ANIMAL TRIAL OF SEPTIC SHOCK WITH A NOVEL PARS INHIBITOR

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Nitric oxide (NO) and peroxynitrite are reactive, short-lived species that are important mediators of cellular injury in shock and ischemia-reperfusion. In particular, peroxynitrite, a short-lived potent oxidant, produced from superoxide and NO, can initiate a range of cytotoxic processes. Agents which scavenge NO or peroxynitrite, or agents that prevent NO-or peroxynitrite induced vascular and cytotoxic processes can be useful tools in treating shock, when applied alone, or in combination with other agents. Inotek Corporation is developing a unique tool, 5-amino-6-iodo-1,2-benzopyrone (INH2BP), a potent, cell-permeable inhibitor of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Studies in cell culture and in rodent models of shock demonstrate that endotoxin induces peroxynitrite generation, DNA injury, and subsequent PARS activation. These processes can lead to acute cellular dysfunction and cell death. Accordingly, in rodent models of endotoxic shock, pharmacological inhibition of PARS improves survival and vascular function. The specific aim of the present proposal is to synthesize large quantities of INH2BP, and perform studies in a large animal model of septic shock in order to obtain definitive proof of principle that this agent can reduce the tissue injury and improve hemodynamics and survival in septic shock. The applicants' intention is to test the INH2BP for its potential against shock. The results of the present application will provide ultimate proof of principle and permit application for Phase 2 SBIR funding to support: pre-clinical pharmaceutical testing (advanced toxicity determinations, pathology, stability, pharmacokinetics, in vivo efficacy), investigational drug application to the FDA and Phase 1 clinical trial. PROPOSED COMMERCIAL APPLICATION: Worldwide the market for an effective, safe anti-shock pharmaceutical is estimated to be $20 billion per year, based upon 2 million patients @ $10,000 per treatment course. The demand for effective treatment of shock is expected to increase steadily over the next 15 years. Funding of SBIR Phase I and II will allow for market entry in 3.5 years.