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

描述（由申请人提供）：最近在头部损伤患者中进行的几项III期临床试验（药理学和非药理学）的失败强调了改进治疗方式的必要性。人类TBI是一种异质性疾病，在严重程度、位置、病因、临床表现和神经病理学方面存在很大差异。这与TBI实验研究不同，在TBI实验中，多个变量被仔细控制。TBI后的急性和慢性分子、细胞、生物化学和病理生理学事件是复杂的和多因素的。可能没有一种“灵丹妙药”药物可以完全成功地预防脑损伤后的继发性损伤。相反，靶向继发性病变的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和给予环孢菌素A（CsA）以及随后补充膳食胆碱后的细胞和功能结果。CsA和胆碱的组合是根据这些药物的临床效用、先前发表的工作以及Pauly/Scheff/Sullivan实验室生成的初步数据选择的。该建议的总体假设是，与单一或双重治疗方式相比，组合方法将优化结果。这些实验将促进对TBI的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恢复的联合药理学/行为方法的功效。结果的措施，建议将提供重要的新的信息，神经生物学的结果TBI。TBI中的动物研究通常不使用组合疗法。然而，考虑到人脑损伤的可变性和复杂性，针对特定神经病理事件使用多种药物的治疗策略似乎是一种可以优化结果的务实方法。这项研究的研究是非常重要的，可以增加我们对创伤性脑损伤患者的病理生理学和治疗的理解。如果研究显示联合使用CsA和胆碱的益处，PI将与临床研究者会面，以确定这是否可能是一项新的试验或正在考虑资助的CsA试验的附加试验。虽然所提出的药理学实验不是特别机械的，但它们是可行的，并且可以直接转化为人类患者。NIH的路线图认为，如果治疗方法可以直接转化为人类，那么机制研究就不是最初的优先事项。在这些实验中将使用两种不同的大鼠TBI模型，即局灶性损伤的皮质挫伤模型和弥漫性损伤的内侧流体撞击模型。PI将测试的组合结果测量可以提供比以前在CCI或MFPI模型中使用的更好的恢复表征。最后，在认知方面的功能恢复是这项赠款的一个主要重点。这些研究是转化的，因为环孢菌素和胆碱都被批准用于人类患者。然而，动物文献有差距，特别是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给予TBI患者。TBI中的动物研究通常不使用组合疗法。然而，考虑到人脑损伤的可变性和复杂性，针对特定神经病理事件使用多种药物的治疗策略似乎是一种可以优化结果的务实方法。 公共卫生相关性：最近在创伤性脑损伤（TBI）患者中进行的几项III期临床试验（药理学和非药理学）的失败强调了改进治疗方式的必要性。该建议的总体假设是，与单一治疗方式相比，环孢菌素A（CsA）和膳食胆碱补充剂的组合方法将优化结果。CsA和胆碱都得到了FDA的批准，并在NIH赞助的试验中作为人类TBI患者的单药治疗积极进行。PI的假设将在两种不同的大鼠TBI模型中进行评估，这两种模型具有不同的神经病理学机制和时间。这些研究是目前TBI试验的逻辑延伸，并将使用一组可验证的假设来提供有关该药物组合的临床相关信息。

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.