Complementary Neurosteroid Intervention in Gulf War Veterans Illnesses (GWVI)

描述（由申请人提供）： 海湾战争退伍军人疾病（GWVI）深刻影响了许多退伍军人的生活质量和功能结果与部署到波斯湾战区的历史。虽然这些复杂的症状星座的精确生理基础的阐明仍然是正在进行的科学调查的重点，很明显，多系统参与是GWVI的标志之一。 目前缺乏研究GWVI的随机对照试验（RCT），迫切需要有效的新干预措施来改善海湾战争退伍军人的功能结局，并有效治疗跨越多个临床领域的持续慢性症状-包括疼痛症状，认知症状，疲劳和整体心理症状。最佳的药理学干预可能靶向所有这些功能和临床领域。鉴定生物标志物以预测对干预的治疗反应也将是至关重要的。此外，一个快速的轨迹， 治疗方法的开发和推广将是理想的。令人信服的临床前和临床数据表明，神经类固醇干预可能符合所有这些重要标准。 神经甾体是在人脑中富集并在中枢神经系统（CNS）中由胆固醇从头合成的内源性分子。神经类固醇具有可能与GWVI中的多个功能和临床领域相关的多效性作用-包括镇痛作用、抗炎作用、啮齿动物模型中学习和记忆的增强（以及与初步临床研究中认知改善的关联）、神经营养和抗抑郁特性、神经发生促进作用和显著的神经保护作用。由于神经类固醇如双烯醇酮在美国作为膳食补充剂可在非处方药中获得，因此它们转化为临床治疗可能非常迅速。例如，我们在退伍军人队列中进行了试点RCT，并持有FDA研究性新药编号，用于创伤性脑损伤[TBI]（FDA IND #78，270）和精神病性障碍（FDA IND #71，768）中使用神经类固醇。我们的初步数据也支持神经类固醇可能是治疗反应的预测因子的可能性。因此，我们假设，神经类固醇干预与多效性行动可能是有利的GWVI的不同临床表现。因此，我们提出了一个随机对照试验与神经类固醇干预海湾战争退伍军人的部署和症状的GWVI的历史。我们还建议通过质谱法进行神经甾体生物标志物研究，以表征双烯醇酮的代谢特征，获得有价值的药代动力学数据，并确定最佳治疗效果的可能窗口和临床反应的潜在神经甾体预测因子。 具体目标1：在140名患有GWVI并有部署史的海湾战争退伍军人中使用神经甾体双烯醇酮进行RCT（70名退伍军人随机接受双烯醇酮治疗，70名退伍军人随机接受安慰剂治疗），以SF-36评估的功能结局作为主要终点。 根据我们神经类固醇干预的初步数据，次要终点将是疼痛症状、认知症状、疲劳和整体心理功能。 具体目标二：进行候选生物标志物研究，使用基于质谱的方法在基线、治疗期间和用阿替烯醇酮治疗后定量阿替烯醇酮和阿替烯醇酮代谢物水平（别孕烯醇酮、孕烯醇酮、雄甾酮等），以便：a.）表征阿替烯醇酮的药代动力学及其代谢概况-这可以产生有价值的给药信息并鉴定最佳治疗功效的药理学窗口，和B.）确定治疗反应的潜在神经类固醇预测因子，这可能导致新的神经类固醇干预策略的发展，这些策略建立在当前的研究基础上，并显示出作为GWVI药理学候选物的前景。

DESCRIPTION (provided by applicant): Gulf War Veterans' Illnesses (GWVI) profoundly influence quality of life and functional outcome in many Veterans with a history of deployment to the Persian Gulf Theater. Although elucidation of the precise physiological underpinnings of these complex symptom constellations remain a focus of ongoing scientific inquiry, it is clear that multi-system involvement is one of the hallmarks of GWVI. There is currently a dearth of randomized controlled trials (RCTs) investigating GWVI, and effective new interventions are urgently needed to enhance functional outcomes in Gulf War Veterans and to effectively treat persistent chronic symptoms spanning multiple clinical domains - including pain symptoms, cognitive symptoms, fatigue, and global psychological symptoms. An optimal pharmacological intervention would potentially target all of these functional and clinical domains. The identification of biomarkers for the prediction of therapeutic response to the intervention would also be critical. In addition, a rapid trajectory to therapeutic development and dissemination would be ideal. Compelling preclinical and clinical data suggest that neurosteroid interventions may potentially meet all of these important criteria. Neurosteroids are endogenous molecules that are enriched in human brain and synthesized de novo from cholesterol in the central nervous system (CNS). Neurosteroids have pleiotropic actions that are potentially relevant to multiple functional and clinical domains in GWVI - including analgesic actions, anti-inflammatory effects, enhancement of learning and memory in rodent models (and associations with cognitive improvements in pilot clinical studies), neurotrophic and antidepressant properties, neurogenesis-promoting effects, and pronounced neuroprotective actions. Because neurosteroids such as pregnenolone are available over-the-counter as dietary supplements in the United States, their translation to clinical therapeutics is potentially very rapid. For example, we have conducted pilot RCTs in Veteran cohorts and hold FDA Investigational New Drug numbers for the use of neurosteroids in traumatic brain injury [TBI] (FDA IND #78,270) and psychotic disorders (FDA IND #71,768). Our preliminary data also support the possibility that neurosteroids may be predictors of therapeutic response. We thus hypothesize that a neurosteroid intervention with pleiotropic actions could be advantageous for the diverse clinical manifestations in GWVI. We therefore propose an RCT with a neurosteroid intervention in Gulf War Veterans with a history of deployment and symptoms of GWVI. We also propose to conduct neurosteroid biomarker investigations by mass spectrometry to characterize the metabolic profile of pregnenolone, to obtain valuable pharmacokinetic data, and to identify possible windows of optimal therapeutic efficacy and potential neurosteroid predictors of clinical response. Specific Aim 1: To conduct an RCT with the neurosteroid pregnenolone in 140 Gulf War Veterans with GWVI and a history of deployment (70 Veterans randomized to adjunctive pregnenolone, 70 Veterans randomized to placebo), targeting functional outcome as the primary endpoint as assessed by the SF-36. Based on our preliminary data with neurosteroid interventions, secondary endpoints will be pain symptoms, cognitive symptoms, fatigue, and global psychological functioning. Specific Aim 2: To conduct candidate biomarker investigations quantifying pregnenolone and pregnenolone metabolite levels (allopregnanolone, pregnanolone, androsterone, others) at baseline, during treatment, and post-treatment with pregnenolone using mass spectrometry-based methodologies in order to: a.) characterize the pharmacokinetics of pregnenolone and its metabolic profile - which could yield valuable dosing information and identify pharmacological windows of optimal therapeutic efficacy, and b.) identify potential neurosteroid predictors of therapeutic response, which could lead to the development of new neurosteroid interventional strategies that build on the current investigation and exhibit promise as pharmacological candidates in GWVI.