Department of Pediatrics,Center for Inherited Disorders of Metabolism, University Hospitals Case Medical Center, Rainbow Babies and Childrens Hospital, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-6004, USA.
Mol Genet Metab. 2010 Mar;99(3):246-55. doi: 10.1016/j.ymgme.2009.11.005. Epub 2009 Nov 26.
While many treatments for mitochondrial electron transport (respiratory) chain disorders have been suggested, relatively few have undergone controlled clinical trials. This review focuses on the recent history of clinical trials of dichloroacetate (DCA), arginine, coenzyme Q(10), idebenone, and exercise in both primary (congenital) disorders and secondary (degenerative) disorders. Despite prior clinical impressions that DCA had a positive effect on mitochondrial disorders, two trials of diverse subjects failed to demonstrate a clinically significant benefit, and a trial of DCA in MELAS found a major negative effect of neuropathy. Arginine also has been used to treat MELAS with promising effects, although a controlled trial is still needed for this potentially toxic agent. The anti-oxidant coenzyme Q(10) is very widely used for primary mitochondrial disorders but has not yet undergone a controlled clinical trial; such a trial is now underway, as well as trials of the co-Q analogue idebenone for MELAS and LHON. Greater experience has accumulated with multi-center trials of coenzyme Q(10) treatment to prevent the progression of Parkinson disease. Although initial smaller trials indicated a benefit, this has not yet been confirmed in subsequent trials with higher doses; a larger Phase III trial is now underway. Similarly, a series of trials of idebenone for Friedreich ataxia have shown some benefit in slowing the progression of cardiomyopathy, and controlled clinical trials are now underway to determine if there is significant neurological protection. Uncontrolled trials of exercise showed an increase of exercise tolerance in patients with disorders of mitochondrial DNA, but did not selectively increase the percentage of normal mtDNA; a larger partially controlled trial is now underway to evaluate this possible benefit. In summary, none of the controlled trials so far has conclusively shown a benefit of treatment with the agents tested, but some promising therapies are currently being evaluated in a controlled manner. These experiences underscore the importance of controlled clinical trials for evaluation of benefits and risks of recommended therapies. Application of such clinical trials to future more effective therapies for mitochondrial disorders will require multi-center collaboration, organization, leadership, and financial and advocacy support.
虽然已经提出了许多治疗线粒体电子传递（呼吸）链疾病的方法，但经过对照临床试验检验的方法相对较少。本文重点介绍了二氯乙酸（DCA）、精氨酸、辅酶 Q(10)、艾地苯醌和运动在原发性（先天性）疾病和继发性（退行性）疾病中的临床试验的最新历史。尽管先前的临床印象表明 DCA 对线粒体疾病有积极的影响，但两项不同受试者的试验未能显示出临床显著的益处，而在 MELAS 中进行的 DCA 试验发现神经病变有很大的负面影响。精氨酸也被用于治疗 MELAS，效果显著，尽管这种潜在的有毒药物仍需要进行对照试验。抗氧化辅酶 Q(10) 广泛用于原发性线粒体疾病，但尚未经过对照临床试验检验；目前正在进行这项试验，以及辅酶 Q(10)类似物艾地苯醌治疗 MELAS 和 LHON 的试验。辅酶 Q(10) 预防帕金森病进展的多中心试验积累了更多的经验。虽然最初的小型试验表明有疗效，但在随后的高剂量试验中尚未得到证实；目前正在进行一项更大的 III 期试验。同样，一系列弗里德赖希共济失调的艾地苯醌临床试验表明，在减缓心肌病进展方面有一定的益处，目前正在进行对照临床试验以确定是否有显著的神经保护作用。未经对照的运动试验表明，线粒体 DNA 疾病患者的运动耐量增加，但不能选择性地增加正常 mtDNA 的比例；目前正在进行一项更大的部分对照试验来评估这种可能的益处。总之，迄今为止，没有一项对照试验能明确证明所测试药物治疗的益处，但一些有前途的治疗方法目前正在对照评估中。这些经验强调了对照临床试验对于评估推荐疗法的益处和风险的重要性。将这些临床试验应用于未来更有效的线粒体疾病治疗方法，将需要多中心合作、组织、领导以及财务和宣传支持。
