PROLONGED DURATION LOCAL ANESTHESIA

延长局部麻醉时间

基本信息

批准号：
6712087
负责人：
Daniel S Kohane
金额：
$ 12.45万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2005-02-28
项目状态：
已结题

项目摘要

I am a pediatric intensivist and anesthesiologist with a PhD in physiology. My principal clinical interests are neuronal injury and chronic pain. This research proposal develops the principles and methods of controlled release technology to produce prolonged duration local anesthetics. This mentored research in chemical engineering, molecular biology and neurobiology, in conjunction with appropriate coursework, will foment competence in biotechnological approaches to medical problems. These approaches are potentially germane to a wide range of medical applications and substrates (peptides, genes, even cells). Thus, this program will foster the abilities and mindset necessary to train me to be an independent investigator. Chronic pain is a major cause of morbidity, particularly in patients suffering from cancer or neuropathic conditions. These painful states are often refractory to therapy. This research will endeavor to produce polymer-based particles containing compounds with local anesthetic properties in order to achieve pain relief lasting many weeks. In particular, the novel formulations will take advantage of synergistic interactions between conventional amino amide local anesthetics and site 1 sodium channel blockers, as well as the potentiating effect of adjuncts such as glucocorticoids. Selection of the optimal site 1 sodium channel blocker for this project will result from a pharmacological comparison in terms of efficacy, functional selectivity, and toxicity. The selected toxin 'will then be encapsulated in poly-(lactic- co-glycolic) acid microspheres, which will then be optimized in term of loading and in vitro release kinetics. These microspheres will be tested with respect to efficacy (depth, duration, and functional selectivity of nerve blockade) and systemic toxicity (systemiC analgesia, weakness, respiratory distress, seizures, death) when injected alone, or in conjunction with microspheres containing bupivacaine and/or dexamethasone. The biological consequences and local neurotoxicity of these formulations will be investigated by a) histologic assessment of inflammation, b) examination for the development of pain-related behaviors such as autotomy, which are believed to be related to neuropathic pain, c) measuring their impact on the expression of Growth Associated Peptide-43 (GAP-43), a cytoskeletal phosphoprotein that has been associated with the neural response to injury, in the dorsal root ganglia of the sciatic nerve. Finally, we will study the effectiveness of prolonged duration local anesthesia in preventing or mitigating the development of pain-related behaviors and the rise in GAP-43 expression following nerve crush injury.

我是一名儿科重症监护医师和麻醉师，拥有生理学博士学位。我的主要临床兴趣是神经元损伤和慢性疼痛。该研究计划开发了控释技术的原理和方法，以生产延长持续时间的局部麻醉剂。这项在化学工程、分子生物学和神经生物学方面的指导研究，与适当的课程相结合，将培养用生物技术方法解决医学问题的能力。这些方法可能与广泛的医学应用和底物（肽、基因，甚至细胞）密切相关。因此，这个项目将培养我成为一名独立调查员所需的能力和心态。慢性疼痛是发病的主要原因，尤其是患有癌症或神经性疾病的患者。这些痛苦的状态通常难以治疗。这项研究将致力于生产含有具有局部麻醉特性的化合物的聚合物颗粒，以实现持续数周的疼痛缓解。特别是，新制剂将利用传统氨基酰胺局麻药和位点 1 钠通道阻滞剂之间的协同相互作用，以及糖皮质激素等辅助剂的增强作用。该项目的最佳位点 1 钠通道阻滞剂的选择将通过功效、功能选择性和毒性方面的药理学比较得出。然后，选定的毒素将被封装在聚（乳酸-乙醇酸）微球中，然后在负载和体外释放动力学方面对其进行优化。当单独注射或与含有布比卡因和/或的微球一起注射时，将测试这些微球的功效（神经阻滞的深度、持续时间和功能选择性）和全身毒性（全身镇痛、虚弱、呼吸窘迫、癫痫发作、死亡）。或地塞米松。这些制剂的生物学后果和局部神经毒性将通过以下方式进行研究：a) 炎症的组织学评估，b) 检查疼痛相关行为的发生，例如自切，据信与神经性疼痛有关，c) 测量其影响坐骨神经节背根神经节中生长相关肽 43 (GAP-43) 的表达，这是一种细胞骨架磷蛋白，与损伤的神经反应相关神经。最后，我们将研究长时间局部麻醉在预防或减轻疼痛相关行为的发生以及神经挤压损伤后 GAP-43 表达升高的有效性。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lipid-sugar particles for intracranial drug delivery: safety and biocompatibility.

用于颅内药物递送的脂糖颗粒：安全性和生物相容性。

DOI：
10.1016/s0006-8993(02)02878-0
发表时间：
2002
期刊：
Brain research
影响因子：
2.9
作者：
Kohane,DanielS;Plesnila,Nikolaus;Thomas,SunuS;Le,Dean;Langer,Robert;Moskowitz,MichaelA
通讯作者：
Moskowitz,MichaelA

High concentrations of adrenergic antagonists prolong sciatic nerve blockade by tetrodotoxin.

高浓度的肾上腺素能拮抗剂可延长河豚毒素对坐骨神经的阻滞时间。