USE OF A SELECTIVE BRADYKININ ANTAGONIST IN A CANINE MODEL OF SEPTIC SHOCK

选择性缓激肽拮抗剂在犬感染性休克模型中的应用

• 批准号: 3752181
• 负责人: C 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/3752181
• 关键词: bradykinin; disease /disorder model; dogs; hemodynamics; hypotension; inhibitor /antagonist; leukopenia; lipopolysaccharides; microorganism disease chemotherapy; nonhuman therapy evaluation; peritonitis; tumor necrosis factor alpha

Despite aggressive medical and surgical therapy, septic shock continues to be the most common cause of morbidity and mortality in the intensive care unit. One common sequelae of septic shock is the development of systemic inflammation and resultant multiple organ dysfunction. Abundant evidence supports a prominent role for bradykinins in this inflammatory response. The kallikrein-kininogen- kinin system is activated by the administration of lipopolysaccharide (LPS). In addition, the administration of exogenous bradykinin reproduces the hemodynamic abnormalities of sepsis. These observations suggest that bradykinin inhibition may represent a novel strategy for the treatment of septic shock. A number of bradykinin antagonists of varying selectivities have been developed. Administration of these antagonists in rodent models have been demonstrated to mitigate the hypotension, leukopenia, and increases in circulating tumor necrosis factor levels induced by LPS administration. In addition, the bradykinin antagonist NPC 15669, in conjunction with antibiotics, has been demonstrated to improve outcome in a rodent fecal peritonitis model. We have developed a canine peritonitis model of septic shock which simulates the cardiovascular and hemodynamic abnormalities encountered in humans. This has become a useful model for evaluating novel therapies in sepsis. Scios Nova Inc. (Mountain View, CA) has a selective bradykinin antagonist. We will apply this agent in our canine model in order to assess its effect on the hemodynamic, cardiovascular, and biochemical derangements of sepsis. This will provide critical information as to whether this therapy should go on to be studied in humans with septic shock.

尽管进行了积极的内科和外科治疗，感染性休克 仍然是#年发病率和死亡率的最常见原因 重症监护室。败血症休克的一个常见后遗症是 全身性炎症的发展和由此产生的多器官 功能障碍。充分的证据表明， 缓激肽在炎症反应中的作用。激肽释放酶-激肽原- 激肽系统被内毒素激活 (LP)。此外，外源性缓激肽的应用 再现脓毒症的血流动力学异常。这些观察结果 提示缓激肽抑制可能代表了一种新的治疗策略 感染性休克的治疗。一些缓激肽拮抗剂 已经开发出了不同的选择性。这些项目的管理 啮齿动物模型中的拮抗剂已被证明可以缓解 低血压、白细胞减少和循环肿瘤坏死增加 脂多糖诱导的因子水平。此外， 缓激肽拮抗剂npc 15669与抗生素联合使用 已证实可改善啮齿动物粪便腹膜炎的预后 模特。我们建立了一种感染性休克的犬腹膜炎模型。 它模拟了心血管和血流动力学异常 在人类身上遇到过。这已经成为一个有用的评估模型 脓毒症的新疗法。Scios Nova Inc.(加利福尼亚州山景城)拥有 选择性缓激肽拮抗剂。我们将把这个代理应用于我们的 为了评估其对血流动力学的影响， 败血症的心血管和生化紊乱。这将是 提供关键信息，说明这种疗法是否应该继续下去 在感染性休克的人类身上进行研究。