Diener Hans-Christoph, AlKhedr Abdullatif, Busse Otto, Hacke Werner, Zingmark Per-Henrik, Jonsson Niclas, Basun Hans
Department of Neurology, University Essen, Hufelandstr. 55, 45122 Essen, Germany.
J Neurol. 2002 May;249(5):561-8. doi: 10.1007/s004150200065.
A low-affinity, use-dependent N-Methyl-D-Aspartate (NMDA) antagonist AR-R15896AR has neuroprotective properties in animal models of ischaemic stroke. The aim of the present study was to examine the safety and tolerability of a new and higher dosage regimen that would enable acute stroke patients to achieve and maintain neuroprotective plasma concentrations.
A randomised, multi-centre, double-blind, placebo-controlled, parallel group study was carried out at 19 centres in France, Germany and the Netherlands in patients with a clinical diagnosis of acute ischaemic stroke, and onset of symptoms within 12 hours before start of study drug administration. Two loading doses of 3.5 mg/kg of AR-R15896AR over 60 minutes, followed by a 2.5 mg/kg infusion over the next 120 minutes were given. Eight hours after the start of the loading dose infusion, the first maintenance dose (120 mg) was administered over 60 minutes. Eight further maintenance infusions were administered at intervals of 8 hours over a total treatment period of 3 days. Main variables were safety, tolerability and pharmacokinetics. Follow-up assessments also included the Barthel Index (BI) and the NIH Stroke Scale (NIHSS) at 4-7 days after the end of the last infusion and at 30 days after the onset of stroke.
103 patients with acute ischaemic stroke were randomised to either treatment with AR-R15896AR (70 patients) or placebo (33 patients). Mortality was not significantly different in the AR-R15896AR group compared with the placebo group (10 % vs. 6 %). Serious adverse events during treatment due to psychiatric conditions were associated with AR-R15896AR (3 vs. 0). Other side effects were more common in the group treated with AR-R15896AR: vomiting (29 % vs. 9 %), nausea (23 % vs. 12 %), fever (17 % vs. 12 %), agitation (7 % vs. 3 %), dizziness (7 % vs. 0 %), and hallucinations (6 % vs. 0 %). No significant difference between the two groups (with respect to the proportions of patients with favourable outcome) was detected in either the analysis of the BI or the NIHSS. Pharmacokinetic data showed that plasma concentrations of AR-R15896AR were in the expected neuroprotective range.
In most of the patients with acute stroke receiving AR-R15896AR the intended high plasma levels were reached within a short time period. However, active treatment produced more side effects than placebo, thus indicating safety concerns and tolerability issues for use in high doses in an acute stroke population.
低亲和力、使用依赖性N-甲基-D-天冬氨酸（NMDA）拮抗剂AR-R15896AR在缺血性中风动物模型中具有神经保护特性。本研究的目的是检验一种新的更高剂量方案的安全性和耐受性，该方案能使急性中风患者达到并维持神经保护血浆浓度。
在法国、德国和荷兰的19个中心开展了一项随机、多中心、双盲、安慰剂对照、平行组研究，纳入临床诊断为急性缺血性中风且在研究药物给药开始前12小时内出现症状的患者。给予两次负荷剂量的AR-R15896AR，3.5mg/kg，60分钟内输注完毕，随后在接下来的120分钟内给予2.5mg/kg的输注。在负荷剂量输注开始8小时后，给予首次维持剂量（120mg），60分钟内输注完毕。在总共3天的治疗期间，每隔8小时再给予8次维持输注。主要变量为安全性、耐受性和药代动力学。随访评估还包括末次输注结束后4 - 7天以及中风发作后30天的Barthel指数（BI）和美国国立卫生研究院卒中量表（NIHSS）。
103例急性缺血性中风患者被随机分为AR-R15896AR治疗组（70例）或安慰剂组（33例）。AR-R15896AR组的死亡率与安慰剂组相比无显著差异（10%对6%）。治疗期间因精神疾病导致的严重不良事件与AR-R15896AR相关（3例对0例）。其他副作用在AR-R15896AR治疗组更常见：呕吐（29%对9%）、恶心（23%对12%）、发热（17%对12%）、激越（7%对3%）、头晕（7%对0%）和幻觉（6%对0%）。在BI或NIHSS分析中，两组之间（在预后良好患者比例方面）未检测到显著差异。药代动力学数据显示AR-R15896AR的血浆浓度处于预期的神经保护范围内。
大多数接受AR-R15896AR治疗的急性中风患者在短时间内达到了预期的高血浆水平。然而，与安慰剂相比，积极治疗产生了更多副作用，这表明在急性中风人群中高剂量使用存在安全性问题和耐受性问题。
