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1号位钠通道阻滞剂的颗粒状长效局麻药(PDLA)，如肉毒杆菌毒素(STX)。到目前为止，这条调查路线一直非常富有成效；自3.5年前开始目前的R01以来，我们已经完成了31篇论文，达到或超过了我们特定目标的目标。潜在的假设--在前面的研究中得到了验证--是STX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。我们的研究可能适用于任何可兴奋的组织，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。我们的基础配方是一种含有萨曲霉毒素和其他药物的脂质体，我们已经证明，我们可以获得持续一周的神经阻滞，全身和局部毒性最小。我们提出了一系列可能的修改，以在保持安全的同时生产更长的块。这些措施包括生产单剂微粒、构建二次聚合物外壳、在微粒内外使用水凝胶，以及设计宏观装置。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，并通过跟踪血清药物水平来在体内评估这些新配方的有效性和毒性。这项研究的另一个关键方面尚未得到足够的重视，将研究这些制剂的炎症、肌肉毒性和神经毒性的发展，以及预防它们的方法。 与公共健康相关：手术后的长期疼痛和慢性疼痛折磨着美国和全球数百万人。这项应用的目的是开发一种方法，通过一次注射治疗这种局部疼痛，这种注射可以持续几天到几周，而患者不必服用会影响他们大脑的止痛药。

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.