CONTROLLED TRIAL OF TYROSINE KINASE INHIBITORS IN CANINE MODEL OF SEPTIC SHOCK

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Septic shock appears to result from excessive release of cytokines (e.g., tumor necrosis factor-alpha [TNF-alpha]), interleukin-2F and other proinflammatory substances (e.g., nitric oxide [NO.]) from cells of the monocyte/macrophage lineage in response to infection or lipopolysaccharide (LPS) administration. Both the production and action of these cytokines are mediated by signal transduction events that induce protein tyrosine phosphorylation. Theoretically, inhibition of protein tyrosine phosphorylation may be beneficial in sepsis. These compounds would block the potentially high cytokine production, which depends on tyrosine phosphorylation. These protein kinase inhibitors would block both activation or production of cytokinase by bacterial products and the effects of cytokines on target cells. Tyrphostins AG 126 and AG 556 are both protein kinase inhibitors and have been shown to improve outcome in small animal models during both LPS and live bacterial challenge. Further, both AG 126 and AG 556 have been shown to inhibit LPS-induced tumor necrosis factor production from dog peripheral blood mononuclear cells in vitro. To establish the efficacy and safety of these compounds before human clinical trials, studies in a large animal model are needed. In collaboration with Dr. Novogrodsky and his colleagues, we evaluated AG 126 and AG 556 in our canine peritonitis model. In a controlled clinical trial in 100 animals over 6 months, AG 556, but not AG 126, significantly improved survival and prevented multiorgan failure during canine septic shock. This therapeutic agent is proceeding to human clinical trials.