application): Septic shock accounts for more than 200,000 deaths in the United States per annum. Current treatment regimens are supportive, as there are no pharmaceuticals which halt or reverse progression of septic shock. The applicant proposes to test the feasibility of the therapeutic MEG in a definitive large animal model of septic shock. In experimental rodent models of septic shock, when given as a post-treatment, MEG increases survival and prevents end- organ injury. MEG owes its efficacy in septic shock to its combined action as a (1) highly potent and selective inhibitor of the toxin- generating inducible nitric oxide synthase, (2) a potent scavenger of peroxynitrite, a powerful oxidant produced in septic shock, and (3) an inhibitor of cyclooxygenase, a prostaglandin-producing enzyme which is overexpressed in septic shock and contributes to the loss of vascular tone. The applicant proposes to establish proof-of-principle in a sheep model of P. aerugo induced septic shock, as assessed by survival, tissue injury and hemodynamics. Upon confirmation of MEG's efficacy in this stringent and clinically relevant model, the applicant intends to apply for Phase II SBIR funding to support formal toxicology studies and a Phase I FDA-regulated clinical trial.
There is no effective treatment for circulatory shock. For an effective anti-shock agent, world-wide annual gross revenues are estimated in the range of 1 billion dollars.
