Preclinical and Clinical Investigations in Septic Shock

感染性休克的临床前和临床研究

• 批准号: 7593067
• 负责人: ROBERT L DANNER
• 金额: $ 13.08万
• 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/7593067
• 关键词: Acetylcysteine; Address; Anti-Inflammatory Agents; Antibodies; Arginine; Blood Pressure; Canis familiaris; Cause of Death; Cessation of life; Clinical Trials; Condition; Counterpulsation; Critical Illness; Endotoxemia; Endotoxins; Functional disorder; Genus staphylococcus; Ibuprofen; Infection; Intensive Care Units; Investigation; Lilly brand of drotrecogin alfa activated; Lipid A; Marketing; Mediator of activation protein; Modeling; Nitric Oxide; Nitric Oxide Synthase; Organism; Pathogenesis; Patients; Pneumonia; Production; Risk; Role; Sepsis; Septic Shock; Severity of illness; Syndrome; Treatment Efficacy; United States Food and Drug Administration; Vasodilation; analog; healthy volunteer; inhibitor/antagonist; novel therapeutics; pre-clinical; volunteer

Early studies focused on pathophysiology comparing gram positive and gram negative organisms, the role of endotoxemia, and the efficacy of anti-endotoxin therapies such as lipid A analogs and antibodies. Nitric oxide was examined as an important mediator of septic shock. Non-selective nitric oxide synthase inhibitors were sometimes toxic and never beneficial. Normal volunteers challenged with endotoxin were found to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation. Severity of illness (risk of death) was found to influence the therapeutic efficacy of anti-inflammatory agents in septic shock. This finding was used by the FDA to re-analyze the PROWESS trial of rhAPC (Xigris) and led to initial approval only for patients with a high risk of death. The lack of rhAPC efficacy in patients with a low risk of death was confirmed in the ADDRESS trial. The administration of L-arginine without or with N-acetylcysteine in a canine model of septic shock was found to be harmful. L-arginine is a common component of immunonutrition formulas that are marketed for use in critically ill patients. Intra-aortic balloon counterpulsation was found to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock.

早期研究的重点是比较革兰氏阳性和革兰氏阴性生物，内毒素血症的作用以及抗内毒素疗法（例如脂质A类似物和抗体）的疗效的病理生理学。 一氧化氮被检查为败血性休克的重要介质。 非选择性一氧化氮合酶抑制剂有时有毒，从不有益。 发现受内毒素挑战的正常志愿者释放增加一氧化氮量增加。 尽管布洛芬阻塞了内毒素诱导的一氧化氮产生增加，但血压不受影响，表明其他机制得到了补偿以维持血管舒张。 发现疾病的严重程度（死亡风险）会影响抗炎药在败血性休克中的治疗功效。 FDA使用了这一发现来重新分析RHAPC（XIGRIS）的实力试验，并仅对死亡风险高的患者获得了初步认可。在地址试验中证实了死亡风险低的患者缺乏RHAPC功效。 发现在败血性休克犬模型中无需N-乙酰半胱氨酸的L-精氨酸是有害的。 L-精氨酸是免疫公式的常见组成部分，用于重病患者。 在葡萄球菌肺炎肺炎肺炎的低动力犬模型中，发现了运动内球囊反脉冲可延长生存率。