Prolonged duration and triggered local anesthesia

持续时间延长并引发局部麻醉

• 批准号: 10609009
• 负责人: Daniel S Kohane
• 金额: $ 64.8万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609009
• 关键词: Address; Anesthesia procedures; Biocompatible Materials; Charge; Clinical; Devices; Drug Delivery Systems; Energy-Generating Resources; Event; General Anesthesia; Histologic; Hour; Inflammation; Injectable; Injections; Journals; Light; Liposomes; Local Anesthetics; Local anesthesia; Nerve; Nerve Block; Operative Surgical Procedures; Opioid; Pain; Pain management; Paper; Patients; Perioperative; Persistent pain; Persons; Pharmaceutical Preparations; Postoperative Pain; Procedures; Rattus; Reaction; Research; Safety; Saxitoxin; Science; Site; Sodium Channel Blockers; Steroids; System; Technology; Tetrodotoxin; Time; Tissues; Toxic effect; Toxicogenomics; Water; Work; addiction liability; chronic pain; cost effective; improved; liposomal formulation; nanoscience; novel strategies; opioid use; pain relief; sciatic nerve; side effect; surgical pain; systemic toxicity; ultrasound

Pain is a very common clinical problem, causing suffering in millions of people. Treatment of pain that lasts longer than a brief procedure can be difficult and can entail the use of opioids, with their side effects and potential for addiction and diversion. In this research we seek to develop injectable drug delivery systems (DDS) using sustained release technology to provide continuous prolonged duration local anesthesia (PDLA) lasting many hours to days for perioperative pain, or even weeks for chronic pain. In addition, we are developing DDS where the patient could determine when she or he receives local anesthesia, how intense the anesthesia is, and how long it lasts. Those on-demand DDS (termed triggered local anesthetics) are controlled by external energy sources such as near-infrared light and ultrasound. Both the continuous and triggered DDS have the potential to revolutionize pain management, and advance the science of drug delivery. They could also mitigate or obviate opioid use. All the DDS should ideally: be delivered by a single injection; be easy to administer; not require general anesthesia or surgery to initiate; last days-weeks; cause no local inflammation, local neuro- or myotoxicity, or systemic toxicity; be fully biodegradable and reversible; be cost effective, easy to make, and stable. Triggerable systems should be easy to use with a safe and convenient device. Our strategy has been to use sustained release vehicles to deliver site 1 sodium channel blockers (S1SCBs) such as saxitoxin and tetrodotoxin in combination with compounds that are known to enhance their duration of nerve blockade, such as conventional local anesthetics and steroids. In PDLA, we have achieved a liposomal formulation containing S1SCBs and other drugs, which can achieve sciatic nerve blocks in the rat lasting a week with minimal systemic and local toxicity. In triggered local anesthesia, we have produced liposomes containing S1SCBs and other drugs which produce an initial nerve block that resolves, after which nerve block can be safely and repeatedly re-induced by targeting the injection site with near-infrared light or ultrasound. This work produced 31 papers in the past 5 years, many in prominent journals. In PDLA, we propose a spectrum of potential approaches to produce yet longer blocks while improving safety. In triggered LA, we propose means to modulate or negate the initial nerve block, extend the number of triggerable events, and extend the time frame over which they can be triggered – allowing use in chronic pain. Addressing these challenges will entail overcoming challenges in biomaterials / drug delivery / nanoscience, including enhancing the loading of highly water-soluble charged drugs in DDS, minimizing their initial rapid (“burst”) release, extending their duration of release, and /or minimizing their baseline (un-triggered) release. Importantly, the impact of new approaches on tissue reaction will be studied, using histological and toxicogenomic approaches.

疼痛是一种非常常见的临床问题，给数百万人带来持续疼痛的治疗。 比简短的手术更长的时间可能会很困难，并且可能需要使用阿片类药物，其副作用和 在这项研究中，我们寻求开发注射药物输送系统。 (DDS) 使用缓释技术提供持续长时间的局部麻醉 (PDLA) 围手术期疼痛持续数小时至数天，慢性疼痛甚至持续数周。 开发 DDS，患者可以确定她或他何时接受局部麻醉、麻醉强度如何 麻醉的时间和持续时间是受控制的。 通过外部能源，例如近红外光和超声波，连续 DDS 和触发 DDS。 有潜力彻底改变疼痛管理，并推进药物输送科学。 还可以减少或避免阿片类药物的使用。 所有 DDS 理想情况下应： 通过单次注射进行给药； 不需要常规给药； 麻醉或手术开始；最后几天或几周没有引起局部炎症、局部神经或肌肉毒性，或 全身毒性；可完全生物降解且可逆；成本效益高、易于制造且稳定。 可触发系统应该易于使用安全、方便的设备。 我们的策略是使用缓释载体来递送位点 1 钠通道阻滞剂 (S1SCB)，例如石房蛤毒素和河豚毒素，与已知可增强其作用的化合物相结合 在 PDLA 中，我们已经实现了神经阻滞的持续时间，例如常规局部麻醉剂和类固醇。 含有S1SCBs等药物的脂质体制剂，可实现大鼠坐骨神经阻滞 持续一周，全身和局部毒性最小。在触发局部麻醉中，我们生产了。 含有 S1SCB 和其他药物的脂质体可产生初始神经阻滞，随后缓解 通过用近红外光或近红外光瞄准注射部位，可以安全、重复地重新诱导神经阻滞 这项工作在过去 5 年中发表了 31 篇论文，其中许多发表在著名期刊上。 在 PDLA 中，我们提出了一系列潜在方法来生产更长的块，同时改进 在触发性 LA 中，我们提出了调节或取消初始神经阻滞、延长神经阻滞次数的方法。 可触发事件，并延长触发事件的时间范围——允许用于慢性疼痛。 应对这些挑战将需要克服生物材料/药物输送/纳米科学方面的挑战， 包括增强 DDS 中高水溶性药物的负载量，最大限度地减少其初始快速反应 （“突发”）释放，延长其释放持续时间，和/或最大限度地减少其基线（未触发）释放。 重要的是，将利用组织学和方法研究新方法对组织反应的影响。 毒理学方法。