Overcoming Membrane Transporters to Improve CNS Drug Therapy

克服膜转运蛋白以改善中枢神经系统药物治疗

基本信息

批准号：
8481596
负责人：
Robert S B Clark
金额：
$ 43.85万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8481596
关键词：
ABCC1 gene ATP-Binding Cassette Transporters Acetaminophen Acetylcysteine Adult Age Antibiotic Therapy Antioxidants Arterial Lines Back Biological Availability Blood Brain Brain Injuries Cause of Death Cells Cerebrospinal Fluid Child Clinical Clinical Trials Coupled Cysteine Data Disease Dose Drug Kinetics Effectiveness Electroencephalography Enrollment Extracellular Fluid FDA approved Failure Fentanyl Genetic Polymorphism Genotype Glasgow Coma Scale Histopathology In Vitro Intracranial Pressure Measures Membrane Membrane Transport Proteins Mitochondria Modeling Monitor Morbidity - disease rate Multidrug Resistance-Associated Proteins Mus Neurological outcome Neurons Organic Anion Transporters Outcome Oxidative Stress P-Glycoproteins Patients Penicillins Pharmaceutical Preparations Pharmacogenomics Pharmacotherapy Phase Phase III Clinical Trials Phenytoin Physiological Probenecid Reduced Glutathione Reporting Rodent Safety Serum Small Interfering RNA Soldier Staging Stretching Testing Therapeutic Time Toxic effect Transgenic Mice Transmembrane Transport Trauma Traumatic Brain Injury World War II blood cerebrospinal fluid barrier central nervous system injury controlled cortical impact disability drug development effective therapy functional outcomes improved in vivo in vivo Model inhibitor/antagonist injured morris water maze mortality novel organic acid prototype public health relevance reuptake solute transport inhibitor uptake young adult

项目摘要

DESCRIPTION (provided by applicant): There is a sense of urgency to move forward with pharmacological therapies that improve outcome after brain injury. Notably, traumatic brain injury (TBI) remains the leading cause of death and disability amongst children and young adults. To date, all clinical trials exploring single agents or therapies for TBI have failed. Unique impediments to effective treatment for TBI are ATP-binding cassette transporters and solute carriers on the blood-brain (BBB) and blood-cerebrospinal fluid (CSF) barriers which limit bioavailability of drugs to normal and injured brain by active and rapid re-uptake and export of drug back into blood. These barriers are often cited as a major explanation for the failure of clinical drug trials for CNS injury, and clearly limit the therapeutic indications for many drugs otherwise effective in non-CNS diseases. Membrane transporters include the multidrug resistance proteins, multidrug resistance-associated proteins, and organic anion transporters. Importantly, pharmacological inhibitors of these transporters have existed for decades, used to enhance bioavailability of drugs that are membrane transporter substrates. A prototype membrane transporter inhibitor is probenecid. Probenecid is currently in clinical use to treat uric acidemia, and was developed during World War II to increase the bioavailability of penicillin to wounded soldiers. The combination of probenecid or any membrane transporter inhibitor with a potentially neuroprotective substrate has never been evaluated for the treatment of TBI, although probenecid alone has been used (safely) to evaluate brain-CSF concentrations of organic acids after TBI. Since these inhibitors utilize reduced glutathione (GSH) to co-export substances out of cells, probenecid also maintains intracellular stores of GSH, a prominent endogenous antioxidant. As such, probenecid itself may be neuroprotective by maintaining endogenous antioxidant reserves (AOR), complimenting its capacity to improve brain bioavailability of exogenous treatments by reducing efflux across membrane barriers. The PIs have provocative preliminary data showing that the combination of probenecid and the FDA-approved antioxidant N-acetylcysteine (NAC), whose CNS use is limited by poor brain bioavailability, synergistically restore total AOR in injured brain after TBI in mice. This coupled with the PIs' previous report showing that total AOR in CSF from patients are reduced by > 50% after TBI, provides compelling translational data in support of this combinational strategy. The PIs' hypothesis is that combinational strategies that include therapies that overcome membrane transport barriers will synergistically improve bioavailability and efficacy of both clinically used and novel therapies after TBI. Specific aims are to define the capacity of the combination of probenecid and NAC to synergistically reduce oxidative stress and improve neurological outcome in neurons after stretch-induced trauma in vitro and in mice after TBI in vivo; and to define the capacity of the combination of probenecid and NAC to safely and synergistically reduce oxidative stress in children with severe TBI.

描述（由申请人提供）：迫切需要推进药物治疗以改善脑损伤后的结果。值得注意的是，创伤性脑损伤（TBI）仍然是儿童和年轻人死亡和残疾的主要原因。迄今为止，所有探索单一药物或疗法治疗 TBI 的临床试验都失败了。有效治疗 TBI 的独特障碍是血脑 (BBB) 和血脑脊液 (CSF) 屏障上的 ATP 结合盒转运蛋白和溶质载体，它们通过主动和快速的再摄取限制了药物在正常和受损大脑中的生物利用度并将药物输出回血液中。这些障碍经常被认为是中枢神经系统损伤临床药物试验失败的主要原因，并明确限制了许多原本对非中枢神经系统疾病有效的药物的治疗适应症。膜转运蛋白包括多药耐药蛋白、多药耐药相关蛋白和有机阴离子转运蛋白。重要的是，这些转运蛋白的药理学抑制剂已经存在了几十年，用于增强作为膜转运蛋白底物的药物的生物利用度。原型膜转运蛋白抑制剂是丙磺舒。丙磺舒目前在临床上用于治疗尿酸血症，是在第二次世界大战期间开发的，用于提高受伤士兵青霉素的生物利用度。丙磺舒或任何膜转运蛋白抑制剂与潜在神经保护底物的组合从未被评估用于治疗 TBI，尽管单独使用丙磺舒已（安全地）用于评估 TBI 后脑脊液中有机酸的浓度。由于这些抑制剂利用还原型谷胱甘肽 (GSH) 将物质共同输出到细胞外，丙磺舒还可以维持细胞内谷胱甘肽（一种重要的内源性抗氧化剂）的储存。因此，丙磺舒本身可能通过维持内源性抗氧化剂储备（AOR）来发挥神经保护作用，并通过减少跨膜屏障的外流来补充其提高外源性治疗的大脑生物利用度的能力。 PI 的初步数据具有争议性，表明丙磺舒和 FDA 批准的抗氧化剂 N-乙酰半胱氨酸 (NAC) 的组合可以协同恢复小鼠 TBI 后受损大脑的总 AOR（NAC 的 CNS 使用受到大脑生物利用度差的限制）。这与 PI 之前的报告相结合，显示 TBI 后患者脑脊液中的总 AOR 减少了 > 50%，为支持这种组合策略提供了令人信服的转化数据。 PI 的假设是，包括克服膜转运障碍的疗法在内的组合策略将协同提高 TBI 后临床使用的疗法和新疗法的生物利用度和疗效。具体目标是确定丙磺舒和 NAC 组合在体外拉伸诱发创伤后的神经元和体内 TBI 后的小鼠中协同减少氧化应激并改善神经系统结果的能力；并确定丙磺舒和 NAC 组合安全、协同减少严重 TBI 儿童氧化应激的能力。