Mechanisms and translation of lipid resuscitation

脂质复苏的机制和转化

• 批准号: 8764697
• 负责人: Israel Rubinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764697
• 关键词: Accounting; Acute; Admission activity; Adrenergic beta-Antagonists; Aging; Alcohols; American; American Heart Association; Animal Model; Animals; Antidotes; Award; Binding; Blood capillaries; Blood flow; Brain; Bupivacaine; Bypass; Calcium Channel Blockers; Cardiac; Cardiopulmonary Resuscitation; Cardiotoxicity; Cardiovascular Physiology; Case Study; Cells; Cessation of life; Cocaine; Conduction Anesthesia; Cyclodextrins; Data Set; Development; Diffusion; Drug Prescriptions; Drug abuse; Drug toxicity; Elderly; Electron Microscopy; Emulsions; Endothelium; Fatty acid glycerol esters; Funding; Generic Drugs; Goals; Great Britain; Guidelines; Gunshot wound; Health; Heart; Histologic; Indium; Information Systems; Infusion procedures; Inpatients; Instruction; Intoxication; Intravenous Fat Emulsions; Ireland; Ischemia; Life; Lipids; Liposomes; Local Anesthetics; Measures; Medical; Metabolic; Military Personnel; Modification; Morbidity - disease rate; Myocardial; Neurologic; Neurologic Manifestations; Normal tissue morphology; Organ; Outcome; Overdose; Pharmaceutical Preparations; Phase; Physicians; Plasma; Play; Poisoning; Population; Prevalence; Process; Publishing; Radiolabeled; Rattus; Reaction Time; Recovery; Reperfusion Therapy; Resistance; Resuscitation; Risk; Signal Transduction; Site; Societies; Symptoms; Testing; Time; Tissues; Toxic effect; Toxicity Tests; Toxin; Translating; Translations; Treatment Protocols; Tricyclic Antidepressive Agents; United States; Veterans; Work; aqueous; base; capillary; clinical practice; cocaethylene; cocaine overdose; cocaine use; effective therapy; fatty acid metabolism; improved; in vivo; inhibitor/antagonist; light microscopy; migration; nanomedicine; novel; novel strategies; particle; patient safety; prevent; radiotracer; research study; soy; uptake; vehicular accident

DESCRIPTION (provided by applicant): Work funded under the PI's previous VA Merit award has contributed directly to a novel and now widely accepted life-saving treatment for local anesthetic systemic toxicity (LAST). Intravenous lipid emulsion (ILE) resuscitation has also been used in many instances to rapidly reverse acute cardiac and neurological symptoms of toxicity caused by a wide range of lipophilic (fat soluble) medications. In many published case reports involving LAST or other overdoses, ILE was effective even after standard resuscitation measures had failed. ILE is now a principle element in treatment guidelines published by the American Society of Regional Anesthesia, the Anaesthetists of Great Britain and Ireland, the Resuscitation Council (UK) and was added to the most recent American Heart Association ACLS guidelines for treating LAST. Drug overdose is the second leading cause of accidental death in the United States contributing to 36,000 fatalities in 2007 placing it ahead of gunshot wounds and just behind motor vehicle accidents. Moreover, veterans are at particular risk given the prevalence of both illicit drug abuse and the difficulty for a geriatric population to adhere to instructions for such prescription drugs as long acting calcium channel blockers that can be potentially fatal in overdose. Notably, ILE has been used effectively in treating overdose of many common prescription medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that can be highly resistant to standard resuscitation measures. Identifying the precise mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses. However, the precise mechanisms of ILE are not well understood. The conventional explanation involves partitioning of the offending toxin into the newly created lipemic plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the sink alone, indicating that other, less well-understood, mechanisms are also at play. We believe that ILE also directly benefits cardiovascular function and have confirmed in preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is well-established tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion of drug away from cells and diminish the response time to lipid signal effectors. We hypothesize that extravascular migration of lipid particles contributes to the overall efficacy of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of ILE and transendothelial migration of lipid particles. Finally, we seek to improve the translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the over-arching goals of this project.

描述（由申请人提供）： 根据PI先前的VA优异奖资助的工作直接为局部麻醉系统毒性（最后）的新颖而广泛接受的救生治疗做出了贡献（最后）。在许多情况下，静脉注射脂质乳液（ILE）复苏也已被用来迅速逆转急性心脏和神经系统症状，这是由多种亲脂性（脂肪溶于）药物引起的。在许多涉及上次或其他过量服用的案例报告中，即使在标准复苏措施失败之后，ILE也有效。 ILE现在是美国地区麻醉学会，大不列颠和爱尔兰的麻醉师，复苏委员会（英国）发表的治疗指南的主要要素，并被添加到最近的美国心脏协会ACLS ACLS ACLS指南中。药物过量是美国意外死亡的第二大主要原因，2007年造成36,000人死亡，将其置于枪伤之前，仅次于机动车事故。此外，鉴于非法滥用药物的普遍性和老年人群的困难既有遵守此类处方药的指示，例如长期表现钙通道阻滞剂可能会导致过量的致命性致命。值得注意的是，ILE已被有效地用于治疗许多常见处方药（例如β受体阻滞剂，三环抗抑郁药或钙通道阻滞剂），这些药物可能对标准复苏措施具有高度抗性。确定ILE的确切机制具有提高其疗效的希望，并为一系列威胁生命的有毒药物过量药物提供有效的通用解毒疗法。但是，ILE的确切机制尚不清楚。传统的解释涉及将违规毒素分配到新创建的脂肪血浆相或“脂质水槽”中。但是，即使这种机制也没有在体内进行严格的测试。此外，我们已经观察到，Ile的关键方面不能单独用水槽来解释，这表明其他，不太理解的机制也在起作用。我们认为，ILE还直接使心血管功能受益，并在初步实验中证实，完整大鼠完整大鼠中脂质乳液的输注对心脏收缩和主动脉血流产生阳性效率。我们假设这部分是由于DireC的一部分，这是脂肪酸代谢对心脏功能的积极影响。此外，它已建立的THA组织缺血会导致细胞间内皮间隙扩展，从而使脂质体迁移到心肌间质中。这种被动靶向脂质颗粒，本质上是 纳米中心，将绕过正常的组织屏障，以从细胞中扩散药物并减少对脂质信号效应子的响应时间。我们假设脂质颗粒的血管外迁移有助于ILE在逆转心脏药物毒性方面的总体功效。 W提出了研究脂质颗粒的ILE和跨内皮迁移的代谢作用的研究。最后，我们试图改善ILE向可卡因相关的毒性的翻译和持续过量的过量毒性，例如钙通道阻滞剂毒性。改善患者的安全性和药物毒性结果是该项目的整理目标。