Mechanistic Assessment of N-Acetylcysteine as an Antioxidant Therapy for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Through Dose Response and Treatment Target Engagement

通过剂量反应和治疗目标参与对 N-乙酰半胱氨酸作为肌痛性脑脊髓炎/慢性疲劳综合征 (ME/CFS) 抗氧化疗法的机制评估

• 批准号: 10210456
• 负责人: Dikoma C Shungu
• 金额: $ 58.31万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210456
• 关键词: Acetylcysteine; Address; Antioxidants; Automobile Driving; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Chronic Fatigue Syndrome; Clinical; Clinical Trials; Clinical assessments; Complement; Development; Diagnostic tests; Disease; Dose; Double-Blind Method; Enzymes; Fatigue; Feedback; Free Radicals; Funding; Future; Glutathione; Headache; Heterogeneity; Impairment; In Situ; Knowledge; Lead; Light; Lipids; Magnetic Resonance Spectroscopy; Malaise; Measures; Medical; Modeling; Musculoskeletal Pain; National Institute of Nursing Research; Neurobiology; Oral; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Peripheral; Phenotype; Placebos; Plasma; Prodrugs; Production; Protons; Psyche structure; Public Health; Randomized Clinical Trials; Reporting; Research; Research Project Grants; Rest; Scanning; Selection Criteria; Short-Term Memory; Sleep disturbances; Sore Throat; Supplementation; Symptoms; Tissues; Treatment outcome; antioxidant enzyme; antioxidant therapy; base; circulating biomarkers; cohort; dietary; dietary supplements; effective therapy; efficacy clinical trial; enzyme activity; exhaustion; expectation; functional disability; healthy volunteer; in vivo; indexing; insight; nervous system disorder; neuroprotection; novel; oxidative DNA damage; prevent; response; restoration; targeted treatment; treatment response

ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an unexplained multisystem/multisymptom disorder characterized by severe and debilitating fatigue for which there are currently no validated diagnostic tests nor accepted therapies. The present proposal focuses on exploring a naturally occurring and widely available dietary supplement, N-acetylcysteine (NAC) – a prodrug for in situ synthesis of the primary intracellular antioxidant, glutathione (GSH) – as a highly promising treatment for ME/CFS. Driving this exploratory clinical trial are recent compelling preliminary findings by the applicants which showed that 4 weeks of daily supplements of 1800mg of NAC (a) alleviated a significant in vivo brain GSH deficit in patients with ME/CFS as measured directly with proton magnetic resonance spectroscopy (1H MRS) (b) ameliorated ME/CFS symptoms and (c) decreased the levels of plasma markers of oxidative stress in ME/CFS patients while eliciting no changes in healthy controls. The significance of these novel findings is that they represent the clearest and most direct evidence to date that NAC has the ability to spur in situ synthesis and restoration of brain GSH levels, and that GSH regulates its own synthesis through a "feedback inhibition" mechanism whereby GSH synthesis is turned on or off depending whether tissue GSH levels are low or normal, respectively. The main objective of the present proposal is to further investigate through a double-blind, placebo-controlled, randomized clinical trial, the mechanism(s) of in situ GSH synthesis control by administering different doses of NAC or placebo only to ME/CFS patients shown by 1H MRS to have a significant cortical GSH deficit at baseline. We postulate that this narrow requirement for a GSH deficit at baseline will represent a cohort selection refinement that would identify patients who would be most likely to show cortical GSH elevations in response to NAC treatment because GSH synthesis would not be feedback- inhibited. The expectation is that if successfully completed, the proposed study would advance our understanding of the mechanism(s) of action of NAC in in vivo cortical GSH synthesis, confirm oxidative stress as a viable treatment target for dietary NAC, and establish changes in 1H MRS measures of cortical GSH and in plasma markers of oxidative stress as biomarkers of treatment target engagement and of therapeutic response and, importantly, suggest optimal experimental conditions (cohort selection criteria, NAC dose) that would be suitable for use in future full-scale efficacy clinical trials of NAC for treatment of ME/CFS or other conditions in which redox imbalance has been postulated.

抽象的 肌痛性脑脊髓炎/慢性疲劳综合征（ME/CFS）是一种无法解释的多系统/多症状 以严重和衰弱性疲劳为特征的疾病，目前尚无有效的诊断方法 目前的建议侧重于探索自然发生且广泛存在的疗法。 可用的膳食补充剂，N-乙酰半胱氨酸（NAC）——一种原位合成初级药物的前药 细胞内抗氧化剂谷胱甘肽 (GSH)——作为治疗 ME/CFS 的一种非常有前途的治疗方法。 探索性临床试验是申请人最近令人信服的初步发现，表明 4 连续数周每日补充 1800 毫克 NAC (a) 可缓解患者体内显着的脑部 GSH 缺乏 使用质子磁共振波谱 (1H MRS) 直接测量的 ME/CFS (b) 得到改善 ME/CFS 症状和 (c) ME/CFS 患者血浆氧化应激标志物水平降低 这些新发现的意义在于它们代表了健康对照的情况。 迄今为止最清晰、最直接的证据表明 NAC 有能力刺激原位合成和恢复 大脑中的 GSH 水平，并且 GSH 通过“反馈抑制”机制调节其自身的合成 因此，GSH 合成的开启或关闭取决于组织 GSH 水平是否较低或正常， 本提案的主要目标是通过双盲进一步调查， 安慰剂对照、随机临床试验，原位 GSH 合成控制的机制 仅对经 1H MRS 显示具有缓解症状的 ME/CFS 患者施用不同剂量的 NAC 或安慰剂 我们假设，这种对 GSH 缺乏的狭窄要求是在基线时显着的皮质 GSH 缺乏。 基线将代表队列选择的细化，该细化将确定最有可能的患者 显示皮质 GSH 因 NAC 治疗而升高，因为 GSH 合成不会反馈- 预计如果成功完成，拟议的研究将推进我们的研究。 了解 NAC 在体内皮质 GSH 合成中的作用机制，确认氧化 压力作为饮食 NAC 的可行治疗目标，并建立皮质 1H MRS 测量的变化 GSH 和血浆氧化应激标志物作为治疗目标参与和治疗目标的生物标志物 响应，重要的是，建议最佳治疗实验条件（队列选择标准，NAC 剂量），适合用于未来 NAC 治疗 ME/CFS 的全面疗效临床试验或 假定氧化还原不平衡的其他条件。