Prolonged duration local anesthesia

长时间局部麻醉

• 批准号: 7657300
• 负责人: Daniel S Kohane
• 金额: $ 28.83万
• 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/7657300
• 关键词: Address; Affect; Agonist; Amides; Attention; Award; Binding; Biological; Bupivacaine; Chemosensitization; Clinical; Development; Dexamethasone; Dose; Drug Formulations; Encapsulated; Engineering; Environment; Esters; Evolution; Glucocorticoid Receptor; Glucocorticoids; Glycolates; 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; Rabies; Rattus; Refractory; Reporting; Research; Serum; Site; Sodium Channel; Sodium Channel Blockers; Steroids; System; Tetrodotoxin; Tissues; Toxic effect; Toxin; Uterus; Work; base; brain tissue; chronic pain; controlled release; in vivo; nerve injury; nervous system disorder; neurobehavioral test; neurotoxicity; painful neuropathy; particle; 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——尤其是慢性疼痛——是发病的主要原因，尤其是患有癌症或神经性疼痛的患者。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剂 (PDLA)，采用 1 号位点钠通道阻滞剂，例如河豚毒素 (TTX)。基本假设（已在之前的研究中得到验证）是，TTX 与传统局部麻醉剂和类固醇等化合物结合封装，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来治疗慢性疼痛，或者可以针对其他（例如围手术期）应用进行定制以缩短持续时间。该研究可能适用于任何可兴奋的组织（大脑、肌肉、心脏、子宫），实际上适用于任何可以使用控释的环境。这项研究的一个具体目标是解决困难的配方问题，例如在封装潜在有毒的亲水性分子时出现的突发释放问题。含有 TTX、布比卡因和地塞米松的 α-羟基酯聚合物（例如 PLGA）微球将根据需要依次进行修饰，以最大程度地减少突释并延长体外释放。潜在的修改范围包括构建二级聚合物壳、在颗粒内部或外部使用可交联的透明质酸、使用聚酸酐等替代聚合物，以及设计仅使用 TTX 的系统，因为 TTX 与传统的局部麻醉剂不同，据信不会引起肌肉或神经毒性。同样重要的目标是通过大鼠和兔子的神经行为测试以及跟踪血清水平来体内评估这些新制剂的功效和毒性。该研究的另一个尚未得到足够重视的重要方面是了解导致 PLDA 制剂产生炎症、肌肉毒性和神经毒性的因素，并可能减轻或避免这些因素。