Prolonged duration local anesthesia

长时间局部麻醉

• 批准号: 7612459
• 负责人: Daniel S Kohane
• 金额: $ 11.72万
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612459
• 关键词: Address; Affect; Agonist; Amides; Attention; Award; Binding; Biological; Bupivacaine; Chemosensitization; Clinical; Condition; Controlled Environment; Development; Dexamethasone; Dose; Drug Formulations; Encapsulated; Engineering; Esters; Evolution; Glucocorticoid Receptor; Glucocorticoids; Grant; Growth and Development function; Hyaluronic Acid; In Vitro; Inflammation; Injectable; Investigation; Local Anesthetics; Local anesthesia; Malignant Neoplasms; Methodology; Methods; Microspheres; Modeling; Modification; Morbidity - disease rate; Muscle; Myocardium; Nerve; Nerve Block; Oryctolagus cuniculus; Pain; Patients; Perioperative; Polyanhydrides; Polymers; Postoperative Period; Preparation; Principal Investigator; Problem Formulations; Process; Publications; Purpose; Rabies; Rattus; Refractory; Reporting; Research; Serum; Site; Sodium Channel; Sodium Channel Blockers; Steroids; System; Tetrodotoxin; Tissues; Toxic effect; Toxin; Uterus; Week; Work; base; brain tissue; chronic pain; controlled release; day; in vivo; nerve injury; nervous system disorder; neurobehavioral test; neurotoxicity; painful neuropathy; particle; poly (lactic-co-glycolic acid); polylactic acid-polyglycolic acid copolymer; relating to nervous system; sciatic nerve

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 microparticle based prolonged duration local anesthetics (PDLA) employing site 1 sodium channel blockers such as tetrodotoxin (TTX). The underlying hypothesis - which was validated in preceding research - is that TTX, 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. The research could potentially be applicable to any excitable tissue (brain, muscle, heart, uterus), 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. Microspheres of a-hydroxy ester polymers such as PLGA, containing TTX, bupivacaine, and dexamethasone will be modified sequentially as needed to minimize burst release and extend release in vitro. The spectrum of potential modifications includes constructing secondary polymeric shells, use of cross- linkable hyaluronic acids inside or outside of the particles, using alternative polymers such as polyanhydrides, and devising TTX-only systems, since TTX - unlike conventional local anesthetics - is not believed to cause myo- or neurotoxicity. 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 levels. Another crucial aspect of the research, which has not received sufficient attention, will be to understand of factors that contribute to the development of inflammation, myotoxicity, and neurotoxicity with PLDA formulations, and perhaps mitigating or avoiding those.

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基于微粒的长效局部麻醉药（PDLA），其采用位点1钠通道阻断剂如河豚毒素（TTX）。在先前的研究中得到验证的基本假设是，TTX与传统的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。这项研究可能适用于任何易兴奋的组织（大脑，肌肉，心脏，子宫），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。含有TTX、布比卡因和地塞米松的α-羟基酯聚合物如PLGA的微球将根据需要依次修饰，以使突释最小化并延长体外释放。潜在修饰的范围包括构建第二聚合物壳，在颗粒内部或外部使用交联透明质酸，使用替代聚合物如聚酸酐，以及设计仅TTX系统，因为TTX -与常规局部麻醉剂不同-不被认为会引起肌肉或神经毒性。同样重要的目的是通过大鼠和兔的神经行为试验以及通过以下血清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，将是了解导致PLDA制剂炎症，肌肉毒性和神经毒性发展的因素，并可能减轻或避免这些因素。