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

酪氨酸激酶抑制剂在犬感染性休克模型中的对照试验

• 批准号: 2456661
• 负责人: C 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/2456661
• 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-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.

脓毒性休克似乎是由于细胞因子的过度释放 (e.g.,肿瘤坏死因子-α [TNF-α]），白细胞介素-2F和 其它促炎物质（例如，一氧化氮[NO.]）从 单核细胞/巨噬细胞谱系细胞对感染的反应，或 脂多糖（LPS）给药。生产部门和 这些细胞因子的作用由信号转导事件介导 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 败血症这些化合物将阻断潜在的高细胞因子 生产，这取决于酪氨酸磷酸化。这些蛋白质 激酶抑制剂将阻断激活或产生 细胞激酶的细菌产物和细胞因子的影响， 靶细胞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果 在LPS和活细菌挑战期间的模型。此外，两者 AG 126和AG 556已显示出抑制LPS诱导的肿瘤 犬外周血单核细胞产生坏死因子 体外细胞 为了在人体前确定这些化合物的有效性和安全性， 临床试验，需要在大型动物模型中进行研究。在 与Novogrodsky博士及其同事合作，我们评估了 AG 126和AG 556在我们的犬腹膜炎模型中的作用。以受控 在100只动物中进行了6个月的临床试验，AG 556，但非AG 126， 显著提高生存率，预防多器官衰竭 感染性休克的时候这种治疗剂正在进行 人体临床试验。