Novel xanthine oxidase inhibitor for hemorrhagic shock

DESCRIPTION (provided by applicant): Death from penetrating and blunt trauma remains an urgent national civilian and military problem. This proposal is intended to establish a new pharmacologic approach to save the lives of severely injured trauma victims with hemorrhagic shock. Inhibition of the purine degradative enzyme xanthine oxidase (XO) shows clear benefit in experimental in vivo models of hemorrhagic shock. XO inhibitors increase tissue high-energy phosphate concentrations, block superoxide anion formation, attenuate free radical induced pro-inflammatory cytokine expression, decrease bacterial translocation across the gut mucosa, and increase survival. Currently available XO inhibitors, however, are relatively weak and do not completely block enzymatic activity in vivo. To address this market opportunity, we have invented a novel ultrapotent XO inhibitor (entitled "AHPP-IV") that is three logs more potent than allopurinol and oxypurinol. We expect that the AHPP-IV will totally suppress XO in vivo activity and thereby provide profound benefits in the acute resuscitation of hemorrhagic shock. Accordingly, the Specific Aim of this proposal is: Characterize the pharmacodynamic profile of AHPP-IV in a rodent model of hemorrhagic shock. We will define the cardiovascular (heart rate, blood pressure), metabolic (serum lactate and glucose concentration), and survival dose-responses in a rat model of severe fixed-pressure hemorrhagic shock. These alterations will be correlated with serum drug concentrations, in order to establish a pharmacodynamic profile. The benefit of AHPP-IV will be compared with oxypurinol, the sole parenteral XO inhibitor currently approved for human use. The results of the present application will justify Phase II SBIR funding to support pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, and stability), a large animal trial, formulation and GMP-grade pilot production, an investigational drug application to the FDA, and a Phase I clinical trial. PROPOSED COMMERCIAL APPLICATION: The annual domestic impact of hemorrhagic shock on the health care market is estimated at > $200 million. the worldwide market in hemorrhagic shock (developed countries only) is four times larger. Given the absence of a specific and completely effective therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high-sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $800 million (annual).