PARP inhibitory therapy of acute ischemic stroke

PARP抑制治疗急性缺血性脑卒中

• 批准号: 6785744
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 43.42万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6785744
• 关键词: cerebral ischemia /hypoxia; clinical research; clinical trial phase I; dosage; drug screening /evaluation; enzyme inhibitors; human middle age (35-64); human old age (65+); human subject; human therapy evaluation; neuroprotectants; patient oriented research; pentosyltransferase; pharmacokinetics; stroke therapy

DESCRIPTION (provided by applicant): Stroke activates the nuclear enzyme poly (ADP-ribose) polymerase ("PARP"), triggering cells to undergo necrosis and inflammation. Inotek's ultrapotent clinical PARP inhibitor ("INO-1001') profoundly reduces tissue necrosis and neurologic dysfunction in transient and permanent ischemic rat stroke models. Our data are in agreement with genetic deletion studies in stroked mice, which demonstrate > 80% neuroprotection in MCA occlusion models. We now propose a clinical study of INO-1001 to confirm tolerability, pharmacokinetics, and safety in a population with acute stroke. Based on clinical studies of INO-1001 in healthy subjects, we expect that INO-1001 will be Well-tolerated and safe, and maintain therapeutic drug plasma concentrations for 24 hours after a single bolus. We will test this hypothesis by carrying out a prospective, open-label multi-center study of n=30 subjects presenting with a clinical diagnosis and CT confirmation of acute non-lacunar ischemic stroke. A dose-escalation is planned, structured in cohorts of n=10 subjects per dose level. Subjects will be continuously monitored and observed for alterations in vital signs, physical exam, electrocardiogram, metabolic status, and clinical chemistries, hematologic and coagulation parameters, and plasma drug concentration. Whilst clinical outcome will be recorded, this is not intended to be a therapeutic trial, and wall include stable patients, who are able to consent themselves and report symptoms, with more detailed pharmacokinetic and tolerability monitoring than would be typical in a large multi-center investigation of efficacy. In a follow-on Phase 2 SBIR, we will carry out a pivotal study of INO-1001 in 900 patients to establish efficacy in a population with acute non-lacunar ischemic stroke. We will assess the effect of INO-1001 on 1) brain infarction, as quantitated by MRI, and 2) neurologic dysfunction, as assessed at baseline, 4 days, I week, 2 weeks, and I month by (a) NIHSS modified Rankin and Barthel score.

描述（由申请人提供）：中风激活核酶聚（ADP-核糖）聚合酶（“ PARP”），触发细胞发生坏死和炎症。 Inotek的超能力临床PARP抑制剂（“ INO-1001”）深刻地降低了瞬态和永久性缺血性大鼠卒中模型中的组织坏死和神经系统功能障碍。我们的数据与中风小鼠中的遗传缺失研究一致，这在MCA固定小鼠中> 80％的新神经前测>模型。 根据健康受试者INO-1001的临床研究，我们预计INO-1001将是 耐受耐受性和安全，并在A后24小时保持治疗性药物血浆浓度 单一注。我们将通过进行一项前瞻性开放标签多中心研究来检验这一假设 n = 30受试者的临床诊断和CT确认急性非乳牙的受试者 缺血性中风。计划剂量降低，以n = 10个受试者的同类构造。 对受试者将不断监测并观察到生命体征，身体检查， 心电图，代谢状态和临床化学，血液学和凝结 参数和血浆药物浓度。虽然将记录临床结果，但这不是 打算是一项治疗试验，墙壁包括能够同意自己的稳定患者 并报告症状，具有比更详细的药代动力学和耐受性监测 在大量的多中心疗效研究中要典型。在后续第2阶段SBIR中，我们将携带 在900例患者中，对INO-1001的关键研究以急性为疗效 非乳牙缺血性中风。我们将评估INO-1001对1）脑梗塞的影响 由MRI定量，2）神经功能障碍，如基线时评估，4天，I周，2周， （a）NIHSS修改后的Rankin和Barthel得分我的一个月。