Nitrite Supplementation to Mitigate Fatigability and Increase Function in Long COVID Patients

补充亚硝酸盐可减轻长期新冠患者的疲劳并增强功能

• 批准号: 10590380
• 负责人: Daniel E. Forman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590380
• 关键词: Acute; Address; Adult; Aerobic; Amino Acids; Anaerobic Threshold; Arginine; Beverages; COVID-19; COVID-19 impact; COVID-19 patient; Chronic Obstructive Pulmonary Disease; Citrulline; Clinical; Communities; Consumption; Data; Diet; Disease; Elderly; Exercise; Exertion; Fatigue; Foundations; Functional disorder; Health Care Costs; Healthcare; Healthcare Systems; Heart failure; Hour; Ingestion; Intervention; Investigational Drugs; Ischemia; Juice; Lead; Left; Long COVID; Measures; Mediating; Mission; Mitochondria; Muscle Mitochondria; Myalgia; Nitrates; Nitric Oxide; Nitrites; Oxygen; Participant; Personal Satisfaction; Physical Function; Physical Performance; Physical therapy; Physiological; Placebos; Plants; Prevalence; Principal Investigator; Pulmonary function tests; Quality of life; Randomized, Controlled Trials; Regimen; Rehabilitation therapy; Research; Residual state; Respiration; Risk; SARS-CoV-2 infection; Serology; Serum; Shortness of Breath; Signal Transduction; Signaling Molecule; Skeletal Muscle; Source; Standardization; Stress; Supplementation; Survivors; Symptoms; Therapeutic; Therapeutic Uses; United States Department of Veterans Affairs; Veterans; Walking; Work; capsule; cardiorespiratory fitness; coronavirus disease; design; disability; efficacy study; exercise regimen; functional decline; functional independence; hemodynamics; improved; indexing; innovation; novel; patient population; post SARS-CoV-2 infection; primary endpoint; programs; pulmonary function; randomized placebo controlled trial; rehabilitation research; research and development; research study; sedentary; young adult

Prevalence of long COVID is surging among Veterans, and Veterans afflicted with this disease typically incur progressive declines in function, diminished quality of life and increased disability. Skeletal muscle pathophysiology has been implicated as a significant determinant of long COVID pathophysiology and clinical declines. Dr. Forman is a cardiologist and geriatrician who is currently engaged in research studying benefits of nitrite supplementation with investigational new drug (IND) nitrite capsule supplements in older adults with sedentariness and/or heart failure. In that work, he is focusing primarily on the utility of nitrites to increase skeletal muscle mitochondrial respiration. Secondarily, he is exploring if mitochondrial respiration changes correlate to changes in physical function. In particular, he is studying if increased serum and skeletal muscle nitrite elevations correlate to improvements in cardiorespiratory fitness (i.e., peak oxygen utilization [VO2]), and to decreased fatigability (i.e., rating of perceived exertion [RPE] during steady-state submaximal [1.5 miles per hour] walking). In this SPiRE application, Dr. Forman proposes to redirect his expertise in nitrite therapeutics to Veterans with long COVID. Nitrites will be administered as nitrate-rich beetroot juice versus nitrate-poor placebo. When beetroot juice is ingested, nitrates are metabolized to nitrite. Compared to IND nitrite capsules, beetroot juice is relatively easier to administer, less expensive, and hemodynamically safer. Whereas serum nitrite levels have not been consistently high in studies of beetroot juice interventions as compared to nitrite capsules, this proposal aims to optimize nitrite levels using 210 ml per day of Beet-It nitrate beverage (James White Drinks Ltd., Ipswich, UK) to provide 16 mmol of nitrate/day for 14 days versus a 210 ml of nitrate- depleted placebo. All participants will also undergo physical therapy. Endpoints in this SPiRE study are oriented principally to physical function. Endpoints (measured pre- and post- the 2-week intervention) include fatigability as well as walking efficiency (VO2/kg) during steady-state walking. Furthermore, traditional functional indices of peak VO2, VO2 at anaerobic threshold, 6-minute walk distance, short physical performance battery, and pulmonary function tests will also be assessed. Nitrite levels (both serologically and in the skeletal muscle itself) will be measured to best ascertain the relationship of nitrite and putative clinical changes. In addition, analyses of skeletal muscle will clarify if nitrite-mediated changes in physical function correlate to changes in skeletal muscle respiration. Overall, this proposal aligns with the Veteran’s Affairs Office of Research and Development’s commitment to research that helps Veterans affected by COVID-19, and it also aligns with the Rehabilitation Research and Development’s mission to maximize Veterans’ functional independence, quality of life and participation in their lives and community. Dr. Forman anticipates applying the data and momentum from this compelling SPiRE-based analysis to pursue a subsequent MERIT trial that reinforces the value of nitrite therapeutics more definitively for long COVID patients.

长期兴趣率在退伍军人之间激增，而患有这种疾病的退伍军人通常会发生 渐进的功能下降，生活质量下降和残疾增加。骨骼肌 病理生理学已被暗示为长期相邻病理生理学和临床的重要决定因素 下降。 Forman博士是心脏病专家和老年医生，目前正在研究研究好处 用研究新药物（IND）亚硝酸盐胶囊补充剂补充一质子的老年人 久坐和/或心力衰竭。在这项工作中，他主要关注亚硝酸盐的实用性 骨骼肌线粒体呼吸。次要，他正在探索线粒体呼吸是否改变 与身体功能的变化相关。特别是，他正在研究血清和骨骼肌是否增加 亚硝酸盐高程与心肺适应性的改善相关（即峰值氧利用[VO2]）和 减轻疲劳性（即，在稳态次临时[1.5英里 / 小时]步行）。在此尖峰应用中，福尔曼博士提出的，将其在亚硝酸盐疗法方面的专业知识重定向到 长期兴趣的退伍军人。亚硝酸盐将作为富含硝酸盐的甜菜根汁与硝酸盐贫困 安慰剂。摄入甜菜根汁时，将硝酸盐代谢为亚硝酸盐。与Int亚硝酸盐胶囊相比 甜菜根汁相对易于施用，价格较低，并且在血液动力学上是安全的。而序列 与亚硝酸盐相比 胶囊，该提案旨在使用每天的甜菜 - 硝酸盐卧室优化亚硝酸盐水平（詹姆斯 英国伊普斯维奇的白饮料有限公司）提供16 mmol的硝酸盐/天14天，而210毫升的硝酸盐 - 耗尽的安慰剂。所有参与者也将接受物理治疗。这项尖峰研究的终点是 主要针对身体功能。终点（2周前后测量的前后）包括 稳态步行期间的疲劳以及步行效率（VO2/kg）。此外，传统 峰值VO2的功能指标，厌氧阈值处的Vo2，步行6分钟，较短的物理 性能电池和肺功能测试也将进行评估。亚硝酸盐水平（包括血清学和 在骨骼肌本身中）将测量以最好地确定亚硝酸盐和推定临床的关系 更改。此外，对骨骼肌的分析将阐明亚硝酸盐介导的身体机能变化是否 与骨骼肌呼吸的变化相关。总体而言，该提议与退伍军人事务保持一致 研发办公室对研究的承诺，帮助受到Covid-19的退伍军人， 它还与康复研究与发展的使命一致，以最大化退伍军人 功能独立性，生活质量以及对生活和社区的参与。福曼博士期望 应用此引人入胜的基于尖峰的分析中的数据和动力以追求随后的优点 试验更明确地增强亚硝酸盐疗法对长期互联患者的价值。