TYROSINE KINASE INHIBITION IN A CANINE MODEL OF S. AUREUS INFECTION

我们之前的研究表明，酪氨酸激酶抑制剂tyrphostin AG556可以降低血清肿瘤坏死因子水平，提高犬腹腔内大肠杆菌脓毒症模型的存活率。然而，在临床上引入这种药物之前，我们进行了额外的研究，首先在大鼠模型中，然后在犬模型中，以确定这种药物对金黄色葡萄球菌的影响。在这些研究中，tyrphostin AG556并没有一致的有益作用。然而，对照死亡率和AG556效应的图表明，感染的严重程度解释了我们在AG556效应中观察到的大部分变异性。在严重致死性感染时，AG556可提高生存率，而在轻度感染时，AG556则是有害的。为了进一步测试这种可能性，我们在大鼠身上进行了研究，评估了AG556与大肠杆菌、金黄色葡萄球菌或内毒素产生低、中、高对照死亡率的影响。对这些数据的分析表明，正如我们之前所看到的，AG556对每次攻击的影响与感染的严重程度密切相关。这些研究表明，tyrphostin AG556可能仅对与潜在感染相关的死亡可能性很高的患者有益。它对死亡可能性较低的患者可能有害。进一步的研究正在进行中，以确定AG556在这些研究中的可变效应的基础。

We previously showed that a tyrosine kinase inhibitor, tyrphostin AG556 reduced serum tumor necrosis factor levels and improved survival in a canine model of intraperitoneal E. coli sepsis. Prior to the introduction of this drug clinically however, we performed additional studies, first in a rat model and then again in a canine model to determine the effects of this agent with S. aureus. In these studies, tyrphostin AG556 did not have consistent beneficial effects. Plots of control mortality and the effects of AG556 suggested however that severity of infection explained much of the variablity we had observed in the effects of AG556. With very lethal infection AG556 improved survival but with mild infection it was harmful. To test this possibility further, we did studies in rats assessing the effects of AG556 with doses of either E. coli, S. aureus, or endotoxin produc-ing low, medium, or high control mortalities. Analysis of this data showed that the effects of AG556 for each challenge were closely associated with the severity of infection as we had seen earlier. These studies suggest that tyrphostin AG556 may only be beneficial in patients with a high likelihood of dying related to their underlying infection. It may be harmful in patients with a low likelihood of dying. Additional studies are underway to determine the basis for the variable effects of AG556 in these studies.