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

脓毒性休克似乎是由于单核/巨噬细胞系在感染或脂多糖（LPS）给药时过度释放细胞因子[如肿瘤坏死因子-a （TNF-a）、白细胞介素-2等]和其他促炎物质[如一氧化氮（NO）]所致。这些细胞因子的产生及其作用是由诱导蛋白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作用。Tyrphostins AG 126和AG 556都是蛋白激酶抑制剂，在LPS和活细菌攻击的小动物模型中显示出改善结果。此外，在体外实验中，AG 126和AG 556均可抑制lps诱导的犬外周血单个核细胞产生TNF。在Novogrodsky博士及其同事的合作下，我们在犬腹膜炎模型中评估了ag126和AG 556。在一项为期6个月的100只动物对照临床试验中，AG 556而不是AG 126显著提高了犬感染性休克的存活率，并防止了多器官衰竭。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担。研究表明，在具有高死亡率的对照组中，抗炎治疗改善了患者的生存。相反，在对照组中显示出较低死亡率的研究表明，抗炎剂没有任何益处，可能还有一些危害。因此，脓毒症的人体临床试验没有显示出益处的原因可能是，抗炎药被给予不同程度疾病的个体，而疾病负担较高的亚组患者可能会受益于抗炎治疗。本研究旨在观察滴定ag556对高感染负荷和低感染负荷感染犬的疾病严重程度的影响。在我们的犬腹膜炎模型中，将研究大肠杆菌腹膜炎血块负担高或低的动物队列。我们将比较标准剂量2.5 mg/kg AG 556与安慰剂、滴定剂量1mg/kg，然后根据动物在6小时时间点的血压1或4 mg/kg的疗效。据我们所知，这项研究是第一次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，并对未来抗炎药物在败血症中的人类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), 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