Complementary Neurosteroid Intervention in Gulf War Veterans Illnesses (GWVI)

海湾战争退伍军人疾病的补充神经类固醇干预 (GWVI)

• 批准号: 9335270
• 负责人: Christine E. Marx
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335270
• 关键词: Aftercare; Allopregnanolone; Analgesics; Androsterone; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Area; Biological Markers; Brain; Central Nervous System Diseases; Cholesterol; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cognitive; Complex; Data; Development; Dose; Drug Kinetics; Exhibits; Fatigue; Gulf War; Human; Intervention; Investigation; Investigational Drugs; Lead; Learning; Mass Spectrum Analysis; Memory; Methodology; Neuraxis; Neurobehavioral Manifestations; Persian Gulf; Pharmacology; Physiological; Placebos; Pregnanolone; Pregnenolone; Property; Psychotic Disorders; Quality of life; Randomized; Randomized Controlled Trials; Recording of previous events; Rodent Model; SF-36; Scientific Inquiry; Serum; Symptoms; Therapeutic; Translations; Traumatic Brain Injury; Treatment Efficacy; United States; Veterans; animal data; base; biomarker identification; candidate marker; clinical predictors; cohort; dietary supplements; functional outcomes; improved; metabolic profile; neurogenesis; neurosteroids; pain symptom; persistent symptom; pre-clinical; psychologic; psychological symptom; response; response biomarker; therapeutic development; treatment response

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.

描述（由申请人提供）： 海湾战争退伍军人疾病 (GWVI) 深刻影响着许多曾被部署到波斯湾战区的退伍军人的生活质量和功能结果。尽管阐明这些复杂症状群的精确生理基础仍然是正在进行的科学探究的焦点，但很明显，多系统参与是 GWVI 的标志之一。 目前缺乏调查 GWVI 的随机对照试验 (RCT)，迫切需要有效的新干预措施来增强海湾战争退伍军人的功能结果，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。最佳的药物干预可能会针对所有这些功能和临床领域。鉴定用于预测干预治疗反应的生物标志物也至关重要。此外，快速轨迹 治疗方法的开发和传播将是理想的。令人信服的临床前和临床数据表明，神经类固醇干预措施可能满足所有这些重要标准。 神经类固醇是人脑中富含的内源性分子，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作用，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（以及与试点临床研究中认知改善的相关性）、神经营养和抗抑郁特性、神经发生促进作用和显着的神经保护作用。由于孕烯醇酮等神经类固醇在美国可以作为膳食补充剂非处方药购买，因此它们向临床治疗的转化可能非常快。例如，我们在退伍军人队列中进行了试点随机对照试验，并持有神经类固醇在创伤性脑损伤 [TBI]（FDA IND #78,270）和精神障碍（FDA IND #71,768）中使用的 FDA 研究新药编号。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素的可能性。因此，我们假设具有多效作用的神经类固醇干预可能有利于 GWVI 的不同临床表现。因此，我们建议对有服役史和 GWVI 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。我们还建议通过质谱法进行神经类固醇生物标志物研究，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临床反应的潜在神经类固醇预测因子。 具体目标 1：对 140 名患有 GWVI 且有服役史的海湾战争退伍军人（70 名退伍军人随机接受孕烯醇酮辅助治疗，70 名退伍军人随机接受安慰剂）进行神经类固醇孕烯醇酮随机对照试验，将功能结果作为 SF-36 评估的主要终点。 根据我们对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 2：使用基于质谱的方法在基线、治疗期间和孕烯醇酮治疗后进行候选生物标志物研究，量化孕烯醇酮和孕烯醇酮代谢物水平（别孕烯醇酮、孕烯醇酮、雄甾酮等），以便：a.) 表征孕烯醇酮的药代动力学及其代谢特征——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学窗口，b.) 确定治疗反应的潜在神经类固醇预测因子，这可能导致基于当前研究的新神经类固醇介入策略的开发，并显示出作为 GWVI 药物候选者的前景。