Prolonged Duration Local Anesthesia

长时间局部麻醉

• 批准号: 7985350
• 负责人: Daniel S Kohane
• 金额: $ 37.12万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985350
• 关键词: Address; Adverse effects; Agonist; Analgesics; Animals; Area; Attention; Award; Basic Science; Biological; Bupivacaine; Chemicals; Clinical Trials; Development; Devices; Dexamethasone; Drug Formulations; Encapsulated; Enhancers; Environment; Evolution; Extravasation; Genomics; Glucocorticoids; Glycolates; Goals; Growth and Development function; Hydrogels; Inflammation; Injectable; Injection of therapeutic agent; Injury; Investigation; Lead; Liposomes; Literature; Local Anesthetics; Local anesthesia; Methods; Microspheres; Mind; Modeling; Modification; Morbidity - disease rate; Nerve; Nerve Block; Neuraxis; Oryctolagus cuniculus; Pain; Paper; Particulate; Patients; Perioperative; Pharmaceutical Preparations; Postoperative Period; Principal Investigator; Problem Formulations; Process; Progress Reports; Publishing; Rattus; Refractory; Research; Safety; Saxitoxin; Scientist; Sensory; Serum; Site; Sodium Channel Blockers; Steroids; Technology; Tetrodotoxin; Tissues; Toxic effect; Work; base; cancer pain; chronic pain; controlled release; design; in vivo; meetings; mortality; nanoparticle; nervous system disorder; neurobehavioral test; neurotoxicity; painful neuropathy; particle; prevent; relating to nervous system; sciatic nerve; skills; success; surgical pain; tool

DESCRIPTION (provided by applicant): Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. These conditions are often refractory to treatment. The purpose of this research is to develop particulate prolonged duration local anesthetics (PDLA) employing site 1 sodium channel blockers such as saxitoxin (STX). To date, this line of inquiry has been very productive; since the current R01 began 3.5 years ago, we have produced 31 papers, and met or exceeded the goals of our Specific Aims. The underlying hypothesis - which was validated in the preceding research - is that STX, encapsulated in combination with compounds such as conventional local anesthetics and steroids, can produce extremely long nerve blocks. As envisioned here, PDLA could last weeks to months for chronic pain, or could be tailored to shorter durations for other (e.g. perioperative) applications. Our research could potentially be applicable to any excitable tissue, and in fact to any environment where controlled release could be useful. One specific aim of this research is to resolve difficult formulation problems such as burst release, which arise in encapsulating potentially toxic hydrophilic molecules. Our base formulation is a liposome containing saxitoxin and other drugs, where we have shown we can obtain nerve blocks lasting a week with minimal systemic and local toxicity. We propose a spectrum of potential modifications to produce yet longer blocks while maintaining safety. These include producing single-agent microparticles, constructing secondary polymeric shells, use of hydrogels inside or outside of the particles, and devising macroscopic devices. An equally important aim will be the in vivo assessment of the efficacy and toxicity of these new formulations by neurobehavioral tests in rats and rabbits, and by following serum drug levels. Another crucial aspect of the research, which has not received sufficient attention, will be to study the development of inflammation, myotoxicity, and neurotoxicity with these formulations, and means of preventing them. PUBLIC HEALTH RELEVANCE: Prolonged pain after surgery and chronic pain afflict millions of people in the U.S. and across the globe. The purpose of this application is to develop means of treating such localized pain with a single injection that would last for days to weeks without patients having to take pain medications that would cloud their minds.

描述（由申请人提供）：疼痛-特别是慢性疼痛-是发病的主要原因，特别是在癌症或神经性疼痛患者中。这些病症通常难以治疗。本研究的目的是开发使用1号位点钠通道阻滞剂（例如蛤蚌毒素（STX））的颗粒状长效局部麻醉剂（PDLA）。到目前为止，这条调查路线已经非常富有成效;自从目前的R 01开始3.5年前，我们已经产生了31篇论文，并达到或超过了我们的具体目标的目标。在先前的研究中得到验证的基本假设是，STX与传统局部麻醉剂和类固醇等化合物结合使用，可以产生极长的神经阻滞。正如这里所设想的，PDLA可以持续数周至数月用于慢性疼痛，或者可以针对其他（例如围手术期）应用定制更短的持续时间。我们的研究可能适用于任何可兴奋的组织，事实上，任何环境中，控制释放可能是有用的。这项研究的一个具体目的是解决困难的配方问题，如突发释放，这出现在封装潜在的有毒亲水性分子。我们的基础配方是含有石房蛤毒素和其他药物的脂质体，我们已经证明我们可以获得持续一周的神经阻滞，全身和局部毒性最小。我们提出了一系列潜在的修改，以产生更长的块，同时保持安全。这些包括生产单剂微粒，构建二次聚合物壳，在颗粒内部或外部使用水凝胶，以及设计宏观装置。同样重要的目的是通过大鼠和家兔的神经行为试验以及通过跟踪血清药物水平，对这些新制剂的疗效和毒性进行体内评估。研究的另一个关键方面尚未得到足够的关注，将研究这些制剂的炎症，肌肉毒性和神经毒性的发展以及预防它们的方法。 公共卫生相关性：手术后的长期疼痛和慢性疼痛困扰着美国和地球仪的数百万人。本申请的目的是开发用单次注射治疗这种局部疼痛的方法，该方法将持续数天至数周，而患者不必服用会使他们的头脑模糊的止痛药。