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号位点钠通道阻滞剂如蛤蚌毒素（STX）开发颗粒延长持续时间局部麻醉剂（PDLA）。迄今为止，这方面的研究成果颇丰；本次R01从3.5年前开始至今，我们已经发表了31篇论文，达到或超过了我们的具体目标。潜在的假设——在之前的研究中得到了验证——是STX，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。我们的研究可能适用于任何可兴奋的组织，事实上，在任何环境中，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，如爆发释放，这是出现在封装潜在有毒的亲水分子。我们的基本配方是含有蛤蚌毒素和其他药物的脂质体，我们已经证明，我们可以在最小的全身和局部毒性的情况下获得持续一周的神经阻滞。我们提出了一系列潜在的修改，以生产更长的区块，同时保持安全。这些包括生产单剂微粒，构建二级聚合物外壳，在微粒内部或外部使用水凝胶，以及设计宏观装置。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，并通过跟踪血清药物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研究这些配方的炎症、肌肉毒性和神经毒性的发展，以及预防它们的方法。

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.