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）：有一种紧迫感，可以通过药理学疗法来改善脑损伤后的预后。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TBI疗法的临床试验都失败了。对TBI有效治疗的独特障碍是ATP结合磁带转运蛋白和血脑纤维（BBB）和血红脊髓液（CSF）屏障的溶质转运蛋白，这些障碍将药物的生物可利用度限制在正常的生物利用度中，并通过主动，快速再杀伤和导出药物的脑部受伤，并将药物造成的药物恢复到血液中。这些障碍通常被认为是CNS损伤临床药物试验失败的主要解释，并显然限制了许多在非CNS疾病中有效的药物的治疗适应症。膜转运蛋白包括多药电阻蛋白，多药抗性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抑制剂已经存在数十年，用于增强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概率的。 Probenecid目前正在临床治疗尿酸血症，并在第二次世界大战期间开发，以增加青霉素对受伤的士兵的生物利用度。尽管仅使用概率（安全地）来评估TBI之后的有机酸的脑CSF浓度，但从未评估过探针类或任何膜转运蛋白抑制剂与潜在神经保护底物的结合。由于这些抑制剂利用还原谷胱甘肽（GSH）从细胞中共同出口物质，因此ProbEnecid还维持了GSH的细胞内存储，GSH是一种突出的内源性抗氧化剂。因此，探针本身可以通过维持内源性抗氧化剂储量（AOR）来获得神经保护作用，从而通过减少跨膜障碍物的外排来称赞其改善外源治疗的大脑生物利用度的能力。 PI具有挑衅性的初步数据，表明ProbEnecid和FDA批准的抗氧化剂N-乙酰半胱氨酸（NAC）的结合，其CNS的使用受到脑生物利用度较差的限制，在TBI后大脑中，大脑受伤的总AOR可恢复全部AOR。这加上PIS的先前报告表明，在TBI之后，患者的CSF中的总AOR降低了50％，提供了令人信服的转化数据，以支持这种组合策略。 PIS的假设是，包括克服膜运输障碍的疗法的组合策略将协同提高TBI后临床使用和新型疗法的生物利用度和疗效。具体的目的是定义探针和NAC结合的能力，以协同减少氧化应激，并改善伸展诱导的体外创伤后神经元的神经系统结合，并在体内TBI后小鼠中的小鼠。并确定概率和NAC结合的能力，可以安全，协同减少严重TBI儿童的氧化应激。