The Combination of Cyclosporin and Choline Optimizes Outcomes In Focal and Diffus

环孢素和胆碱的组合优化了局灶性和弥漫性的结果

• 批准号: 8101323
• 负责人: JAMES R PAULY
• 金额: $ 26.72万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101323
• 关键词: Acute; Affect; Animal Model; Animals; Behavioral; Biochemical; Brain; Brain Injuries; Characteristics; Chemicals; Choline; Chronic; Chronic Phase; Clinical; Clinical Investigator; Clinical Trials; Cognition; Cognitive; Combination Drug Therapy; Combined Modality Therapy; Complex; Cortical Contusions; Craniocerebral Trauma; Critical Care; Cyclosporine; Cyclosporins; Cytidine Diphosphate Choline; Data; Development; Diffuse; Diffuse Brain Injury; Dose; Drug Combinations; Drug Kinetics; Environment; Etiology; Event; FDA approved; Failure; Functional disorder; Funding; Grant; Human; Individual; Injury; Liquid substance; Literature; Location; Magic; Maps; Measures; Medial; Modality; Modeling; Molecular; Nerve Degeneration; Neurobiology; Neurologic; Neuroprotective Agents; Outcome; Outcome Measure; Pathology; Patients; Percussion; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phase III Clinical Trials; Publishing; Rattus; Recording of previous events; Recovery; Recovery of Function; Research; Safety; Severities; Staging; Supplementation; TBI Patients; Testing; Therapeutic; Time; Traumatic Brain Injury; United States National Institutes of Health; Work; base; clinically relevant; cognitive recovery; combinatorial; controlled cortical impact; dietary supplements; drug efficacy; fluid percussion injury; functional outcomes; improved; innovation; meetings; neurochemistry; neuropathology; neuroprotection; prevent; public health relevance; research study; response; treatment strategy

DESCRIPTION (provided by applicant): The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with head injury underscores the need for improved therapeutic modalities. TBI in humans is a heterogeneous condition that differs substantially in severity, location, etiology, clinical presentation and neuropathology. This differs from experimental TBI studies where multiple variables are carefully controlled. The acute and chronic molecular, cellular, biochemical and pathophysiological events that follow TBI are complex and multi-factorial. There may not be a single "magic bullet" drug that will be completely successful in preventing secondary damage following brain injury. Rather, combinatorial drug treatments that target specific windows of secondary pathology may be more efficacious than treatment with a single drug. In the proposed experiments, the PIs will evaluate cellular and functional outcomes following TBI and administration of Cyclosporin A (CsA), followed by dietary choline supplementation. The combination of CsA and choline was chosen based on the clinical utility of these drugs, previously published work, and preliminary data generated by the Pauly/Scheff/Sullivan labs. The overall hypothesis of this proposal is that a combinatorial approach will optimize outcome compared to single or dual treatment modalities. The experiments will advance the understanding of the neurobiological consequences of TBI and determine the efficacy of a combined pharmacological/behavioral approach to recovery in two different models of brain injury. The outcome measures proposed will provide important new information about neurobiological outcomes following TBI. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However, given the variability and complexity of human brain injuries, a treatment strategy that uses multiple agents, targeted at specific neuropathological events, seems to be a pragmatic approach that may optimize outcome. The studies proposed for this research are highly significant and could add to our understanding of the pathophysiology and therapeutic treatment of individuals with traumatic brain injuries. If the studies show benefit of combining CsA and choline, the PIs will meet with clinical investigators to see if this could possibly be a new trial or an add-on to the CsA trial under consideration for funding. Although the pharmacological experiments proposed are not particularly mechanistic, they are feasible and directly translatable into human patients. The NIH road map contends that if therapeutics are directly translatable to humans, mechanistic studies are not the initial priority. Two different models of rat TBI will be used in these experiments, the cortical contusion model of focal injury, and the medial fluid percussion model of diffuse injury. The combined outcome measure the PIs will test may provide better characterization of recovery than previously used in either the CCI or MFPI model. Finally, functional recovery in terms of cognition is a major focus of this grant. These studies are translational since both cyclosporin and choline are both approved for use in human patients. However, the animal literature has gaps, especially for the effects of CsA on cognitive recovery. Choline is readily available and could be administered to TBI patients outside of a critical care setting. Animal studies in TBI have generally not utilized combinatorial approaches to therapy. However, given the variability and complexity of human brain injuries, a treatment strategy that uses multiple agents, targeted at specific neuropathological events, seems to be a pragmatic approach that may optimize outcome. PUBLIC HEALTH RELEVANCE: The recent failure of several Phase III clinical trials (pharmacological and non-pharmacological) in patients with traumatic brain injury (TBI) underscores the need for improved therapeutic modalities. The overall hypothesis of this proposal is that a combinatorial approach with cyclosporin A (CsA) and dietary choline supplementation will optimize outcome compared to single treatment modalities. CsA and choline are both approved by the FDA and actively being pursued in NIH-sponsored trials as monotherapy for human TBI patients. The PIs' hypothesis will be evaluated in two different models of rat TBI that have different mechanisms and timing of neuropathology. These studies are a logical extension of current trials in TBI, and will use a set of testable hypotheses to provide clinically relevant information about this drug combination.

