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

犬金黄色葡萄球菌感染模型中酪氨酸激酶的抑制

• 批准号: 6289408
• 负责人: Peter Q Eichacker
• 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/6289408
• 关键词: Staphylococcus aureus; antibiotics; bacterial disease; disease /disorder model; dogs; drug screening /evaluation; enzyme inhibitors; gram negative bacteria; laboratory rat; peritonitis; protein tyrosine kinase

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.

我们以前发现，酪氨酸激酶抑制剂tyrphostin AG 556降低了血清肿瘤坏死因子水平，提高了腹腔内大肠杆菌犬模型的存活率。大肠杆菌败血症。然而，在临床上引入该药物之前，我们进行了额外的研究，首先在大鼠模型中，然后再次在犬模型中，以确定该药物对S.金黄色。在这些研究中，tyrphostin AG556没有一致的有益效果。然而，控制死亡率和AG556效应的曲线表明，感染的严重程度解释了我们在AG556效应中观察到的大部分可变性。对于非常致命的感染，AG556改善了存活率，但对于轻度感染，它是有害的。为了进一步测试这种可能性，我们在大鼠中进行了研究，评估AG556与E. coli、S.金黄色葡萄球菌，或产生低、中或高对照死亡率的内毒素。对这些数据的分析表明，AG556对每次攻击的影响与我们之前看到的感染严重程度密切相关。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高的患者有益。它可能对死亡可能性较低的患者有害。正在进行其他研究，以确定AG556在这些研究中的可变效应的基础。