological deficits in the GV150526-treated patients were less severe.
These preliminary studies suggest that GV150526 is well tolerated by patients with suspected acute stroke. Further pivotal studies testing the efficacy and safety of GV150526 in acute stroke are ongoing.
GV150526是一种选择性甘氨酸位点拮抗剂，可减少局灶性脑缺血大鼠的梗死体积。目前正在研究其对急性中风患者的安全性和有效性。我们试图进一步探讨GV150526治疗临床诊断为急性中风患者的安全性、药代动力学及初步疗效。
在北美进行了两项试验。北美神经保护甘氨酸拮抗剂试验（GAIN 1）（GLYA2001；仅在美国）设计为序贯剂量递增研究。GAIN 2（GLYA2005；在美国和加拿大）旨在进一步评估GAIN 1中耐受的最高剂量的安全性。两项试验均为随机（2:1）、双盲且安慰剂对照。在症状发作后12小时内开始治疗；缺血性中风和原发性脑出血患者均纳入两项试验。
剂量递增研究（GAIN 1）完成了3个给药阶段。由于在一项同时进行的欧洲研究中，有实验室报告称使用该阶段目标剂量的患者胆红素水平短暂升高，因此在升级到第四阶段之前暂停了入组。在全球安全数据由独立安全委员会审查后，第二项研究（GAIN 2）开始。109名患者被随机分组并给予研究药物，即800mg负荷剂量，随后每12小时给予200mg，共3天的GV150526或安慰剂。药物组和安慰剂组严重不良事件的发生率相似。GV150526组输注部位轻度刺激及提示轻度和可逆性精神状态改变的症状报告比安慰剂组更频繁。接受GV150526治疗的患者中有6%报告有高胆红素血症，而接受安慰剂治疗的患者中这一比例为3%。GV150526治疗的患者中风后4周的预后较好，但这些研究的样本量不足以显示统计学意义，且GV150526治疗的患者基线神经功能缺损较轻。
这些初步研究表明，疑似急性中风患者对GV150526耐受性良好。正在进行进一步的关键研究，以测试GV150526在急性中风中的疗效和安全性。
