Effects of N-acetylcystein on Muscle Fatigue in ESRD

N-乙酰半胱氨酸对终末期肾病患者肌肉疲劳的影响

• 批准号: 7217014
• 负责人: KIRSTEN L. JOHANSEN
• 金额: $ 19.7万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217014
• 关键词: acetylcysteine; biopsy; blood chemistry; chronic renal failure; clinical research; clinical trials; exercise; fatigue; functional ability; hemodialysis; human subject; human therapy evaluation; longitudinal human study; medical records; muscle cells; muscle function; oxidative stress; patient oriented research; quality of life; questionnaires; time resolved data

DESCRIPTION (provided by applicant): Muscle dysfunction is a major problem for patients with end-stage renal disease (ESRD). These patients have reduced maximal exercise capacity, poor physical performance, and low self-reported physical functioning compared to individuals without kidney disease. We recently reported that ESRD patients experience approximately three-fold greater muscle fatigue of the lower extremities during intermittent submaximal contractions than healthy sedentary control subjects, and patients with ESRD usually report stopping maximal treadmill testing because of leg fatigue. Thus, a treatment that could ameliorate muscle fatigue in this population has the potential to increase endurance during activities of daily living and improve quality of life. Data from other patient populations has shown that muscle fatigue is linked to generation of reactive oxygen species, or oxidative stress, within myocytes, particularly among patients with COPD, in which there is an exaggerated degree of oxidative stress in response to exercise and excessive muscle fatigue. Patients with ESRD have been shown to have high levels of various markers of oxidative stress, both in the plasma and in skeletal muscle. Thus, patients with ESRD have excessive muscle fatigue and oxidative damage within myocytes, but the direct link between oxidative stress and muscle fatigue has not been established. Pretreatment with a single large dose of the antioxidant N-acetylcysteine resulted in reduced muscle fatigue during intermittent submaximal contractions in healthy individuals, but this protocol was associated with side effects in most patients. On the other hand, N-acetylcysteine was well tolerated when administered to patients with ESRD in several studies ranging from 4 weeks to an average follow-up of 14.5 months designed to reduce cardiovascular events or decrease homocysteine levels. Although it seems highly likely that patients with ESRD have an exaggerated oxidative response to exercise similar to patients with COPD and that muscle fatigue could be improved by treatment with N-acetylcysteine, this has never been tested. We propose a pilot study with the following specific aims. To determine whether patients with ESRD generate excessive oxidative stress in response to exercise and whether muscle fatigue can be ameliorated by short-term treatment with N-acetylcysteine.

描述（由申请人提供）：肌肉功能障碍是终末期肾病（ESRD）患者的主要问题。与无肾脏疾病的个体相比，这些患者的最大运动能力降低，身体表现较差，自我报告的身体功能较低。我们最近报道，ESRD患者在间歇性次最大收缩期间下肢肌肉疲劳比健康久坐对照受试者大约3倍，ESRD患者通常报告由于腿部疲劳而停止最大跑步机测试。因此，可以改善该人群中肌肉疲劳的治疗有可能增加日常生活活动期间的耐力并改善生活质量。来自其他患者人群的数据表明，肌肉疲劳与肌细胞内活性氧或氧化应激的产生有关，特别是在COPD患者中，其中存在对运动和过度肌肉疲劳的过度氧化应激程度。研究表明，ESRD患者的血浆和骨骼肌中各种氧化应激标志物水平很高。因此，终末期肾病患者有过度的肌肉疲劳和心肌细胞内的氧化损伤，但氧化应激和肌肉疲劳之间的直接联系尚未建立。用单次大剂量的抗氧化剂N-乙酰半胱氨酸预处理可减少健康个体间歇性次最大收缩期间的肌肉疲劳，但该方案与大多数患者的副作用有关。另一方面，在几项旨在减少心血管事件或降低同型半胱氨酸水平的研究中，从4周至平均随访14.5个月，N-乙酰半胱氨酸对ESRD患者的耐受性良好。尽管ESRD患者对运动的氧化反应与COPD患者相似，并且肌肉疲劳可以通过N-乙酰半胱氨酸治疗得到改善，但这一点从未得到过检验。我们建议进行一项试点研究，具体目标如下。确定终末期肾病患者是否会因运动而产生过度氧化应激，以及N-乙酰半胱氨酸短期治疗是否可以改善肌肉疲劳。