Prolonged duration local anesthesia

长时间局部麻醉

• 批准号: 7012054
• 负责人: Daniel S Kohane
• 金额: $ 29.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012054
• 关键词: anesthetics; chemical synthesis; chronic pain; combination therapy; corticosteroid receptors; dexamethasone; dosage forms; drug design /synthesis /production; glycolates; inflammation; ion channel blocker; laboratory rabbit; laboratory rat; lactates; local anesthesia; microcapsule; neuropharmacology; neuropsychological tests; neurotoxicology; pharmacokinetics; piperidine; polymers; slow release drug; sodium channel; tetrodotoxin; toxicant screening

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.

描述（由申请人提供）：疼痛 - 尤其是慢性疼痛 - 是发病率的主要原因，尤其是在癌症或神经性疼痛的患者中。这些疾病通常是对治疗的难治性。这项研究的目的是开发基于微粒的延长持续时间局部麻醉（PDLA），该麻醉（PDLA）采用位点1钠通道阻滞剂，例如四毒素（TTX）。基本假设（在先前的研究中得到了验证）是，与常规局部麻醉剂和类固醇等化合物结合使用的TTX可以产生极长的神经阻滞。如这里设想的那样，PDLA可能会持续数周到几个月来缓解慢性疼痛，或者可以针对其他（例如围手术期）应用定制为较短的持续时间。这项研究可能适用于任何可激发的组织（大脑，肌肉，心脏，子宫），实际上是在任何受控释放的环境中都可能有用的。这项研究的一个具体目的是解决困难的制剂问题，例如爆发，这是在封装潜在有毒的亲水分子的过程中出现的。 A-羟基酯聚合物的微球，例如PLGA，含有TTX，Bupivacaine和地塞米松的微球，根据需要进行依次修改，以最大程度地减少爆发释放并在体外扩展释放。潜在修饰的光谱包括构建二次聚合物壳，使用颗粒内部或外部的跨透明质酸的使用，使用替代聚合物（例如多丙二醇），以及设计唯一的TTX系统，因为TTX-与常规的局部麻醉剂一样，不会引起肌毒性的常规麻醉。同样重要的目的是通过神经行为测试在大鼠和兔子中对这些新制剂的疗效和毒性进行体内评估，并通过遵循血清水平来评估。该研究的另一个关键方面尚未受到足够的关注，将是了解有助于使用PLDA配方的炎症，肌毒性和神经毒性发展的因素，并可能减轻或避免。