Bases on promising in vitro and in vivo data, the applicants are developing novel classes of compounds with anti-shock effects, and with significant therapeutic potential. In this proposal, we present evidence that selected novel inhibitors of poly(DP-ribose) synthetase (PARS) are (1) cytoprotective agents and inhibitors of oxidant-induced cell necrosis in vitro, (2) inhibitors of the production of macrophage-derived pro-inflammatory mediators in vitro, (3) potent anti-shock systemic inflammation in rats and mice and, finally (4), a selected, potent member of this novel class of PARS inhibitors (e.g. PJ34) provides dramatic protection in a porcine model of severe homodynamic collapse and shock . These observations, coupled with data from the applicant's laboratories and several other research groups, demonstrating that PARS knockout mice are massively protected against various forms of shock, collectively support the applicant's proposal, which is that potent pharmacological inhibitors of PARS can be developed as a novel class of anti-shock agents. The applicant's intend to develop PJ34 as an anti-shock drug. The first specific aims of the present proposal is to perform additional studies in the rodent and porcine system with PJ34 to determine the window of intervention, the most appropriate dose of administration, and to determine the optimal strategy for discontinuation of the agent. An additional specific aim of the proposal is to synthesize large GMP-quantities of the PJ34 compound, and to formulate as an intravenous injectable. These studies will be performed in the second year, followed by formal preclinical toxicity studies, and Phase I a study in normal human volunteers. The current project will enable the applicants to move forward in two years, near to the level of the beginning of Phase II efficacy trial in septic patients.
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