Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction: Rational Design of Chemoprevention Trials

Abstract

An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed “mitochondrial nutrients” (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with “classical” antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed.

Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence

“…In Germany injected ALA is a prescription medicine to treat type II diabetes [16] [17]. On the other hand, clinical trials with ALA have failed to produce data that are consistent with the results reported by Xiong et al, although specific endpoints consistent with this report have not explored [18] [19] [20] [21].…”

Mitoprotective Clinical Strategies in Type 2 Diabetes and Fanconi Anemia Patients: Suggestions for Clinical Management of Mitochondrial Dysfunction

“…As predicted by Luft in 1994 [1], "mitochondrial medicine" has met a broad and growing flow of basic and clinical investigations, with extensive implications in a number of disorders related to several medical disciplines [2,7]. This is the case for both T2D and FA, through different pathogenetic mechanisms and background information, and pointing to the prospects of utilizing mitochondrial-targeted adjuvant treatments.…”

“…In view of the recognized roles of MNs in mitochondrial functions, a body of literature has focused on the beneficial outcomes of treating diabetic patients with each MN, leading to clinical improvements following patients' treatment with ALA, or coQ10, or CARN, as summarized in Table 1 (reviewed in [7]). Since early clinical studies in the 1990s, ALA has been demonstrated to provide adjuvant support in ameliorating the clinical conditions of T2D patients [34][35][36][37][38][39][40][41][42][43][44][45][46][47][48], with the recognition of ALA as a prescription drug in diabetic patients by the German Drug Index [49].…”

“…CARN and its active stereoisomer acetyl-L-carnitine (ALC) have been used in a number of human studies alone or as part of a combination therapy since early reports [132]. Administration of CARN in clinical studies including Alzheimer's disease, depression, aging, diabetes, ischemia, and other neurological diseases did not report major toxic effects (reviewed in [7]). CARN/ALC and different chemical analogs have been used extensively as adjuvant treatment in neurological disorders or to prevent adverse side effects of different chemotherapeutic treatments, such as reducing brain injury after hypoxic-ischemia in newborn rats [133].…”

“…Redox and mitochondrial anomalies are recognized-since the pioneering report by Luft (1994) [1] on "mitochondrial medicine"-in an extensive number of disorders that are afferent to several medical disciplines [2][3][4][5], including diabetes, aging, and genetic, neurologic and neuropsychiatric, and cardio-vascular diseases. Thus, several clinical studies have attempted, with varying success, to provide adjuvant treatments aimed at counteracting OS/MDF-related disorders by means of essential mitochondrial cofactors [6,7]. As stated by Wesselink et al [6], mitochondria-focused treatments can…”