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.

退伍军人中长期感染新冠病毒的患病率正在飙升，患有这种疾病的退伍军人通常会发生 功能进行性下降、生活质量下降和骨骼肌残疾增加。 病理生理学已被认为是长期新冠肺炎病理生理学和临床的重要决定因素 福尔曼博士是一位心脏病专家和老年病学家，目前正在从事研究其益处的研究。 患有老年痴呆症的老年人用研究性新药 (IND) 亚硝酸盐胶囊补充剂补充亚硝酸盐 在这项工作中，他主要关注亚硝酸盐增加的效用。 其次，他正在探索线粒体呼吸是否发生变化。 特别是，他正在研究血清和骨骼肌是否增加 亚硝酸盐升高与心肺健康（即峰值氧利用率 [VO2]）的改善相关，并且 降低疲劳性（即，在稳态次最大[1.5英里/ 小时]步行）。在这个 SPiRE 应用中，Forman 博士建议将他在亚硝酸盐治疗方面的专业知识转移到 患有长期新冠肺炎的退伍军人将服用富含硝酸盐的甜菜根汁，而不是缺乏硝酸盐的退伍军人。 与 IND 亚硝酸盐胶囊相比，摄入甜菜根汁时，硝酸盐会代谢为亚硝酸盐。 甜菜根汁相对更容易管理，更便宜，并且血液动力学更安全。 与亚硝酸盐相比，在甜菜根汁干预研究中，亚硝酸盐含量并不一直很高 胶囊，该提案旨在每天使用 210 毫升 Beet-It 硝酸盐饮料来优化亚硝酸盐水平（James 英国伊普斯威奇的 White Drinks Ltd.）每天提供 16 毫摩尔硝酸盐，持续 14 天，而相比之下，提供 210 毫升硝酸盐 SPiRE 研究的终点是所有参与者都将接受物理治疗。 主要针对身体功能的终点（在两周干预之前和之后测量）包括 此外，传统步行期间的疲劳度和步行效率（VO2/kg）。 峰值摄氧量、无氧阈摄氧量、6分钟步行距离、短距离体能功能指标 还将评估性能电池和肺功能测试（血清学和肺功能测试）。 骨骼肌本身）将被测量，以最好地确定亚硝酸盐和假定的临床的关系 此外，对骨骼肌的分析将阐明亚硝酸盐是否介导身体功能的变化。 总体而言，该提案与退伍军人事务部一致 研究与发展办公室致力于帮助受 COVID-19 影响的退伍军人的研究， 它还符合康复研究与发展部的使命，即最大限度地提高退伍军人的康复能力 福尔曼博士期望功能独立、生活质量以及对生活和社区的参与。 应用基于 SPiRE 的引人注目的分析中的数据和动力来追求后续的 MERIT 该试验更明确地强调了亚硝酸盐疗法对长期新冠患者的价值。