Trial of GlyNAC in Older Adults with COVID-19: Glutathione, Inflammation and Recovery

GlyNAC 在患有 COVID-19 的老年人中的试验：谷胱甘肽、炎症和恢复

• 批准号: 10157755
• 负责人: Rajagopal Viswanath Sekhar
• 金额: $ 52.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157755
• 关键词: 2019-nCoV; Acetylcysteine; Age; Aging; Amino Acids; Antioxidants; COVID-19; Cells; Cessation of life; Chronic; Clinical; Cognition; Cognitive; Confidence Intervals; Coronavirus Infections; Cysteine; Data; Defect; Diagnosis; Dietary Intervention; Double-Blind Method; Elderly; Erythrocytes; F2-Isoprostanes; Funding; Glutathione; Glycine; Health; Height; Human; Immune; Immune System Diseases; Impaired cognition; Impairment; Infection; Inflammation; Inflammatory; Interleukin-6; Intervention; Italy; Knowledge; Link; Lymphocyte; Mitochondria; Modeling; Outcome; Outcome Measure; Oxidative Stress; Patients; Peripheral; Pilot Projects; Placebos; Plasma; Population; Production; Proteins; Randomized; Randomized Clinical Trials; Recovery; Reporting; Respiration; Rodent; Safety; Side; Statistical Data Interpretation; Supplementation; Testing; Thiobarbituric Acid Reactive Substances; United States National Institutes of Health; World Health Organization; base; combat; coronavirus disease; cytokine; cytokine release syndrome; dietary supplements; fatty acid oxidation; functional improvement; high risk; high risk population; immune function; improved; influenzavirus; irritation; mitochondrial dysfunction; mortality; mortality risk; novel; novel coronavirus; pandemic disease; pilot trial; prevent; primary outcome; protein function; randomized placebo-controlled clinical trial; research study; response; secondary outcome; treatment arm

The global pandemic caused by the novel Coronavirus SARS-Cov-2 results in COVID-19 and is associated with a very high mortality rate ranging from 3% (in USA) to 14% (in Italy) Increased age is identified as a high-risk group for COVID-19 due to significantly high mortality in older adults (OA). It is not clear why COVID-19 is associated with high mortality, but emerging evidence from hospitalized patients has identified a `cytokine storm' with severely elevated inflammatory cytokines (especially IL-6) as a potential contributor. Increased inflammation in patients with COVID-19 is reported to correlate negatively with peripheral lymphocyte populations, and contributes to immune dysfunction. We have studied aging for >20 years, and found that correcting the deficiency of the endogenous antioxidant protein glutathione (GSH) is critically important to lower inflammation, elevated oxidative stress (OxS) and impaired mitochondrial fatty-acid oxidation (MFO) in OA. GSH is the most abundant endogenous, intracellular, antioxidant protein and functions by protecting cells from toxic OxS generated during mitochondrial energy production. OA are deficient in GSH. We have identified and validated an effective, simple and safe nutritional intervention called GlyNAC (combination of GSH precursors glycine and NAC-N- acetylcysteine) to correct GSH deficiency in OA. GSH is identified as a potential candidate to combat COVID-19, but has not been studied in OA with COVID-19. We recently completed a 16-week NIH-funded double-blind placebo-controlled randomized clinical trial in OAwith outcomes measured at 2-weeks and 16-weeks. GlyNAC supplementation for 14-days led to: (1) RBC-GSH ­40%; (2) lowered inflammation; (3) lower OxS; (4) improved mitochondrial function. In earlier pilot studies in OA we found that: (1) OA had striking GSH deficiency, elevated OxS and impaired MFO; (2) GSH deficiency in OA occurs due to diminished synthesis, caused by decreased availability of its precursor amino-acids glycine and cysteine, and can be improved by supplementing GlyNAC for 14-days [; (3) GlyNAC supplementation improved inflammation, OxS , MFO, cognition and function. These results are highly relevant to OA with COVID-19 because: (1) OA with COVID-19 have a high mortality risk; (2) increased inflammation is associated with high mortality in COVID-19; (3) GSH is identified as a potential candidate to combat COVID-19; (4) OA have GSH deficiency, chronic inflammation and cognitive impairment and GlyNAC corrects these defects in OA; (5) GlyNAC has a strong safety profile in our trials; (6) GlyNAC, GSH and OxS have not been studied in COVID-19. (7) GSH prevents replication of the influenza virus in rodents. Based on these data, we propose an exploratory pilot randomized clinical trial to test the effect of supplementing GlyNAC vs. placebo for 14-days in hospitalized in OA with COVID-19 to determine the impact on clinical improvement, recovery, survival, cognition, function, inflammation, immune and mitochondrial function, GSH concentrations and oxidative stress. If successful, this could identify GlyNAC as a novel nutritional supplement to improve the health of patients with COVID.

