Local Anesthetic Cardiotoxicity: Nanotechnology Therapy

局部麻醉心脏毒性：纳米技术治疗

• 批准号: 7087698
• 负责人: DONN MICHAEL DENNIS
• 金额: $ 25.01万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7087698
• 关键词: adsorption; anesthesia complication; cardiac myocytes; cardiotoxin; clinical research; detoxification; drug adverse effect; electrocardiography; electron spin resonance spectroscopy; electrophysiology; guinea pigs; heart ventricle; high performance liquid chromatography; human tissue; infrared spectrometry; local anesthesia; nanotechnology; ultraviolet spectrometry

DESCRIPTION (provided by applicant): Local anesthetics (LAs) reversibly prevent impulse transmission in nerves by voltage-, time- and frequency-dependent blockade of sodium channel conductance (I-Na). These pharmacological actions underlie the therapeutic use of LAs in clinical care to provide regional anesthesia (e.g., epidural blockade) for patients undergoing surgical procedures or childbirth. However, inadvertent intravascular injection or overdose may lead to undesired INa blockade in other tissues (e.g., heart, central nervous system) and thereby cause potentially life threatening adverse events (e.g., cardiac arrest, seizures). Although seizure activity and respiratory depression caused by LA overdose are potentially life threatening, these events can be readily treated with antiepileptic medications and controlled artificial ventilation, respectively. Of equal or greater importance, few options (e.g., ACLS) currently exist for treatment of cardiac toxicity caused by intravascular injection. For these reasons, an agent or technique allowing rapid, efficacious treatment of the cardiac effects of LA toxicity would be useful. The objectives of this grant are to generate the knowledge necessary to create agents specifically designed to treat patients suffering from the toxic effects of LAs. Recent advances in particle science engineering now afford new and exciting opportunities to develop highly effective therapeutic strategies aimed at successfully treating drug poisonings. Specifically, the recent advent of nanotechnology with its tremendous potential to solve major biomedical problems now offers unparalleled opportunities to solve the problem of LA toxicity. Four types of biocompatible and biodegradable nanoparticles (NPs) with 10-100 nm diameter will be synthesized by colleagues in the NSF Engineering Research Center for Particle Science and Technology for detoxification of LAs. These NPs will rely on absorption (microemulsions), adsorption (electron acceptor), or both mechanisms (2 types of "smart" microemulsions) to reduce the free concentration of LA in various media and decrease the biological effects of LA in tissues and intact organisms. The NPs will be studied to 1) detail the physicochemical characterization of the NP-LA interaction (Objective A), and 2) determine whether the cardiotoxic effects of LAs can be attenuated by NPs in biological systems (Objective B). This highly multidisciplinary project spanning organic chemistry, engineering, and medicine contains two objectives and three specific aims: Specific Aim #1: Determine the extraction efficiency of NPs to remove LAs from simple (normal saline) and complex (human plasma and blood) media. Optimize LA extraction efficiency of the various NPs. Specific Aim #2: Determine the molecular mechanisms whereby the different types of NPs can efficiently extract LAs. Specific Aim #3: Determine the effectiveness of nanoparticles to attenuate or reverse the cardiotoxic effects of LAs at three functional levels: 1) single cell (ventricular myocytes), 2) tissue (isolated hearts), and 3) intact rat (closed chest).

描述（由申请人提供）：局部麻醉剂（LA）通过钠通道电导（I-Na）的电压、时间和频率依赖性阻滞可逆地阻止神经中的脉冲传输。这些药理作用是LA在临床护理中提供局部麻醉（例如，硬膜外阻滞）用于接受外科手术或分娩的患者。然而，无意的血管内注射或过量可能导致其他组织中不期望的INa阻断（例如，心脏，中枢神经系统）并由此引起潜在的危及生命的不良事件（例如，心脏骤停、癫痫发作）。尽管LA过量引起的癫痫发作和呼吸抑制可能危及生命，但这些事件可分别通过抗癫痫药物和受控人工通气治疗。同等或更重要的是，很少有选择（例如，ACLS）目前存在用于治疗由血管内注射引起的心脏毒性。由于这些原因，允许快速、有效治疗LA毒性的心脏效应的试剂或技术将是有用的。该补助金的目的是产生必要的知识，以创造专门设计用于治疗LA毒性作用患者的药物。粒子科学工程的最新进展为开发旨在成功治疗药物中毒的高效治疗策略提供了新的令人兴奋的机会。具体来说，最近出现的纳米技术，其巨大的潜力，以解决主要的生物医学问题，现在提供了无与伦比的机会，以解决问题的LA毒性。NSF粒子科学与技术工程研究中心的同事将合成四种直径为10-100 nm的生物相容性和可生物降解的纳米颗粒（NP），用于LA的解毒。这些NP将依赖于吸收（微乳液）、吸附（电子受体）或两种机制（2种类型的“智能”微乳液）来降低各种介质中LA的游离浓度，并降低LA在组织和完整生物体中的生物学效应。将对NP进行研究，以1）详细描述NP-LA相互作用的物理化学表征（目的A），2）确定生物系统中NP是否可以减弱LA的心脏毒性作用（目的B）。这个高度跨学科的项目涵盖有机化学，工程和医学，包含两个目标和三个具体目标：具体目标#1：确定NP从简单（生理盐水）和复杂（人血浆和血液）介质中去除LA的提取效率。优化各种NP的LA提取效率。具体目标#2：确定不同类型的NP可以有效提取LA的分子机制。具体目标#3：确定纳米颗粒在三个功能水平上减弱或逆转LA的心脏毒性作用的有效性：1）单细胞（心室肌细胞），2）组织（离体心脏）和3）完整大鼠（闭胸）。