Mitochondrial medicine therapies: rationale, evidence, and dosing guidelines.
Mitochondrial medicine therapies: rationale, evidence, and dosing guidelines.
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DOI：
10.1097/mop.0000000000000954
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发表时间：
2020-12
影响因子：
3.6
通讯作者：
Falk MJ
中科院分区：
文献类型：
--
作者：
Barcelos I;Shadiack E;Ganetzky RD;Falk MJ
原发线粒体疾病是一种高度异质性但共同常见的遗传性代谢紊乱，至少每4,300人中就有1人受到影响。线粒体疾病的治疗通常包括基于生化推理、历史经验和一致的专家意见的酶辅助因子、抗氧化剂和氨基酸以及其他营养补充剂的经验性处方。随着该领域的持续快速发展，我们在此回顾了常见线粒体药物疗法的临床前和临床证据，以及具体的剂量指南，以指导医生的处方实践。自2009年出版线粒体医学学会线粒体药物治疗管理指南以来，出现的数据支持考虑使用更多的治疗药物和停止使用几种以前使用的药物。临床前的动物模型数据表明，维生素C作为抗氧化剂对原发线粒体疾病缺乏疗效，但为维生素E和N-乙酰半胱氨酸提供了强有力的证据。临床资料提示，L-卡尼汀可能加速动脉粥样硬化性疾病。对L-精氨酸预防代谢性中风的长期随访提供了更多的数据支持其在MELAS和Leigh综合征患者中的临床应用。此外，针对特定的分子病因和/或共同的原发性线粒体疾病的临床表型，已经开发了几种精确的治疗方法。我们根据现有证据和我们的单中心临床经验，提供线粒体药物治疗的全面更新，以支持或驳斥它们的使用，并为线粒体疾病的临床管理提供详细的剂量指南。经验性线粒体药物的总体目标是利用具有良好的风险效益曲线的治疗方法，这些治疗方法可以稳定和增强残余代谢功能，以提高细胞的弹性，减缓临床疾病的进展和/或防止急性失代偿。
Primary mitochondrial disease is highly heterogeneous but collectively common inherited metabolic disorder, affecting at least 1 in 4,300 individuals. Therapeutic management of mitochondrial disease typically involves empiric prescription of enzymatic co-factors, antioxidants, and amino acid as well as other nutrient supplements, based on biochemical reasoning, historical experience and consensus expert opinion. As the field continues to rapidly advance, we review here the pre-clinical and clinical evidence, and specific dosing guidelines, for common mitochondrial medicine therapies to guide practitioners in their prescribing practices. Since publication of Mitochondrial Medicine Society guidelines for mitochondrial medicine therapies management in 2009, data has emerged to support consideration for using additional therapeutic agents and discontinuation of several previously used agents. Pre-clinical animal modeling data have indicated a lack of efficacy for vitamin C as an antioxidant for primary mitochondrial disease, but provided strong evidence for vitamin E and N-acetylcysteine. Clinical data has suggested L-carnitine may accelerate atherosclerotic disease. Long-term follow up on L-arginine use as prophylaxis against metabolic strokes has provided more data supporting its clinical use in individuals with MELAS and Leigh syndrome. Further, several precision therapies have been developed for specific molecular etiologies and/or shared clinical phenotypes of primary mitochondrial disease. We provide a comprehensive update on mitochondrial medicine therapies based on current evidence and our single-center clinical experience to support or refute their use, and provide detailed dosing guidelines, for the clinical management of mitochondrial disease. The overarching goal of empiric mitochondrial medicines is to utilize therapies with favorable benefit-to-risk profiles that may stabilize and enhance residual metabolic function to improve cellular resiliency and slow clinical disease progression and/or prevent acute decompensation.