This research program is based on the thesis that oxygen free radicals are important mediators of the deleterious effects of reperfusion after a tissue or organ is deprived of oxygen (ischemia). The goal of this research program is to develop a drug capable of reducing ischemia reperfusion injury by capitalizing on the excellent free radical scavenging capabilities of a series of compounds originally developed as anticancer drugs. One member of this series is currently in clinical trial. The Phase l studies demonstrated that this family of compounds can decrease ischemia reperfusion injury in several isolated heart models and are remarkably effective at scavenging .O2-, .OH and organic radicals. The Phase II effort is directed towards determining if the most efficacious compounds from Phase l can ameliorate ischemia reperfusion injury in vivo. The initial experiment projected for Phase II is to determine drug efficacy at preventing polymorphonuclear leukocytes (PMN) mediated reperfusion injury in an isolated rat heart model. In preparation for whole animal experiments, the toxicological and pharmacokinetic characteristics of the potential drug will be investigated. Lastly, the efficacy of the best compound(s) to reduce ischemia reperfusion injury will be assessed by measuring the drugs' ability to decrease infarct size and preserve endothelial function and vascular reactivity in in vivo rat and canine models of regional ischemia and reflow.
