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

感染性休克似乎是由于细胞因子[如肿瘤坏死因子-a、白介素2等]过度释放所致。和其他促炎物质[例如，一氧化氮(NO)]从单核/巨噬细胞系的细胞中释放出来，以应对感染或内毒素(LPS)注射。这些细胞因子的产生以及它们的作用是通过诱导蛋白质酪氨酸磷酸化的信号转导事件来调节的。理论上，抑制蛋白酪氨酸磷酸化可能有益于脓毒症。这些化合物将阻断依赖于酪氨酸磷酸化的潜在高细胞因子的产生。这些蛋白激酶抑制剂将阻断细菌产物对细胞激活酶的激活或产生，以及细胞因子对靶细胞的影响。TyrPhostins AG 126和AG 556都是蛋白激酶抑制剂，在小动物模型中已被证明在内毒素和活菌攻击中都能改善结果。此外，AG 126和AG 556都已被证明在体外抑制内毒素诱导的狗外周血单个核细胞产生肿瘤坏死因子。在我们开始人体临床试验以确定这些化合物的有效性和安全性之前，需要在大型动物模型中进行研究。在Novogrodsky博士和他的同事的合作下，我们在我们的犬腹膜炎模型中评估了AG 126和AG 556。在一项对100只动物进行的超过6个月的对照临床试验中，AG 556而不是AG 126显著提高了犬的存活率，并防止了犬感染性休克时的多器官衰竭。这种治疗剂(AG556)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 pro-inflammatory 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 which 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 large animal model are needed before we can begin 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 (AG556) is proceeding to human clinical trials.