The investigators have compelling preliminary data which indicate that selective agonists of A2A adenosine receptors (A2A) produce inhibitory effects on the inflammatory cells, including neutrophills, monocytes, and others. In addition, the intravenous infusion of these compounds into animals produces a remarkably potent inhibition of while cell accumulation in animal models of meningitis, infectious arthritis, and peritonitis. The first goal of this proposal is to synthesize new A2A agonists that are optimized in terms of potency, selectivity, and stability. New compounds will be evaluated in radioligand binding assays for potency over other recombinant human adenosine receptor subtypes, human inflammatory cell assays, and in murine models of peritonitis. The investigators will also determine the time window required for A2A agonist administration to effectively inhibit inflammation. A second goal is to prove a beneficial effect of A2A agonists combined with antibiotics in limiting bacteria-induced inflammation and collateral damage without inhibiting host defense. This will be achieved by evaluating the effects of new compounds on inflammation, bacterial killing and host killing in mice infected with bacteria and either not treated or treaded with antibiotics.
In some instances of infection, particularly in acute infections treated with antibiotics, there is an acute inflammatory response produced by dead and dying cells that can lead to severe morbidity and mortality. Currently, there is no pharmaceutical product that can inhibit the collateral damage of infection without significantly compromising host defenses. The goal of this research is to develop a pharmaceutical product that will serve as adjunct therapy to standard antibiotics and will address this unmet medical need.
| Sullivan, Gail W; Fang, Guodong; Linden, Joel et al. (2004) A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis. J Infect Dis 189:1897-904 |
