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

酪氨酸激酶抑制剂在犬败血性休克模型中的对照试验

• 批准号: 6103574
• 负责人: CHARLES NATANSON
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6103574
• 关键词: cytokine; disease /disorder model; dogs; drug screening /evaluation; enzyme activity; enzyme inhibitors; lipopolysaccharides; macrophage; microorganism disease chemotherapy; monocyte; nonhuman therapy evaluation; phosphorylation; protein tyrosine kinase; septic shock; tissue /cell culture; tumor necrosis factor alpha

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.

感染性休克似乎是由于过量 细胞因子的释放（例如肿瘤坏死因子-a (TNF-a)、IL-2、 等）和其他促炎物质（例如一氧化氮 (NO)） 来自单核细胞/巨噬细胞谱系的细胞响应 感染或脂多糖（LPS）给药。这 这些细胞因子的产生及其作用是由 诱导蛋白质酪氨酸的信号转导事件 磷酸化。理论上，抑制蛋白质酪氨酸 磷酸化可能对脓毒症有益。这些化合物 会阻止潜在的高细胞因子产生，即 依赖于酪氨酸磷酸化。这些蛋白激酶 抑制剂会阻止细胞激酶的激活或产生 细菌产物和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 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 已被证明可以抑制 LPS 诱导的 TNF 在体外由狗外周血单核细胞产生。 在人类临床之前需要对大型动物模型进行研究 试验，以确定这些化合物的功效和安全性。在 与Novogrodsky博士和他的同事合作，我们 在我们的犬腹膜炎模型中评估了 AG 126 和 AG 556。在一个 在 6 个月内对 100 只动物进行对照临床试验，AG 556 但 不是 AG 126 显着提高了生存率并预防了 犬感染性休克期间的多器官衰竭。这种治疗 该药物正在进行人体临床试验。