EPIDURAL ANALGESICS: IN VITRO AND IN VIVO STUDIES

硬膜外镇痛药：体外和体内研究

• 批准号: 3213970
• 负责人: CHRISTOPHER M BERNARDS
• 金额: $ 28.93万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-13 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3213970
• 关键词: analgesics; cyclodextrins; dogs; drug administration routes; drug delivery systems; dura mater; epidural anesthesia; intracellular transport; lipid transport; liposomes; meninges; molecular weight; morphine; opiate alkaloid; opioid receptor; spinal cord; tissue /cell culture

Our long-term goal is to develop means of improving the quality of epidural opioid analgesia for patients in pain following surgery, trauma or cancer and its treatment. This research is designed to identify molecular characteristics that determine the balance between diffusion of opioids and other drugs across the meninges and drug uptake by the epidural venous plexus. The specific aims of this consortium project are to 1) determine which meningeal tissue - dura, arachnoid, or pia mater - is the principal barrier to diffusion of opioids, 2) identify physicochemical factors that influence meningeal permeability of drugs, 3) apply physicochemical information to prediction of meningeal permeability of opioids and alpha2-adrenergic agonists, 4) develop methods for modifying epidural analgesic availability to promote their meningeal diffusion, 5) determine the route (cisternal/venous) and kinetics of redistribution of epidurally administered drugs to systemic and supraspinal sites as a function of: molecular weight, lipid partition coefficients and solubility modifying agents, and 6) correlate the time course of redistribution of drug from the epidural space with the effects on spinal (analgesia) and supraspinally mediated responses (ventilatory response to C02 elevation). To address these issues, we will conduct two series of experiments in parallel at FHCRC and UCSD: 1) in vitro diffusion studies using freshly harvested meningeal tissue to determine the feasibility of predicting meningeal permeability from physicochemical properties of analgesic drugs and in vivo studies using a chronically catheterized epidural dog model to identify the routes and extent of redistribution of epidural opioids by monitoring drug concentration over time in lumbar and cisternal cerebrospinal fluid and systemic circulation. Both components of this project will also evaluate the utility of using physical and chemical means to control the rate of release of opioids in the epidural space for improving the spinal selectivity of drug action. These studies will permit us to define the characteristics of spinally administered agents which should be sought in the further development of this important clinical tool to minimize side effects and optimize the therapeutic advantages.

我们的长期目标是开发提高质量的手段 手术后疼痛患者的硬膜外阿片类镇痛 或癌症及其治疗。 这项研究旨在确定 确定扩散之间平衡的分子特征 阿片类药物和其他脑膜的药物和药物吸收 硬膜外静脉丛。 该财团项目的具体目的是 至1）确定哪种脑膜组织 - 硬脑膜，蛛网膜或PIA孕妇 - 是阿片类药物扩散的主要障碍，2）确定 影响药物脑膜通透性的理化因素， 3）将物理化学信息应用于脑膜的预测 阿片类药物和α2-肾上腺素能激动剂的渗透性，4） 修改硬膜外镇痛药的方法以促进其 脑膜扩散，5）确定途径（蓄水池/静脉）和 硬尿药物的重新分布的动力学 和脊柱上位点的函数：分子量，脂质分区 系数和溶解度修饰剂，6）将时间关联 从硬膜外空间重新分配药物的过程以及效果 在脊柱（镇痛）和上介导的反应上（通风 对C02高程的响应）。 为了解决这些问题，我们将进行两个 FHCRC和UCSD并行的一系列实验：1）体外 扩散研究使用新鲜收获的脑膜组织来确定 预测物理化学的脑膜通透性的可行性 镇痛药和体内研究的特性使用长期进行 导管硬膜外狗模型以识别 通过监测药物浓度对硬膜外阿片类药物的重新分布 腰部和脑脊液脑脊液和全身时间 循环。 该项目的两个组成部分还将评估 使用物理和化学方法控制速率的实用性 在硬膜外空间中释放阿片类药物以改善脊柱 药物作用的选择性。 这些研究将使我们能够定义 应在 这种重要的临床工具的进一步开发以最大程度地减少侧面 影响并优化治疗优势。