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

描述（由申请人提供）：脓毒症是感染期间发生的全身炎症反应综合征。在美国，其发病率约为每年750，000例，死亡率为30%至50%，每年的费用为170亿美元。严重时，脓毒症常伴有严重低血压、大量血管舒张、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，这可能危及生命，特别是在败血症的情况下。依托咪酯是一种咪唑类全身麻醉药，与其他全身麻醉药的区别在于其对心血管功能的影响较小。这似乎使其成为败血症危重患者的理想麻醉剂。然而，由于依托咪酯与112-羟化酶具有高亲和力结合，因此它可有效抑制肾上腺皮质类固醇的合成，而肾上腺皮质类固醇对脓毒症期间的应激反应至关重要，有助于恢复体内平衡并提高生存率。依托咪酯的这种“化学肾上腺切除术”排除了其通过连续输注来维持麻醉或镇静的施用，并且已经引起了关于在脓毒症患者中用于麻醉诱导的甚至单次IV推注剂量的施用的关注。我们假设，这种副作用可以通过去除药物中被认为介导与112-羟化酶高亲和力结合的单个原子来“设计”依托咪酯，同时保持依托咪酯有利的麻醉和心血管保护特性。为了验证这一点，我们开发了碳依托咪酯作为一类新型高效吡咯类麻醉剂的先导化合物。初步数据显示，与依托咪酯一样，碳-依托咪酯是一种高效的全身麻醉剂，可增强GABAA受体功能并维持血流动力学稳定性。然而，其抑制肾上腺皮质细胞体外类固醇合成的效力比依托咪酯低三个数量级，并且其在IV推注给药后不抑制体内皮质激素刺激的类固醇合成。这些观察结果表明，碳依托咪酯或类似物可能是非常安全的麻醉剂，用于脓毒症重症患者，这些患者已经处于肾上腺皮质功能不全和死亡的高风险中。作为检验这一假设的第一步，并为未来有前途的新型吡咯类麻醉剂的临床前和临床研究奠定基础，我们提出了初步研究，以确定在脓毒症大鼠模型中，碳依托咪酯输注对肾上腺皮质和细胞因子对脓毒症的反应（目的1）和血流动力学稳定性（目的2）的影响。将这些结果与使用两种最常用的静脉麻醉剂（丙泊酚和依托咪酯）获得的结果进行比较。新型依托咪酯类似物的成功开发，不抑制肾上腺皮质类固醇的合成，节省心血管功能，将显着改善人类健康，允许麻醉诱导和维持更安全的危重病人，特别是那些与败血症。 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，所有的全身麻醉剂都有可能危及这些患者生命的有害副作用。我们开发了一种新型全身麻醉剂，用于脓毒症危重患者，我们的初步数据表明，它可能比目前所有可用的药物更安全。拟议的研究将通过在败血症实验模型中定义其生理作用来测试这一点。

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.