Prolonged duration and triggered local anesthesia

持续时间延长并引发局部麻醉

• 批准号: 9912163
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912163
• 关键词: Address; Anesthesia procedures; Biocompatible Materials; Charge; Clinical; Devices; Drug Delivery Systems; Energy-Generating Resources; Event; Formulation; 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; Pharmaceutical Preparations; Procedures; Rattus; Reaction; Research; Safety; Saxitoxin; Science; Site; Sodium Channel Blockers; Steroids; System; Technology; Tetrodotoxin; Time; Tissues; Toxic effect; Toxicogenomics; Ultrasonography; Water; Work; addiction; chronic pain; cost effective; improved; nanoscience; novel strategies; opioid use; pain relief; sciatic nerve; side effect; surgical pain; systemic toxicity

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，导致数百万人遭受痛苦。持续疼痛的治疗 比简短的程序更长的时间可能是困难的，可能需要使用阿片类药物，其副作用， 成瘾和转移的可能性。在这项研究中，我们寻求开发注射给药系统 (DDS)使用持续释放技术提供持续延长时间的局部麻醉（PDLA） 持续数小时至数天的围手术期疼痛，或甚至数周的慢性疼痛。此外，我们在 开发DDS，患者可以确定何时接受局部麻醉， 麻醉是什么以及能持续多久这些按需DDS（称为触发局部麻醉剂）是受控的 通过外部能源，如近红外光和超声波。连续DDS和触发DDS 有可能彻底改变疼痛管理，并推进药物输送科学。他们可以 也可以减轻或减少阿片类药物的使用。 理想情况下，所有DDS都应：通过单次注射递送;易于管理;不需要一般的药物。 麻醉或手术开始;持续数天-数周;未引起局部炎症、局部神经或肌肉毒性，或 全身毒性;可完全生物降解和可逆;成本有效、易于制备和稳定。 可触发系统应易于使用，设备安全方便。 我们的策略一直是使用缓释车辆提供网站1钠通道阻滞剂 （S1 SCB）如石房蛤毒素和河豚毒素与已知增强其生物活性的化合物的组合。 神经阻滞的持续时间，如传统的局部麻醉剂和类固醇。在PDLA中，我们实现了 含有S1 SCBs和其他药物的脂质体制剂，可在大鼠中实现坐骨神经阻滞 持续一周，全身和局部毒性最小。在触发局部麻醉中，我们产生了 含有S1 SCB和其他药物的脂质体，产生最初的神经阻滞，然后消退， 通过用近红外光瞄准注射部位， 超声.这项工作在过去5年中产生了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的方法来产生更长的块，同时提高 安全为代价的在触发LA中，我们提出了调节或否定初始神经阻滞的方法， 可预测的事件，并延长其可被触发的时间范围-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中高度水溶性的带电药物的负载， 在一些实施方案中，所述药物组合物可包括释放（“爆发”）、延长其释放持续时间和/或使其基线（未触发）释放最小化。 重要的是，新方法对组织反应的影响将进行研究，使用组织学和 毒理基因组学方法。