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

感染性休克似乎是细胞因子过度释放所致 (例如，肿瘤坏死因子-α[TNF-α])、白介素2F和 其他促炎物质(例如，一氧化氮[编号])从… 单核/巨噬细胞系的细胞对感染或 脂多糖(LPS)注射。无论是制作还是 这些细胞因子的作用是由信号转导事件介导的 诱导蛋白质酪氨酸磷酸化。从理论上讲， 抑制蛋白质酪氨酸磷酸化可能有益于 败血症。这些化合物会阻止潜在的高细胞因子 生产，这依赖于酪氨酸磷酸化。这些蛋白质 激酶抑制剂会同时阻止激活或产生 细菌产物产生的细胞激活酶及其对细胞因子的影响 目标单元格。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的结局 模型在细菌内毒素和活体细菌激发过程中。此外，两者都 AG 126和AG 556已被证明能抑制脂多糖诱导的肿瘤 犬外周血单核细胞产生坏死因子的研究 体外培养的细胞。 在人类面前确定这些化合物的有效性和安全性 临床试验，在大型动物模型中的研究是必要的。在……里面 与Novogrodsky博士和他的同事合作，我们评估了 AG 126和AG 556在我们的犬腹膜炎模型中。在受控的 在100只动物中进行了6个月的临床试验，AG 556，但不是AG 126， 显著提高存活率并预防多器官衰竭 在犬感染性休克期间。这种治疗剂正在进行 人体临床试验。

Septic shock appears to result from excessive release of cytokines (e.g., tumor necrosis factor-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.