A Controlled Trial of Tyrosine Kinase Inhibitors in a Canine Model of Septic Shoc

感染性休克似乎是由于过度的 细胞因子的释放（例如，肿瘤坏死因子-α（TNF-α），IL-2， 等等）。和其它促炎物质（例如，一氧化氮（NO） 从单核细胞/巨噬细胞谱系的细胞响应于 感染或脂多糖（LPS）给药。的 这些细胞因子的产生以及它们的作用是由 诱导蛋白酪氨酸信号转导事件 磷酸化理论上，抑制蛋白酪氨酸 磷酸化在脓毒症中可能是有益的。这些化合物 会阻止潜在的高细胞因子的产生， 依赖于酪氨酸磷酸化。这些蛋白激酶 抑制剂将阻断细胞激酶的激活或产生 通过细菌产物和细胞因子对靶细胞的作用。 Tyrphostins AG 126和AG 556都是蛋白激酶抑制剂 并已被证明可以改善小动物模型的结果 在LPS和活细菌挑战期间。此外，AG 126 和AG 556已经显示出抑制LPS诱导的TNF 从犬外周血单核细胞体外产生。 在人类临床应用之前，需要在大型动物模型中进行研究。 试验，以确定这些化合物的有效性和安全性。在 与Novogrodsky博士及其同事合作，我们 在我们的犬腹膜炎模型中评估AG 126和AG 556。中 在100只动物中进行了为期6个月的对照临床试验，AG 556， 而不是AG 126显著提高了生存率， 犬感染性休克时的多器官衰竭这种治疗 该药物正在进行人体临床试验。

Septic shock appears to result from excessive release of cytokines (e.g., tumor necrosis factor-a (TNF-a), IL-2, etc.) and other proinflammatory substances (e.g., nitric oxide (NO)) from cells of the monocyte/macrophage lineage in response to infection or lipopolysaccharide (LPS) administration. The production of these cytokines, as well as their action, is 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 is dependent 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 TNF production from dog peripheral blood mononuclear cells, in vitro. Studies in a large animal model are needed, before human clinical trials, to establish efficacy and safety of these compounds. 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.