SPINAL CORD INJURY, METHYLPREDNISOLONE & P GLYCOPROTEIN

脊髓损伤，甲基泼尼松龙

• 批准号: 6394173
• 负责人: CHRISTOPHER M BERNARDS
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-10 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6394173
• 关键词: P glycoprotein; active transport; adrenocorticotropic hormone; aspartate; cyclic GMP; drug interactions; gene targeting; genetically modified animals; glutamates; glycine; inhibitor /antagonist; intravenous administration; laboratory mouse; lactates; leukocyte count; methylprednisolone; microdialysis; pharmacokinetics; spinal cord injury; swine

Spinal cord injuries causing permanent neurologic damage affect approximately 280,000 Americans. The only currently available therapy shown to reduce the severity of neurologic damage is massive intravenous doses of a glucocorticoid (methylprednisolone) administered during the first 3-48 hrs after injury. Unfortunately, the benefit of methylprednisolone therapy in terms of neurologic recovery is relatively small and the deleterious side effects of huge, immune-suppressive glucocorticoid doses are significant (e.g., sepsis, pneumonia). In fact, there is reason to believe that the deleterious systemic side-effects of high dose methylprednisolone therapy may actually ameliorate some of the potential neurologic benefit. Thus, developing drug delivery strategies that increase the bioavailability of methylprednisolone in the spinal cord and therefore allow a parallel reduction in the required systemic dose may significantly improve outcome. To achieve this goal of improved therapeutic index requires a thorough understanding of methylprednisolone's pharmacokinetics. Unfortunately this information is not currently available. In addition, it is essential to understand why the bioavailability of methylprednisolone in the spinal cord is so poor after intravenous methylprednisolone administration. To achieve these goals we propose the following aims: 1. To thoroughly define methylprednisolone's compartmental pharmacokinetics (spinal cord, plasma, cerebrospinal fluid) following intrathecal and intravenous administration. 2. To identify the role of p-glycoprotein in limiting methylprednisolone penetration of the blood-spinal cord barrier. 3. To identify p-glycoprotein inhibitors that increase the spinal cord bioavailability of intravenously and intrathecally administered methylprednisolone. 4. To determine whether increased spinal cord bioavailability of methylprednisolone decreases secondary damage following spinal cord injury.

脊髓损伤导致永久性神经系统损害影响约280,000名美国人。 唯一显示降低神经系统损害严重程度的目前可用治疗方法是在受伤后的前3-48 hr中施用的大量静脉注射糖皮质激素（甲基强酮）。 不幸的是，在神经系统恢复方面，甲基强酮治疗的益处相对较小，并且巨大的免疫抑制性糖皮质激素剂量的有害副作用很重要（例如，败血症，肺炎）。实际上，有理由相信，高剂量甲基强酮治疗的有害系统性副作用实际上可能会改善某些潜在的神经系统益处。因此，制定了增加脊髓中甲基强酮的生物利用度的药物输送策略，因此可以平行地降低所需的全身剂量。 为了实现改善治疗指数的目标，需要对甲基强酮的药代动力学有透彻的了解。 不幸的是，此信息目前尚不可用。 另外，必须了解为什么静脉内甲基苯甲甲酮酮后，脊髓中甲基硫酸龙的生物利用度如此之差。 为了实现这些目标，我们提出了以下目的：1。彻底定义肠内和静脉内给药后，彻底定义甲基促进性乳酮的隔室药代动力学（脊髓，血浆，脑脊液）。 2。确定p-糖蛋白在限制血液脊髓屏障的甲基强龙渗透方面的作用。 3。鉴定P-糖蛋白抑制剂，以增加静脉内和固定施用的甲基苯二醇酮的脊髓生物利用度。 4。确定甲基强酮的脊髓生物利用度增加是否会减少脊髓损伤后的继发损伤。