ACEA 1021 IN PATIENTS WITH ACUTE STROKE

本研究是一项多中心、双盲、 集中随机、车辆控制、单剂、提高耐受性 设计以评价其安全性、耐受性和药代动力学 急性卒中患者血管紧张素转换酶A 1021的检测45名患者 符合标准的患者将在中风发病后48小时内接受治疗 症状，并将在三点分五个连续给药组进行研究 到五个地点。每组至少由9名患者组成， 其中六人将获得测试品ACEA 1021，三人将 接受车辆控制，0.05M氨丁三醇(Tris)。 将在几个时间点评估患者的安全性和 耐受性。每名患者都将受到密切观察，并将 连续监测输液期间和24小时的心率 在给药完成后几个小时，并将进行实验室检测 (CBC、化学和尿液分析)24小时、48小时、一周和 服药后1个月。在此期间，每名患者都将继续住院治疗。 静脉注射ACEA 1021后48小时。每个人 患者将被视为门诊患者(如果已出院) 在服药后1周和1个月评估其临床疗效 状态。在研究结束时，将在基线上绘制ACEA 1021水平 服药后第一个小时，每隔15分钟输注一次药物， 给药后2、4、8、12、24、48小时。病人将会是 随访30天。 这项研究代表了ACEA在人类中的首次应用。ACEA 1021是一个新的分子实体(5-硝基-6，7-二氯-2，3- 喹恶烷二酮)，作为N-甲基-D-天冬氨酸(NMDA) 甘氨酸部位的拮抗者。它在多个方面提供神经保护 体外和体内的脑缺血模型，以及 癫痫和疼痛的活体模型。它有一个批准的心血管系统和 CNS与其他NMDA拮抗剂和An的安全性比较 单次给药的可接受毒理学概况 人类。 在临床前动物研究中，风险归因于ACEA 1021 包括中枢神经系统影响、肝和肾毒性、轻度贫血和局部 输液部位的刺激感。ACEA 1021的风险包括PCP- 如副作用、呕吐或对血压和心率的影响。 尽管如此，这些参数将在输液期间和 在输液完成后48小时内。最小空泡化 急性给药30 mg/kg时未见神经元坏死 在老鼠身上，在基因毒性研究中相互矛盾的结果也必须是 在风险评估中考虑，但在此期间不能进行监控 学习。

This present study of ACEA 1021 is a multi-center, double-blind, centrally-randomized, vehicle-controlled, single dose, rising tolerance design to evaluate the safety, tolerability, and pharmacokinetics of ACEA 1021 in patients with acute stroke. Forty-five patients who fulfill criteria will be treated within 48 hours of onset of stroke symptoms and will be studied in five sequential dosing groups at three to five sites. Each Group will consist of a minimum of nine patients, of whom six will receive the test article, ACEA 1021, and three will receive the vehicle-control, 0.05 M Tromethamine (TRIS). Patients will be evaluated at several time points for safety and tolerability. Each patient will be closely observed and will have continuous monitoring of cardiac rythm during the infusion and for 24 hours after administration is complete, and will have laboratory tests (CBC, Chemistry, and urinalalysis) at 24 hours, 48 hours, one week, and one month post-dosing. Each patient will remain hospitalized during the infusion and for 48 hours after administration of ACEA 1021. Each patient will be seen as an outpatient (if discharged from hospital) at one week and one month post-dose in order to evaluate their clinical status. ACEA 1021 levels will be drawn at baseline, at the end of study drug infusion, at fifteen minute intervals for the first hour post-dose, and at 2, 4, 8, 12, 24, and 48 hours post-dose. Patients will be followed for 30 days. This study represents the first administration of ACEA in humans. ACEA 1021 is a new molecular entity (5-nitro-6, 7-dichloro-2, 3- quinoxalinedione) which acts as an N-methyl-D-asparate (NMDA) antagonist at the Glycine site. It provides neuroprotection in multiple models of cerebral ischemia, both in vitro and in vivo, as well as in vivo models of seizure and pain. It has an approved cardiovascular and CNS safety profile compared with other NMDA antagonists and an acceptable toxicology profile for administration of a single dose in humans. In the preclinical animal studies, risks attributed to ACEA 1021 included CNS effects, liver and renal toxicity, mild anemia, and local irritation at the infusion site. Risks of ACEA 1021 have included PCP- like side effects, vomiting or effects on blood pressure and heart rate. Nevertheless, these parameters will be monitored during the infusion and for 48 hours after infusion is completed. The minimal vacuolization without necrosis of neurons seen with acute administration of 30 mg/kg in rats, and conflicting results in genetotoxicity studies must also be considered in the risk assessment, but cannot be monitored during this study.