Prolonged Duration Local Anesthesia

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采用 1 号位点钠通道阻滞剂（如石房蛤毒素 (STX)）的微粒长效局麻药 (PDLA)。迄今为止，这一调查工作非常富有成效。自 3.5 年前开始当前的 R01 以来，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。我们的研究可能适用于任何可兴奋的组织，实际上适用于控制释放可能有用的任何环境。这项研究的一个具体目标是解决困难的制剂问题，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。我们的基础配方是含有石房蛤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，并且全身和局部毒性最小。我们提出了一系列潜在的修改，以在保持安全的同时生产更长的区块。这些包括生产单剂微粒、构建二级聚合物壳、在颗粒内部或外部使用水凝胶以及设计宏观装置。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药物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研究这些制剂引起的炎症、肌肉毒性和神经毒性的发展以及预防它们的方法。 公共卫生相关性：手术后的长期疼痛和慢性疼痛困扰着美国和全球数百万人。该应用的目的是开发一种方法，通过单次注射治疗这种局部疼痛，这种方法可以持续数天到数周，而患者不必服用会影响他们思维的止痛药。

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.