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

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          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.

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          Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.

          Dan Ziegler, Alexander Ametov, Alexey Barinov … (2006)
          The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients' global assessment of efficacy. Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P /=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients' global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.
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            Efficacy and Safety of Antioxidant Treatment With α-Lipoic Acid Over 4 Years in Diabetic Polyneuropathy

            Dan Ziegler, Phillip Low, William J. Litchy … (2011)
            OBJECTIVE To evaluate the efficacy and safety of α-lipoic acid (ALA) over 4 years in mild-to-moderate diabetic distal symmetric sensorimotor polyneuropathy (DSPN). RESEARCH DESIGN AND METHODS In a multicenter randomized double-blind parallel-group trial, 460 diabetic patients with mild-to-moderate DSPN were randomly assigned to oral treatment with 600 mg ALA once daily (n = 233) or placebo (n = 227) for 4 years. Primary end point was a composite score (Neuropathy Impairment Score [NIS]–Lower Limbs [NIS-LL] and seven neurophysiologic tests). Secondary outcome measures included NIS, NIS-LL, nerve conduction, and quantitative sensory tests (QSTs). RESULTS Change in primary end point from baseline to 4 years showed no significant difference between treatment groups (P = 0.105). Change from baseline was significantly better with ALA than placebo for NIS (P = 0.028), NIS-LL (P = 0.05), and NIS-LL muscular weakness subscore (P = 0.045). More patients showed a clinically meaningful improvement and fewer showed progression of NIS (P = 0.013) and NIS-LL (P = 0.025) with ALA than with placebo. Nerve conduction and QST results did not significantly worsen with placebo. Global assessment of treatment tolerability and discontinuations due to lack of tolerability did not differ between the groups. The rates of serious adverse events were higher on ALA (38.1%) than on placebo (28.0%). CONCLUSIONS Four-year treatment with ALA in mild-to-moderate DSPN did not influence the primary composite end point but resulted in a clinically meaningful improvement and prevention of progression of neuropathic impairments and was well tolerated. Because the primary composite end point did not deteriorate significantly in placebo-treated subjects, secondary prevention of its progression by ALA according to the trial design was not feasible.
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              Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.

              Clifford Shults, David Oakes, Karl Kieburtz … (2002)
              Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. Academic movement disorders clinics. Eighty subjects with early PD who did not require treatment for their disability. Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d. The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04). Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.
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                Author and article information

                Contributors
                Jaime M. Ross: Role: External Editor
                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 05 November 2014
                Publication date Collection: November 2014
                Volume: 15
                Issue: 11
                Pages: 20169-20208
                Affiliations
                [1 ]Istituto Nazionale Tumori Fondazione G. Pascale—Cancer Research Center at Mercogliano (CROM)—IRCCS, Naples I-80131, Italy; E-Mails: a.aiello@ 123456istitutotumori.na.it (A.A.T.); beppe.castello@ 123456gmail.com (G.C.)
                [2 ]Research Laboratory, Dental School, Universidad de Sevilla, Sevilla 41009, Spain; E-Mail: mdcormor@ 123456us.es
                [3 ]Department of Chemical Sciences, University of Naples “Federico II”, Naples I-80126, Italy; E-Mail: dischia@ 123456unina.it
                [4 ]National Research Council, Institute of Biomembranes and Bioenergetics, Bari I-70126, Italy; E-Mail: marianicola.gadaleta@ 123456uniba.it
                [5 ]CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), University of Valencia—INCLIVA, Valencia 46010, Spain; E-Mail: federico.v.pallardo@ 123456uv.es
                [6 ]“Vinca” Institute of Nuclear Sciences, University of Belgrade, Belgrade 11001, Serbia; E-Mail: dragita.sandra@ 123456gmail.com
                [7 ]Biochemistry Unit, Department of Clinical and Dental Sciences, Polytechnical University of Marche, Ancona I-60131, Italy; E-Mail: l.tiano@ 123456univpm.it
                [8 ]Genetics Unit, Azienda Sanitaria Locale (ASL) Napoli 1 Centro, Naples I-80136, Italy; E-Mail: azatt@ 123456tin.it
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: gbpagano@ 123456tin.it ; Tel.: +39-335-7907261; Fax: +39-825-1911712.
                Article
                Publisher ID: ijms-15-20169
                DOI: 10.3390/ijms151120169
                PMC ID: 4264162
                PubMed ID: 25380523
                SO-VID: 4b6df97d-3579-45e3-9e38-a3d7401f0503
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland.
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 07 October 2014
                Date revision received : 29 October 2014
                Date accepted : 30 October 2014
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: mitochondrial nutrients,mitochondrial dysfunction,oxidative stress,oxidative phosphorylation,krebs cycle
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: mitochondrial nutrients, mitochondrial dysfunction, oxidative stress, oxidative phosphorylation, krebs cycle

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