Dose escalation study of the NMDA glycine-site antagonist licostinel in acute ischemic stroke
Dose escalation study of the NMDA glycine-site antagonist licostinel in acute ischemic stroke
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DOI：
10.1161/01.str.30.3.508
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发表时间：
1999-03-01
期刊：
影响因子：
8.3
通讯作者：
Whitehouse, MJ
中科院分区：
文献类型：
--
作者：
Albers, GW;Clark, WM;Whitehouse, MJ
背景和目的：Licostinel（ACEA 1021; 5-硝基-6，7-dichloro-2，3-quinocyclinedione）是N-甲基-D-天冬氨酸（NMDA）受体甘氨酸的竞争性拮抗剂，是脑缺血动物模型中有效的神经保护剂。本研究的目的是评估的安全性，耐受性，和药物动力学的licostinel在急性stroke. Methods的患者，在这5个中心的剂量递增试验，患者在48小时内登记的缺血性中风和治疗剂量递增的短期输注licostinel或安慰剂。不良反应进行了评估与临床和实验室测量，并与国立卫生研究院中风Scale.Results-Sixty-4例患者（44与递增剂量的利考替奈和20谁接受安慰剂治疗）的患者结果进行了测定。较低剂量的利考替奈（0.03 - 0.60 mg/kg）与任何显著不良反应无关。较高剂量的利考替奈（1.2 - 3.0 mg/kg）与各种轻度至中度不良反应相关，包括神经系统和胃肠道不适。未发生重大拟精神病效应或重大安全性问题。在较高的剂量水平，利可替奈的血浆峰浓度大大高于动物中风模型中神经保护所需的水平，美国国立卫生研究院中风量表评分随着时间的推移，在安慰剂组和利可替奈治疗的patients. Conclusions中观察到类似的改善，短期输注剂量高达3.0 mg/kg的利可替奈在急性中风患者中是安全和耐受的。Licostinel可能是一种比许多先前评价的NMDA拮抗剂更安全且耐受性更好的神经保护剂。
Background and Purpose-Licostinel (ACEA 1021; 5-nitro-6,7-dichloro-2,3-quinoxalinedione) a competitive antagonist of glycine at the N-methyl-D-aspartate (NMDA) receptor, is an effective neuroprotective agent in animal models of cerebral ischemia. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of licostinel in patients with acute stroke.Methods-In this 5-center dose escalation trial, patients were enrolled within 48 hours of an ischemic stroke and treated with ascending doses of a short infusion of licostinel or a placebo. Adverse effects were assessed with clinical and laboratory measurements, and patient outcome was determined with the National Institutes of Health Stroke Scale.Results-Sixty-four patients (44 treated with escalating doses of licostinel and 20 who received placebo) were treated. Lower doses of licostinel (0.03 to 0.60 mg/kg) were not associated with any significant adverse effects. Higher doses of licostinel (1.2 to 3.0 mg/kg) were associated with a variety of mild-to-moderate adverse effects including neurological and gastrointestinal complaints. No major psychotomimetic effects or significant safety concerns occurred. At the higher dose levels, peak plasma concentrations of licostinel were substantially higher than those required for neuroprotection in animal stroke models, A similar improvement in National Institutes of Health Stroke Scale scores over time was seen in both the placebo group and the licostinel-treated patients.Conclusions-A short infusion of licostinel in doses up to 3.0 mg/kg is safe and tolerable in acute stroke patients. Licostinel may be a safer and better tolerated neuroprotective agent than many of the previously evaluated NMDA antagonists.