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: 5201091
• 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/5201091
• 关键词: blood toxicology; bradykinin; cardiovascular disorder chemotherapy; disease /disorder model; dogs; hemodynamics; inflammation; inhibitor /antagonist; kininogens; leukopenia; lipopolysaccharides; microorganism disease chemotherapy; nonhuman therapy evaluation; peritonitis; septic shock; 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.

尽管积极的药物和手术治疗，感染性休克继续， 是重症监护中发病和死亡的最常见原因 单位感染性休克的一个常见后遗症是全身性 炎症和由此产生的多器官功能障碍。大量证据 支持缓激肽在炎症反应中的重要作用。 激肽释放酶-激肽原-激肽系统通过施用 脂多糖（LPS）。此外，外源性 缓激肽再现败血症的血液动力学异常。这些 观察表明，缓激肽抑制可能代表了一种新的 感染性休克的治疗策略。一些缓激肽 已经开发了不同选择性的拮抗剂。管理 这些拮抗剂在啮齿动物模型中已被证明可以减轻 低血压、白细胞减少和循环肿瘤坏死增加 LPS给药诱导的因子水平。此外，缓激肽 拮抗剂NPC 15669与抗生素联合使用， 在啮齿类动物粪便腹膜炎模型中证明了改善结果。我们 已经开发了一种感染性休克的犬腹膜炎模型， 人体中遇到的心血管和血液动力学异常。 这已成为评价脓毒症新疗法的有用模型。 Scios Nova Inc.（山景，CA）具有选择性缓激肽拮抗剂。 我们将在我们的犬模型中应用这种药物，以评估其效果 对血液动力学、心血管和生化紊乱的影响 败血症这将提供关键信息， 应该继续在感染性休克患者身上进行研究。