Local Anesthetic Cardiotoxicity: Nanotechnology Therapy

局部麻醉心脏毒性：纳米技术治疗

• 批准号: 6562963
• 负责人: DONN MICHAEL DENNIS
• 金额: $ 27.72万
• 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/6562963
• 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(申请人提供)：局麻药(LAS)通过电压、时间和频率依赖地阻断钠通道电导(I-Na)，可逆地阻止神经中的脉冲传递。这些药理作用为LAS在临床治疗中的应用奠定了基础，为外科手术或分娩的患者提供区域麻醉(例如，硬膜外阻滞)。然而，不经意的血管内注射或过量注射可能会导致其他组织(例如心脏、中枢神经系统)出现不希望看到的异丙肾上腺素阻断，从而导致潜在的威胁生命的不良事件(例如心脏骤停、癫痫发作)。虽然LA过量导致的癫痫发作和呼吸抑制具有潜在的生命危险，但这些事件可以分别用抗癫痫药物和有控制的人工呼吸机进行治疗。同等或更重要的是，目前治疗血管内注射引起的心脏毒性的选择很少(例如，ACLS)。出于这些原因，一种能够快速、有效地治疗LA毒性的心脏影响的试剂或技术将是有用的。这笔赠款的目的是产生必要的知识，以创造专门为治疗遭受LAS毒性影响的患者而设计的药物。粒子科学工程的最新进展现在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。具体地说，最近出现的纳米技术具有解决重大生物医学问题的巨大潜力，现在为解决LA毒性问题提供了无与伦比的机会。美国国家科学基金会粒子科学与技术工程研究中心的同事们将合成四种直径为10-100 nm的生物兼容和可生物降解的纳米颗粒(NPs)，用于LAS的解毒。这些纳米粒子将依靠吸收(微乳液)或吸附(电子受体)，或两者兼而有之(两种类型的“智能”微乳液)来降低LA在各种介质中的游离浓度，并降低LA在组织和完整生物中的生物效应。将对NPs进行研究，以1)详细描述NP-LA相互作用的物理化学特征(目标A)，以及2)确定在生物系统中NPs能否减弱LAS的心脏毒性作用(目标B)。这个涉及有机化学、工程学和医学的高度多学科项目包含两个目标和三个具体目标：具体目标#1：确定NPs的提取效率，以从简单(生理盐水)和复杂(人体血浆和血液)介质中去除LAS。优化各种纳米粒子的乳酸提取效率。具体目标#2：确定不同类型的NPs有效提取LAS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轻或逆转LAS心脏毒性效应的有效性：1)单个细胞(心室肌细胞)，2)组织(离体心)，3)完整大鼠(关闭胸腔)。