Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands.
Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands.
Eur J Pharmacol. 2017 Nov 15;815:290-297. doi: 10.1016/j.ejphar.2017.09.031. Epub 2017 Sep 21.
Proof-of-pharmacology models to study compounds in healthy subjects offer multiple advantages. Simvastatin is known to induce mitochondrial dysfunction at least partly by depletion of co-enzyme Q10. The goal of this study was to evaluate a model of simvastatin-induced mitochondrial dysfunction in healthy subjects and to determine whether mitochondrial dysfunction could be pharmacologically reversed by treatment with co-enzyme Q10 (ubiquinol). Subjects received simvastatin 40mg/day for 8 weeks. After 4 weeks, subjects were randomized to receive ubiquinol 300mg/day or placebo in a double-blinded fashion. Mitochondrial function was assessed by measuring the phosphocreatine recovery time (τ-PCr) using phosphorous Magnetic Resonance Spectroscopy (P-MRS) after in-magnet exercise. After 4 weeks of simvastatin treatment, τ-PCr prolonged with 15.2% compared to baseline, (95%CI, 2.5-29.4%; P = 0.018, Fig. 3). After 8 weeks, τ-PCr further prolonged to 37.27s in the placebo group (prolongation of 18.5% compared to baseline, still significantly prolonged, 95%CI, 1.1-38.9%; P = 0.037), but shortened to 33.81s in the ubiquinol group (prolongation of 9.1% compared to baseline, no longer significantly prolonged, 95%CI, -7.9 to 29.2%; P = 0.31). At 8 weeks, there was no significant difference between groups (difference of 8.2%, 95%CI, -14.5 to 37.0%; P = 0.51). Simvastatin induces subclinical mitochondrial dysfunction in healthy subjects, which can be partly reversed by treatment with ubiquinol. This model of pharmacologically induced and reversed mitochondrial dysfunction can be used to study the effects of compounds that enhance mitochondrial function in healthy subjects.
在健康受试者中研究化合物的药理学模型具有多种优势。辛伐他汀已知至少部分通过辅酶 Q10 的耗竭来诱导线粒体功能障碍。本研究的目的是评估健康受试者中辛伐他汀诱导的线粒体功能障碍模型,并确定线粒体功能障碍是否可以通过辅酶 Q10(泛醇)治疗来逆转。受试者每天接受辛伐他汀 40mg 治疗 8 周。4 周后,受试者以双盲方式随机接受泛醇 300mg/天或安慰剂治疗。使用磷磁共振波谱(P-MRS)测量磁体内运动后磷酸肌酸恢复时间(τ-PCr)来评估线粒体功能。与基线相比,辛伐他汀治疗 4 周后,τ-PCr 延长了 15.2%(95%CI,2.5-29.4%;P=0.018,图 3)。8 周后,安慰剂组τ-PCr 进一步延长至 37.27s(与基线相比延长 18.5%,仍显著延长,95%CI,1.1-38.9%;P=0.037),但泛醇组缩短至 33.81s(与基线相比延长 9.1%,不再显著延长,95%CI,-7.9 至 29.2%;P=0.31)。8 周时,两组间无显著差异(差异为 8.2%,95%CI,-14.5 至 37.0%;P=0.51)。辛伐他汀在健康受试者中诱导亚临床线粒体功能障碍,可用泛醇治疗部分逆转。这种药理学诱导和逆转线粒体功能障碍的模型可用于研究增强健康受试者线粒体功能的化合物的影响。