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

Tyrphostin AG 556 疗法于 9 月根据新疗法的病情严重程度进行调整

• 批准号: 6103604
• 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/6103604
• 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 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 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. It is therefore 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 1 mg/kg, and then 1 or 4 mg/kg depending upon the blood pressure of animals at the 6 h time point. This study is, to our knowledge, 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 future human clinical trials of anti-inflammatory agents in sepsis.

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 依赖于酪氨酸磷酸化。这些蛋白激酶 抑制剂会阻止细胞因子的激活和产生 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。 我们与Novogrodsky 博士及其同事合作， 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 只动物进行的对照临床试验，AG 556，但是 不是 AG 126，显着提高存活率并预防 犬感染性休克期间的多器官衰竭。最新分析 动物实验数据表明，效果 抗炎药部分取决于潜在的 动物的传染性负担。看来研究其中 对照组表现出高死亡率，表明存活率有所提高 对抗炎治疗的反应。相反，研究其中 对照组表现出较低的死亡率表明抗炎药 代理没有任何好处，甚至可能有一些坏处。因此是 脓毒症人体临床试验的原因可能是 没有显示任何好处是抗炎剂已被 给予患有不同程度疾病的个人，并且 疾病负担较高的患者亚群可能会得到帮助 通过抗炎治疗。本研究旨在检查 滴定 AG 556 对犬科动物疾病严重程度的影响 感染者的感染负担有高有低。在我们的犬类模型中 腹膜炎的动物群，无论是高负荷还是低负荷 将研究大肠杆菌腹膜炎凝块。我们将比较 标准剂量 2.5 mg/kg AG 556 与安慰剂相比的疗效， 滴定剂量为 1 mg/kg，然后根据情况调整为 1 或 4 mg/kg 动物在6小时时间点的血压。这项研究是为了我们 知识，第一项动物模型研究，以检验是否 抗炎治疗的效用取决于 传染源的负担，并对未来有潜在影响 脓毒症抗炎药的人体临床试验。