Complementary Neurosteroid Intervention in Gulf War Veterans Illnesses (GWVI)

描述(由申请人提供)： 海湾战争退伍军人的疾病(GWVI)深刻地影响了许多有波斯湾战区部署历史的退伍军人的生活质量和功能结果。虽然阐明这些复杂症状星座的确切生理基础仍然是正在进行的科学研究的焦点，但很明显，多系统参与是GWVI的特征之一。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，并有效地治疗跨越多个临床领域的持续性慢性症状-包括疼痛症状、认知症状、疲劳和全球心理症状。最佳的药物干预可能针对所有这些功能和临床领域。识别用于预测干预治疗反应的生物标志物也将是至关重要的。此外，一个快速的轨迹是 治疗的发展和传播将是理想的。令人信服的临床前和临床数据表明，神经类固醇干预可能满足所有这些重要标准。 神经类固醇是一种富含在人脑中的内源性分子，由中枢神经系统(CNS)中的胆固醇从头合成。神经类固醇具有多效性，可能与GWVI的多个功能和临床领域相关-包括镇痛作用、抗炎作用、增强啮齿动物模型的学习和记忆(以及与初步临床研究中的认知改善有关)、神经营养和抗抑郁特性、促进神经发生的作用，以及显著的神经保护作用。由于像孕烯醇酮这样的神经类固醇在美国可以作为膳食补充剂在柜台上买到，它们可能会非常迅速地转化为临床疗法。例如，我们在退伍军人队列中进行了试验性随机对照试验，并持有FDA使用神经类固醇治疗创伤性脑损伤[TBI](FDA IND#78,270)和精神障碍(FDA IND#71,768)的调查新药编号。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的多效性干预对GWVI的不同临床表现可能是有利的。因此，我们建议对有GWVI部署史和症状的海湾战争退伍军人进行神经类固醇干预的随机对照试验。我们还建议进行神经类固醇生物标志物的质谱学研究，以表征孕烯醇酮的代谢特征，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潜在的神经类固醇临床反应预测指标。具体目标1：对140名有GWVI和部署史的海湾战争退伍军人进行神经类固醇孕烯醇酮随机对照试验(70名退伍军人随机接受妊娠激素治疗，70名退伍军人随机接受安慰剂治疗)，以SF-36评估的主要终点为功能结局。根据我们的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、疲劳和全球心理功能。具体目标2：利用基于质谱学的方法，对孕烯醇酮和孕烯醇酮代谢物(别孕酮、孕烯醇酮、雄酮等)在基线、治疗期间和孕烯醇酮治疗后的水平进行候选生物标志物研究，以便：a.描述孕烯醇酮的药代动力学及其代谢情况--这可以产生有价值的剂量信息，并确定最佳治疗效果的药理窗口，以及b.)确定潜在的神经类固醇治疗反应预测因子，这可能导致新的神经类固醇干预策略的开发，这些策略建立在当前研究的基础上，并显示出作为GWVI候选药物的前景。

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.