Preclinical Studies of Carbo-etomidate: An Etomidate Analogue for Use in Sepsis

卡博依托咪酯的临床前研究：用于治疗脓毒症的依托咪酯类似物

• 批准号: 7872292
• 负责人: DOUGLAS E RAINES
• 金额: $ 26.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7872292
• 关键词: Adrenal Glands; Adrenalectomy; Adverse effects; Affect; Affinity; Anesthesia procedures; Anesthetics; Binding; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cells; Cessation of life; Chemicals; Clinical Research; Continuous Infusion; Corticosterone; Cortrosyn; Critical Illness; Data; Development; Dose; Escherichia coli; Etomidate; Experimental Models; Future; General Anesthesia; General anesthetic drugs; Health; Homeostasis; Human; Hypotension; Imidazole; In Vitro; Incidence; Infection; Infusion procedures; Intravenous Bolus; Intravenous infusion procedures; Intubation; Lead; Life; Lipopolysaccharides; Mediating; Mental Depression; Mixed Function Oxygenases; Modeling; Multiple Organ Failure; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Physiological; Pilot Projects; Production; Property; Propofol; Pyrroles; Rattus; Sedation procedure; Sepsis; Sepsis Syndrome; Shock; Sprague-Dawley Rats; Steroids; Testing; Therapeutic Intervention; Vasodilation; analog; base; biological adaptation to stress; cost; cytokine; design; hemodynamics; high risk; improved; in vivo; mortality; novel; pre-clinical; preclinical study; pressure; public health relevance; receptor function; response; septic

DESCRIPTION (provided by applicant): Sepsis is the systemic inflammatory response syndrome that occurs during infection. Its incidence is approximately 750,000 per year in the US with a mortality of 30 to 50% and an annual cost of $17 billion. When severe, sepsis is often associated with profound hypotension, massive vasodilatation, shock, and multiple organ failure. Patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, nearly all general anesthetics produce cardiovascular depression, which can be life threatening particularly in the setting of sepsis. Etomidate is an imidazole-based general anesthetic that is distinguished from other general anesthetics by its lesser effects on cardiovascular function. This would seem to make it an ideal anesthetic for use in critically ill patients with sepsis. However because etomidate binds with high affinity to 112-hydroxylase, it potently suppresses synthesis of adrenocortical steroids that are critical for the stress response during sepsis that serves to restore homeostasis and enhance survival. Such "chemical adrenalectomy" by etomidate precludes its administration by continuous infusion to maintain anesthesia or sedation and has raised concerns regarding the administration of even a single IV bolus dose for anesthetic induction in septic patients. We hypothesize that this side effect can be "designed out" of etomidate by removing a single atom in the drug that is thought to mediate high affinity binding to 112-hydroxylase, while maintaining etomidate's favorable anesthetic and cardiovascular-sparing properties. To test this, we have developed carbo-etomidate as the lead compound in a new class of highly potent pyrrole-based anesthetics. Preliminary data show that like etomidate, carbo- etomidate is a highly potent general anesthetic that enhances GABAA receptor function and maintains hemodynamic stability. However, its potency for inhibiting in vitro steroid synthesis by adrenocortical cells is three orders of magnitude lower than that of etomidate and it does not suppress in vivo Cortrosyn-stimulated steroid synthesis following IV bolus administration. These observations suggest that carbo-etomidate or similar analogues could be exceptionally safe anesthetic agents for use in septic critically ill patients who are already at high risk for adrenocortical insufficiency and death. As the first step toward testing this hypothesis and establishing the basis for future preclinical and clinical studies of promising novel pyrrole-based anesthetics, we propose pilot studies to define in a septic rat model the impact of carbo-etomidate infusions on the adrenocortical and cytokine response to sepsis (Aim 1) and hemodynamic stability (Aim 2). These results will be compared to those obtained using the two most commonly used IV anesthetics, propofol and etomidate. The successful development of novel etomidate analogues that spare cardiovascular function without suppressing adrenocortical steroid synthesis will significantly improve human health by permitting anesthesia to be induced and maintained more safely in critically ill patients, and particularly those with sepsis. PUBLIC HEALTH RELEVANCE: Critically ill patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, all general anesthetics have deleterious side effects that can be life threatening to such patients. We have developed a novel general anesthetic for use in septic critically ill patients that our preliminary data suggest could be safer than all currently available agents. The proposed studies will test this by defining its physiological actions in an experimental model of sepsis.

描述(申请人提供)：败血症是感染期间发生的全身性炎症反应综合征。在美国，它的发病率约为每年75万，死亡率为30%至50%，每年造成170亿美元的损失。严重时，败血症常伴有严重低血压、大量血管扩张、休克和多器官衰竭。脓毒症患者通常需要全身麻醉进行重要的治疗干预，如插管和手术。不幸的是，几乎所有的全身麻醉药都会产生心血管抑制，这可能会危及生命，特别是在脓毒症的情况下。依托咪酯是一种以咪唑为基础的全身麻醉剂，与其他全身麻醉药不同的是，它对心血管功能的影响较小。这似乎使它成为一种用于重症脓毒症患者的理想麻醉剂。然而，由于依托咪酯与112-羟基酶有很高的亲和力，它可以有效地抑制肾上腺皮质类固醇的合成，肾上腺皮质类固醇对于脓毒症期间的应激反应至关重要，有助于恢复体内平衡和提高存活率。依托咪酯的这种“化学肾上腺切除术”排除了通过持续输注来维持麻醉或镇静的可能性，并引起了人们对脓毒症患者即使是单次静脉推注麻醉诱导剂量的担忧。我们假设，这种副作用可以通过移除药物中被认为介导与112-羟基酶高亲和力结合的单个原子，同时保持依托咪酯良好的麻醉剂和心血管保护作用来“设计”出依托咪酯。为了测试这一点，我们开发了依托咪酯作为一种新型高效吡咯类麻醉药的先导化合物。初步数据显示，依托咪酯与依托咪酯类似，是一种增强GABAA受体功能、维持血流动力学稳定的高效全身麻醉剂。然而，它在体外抑制肾上腺皮质细胞合成类固醇的效力比依托咪酯低三个数量级，而且在体内静脉推注后不抑制皮质醇刺激的类固醇合成。这些观察表明，依托咪酯或类似物对于已经存在肾上腺皮质功能不全和死亡高风险的脓毒症危重患者来说，可能是非常安全的麻醉剂。作为检验这一假说的第一步，并为未来有前景的新型吡咯类麻醉药的临床前和临床研究奠定基础，我们提议进行先导性研究，以确定在脓毒症大鼠模型中输注依托咪酯对脓毒症大鼠肾上腺皮质和细胞因子反应的影响(目标1)和血流动力学稳定性(目标2)。这些结果将与使用两种最常用的静脉麻醉剂异丙酚和依托咪酯的结果进行比较。新型依托咪酯类似物的成功开发可以在不抑制肾上腺皮质类固醇合成的情况下保留心血管功能，从而使危重患者，特别是脓毒症患者能够更安全地诱导和维持麻醉，从而显著改善人类健康。 公共卫生相关性：重症脓毒症患者通常需要全身麻醉进行重要的治疗干预，如插管和手术。不幸的是，所有的全身麻醉药都有有害的副作用，可能会危及这些患者的生命。我们已经开发出一种用于败血症危重患者的新型全身麻醉剂，我们的初步数据表明，这种麻醉剂可能比目前所有可用的药物都更安全。拟议的研究将通过在脓毒症的实验模型中定义其生理作用来测试这一点。