ACEA 1021 IN PATIENTS WITH ACUTE STROKE

本ACEA 1021研究是一项多中心、双盲、 中心随机化、溶剂对照、单次给药、耐受性升高 旨在评价ACEA的安全性、耐受性和药代动力学 1021例急性卒中患者。 45名患者符合 标准将在中风症状发作后48小时内治疗， 将在三至五个研究中心的五个连续给药组中进行研究。 每组将由至少9名患者组成，其中6名将 接受供试品ACEA 1021，三人将接受 溶剂对照，0.05 M氨丁三醇（Tris）。 将在几个时间点评价患者的安全性， 耐受性 每一个病人都将被密切观察， 在输注期间连续监测心律， 小时后，管理完成，并将有实验室检查 (CBC 24小时、48小时、一周和一周后的尿分析） 给药后1个月。 每名患者将继续住院期间， 输注和ACEA 1021给药后48小时。 每个 患者将被视为门诊患者（如果出院）， 给药后1周和1个月，以评价其临床 status. 将在基线、研究结束时采集ACEA 1021水平 药物输注，给药后第一个小时间隔15分钟， 以及给药后2、4、8、12、24和48小时。 患者将 随访30天。 本研究是ACEA 1021首次用于人体。 ACEA 1021是一种新的分子实体（5-硝基-6，7-二氯-2， 3-喹喔啉二酮），其作为N-甲基-D-喹喔啉酸酯（NMDA） 在甘氨酸位点的拮抗剂。 它提供了多种神经保护， 脑缺血模型，在体外和体内，以及在 癫痫发作和疼痛的体内模型。 它具有批准的心血管和 与其他NMDA拮抗剂相比的CNS安全性特征和可接受的 在人体中单次给药的毒理学特征。 在临床前动物研究中，ACEA 1021的风险包括 CNS影响、肝脏和肾脏毒性、轻度贫血和局部刺激 在输液部位。 ACEA 1021的风险包括PCP样侧 呕吐或对血压和心率的影响。 然而，将在输注期间监测这些参数， 输注完成后48小时。 最小空泡化 30 mg/kg急性给药未观察到神经元坏死 遗传毒性研究中相互矛盾的结果也必须 在风险评估中考虑，但在此期间无法监测 study.

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 rhythm during the infusion and for 24 hours after administration is complete, and will have laboratory tests (CBC, Chemistry, and urinalysis) 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 1021 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.