Asano T, Takakura K, Sano K, Kikuchi H, Nagai H, Saito I, Tamura A, Ochiai C, Sasaki T
Department of Neurosurgery, Saitama Medical Center/School, Japan
J Neurosurg. 1996 May;84(5):792-803. doi: 10.3171/jns.1996.84.5.0792.
A water-soluble, novel synthetic compound, AVS ((+/-)-N, N'-propylenedinicotinamide; nicaraven) has no demonstrable vasoactive properties but scavenges hydroxyl radicals in aqueous environmental conditions at neutral pH. Based on the results of preceding experimental and clinical studies showing marked ameliorative effects of AVS on cerebral vasospasm and ischemic brain damage, a multicenter, placebo-controlled double-blind clinical trial was undertaken to verify its beneficial effects on delayed ischemic neurological deficits (DINDs) due to vasospasm and on the overall outcome of patients with subarachnoid hemorrhage (SAH). A total of 162 patients with SAH who had Glasgow Coma Scale scores between 7 and 15 on admission were enrolled in the trial. Drug administration (4 g AVS or 4 g glucose as placebo; infused intravenously for 6-8 hours once a day) was begun within 5 days post-SAH and continued for 10 to 14 days. Intent-to-treat analysis of these patients revealed that the overall incidence of DINDs, which was defined as an exacerbation of impaired consciousness and/or focal neurological deficits, was significantly reduced, by 34.5% (placebo 54.2%, AVS 35.5%; p < 0.05, Mann-Whitney U-test). The Glasgow Outcome Scale (GOS) score at 1 month was significantly improved by AVS (p < 0.05, U-test). At 3 months, the difference in the GOS scores between the groups became marginal on U-tests (p < 0.10), but the percentage of good outcome tended to increase, with a relative increase of 20.3% (AVS 76.3%, placebo 63.4%; p < 0.10, chi-square test), and the cumulative incidence of death was significantly reduced (p < 0.05, log-rank test). No significant adverse reaction attributable to treatment was observed. the usefulness of AVS in therapy for SAH is strongly indicated by the fact that the agent significantly ameliorated DINDs, leading to a marked improvement in the GOS scores at 1 month, as well as a reduction in the cumulative incidence of death by 3 months.
一种水溶性新型合成化合物AVS（（±）-N，N'-亚丙基二烟酰胺；尼卡文）没有明显的血管活性特性，但在中性pH值的水环境条件下能清除羟自由基。基于先前的实验和临床研究结果显示AVS对脑血管痉挛和缺血性脑损伤有显著改善作用，开展了一项多中心、安慰剂对照双盲临床试验，以验证其对血管痉挛所致延迟性缺血性神经功能缺损（DINDs）以及蛛网膜下腔出血（SAH）患者总体预后的有益影响。共有162例入院时格拉斯哥昏迷量表评分在7至15分之间的SAH患者纳入该试验。在SAH后5天内开始给药（4g AVS或4g葡萄糖作为安慰剂；每天静脉输注6 - 8小时），并持续10至14天。对这些患者的意向性分析显示，DINDs的总体发生率（定义为意识障碍和/或局灶性神经功能缺损加重）显著降低，降低了34.5%（安慰剂组54.2%，AVS组35.5%；p<0.05，曼-惠特尼U检验）。AVS使1个月时的格拉斯哥预后量表（GOS）评分显著改善（p<0.05，U检验）。在3个月时，两组间GOS评分的差异在U检验中变得不显著（p<0.10），但良好预后的百分比有增加趋势，相对增加了20.3%（AVS组76.3%，安慰剂组63.4%；p<0.10，卡方检验），且累积死亡率显著降低（p<0.05，对数秩检验）。未观察到与治疗相关的显著不良反应。AVS在SAH治疗中的有效性得到有力证明，该药物显著改善了DINDs，使1个月时的GOS评分显著提高，同时使3个月时的累积死亡率降低。
