This Phase II SBIR proposal is intended to further develop a new therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock (HS). In a small proportion of trauma, a fatal outcome is assured due to the irreversible loss of vital functions or massive blood loss. Frequently, however, emergent resuscitation is possible. These victims survive to hospitalization and are able to receive the full benefits of modern intensive care and surgery. In spite of fluid resuscitation and surgery to repair vascular and parenchymal injuries, however, not all treated patients survive HS. The principal impediment to a successful outcome in this population is the development of cardiovascular failure, a condition in which HS results in profound hypotension refractory to fluid replacement and inotropic support. There is substantial evidence that HS - induced tissue injury is mediated by profound alterations in the biosynthesis of the free radicals nitric oxide and superoxide anion, and their reaction product peroxynitrite, a toxic oxidant. We are developing novel metalloporphyrin-based molecules that act as peroxynitrite decomposition catalysts. An early development compound, FP15, was protective in experimental models of ischemia-reperfusion injury. Based on these data, the central objective of the Phase I grant proposal was to establish that pharmacological peroxynitrite decomposition can improve hemodynamics, metabolic function, end-organ injury, and survival in a rodent model of hemorrhagic shock. We have addressed this objective by characterizing the pharmacodynamic profile of the catalysts in a rat model of severe fixed-pressure HS. The results of the Phase I application demonstrated the efficacy of WW-85, a next generation potent porphyrinic catalytic antioxidant, and thereby established the technical merit and feasibility of the current project. In the current Phase II grant application, we plan to conduct additional efficacy studies testing WW-85 in clinically relevant rodent and large animal models of uncontrolled hemorrhagic shock. Additional aims of the study include formulation and stability work, as well as pharmacokinetic and metabolic characterization of the compound, and toxicological evaluation, in order to advance the technology to the stage of human clinical testing.
