PARP inhibition for thoraco-abdominal aneurysm surgery

PARP 抑制在胸腹动脉瘤手术中的应用

• 批准号: 6933563
• 负责人: ANDREW Lurie SALZMAN
• 金额: $ 19.1万
• 依托单位: INOTEK PHARMACEUTICALS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933563
• 关键词: aorta aneurysm; cardiovascular pharmacology; cardiovascular surgery; clinical research; drug screening /evaluation; enzyme activity; enzyme inhibitors; human subject; immune response; inflammation; ischemia; patient oriented research; pentosyltransferase; pharmacokinetics; postoperative complications; reperfusion

DESCRIPTION (provided by applicant): Ischemia-reperfusion (I/R) produces tissue injury and systemic inflammatory response syndrome (SIRS). The mechanism by which oxidants effect these changes has recently been ascribed to their impact on genomic integrity. Oxidants rapidly induce DNA single strand breaks that activate the nuclear enzyme poly (ADPribose) polymerase ("PARP"). PARP in turn catalyses an energy-consuming polymerization of ADP-ribose, resulting in NAD consumption, ATP depletion, necrosis, and organ failure. PARP activation also strongly upregulates expression of pro-inflammatory cytokines, chemokines, and endothelial cell adhesion molecules. Blockade of PARP, or its genetic deletion, is profoundly protective in cell and animal models of reperfusion injury and inflammation, but there are no data on the clinical role of PARP. We now propose to test the hypothesis that PARP inhibition can beneficially influence the outcome of I/R injury and SIRS in man. To address this hypothesis, we will utilize a unique drug candidate (a novel nanomolar potent PARP inhibitor termed INO-1001) and a highly controlled period of I/R afforded by elective repair of thoracoabdominal aneurysm (TAA). This surgical procedure produces profound tissue injury that may result in renal and pulmonary insufficiency, paraplegia, and mortality. In the present PHASE I COMPONENT OF OUR FASTTRACK proposal, we will establish the safety profile and pharmacokinetics (PK) of INO-1001 in a population undergoing TAAA repair. We will address this objective by carrying out a prospective, double-blind, randomized, single-center investigation in n= 17 subjects. Administration of INO-1001 will be initiated preoperatively, i.e. prior to the onset of organ injury, and continued for 4 days, the critical period of reperfusion and induction of a systemic inflammatory response, administered in a repeated bolus dosing regimen (100 and 400 mg INO-1001 q12h). The primary clinical endpoints will be safety and pharmacokinetics. Safety studies will focus on biochemical, hematologic, and cardiovascular endpoints. Pharmacokinetic studies will establish whether the half-life and tissue distribution of INO-1001 differ from parameters defined in a healthy population. The FDA has granted Fast-Track IND approval to this investigation.

描述（由申请人提供）： 缺血再灌注（I/R）会产生组织损伤和全身炎症反应综合征（SIRS）。氧化剂影响这些变化的机制最近被归因于它们对基因组完整性的影响。氧化剂迅速诱导DNA单链断裂，从而激活核酶聚(ADP核糖)聚合酶(“PARP”)。 PARP 反过来催化 ADP-核糖的能量聚合，导致 NAD 消耗、ATP 耗尽、坏死和器官衰竭。 PARP 激活还会强烈上调促炎细胞因子、趋化因子和内皮细胞粘附分子的表达。阻断 PARP 或其基因缺失，在再灌注损伤和炎症的细胞和动物模型中具有深远的保护作用，但尚无有关 PARP 临床作用的数据。我们现在提议检验以下假设：PARP 抑制可以有益地影响人类 I/R 损伤和 SIRS 的结果。为了解决这一假设，我们将利用一种独特的候选药物（一种新型纳摩尔级强效 PARP 抑制剂，称为 INO-1001）和通过选择性修复胸腹动脉瘤 (TAA) 提供的高度控制的 I/R 期。这种外科手术会造成严重的组织损伤，可能导致肾和肺功能不全、截瘫和死亡。在目前我们快速通道提案的第一阶段组成部分中，我们将在接受 TAAA 修复的人群中建立 INO-1001 的安全性和药代动力学 (PK)。我们将通过对 17 名受试者进行前瞻性、双盲、随机、单中心调查来实现这一目标。 INO-1001 的给药将在术前开始，即在器官损伤发生之前，并持续 4 天，这是再灌注和诱导全身炎症反应的关键期，以重复推注给药方案（100 和 400 mg INO-1001 q12h）。主要临床终点是安全性和药代动力学。安全性研究将重点关注生化、血液学和心血管终点。药代动力学研究将确定 INO-1001 的半衰期和组织分布是否与健康人群中定义的参数不同。 FDA 已向这项调查授予快速 IND 批准。