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。这项研究的目标是开发持续时间较长的局部麻醉药(PDLA)，根据临床情况(围手术期疼痛与慢性疼痛)，从一次注射开始提供持续数天至数周的局部麻醉。我们的策略一直是使用各种缓释载体来传递现场 1钠通道阻滞剂(S1SCB)，如萨克托毒素(STX)和河豚毒素(TTX)，与已知对神经阻滞持续时间有协同或辅助作用的化合物，如常规局部麻醉药和类固醇。到目前为止，这条调查路线一直很有成效；自3.5年前开始目前的R01以来，我们已经出版了29份出版物，达到或超过了我们特定目标的目标。我们的基础配方是含有S1SCB和其他药物的脂质体，我们已经证明，我们可以在大鼠身上获得持续一周的坐骨神经阻滞，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。一个同样重要的目标是通过对大鼠和兔子进行神经行为测试，通过跟踪血清药物水平，在体内评估这些新配方的有效性和全身毒性。这项研究的另一个关键方面尚未得到足够的重视，将使用组织学和毒素基因组学方法研究这些制剂的炎症、肌肉毒性和神经毒性的发展。

 DESCRIPTION (provided by applicant): Pain - particularly chronic pain - is a major cause of morbidity, especially in patients with cancer or neuropathic pain. The goal of this research is to develop prolonged duration local anesthetics (PDLA) that would provide local anesthesia lasting days to weeks from a single injection, depending on the clinical context (perioperative vs. chronic pain). Our strategy has been to use a variety of sustained release vehicles to deliver site 1 sodium channel blockers (S1SCBs) such as saxitoxin (STX) and tetrodotoxin (TTX) in combination with compounds that are known to have synergistic or adjunctive effects on the duration of nerve blockade, such as conventional local anesthetics and steroids. To date, this line of inquiry has been very productive; since the current R01 began 3.5 years ago, we have produced 29 publications, and met or exceeded the goals of our Specific Aims. Our base formulation is a liposome containing S1SCBs and other drugs, where we have shown we can obtain sciatic nerve blocks in the rat lasting a week with minimal systemic and local toxicity. We propose a spectrum of potential modifications to produce yet longer blocks while maintaining safety. An equally important aim will be the in vivo assessment of the efficacy and systemic toxicity of these new formulations by neurobehavioral tests in rats and rabbits, 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, using histological and toxicogenomic approaches.