UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, California, USA.
Division of Neurology, Department of Medicine, St. Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Ontario, Canada.
Ann Clin Transl Neurol. 2021 Apr;8(4):811-824. doi: 10.1002/acn3.51325. Epub 2021 Mar 6.
To assess feasibility, tolerability, and safety of N-acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo.
Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced-to-oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes.
Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11-points on NAC versus 18-points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (-0.6) and NAC (-0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups.
NAC was well-tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half-life, or lack of effect. REGISTERED: clinicaltrials.gov NCT02804594.
评估 N-乙酰半胱氨酸（NAC）治疗进展性多发性硬化症疲劳的可行性、耐受性和安全性。次要目标评估 NAC 与安慰剂相比对疲劳和氧化途径生物标志物的影响。
将改良疲劳影响量表（MFIS）> t38 的进展性多发性硬化症患者随机分为 2:1 接受 NAC 1250mg 每日三次或安慰剂治疗 4 周。主要结局是耐受性和安全性。评估疗效的次要结局是从基线到第 4 周组间 MFIS 的变化。探索性生物标志物结局包括组间血液 GSH/GSSG 比值（还原型-氧化型谷胱甘肽（GSH））和使用 7T MR 光谱（MRS）的体内相对 GSH 的变化。分类数据采用 Fisher 精确检验，连续数据采用秩和检验。
共 15 例患者被随机分组（NAC 组 10 例，安慰剂组 5 例；平均年龄 56.1 岁，80%为女性，中位 EDSS 6.0）。NAC 组至少有 1 例不良事件（AE）发生的比例为 60%，安慰剂组为 80%（p=0.75）。1 例患者出现 2 例与 NAC 相关的不良事件（腹痛和便秘），NAC 依从率为 94%。第 4 周时，两组的 MFIS 均下降，NAC 组的平均改善值为 11 分，安慰剂组为 18 分（p=0.33）。GSH/GSSG 比值在安慰剂组（-0.6）和 NAC 组（-0.1）均下降（p=0.18）。在前扣带回皮质、岛叶、尾状核、壳核和丘脑的神经递质和总肌酸的 GSH 水平变化在组间无差异。
NAC 在进展性多发性硬化症中具有良好的耐受性，尽管 NAC 对疲劳的缓解作用与安慰剂相似。抗氧化血液和 MRS 生物标志物未因 NAC 而显著改变，这可能与剂量、给药途径、样本采集时间、半衰期短或缺乏疗效有关。注册：clinicaltrials.gov NCT02804594。
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