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. 1997 Apr 15;99(8):1966–1973. doi: 10.1172/JCI119364

Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.

J E Sevransky 1, G Shaked 1, A Novogrodsky 1, A Levitzki 1, A Gazit 1, A Hoffman 1, R J Elin 1, Z M Quezado 1, B D Freeman 1, P Q Eichacker 1, R L Danner 1, S M Banks 1, J Bacher 1, M L Thomas 3rd 1, C Natanson 1
PMCID: PMC508021  PMID: 9109441

Abstract

Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls (P = 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P < or = 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin.

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Selected References

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