权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Etomidate Analogues as Safer General Anesthetics

依托咪酯类似物作为更安全的全身麻醉药

基本信息

批准号：
8401548
负责人：
DOUGLAS E RAINES
金额：
$ 50.57万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401548
关键词：
Adverse effects Affinity Amino Acids Anesthesia procedures Anesthetics Binding Binding Sites Blood Blood Pressure Bolus Infusion Carboxylic Acids Cardiovascular Physiology Cardiovascular system Catalytic Domain Clinical Continuous Infusion Cortrosyn Critical Illness Depressed mood Development Dose Drug Kinetics Enzymes Esters Etomidate General anesthetic drugs Goals Health Heart Rate Heme Iron Homology Modeling Human Imidazole In Vitro Infusion procedures Intravenous Intravenous Bolus Liver Maintenance Mass Spectrum Analysis Measures Mental Depression Metabolism Mixed Function Oxygenases Modeling Molecular Nitrogen Operative Surgical Procedures Patients Pharmaceutical Preparations Pharmacodynamics Plethysmography Property Propofol Rattus Recovery Respiratory physiology Risk Sedation procedure Site Steroids Structure-Activity Relationship Techniques Testing Therapeutic Index Ventilatory Depression Work analog base chemical group clinically relevant design esterase hemodynamics hypnotic improved in vivo mortality novel novel strategies public health relevance receptor function respiratory sedative

项目摘要

DESCRIPTION (provided by applicant): In the U.S. alone, nearly 30 million general anesthetics are administered each year. At the doses required to produce anesthesia, all general anesthetics produce serious side effects. Depression of cardiovascular and respiratory function is of greatest concern, particularly in the critically ill. Such depression explains why anesthetics have among the lowest therapeutic indices of any class of drugs. This proposal focuses on etomidate, which is distinguished from other general anesthetics by its favorable hemodynamic and respiratory effects and its unusually high therapeutic index. However because etomidate potently inhibits 112- hydroxylase, leading to prolonged suppression of adrenocortical steroid synthesis with potentially fatal consequences, its clinical use is effectively limited in the critically ill to single bolus administration for the induction of anesthesia. The broad, long-term goal of this work is to provide the groundwork for the development of novel anesthetics that retain etomidate's beneficial properties, but whose impact on steroid synthesis is greatly reduced. This would extend clinical utility beyond bolus administration to include continuous infusion for anesthetic maintenance and possibly long-term sedation. The proposed studies will define structure-activity relationships for novel etomidate analogues and test new two strategies for developing analogues of etomidate that can be continuously infused because their abilities to inhibit adrenocortical function are significantly reduced in duration or magnitude. The first strategy is to design etomidate analogues that are so rapidly metabolized that suppression of adrenocortical function terminates when their infusion is stopped at the end of surgery rather than persisting for days afterward. Such agents are also expected to produce more rapid and predictable emergence from anesthesia. The second strategy is to design anesthetic etomidate analogues that do not bind to 112-hydroxylase with high affinity and, therefore, do not inhibit steroid synthesis at clinically relevant doses. Specific Aim 1 is to define in vitro structure-activity relationships for novel metabolically-labile etomidate analogues (etomidate esters) and their carboxylic acid metabolites. Specific Aim 2 is to determine in a rat model whether continuous infusions of etomidate esters depress adrenocortical, cardiovascular, or respiratory function and if so, to compare such depression to that produced by continuous infusions of etomidate. Specific Aim 3 is to locate and characterize the etomidate binding site(s) on human 112-hydroxylase and to define structure-activity relationships for novel etomidate analogues whose abilities to coordinate with 112-hydroxylase's heme iron vary.

描述（由申请人提供）：仅在美国，每年就有近3000万例全身麻醉药。在产生麻醉所需的剂量下，所有的全身麻醉剂都会产生严重的副作用。心血管和呼吸功能的抑制是最令人担忧的，特别是在重症患者中。这种抑郁症解释了为什么麻醉药在所有药物中的治疗指数最低。该建议的重点是依托咪酯，它与其他全身麻醉药的区别在于其良好的血流动力学和呼吸作用以及异常高的治疗指数。然而，由于依托咪酯有效抑制112-羟化酶，导致肾上腺皮质类固醇合成的长期抑制，具有潜在的致命后果，因此其临床应用在重症患者中有效地限制为单次推注给药用于麻醉诱导。这项工作的广泛，长期的目标是为开发新的麻醉剂提供基础，这些麻醉剂保留了依托咪酯的有益特性，但其对类固醇合成的影响大大降低。这将扩展推注给药以外的临床效用，以包括用于麻醉维持和可能的长期镇静的连续输注。拟议的研究将定义新型依托咪酯类似物的结构-活性关系，并测试开发依托咪酯类似物的两种新策略，这些类似物可以连续输注，因为它们抑制肾上腺皮质功能的能力在持续时间或幅度上显著降低。第一种策略是设计代谢如此迅速的依托咪酯类似物，以致于当手术结束时停止输注时，肾上腺皮质功能的抑制终止，而不是在手术后持续数天。这类药物也有望使麻醉后的苏醒更加迅速和可预测。第二种策略是设计不以高亲和力结合112-羟化酶的麻醉剂依托咪酯类似物，因此在临床相关剂量下不抑制类固醇合成。具体目标1是确定新型代谢不稳定依托咪酯类似物（依托咪酯酯）及其羧酸代谢产物的体外构效关系。具体目标2是在大鼠模型中确定依托咪酯的连续输注是否抑制肾上腺皮质、心血管或呼吸功能，如果是，则将这种抑制与依托咪酯的连续输注产生的抑制进行比较。具体目标3是定位和表征依托咪酯在人112-羟化酶上的结合位点，并定义新型依托咪酯类似物的结构-活性关系，其与112-羟化酶的血红素铁的配位能力不同。