Prolonged duration local anesthesia

描述（由申请人提供）：疼痛-特别是慢性疼痛-是发病率的主要原因，特别是在癌症或神经性疼痛患者中。这些情况往往难以治疗。本研究的目的是利用1位钠通道阻滞剂如河豚毒素（TTX）开发基于微颗粒的长效局部麻醉剂（PDLA）。潜在的假设——在之前的研究中得到了验证——是TTX，与传统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，对于慢性疼痛，PDLA可以持续数周到数月，或者可以为其他（如围手术期）应用量身定制更短的持续时间。这项研究可能适用于任何可兴奋的组织（大脑、肌肉、心脏、子宫），实际上也适用于任何控制释放可能有用的环境。这项研究的一个具体目的是解决困难的配方问题，如爆发释放，这是出现在封装潜在有毒的亲水分子。含有TTX、布比卡因和地塞米松的a-羟基酯聚合物微球，如PLGA，将根据需要依次修改，以减少体外爆发释放和延长释放。潜在的修饰包括构建二级聚合物外壳，在颗粒内外使用可交联的透明质酸，使用诸如聚酸酐之类的替代聚合物，以及设计仅限TTX的系统，因为TTX不像传统的局部麻醉剂那样被认为不会引起肌肉或神经毒性。一个同样重要的目标将是通过在大鼠和家兔身上进行神经行为试验，并通过跟踪血清水平来评估这些新配方的有效性和毒性。该研究的另一个尚未得到足够重视的关键方面将是了解导致PLDA配方产生炎症、肌肉毒性和神经毒性的因素，并可能减轻或避免这些因素。

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.