Prolonged duration local anesthesia

描述(申请人提供)：疼痛--尤其是慢性疼痛--是发病率的主要原因，尤其是癌症或神经性疼痛的患者。这些情况往往难以治疗。本研究的目的是开发使用河豚毒素(TTX)等钠通道阻滞剂的微粒长效局麻药(PDLA)。潜在的假设--在之前的研究中得到了验证--是TTX与常规的局部麻醉剂和类固醇等化合物结合在一起，可以产生极长的神经阻滞。正如这里所设想的，PDLA可以持续数周到数月来治疗慢性疼痛，或者可以为其他(例如围手术期)应用量身定做较短的持续时间。这项研究可能适用于任何可兴奋的组织(脑、肌肉、心脏、子宫)，实际上也适用于任何可控释放有用的环境。这项研究的一个具体目标是解决困难的配方问题，如突发释放，这些问题在封装潜在有毒的亲水分子时出现。含有TTX、布比卡因和地塞米松的α-羟基酯聚合物微球，如PLGA，将根据需要进行顺序修饰，以最大限度地减少突释和延长体外释放。潜在的修饰包括构建二次聚合物外壳，在颗粒内外使用可交叉连接的透明质酸，使用聚酸酐等替代聚合物，以及设计仅针对TTX的系统，因为TTX-不同于传统的局部麻醉药-被认为不会导致肌肉或神经毒性。一个同样重要的目标是通过在大鼠和兔子身上进行神经行为测试，并通过跟踪血清水平来在体内评估这些新配方的有效性和毒性。这项尚未得到足够重视的研究的另一个关键方面是了解导致PLDA制剂炎症、肌肉毒性和神经毒性发展的因素，并可能缓解或避免这些因素。

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.