由新型冠状病毒SARS-Cov-2引起的全球大流行导致COVID-19，并与非常高的 死亡率从3%（美国）到14%（意大利）年龄增长被确定为COVID-19的高风险人群 因为老年人（OA）的死亡率很高。目前尚不清楚COVID-19与高死亡率相关的原因，但 来自住院患者的新证据已经确定了“细胞因子风暴”， 细胞因子（特别是IL-6）作为潜在的贡献者。据报道，COVID-19患者的炎症增加 与外周淋巴细胞群呈负相关，并导致免疫功能障碍。我们研究了衰老 20多年来，发现纠正内源性抗氧化蛋白谷胱甘肽（GSH）的缺乏至关重要， 重要的是降低炎症，氧化应激（OxS）和受损的线粒体脂肪酸氧化（MFO） 在OA。GSH是最丰富的内源性细胞内抗氧化蛋白，其功能是保护细胞免受毒性 OxS在线粒体能量产生过程中产生。OA缺乏GSH。我们已经确定并验证了一个 有效、简单和安全的营养干预，称为GlyNAC（GSH前体甘氨酸和NAC-N- 乙酰半胱氨酸）以纠正OA中的GSH缺乏。GSH被确定为对抗COVID-19的潜在候选药物，但 尚未在COVID-19的OA中进行研究。 我们最近完成了一项为期16周的NIH资助的双盲安慰剂对照随机临床试验， 2周和16周时测量的结果。GlyNAC补充14天导致：（1）RBC-GSH> 40%;（2） 降低炎症;（3）降低OxS;（4）改善线粒体功能。 在早期OA的初步研究中，我们发现：（1）OA具有明显的GSH缺乏，OxS升高和MFO受损;（2） 骨关节炎中GSH缺乏是由于其前体氨基酸的可用性降低导致合成减少 甘氨酸和半胱氨酸，并且可以通过补充GlyNAC 14天来改善[;（3）GlyNAC补充 改善炎症、OxS、MFO、认知和功能。 这些结果与COVID-19 OA高度相关，因为：（1）COVID-19 OA具有高死亡风险;（2） 炎症增加与COVID-19的高死亡率相关;（3）GSH被确定为潜在的候选者， 对抗COVID-19;（4）OA有GSH缺乏症，慢性炎症和认知障碍，GlyNAC纠正 （5）GlyNAC在我们的试验中具有很强的安全性;（6）GlyNAC、GSH和OxS尚未进行研究 在COVID-19。(7)GSH可防止流感病毒在啮齿动物中复制。 基于这些数据，我们提出了一个探索性的试点随机临床试验，以测试补充GlyNAC的效果 vs.在患有COVID-19的OA住院患者中给予安慰剂14天，以确定对临床改善、恢复 存活、认知、功能、炎症、免疫和线粒体功能、GSH浓度和氧化应激。 如果成功，这可以确定GlyNAC作为一种新型营养补充剂，以改善COVID患者的健康。