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.
