Tyrphostin AG 556 Therapy Adjusted to Severity of Illness of New Therapies in Se

Tyrphostin AG 556 疗法根据 Se 中新疗法的疾病严重程度进行调整

• 批准号: 6431789
• 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/6431789
• 关键词: antiinflammatory agents; biological signal transduction; cytokine; dogs; dosage; enzyme inhibitors; lipopolysaccharides; peritonitis; phosphorylation; protein tyrosine kinase; septic shock; 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 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, and 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 that is dependent on tyrosine phosphorylation. These protein kinase inhibitors would block both activation and production of cytokines 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. 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. Recent analysis of animal experimental data suggests that the effect of anti-inflammatory agents is dependent in part on the underlying infectious burden of the animal. It appears that studies in which controls exhibited high mortality showed improved survival in response to anti-inflammatory therapy. Conversely, studies in which controls exhibited lower mortality suggested that anti-inflammatory agents had no benefit, and possibly some harm. Therefore, it is possible that the reason that human clinical trials in sepsis have shown no benefit is that the anti-inflammatory agents have been given to individuals with varying degrees of illness, and that a subgroup of patients with higher burden of illness might be helped by anti-inflammatory therapy. This study is designed to examine the effect of titrating AG 556 to the severity of illness in canines infected with high- and low-infectious burdens. In our canine model of peritonitis, cohorts of animals with either high or low burdens of E. coli peritonitis clots will be studied. We will compare the efficacy with standard dose 2.5 mg/kg AG 556 to placebo, to titrated dosing 1mg/kg and then 1 or 4 mg/kg depending upon the blood pressure of animals at the 6 h time point. This study is the first study in an animal model to examine whether the utility of anti-inflammatory therapy is dependent upon the burden of infectious agent, and has potential implication for human clinical trials of anti-inflammatory agents in sepsis.

感染性休克似乎是由于细胞过度释放细胞因子[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)]所致。单核细胞/巨噬细胞谱系对感染或脂多糖（LPS）给药的反应。这些细胞因子的产生及其作用是由诱导蛋白质酪氨酸磷酸化的信号转导事件介导的。理论上，抑制蛋白质酪氨酸磷酸化可能对脓毒症有益。这些化合物将阻止依赖于酪氨酸磷酸化的潜在高细胞因子产生。这些蛋白激酶抑制剂将阻止细菌产物激活和产生细胞因子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，并已被证明可以改善小动物模型在 LPS 和活细菌攻击期间的结果。此外，AG 126 和 AG 556 均已被证明可以在体外抑制狗外周血单核细胞中 LPS 诱导的 TNF 产生。我们与Novogrodsky 博士及其同事合作，在犬腹膜炎模型中评估了 AG 126 和 AG 556。在一项为期 6 个月、对 100 只动物进行的对照临床试验中，AG 556（而非 AG 126）显着提高了犬感染性休克期间的存活率并预防了多器官衰竭。最近对动物实验数据的分析表明，抗炎药的效果部分取决于动物潜在的感染负担。对照组表现出高死亡率的研究似乎表明，抗炎治疗可提高生存率。相反，对照组死亡率较低的研究表明，抗炎药物没有任何益处，甚至可能有害。因此，脓毒症的人体临床试验没有显示出任何益处的原因可能是抗炎药物已被给予患有不同程度疾病的个体，并且疾病负担较高的患者亚组可能会得到帮助通过抗炎治疗。本研究旨在检查滴定 AG 556 对感染高传染性和低传染性负担的犬科动物疾病严重程度的影响。在我们的犬类腹膜炎模型中，将研究大肠杆菌腹膜炎凝块负荷高或低的动物组。我们将比较标准剂量 2.5 mg/kg AG 556 与安慰剂、滴定剂量 1 mg/kg，然后根据动物在 6 小时时间点的血压而定的 1 或 4 mg/kg 的疗效。这项研究是第一项在动物模型中研究抗炎治疗的效用是否依赖于感染因子的负担的研究，并且对脓毒症抗炎药物的人体临床试验具有潜在的意义。