TYRPHOSTIN AG 556 THERAPY ADJUSTED TO SEVERITY OF ILLNESS OF NEW THERAPIES IN SEP

Tyrphostin AG 556 疗法根据 9 月份新疗法的病情严重程度进行调整

• 批准号: 6289421
• 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/6289421
• 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), interleukin-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, 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 agent shave 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 see 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-hour 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-inflam-matory agents in sepsis

脓毒性休克似乎是由细胞因子的过度释放引起的[例如，肿瘤坏死因子-α（TNF-α）、白细胞介素-2等]和其它促炎物质[例如，一氧化氮（NO）]从单核细胞/巨噬细胞谱系的细胞中释放。这些细胞因子的产生以及它们的作用由诱导蛋白酪氨酸磷酸化的信号转导事件介导。理论上，抑制蛋白酪氨酸磷酸化可能对脓毒症有益。这些化合物将阻断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断细菌产物对细胞因子的激活和产生以及细胞因子对靶细胞的作用。Tyrphostins AG 126和AG 556都是蛋白激酶抑制剂，并且已经显示在LPS和活细菌攻击期间改善小动物模型中的结果。此外，AG 126和AG 556均显示在体外抑制LPS诱导的犬外周血单核细胞的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个月的100只动物的对照临床试验中，AG 556而不是AG 126显著改善了犬败血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，抗炎剂的作用部分取决于动物的潜在感染负荷。似乎对照组显示高死亡率的研究显示抗炎治疗后生存率提高。相反，对照组死亡率较低的研究表明，抗炎药没有益处，可能还有一些危害。因此，脓毒症的人类临床试验没有显示出益处的原因可能是抗炎剂已经给予具有不同程度疾病的个体，并且具有较高疾病负担的患者亚组可能通过抗炎治疗得到帮助。本研究旨在检查滴定AG 556对感染高和低感染负荷犬的疾病严重程度的影响。在我们的犬腹膜炎模型中，用高或低负荷的E。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、滴定剂量1 mg/kg以及随后1或4 mg/kg（取决于6小时时间点动物的血压）的疗效。据我们所知，这项研究是第一个在动物模型中研究抗炎治疗的效用是否取决于感染因子的负担的研究，并对未来脓毒症抗炎药物的人体临床试验具有潜在意义