Tyrphostin Ag 556 Therapy Adjusted To Severity Of Illnes

感染性休克似乎是由于细胞因子[如肿瘤坏死因子-a、白介素2等]过度释放所致。和其他促炎物质[例如，一氧化氮(NO)]从单核/巨噬细胞系的细胞中释放出来，以应对感染或内毒素(LPS)注射。这些细胞因子的产生和它们的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，抑制蛋白酪氨酸磷酸化可能有益于脓毒症。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的产生。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影响。TyrPhostins AG 126和AG 556都是蛋白激酶抑制剂，在小动物模型中已被证明在内毒素和活菌攻击中都能改善结果。此外，AG 126和AG 556都已被证明在体外抑制内毒素诱导的狗外周血单个核细胞产生肿瘤坏死因子。在Novogrodsky博士和他的同事的合作下，我们在我们的犬腹膜炎模型中评估了AG 126和AG 556。在一项对100只动物进行的超过6个月的对照临床试验中，AG 556而不是AG 126显著提高了犬的存活率，并防止了犬感染性休克时的多器官衰竭。最近对动物实验数据的分析表明，抗炎药的效果在一定程度上取决于动物潜在的感染负担。看来，对照组死亡率高的研究表明，抗炎治疗可以改善患者的存活率。相反，对照组死亡率较低的研究表明，抗炎药没有好处，可能还会有一些伤害。因此，人类临床试验没有显示出任何益处的原因可能是，抗炎药已经被给予了不同程度疾病的患者，而疾病负担更高的患者亚群可能会得到抗炎治疗的帮助。本研究旨在研究滴定AG 556对感染高感染负荷和低感染负荷的犬的病情严重程度的影响。在我们的犬腹膜炎模型中，将研究具有高或低大肠杆菌腹膜炎凝块负荷的动物队列。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1 mg/kg或4 mg/kg的疗效，具体取决于动物在6小时时间点的血压。这项研究是首次在动物模型中检验抗炎治疗的有效性是否依赖于感染剂的负担，并对人类抗炎药在脓毒症中的临床试验具有潜在的意义。

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.