描述（由申请人提供）：头部损伤患者的几项III期临床试验（药理和非药理学）最近失败，强调了改善治疗方法的需求。人类中的TBI是一种异质疾病，在严重程度，位置，病因，临床表现和神经病理学方面有很大差异。这与实验性TBI研究不同，该研究仔细控制了多个变量。 TBI遵循的急性和慢性分子，细胞，生化和病理生理事件是复杂且多因素的。可能没有一种“魔术子弹”药物可以完全成功地预防脑损伤后的继发损伤。相反，针对二级病理特定窗口的组合药物治疗可能比用单一药物治疗更有效。在拟议的实验中，PI将评估TBI和施用环孢菌素A（CSA）后的细胞和功能结果，然后补充饮食胆碱。基于这些药物的临床实用性，先前发表的工作以及Pauly/Scheff/Sullivan Labs生成的初步数据，选择了CSA和胆碱的组合。该提议的总体假设是，与单一或双重治疗方式相比，组合方法将优化结果。实验将提高对TBI神经生物学后果的理解，并确定在两种不同的脑损伤模型中，结合药理/行为方法恢复的功效。提出的结果措施将提供有关TBI后神经生物学结果的重要新信息。 TBI中的动物研究通常不利用组合方法进行治疗。但是，鉴于人脑损伤的可变性和复杂性，一种使用多种药物（针对特定神经病理事件）的治疗策略似乎是一种务实的方法，可以优化结果。这项研究提出的研究非常重要，可以增加我们对脑损伤患者的病理生理学和治疗治疗的理解。如果研究表明将CSA和胆碱结合起来，则PI将与临床研究人员相遇，以查看这是否可能是新试验或正在考虑的CSA试验中的附件。尽管提出的药理学实验不是特别的机械性，但它们是可行的，可以直接转化为人类患者。 NIH路线图认为，如果治疗学直接转换为人类，机械研究并不是最初的优先级。这些实验将使用两种不同的大鼠TBI模型，即局部损伤的皮质挫伤模型和弥漫性损伤的内侧液体打击乐模型。与CCI或MFPI模型中先前使用的先前相比，PIS测试将测试PIS测试的组合结果可以提供更好的恢复表征。最后，从认知方面的功能恢复是这笔赠款的主要重点。这些研究是转化的，因为环孢菌素和胆碱均被批准用于人类患者。但是，动物文献存在差距，尤其是对于CSA对认知恢复的影响。胆碱很容易获得，可以在重症监护环境之外的TBI患者进行施用。 TBI中的动物研究通常不利用组合方法进行治疗。但是，鉴于人脑损伤的可变性和复杂性，一种使用多种药物（针对特定神经病理事件）的治疗策略似乎是一种务实的方法，可以优化结果。 公共卫生相关性：脑损伤（TBI）患者的几项III期临床试验（药理学和非药物）的最近失败强调了改善治疗方式的需求。该提案的总体假设是与单一治疗方式相比，与环孢菌素A（CSA）和饮食胆碱补充剂的组合方法和补充饮食胆碱相比将优化结果。 CSA和胆碱均由FDA批准，并在NIH赞助的试验中积极追求作为人​​类TBI患者的单一疗法。 PIS的假设将在具有不同机制和神经病理时机的大鼠TBI的两个不同模型中进行评估。这些研究是TBI当前试验的逻辑扩展，并将使用一组可检验的假设来提供有关该药物组合的临床相关信息。

项目成果

Using anesthetics and analgesics in experimental traumatic brain injury.

• DOI: 10.1038/laban.257
• 发表时间: 2013-08
• 期刊: LAB ANIMAL
• 影响因子: 6.9
• 作者: Rowe, Rachel K.;Harrison, Jordan L.;Thomas, Theresa C.;Pauly, James R.;Adelson, P. David;Lifshitz, Jonathan
• 通讯作者: Lifshitz, Jonathan