Preclinical and Clinical Investigations in Septic Shock

感染性休克的临床前和临床研究

• 批准号: 7733589
• 负责人: ROBERT L DANNER
• 金额: $ 4.64万
• 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/7733589
• 关键词: Acetylcysteine; Address; Adult; Animal Model; Anti-Inflammatory Agents; Antibodies; Arginine; Blood Pressure; Canis familiaris; Cardiac Output; Cell Culture System; Cessation of life; Child; Clinical Trials; Counterpulsation; Critical Illness; Dose; Endotoxemia; Endotoxins; Functional disorder; Genus staphylococcus; Glucocorticoids; Ibuprofen; In Vitro; Infection; Inflammatory Response; Investigation; Left Ventricular Function; Lilly brand of drotrecogin alfa activated; Lipid A; Low Cardiac Output; Marketing; Mediator of activation protein; Mineralocorticoids; Modeling; Mus; Nitric Oxide; Nitric Oxide Synthase; Nuclear Receptors; Organism; Pathogenesis; Patients; Pneumonia; Production; Public Health; Risk; Role; Sepsis; Septic Shock; Severity of illness; Syndrome; Time; Treatment Efficacy; United States Food and Drug Administration; Vasodilation; analog; healthy volunteer; hypothalamic-pituitary-adrenal axis; improved; in vivo; inhibitor/antagonist; novel therapeutics; pre-clinical; research study; 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. This result suggests that counterpulsation support of left ventricular function might improve survival in episodes of septic shock associated with compromised cardiac output. A low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock. An investigation of the hypothalamic-pituitary-adrenal axis and potential benefits of glucocorticoids and mineralocorticoids is ongoing in mouse and canine models of septic shock. These experiments are aimed at defining issues of dose and timing as well as glucocorticoid and mineralicorticoid effects at the cellular level. The more general topic of nuclear receptor transrepression of inflammatory responses to sepsis is being explored both in vitro and in vivo.

早期的研究集中在病理生理学比较革兰氏阳性和革兰氏阴性微生物，内毒素血症的作用，以及抗内毒素治疗的疗效，如脂质A类似物和抗体。 一氧化氮被认为是感染性休克的重要介质。 非选择性一氧化氮合酶抑制剂有时是有毒的，从来没有有益的。 正常志愿者挑战内毒素被发现释放增加量的一氧化氮。 虽然布洛芬阻断了内毒素诱导的一氧化氮产生的增加，但血压不受影响，这表明其他机制补偿了维持血管舒张。 发现疾病的严重程度（死亡风险）影响感染性休克中抗炎药的治疗效果。这一发现被FDA用于重新分析rhAPC（Xigris）的PROWESS试验，并导致最初仅批准用于高死亡风险的患者。在ADDRESS试验中证实了rhAPC在低死亡风险患者中缺乏疗效。 在感染性休克犬模型中，L-精氨酸与N-乙酰半胱氨酸联合给药是有害的。L-精氨酸是市场上用于重症患者的免疫营养配方的常见成分。 在金黄色葡萄球菌肺炎诱导的感染性休克的低动力犬模型中，发现主动脉内球囊反搏可延长存活时间。这一结果表明，左心室功能的反搏支持可能会提高与心输出量受损相关的感染性休克发作的生存率。在10%到20%的成人和高达50%的感染性休克儿童中可以看到低心输出量。 目前正在小鼠和犬感染性休克模型中研究下丘脑-垂体-肾上腺轴和糖皮质激素和盐皮质激素的潜在益处。这些实验旨在确定剂量和时间以及糖皮质激素和矿物质皮质激素在细胞水平上的作用。核受体反式抑制脓毒症炎症反应的更一般的主题正在探索在体外和体内。

项目成果

Prophylactic high-dose N(omega)-monomethyl-L-arginine prevents the late cardiac dysfunction associated with lethal tumor necrosis factor-alpha challenge in dogs.

预防性高剂量 N(omega)-单甲基-L-精氨酸可预防与致命性肿瘤坏死因子-α 攻击相关的犬晚期心脏功能障碍。

• 发表时间: 2005
• 期刊: Shock (Augusta, Ga.)
• 作者: Sevransky,Jonathan;Vandivier,RWilliam;Gerstenberger,Eric;Correa,Rosalee;Ferantz,Victor;Banks,StevenM;Danner,RobertL;Eichacker,PeterQ;Natanson,Charles
• 通讯作者: Natanson,Charles

Separating practice guidelines from pharmaceutical marketing.

将实践指南与药品营销分开。

• DOI: 10.1097/01.ccm.0000288106.55246.a5
• 发表时间: 2007
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Eichacker,PeterQ;Natanson,Charles;Danner,RobertL
• 通讯作者: Danner,RobertL

Granulocyte colony-stimulating factor has differing effects comparing intravascular versus extravascular models of sepsis.

与血管内和血管外脓毒症模型相比，粒细胞集落刺激因子具有不同的作用。

• DOI: 10.1097/01.ta.0000105884.75782.4d
• 发表时间: 2004
• 期刊: The Journal of trauma
• 作者: Sevransky,JonathanE;Parent,Chantal;Cui,Xizhong;Karzai,Waheed;Fitz,Yvonne;Banks,StevenM;Gerstenberger,Eric;Danner,RobertL;Natanson,Charles;Eichacker,PeterQ
• 通讯作者: Eichacker,PeterQ

Reassessing recombinant human activated protein C for sepsis: time for a new randomized controlled trial.

重新评估重组人活化蛋白 C 治疗脓毒症：是时候进行新的随机对照试验了。

• DOI: 10.1097/01.ccm.0000183002.26587.ff
• 发表时间: 2005
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Eichacker,PeterQ;Danner,RobertL;Suffredini,AnthonyF;Cui,Xizhong;Natanson,Charles
• 通讯作者: Natanson,Charles

Effective dosing of lipid A analogue E5564 in rats depends on the timing of treatment and the route of Escherichia coli infection.

脂质 A 类似物 E5564 在大鼠中的有效剂量取决于治疗时间和大肠杆菌感染途径。

• DOI: 10.1086/500147
• 发表时间: 2006
• 期刊: The Journal of infectious diseases
• 作者: Solomon,StevenB;Cui,Xizhong;Gerstenberger,Eric;Danner,RobertL;Fitz,Yvonne;Banks,StevenM;Natanson,Charles;Eichacker,PeterQ
• 通讯作者: Eichacker,PeterQ