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.

疼痛是一个非常普遍的临床问题，导致数百万人遭受痛苦。持续的疼痛治疗 比短暂的程序更长可能很困难，并且可能需要使用阿片类药物，并具有其副作用和 成瘾和转移的潜力。在这项研究中，我们试图开发可注射的药物输送系统 （DDS）使用持续释放技术提供持续延长持续时间局部麻醉（PDLA） 持续数小时到几天，以使周期性疼痛，甚至持续数周的慢性疼痛。此外，我们是 开发患者可以确定何时接受局部麻醉的DDS，多么强烈 麻醉是持续的时间。那些按需DDS（称为触发的局部麻醉药）受到控制 通过外部能源，例如近红外光和超声。连续和触发的DD 有可能彻底改变疼痛管理，并推进药物输送科学。他们可以 还减轻或避免使用阿片类药物。 理想情况下，所有DD都应：通过一次注射进行；易于管理；不需要一般 麻醉或手术启动；最后几天；没有局部炎症，局部神经或肌毒性或 系统性毒性；完全可生物降解和可逆；具有成本效益，易于制作和稳定。 可触发的系统应易于与安全方便的设备一起使用。 我们的策略是使用持续的释放车辆提供1个站点1钠通道阻滞剂 （S1SCB），例如萨克西毒素和四毒素与已知可以增强其增强的化合物结合 神经阻滞的持续时间，例如常规的局部麻醉和类固醇。在PDLA中，我们取得了成就 含有S1SCB和其他药物的脂质体配方，可以实现大鼠的坐骨神经块 持续一周，具有最小的系统性和局部毒性。在触发的局部麻醉中，我们已经产生了 含有S1SCB和其他药物的脂质体产生了最初的神经阻滞，以便于此 通过用近红外光或 超声波。在过去的5年中，这项工作产生了31篇论文，其中许多是在著名的期刊中。 在PDLA中，我们提出了一系列潜在方法，以产生更长的块，同时改善 安全。在触发的洛杉矶中，我们提出了调节或否定初始神经阻滞的方法，扩展数量 可触发的事件，并延长可以触发的时间框架 - 允许在慢性疼痛中使用。 应对这些挑战将需要克服生物材料 /药物输送 /纳米科学的挑战， 包括增强高度水溶性充电药物在DDS中的负载，从而最大程度地减少其初始快速 （“爆发”）释放，延长了其释放持续时间和 /或最大程度地减少其基线（未触发）释放。 重要的是，新方法对组织反应的影响将使用组织学和 毒性方法。