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      Improvement of Visual Functions and Fundus Alterations in Early Age-Related Macular Degeneration Treated with a Combination of Acetyl- L-Carnitine, n-3 Fatty Acids, and Coenzyme Q10

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          Abstract

          The aim of this randomized, double-blind, placebo-controlled clinical trial was to determine the efficacy of a combination of acetyl- L-carnitine, n-3 fatty acids, and coenzyme Q10 (Phototrop<sup>®</sup>) on the visual functions and fundus alterations in early age-related macular degeneration (AMD). One hundred and six patients with a clinical diagnosis of early AMD were randomized to the treated or control groups. The primary efficacy variable was the change in the visual field mean defect (VFMD) from baseline to 12 months of treatment, with secondary efficacy parameters: visual acuity (Snellen chart and ETDRS chart), foveal sensitivity as measured by perimetry, and fundus alterations as evaluated according to the criteria of the International Classification and Grading System for AMD. The mean change in all four parameters of visual functions showed significant improvement in the treated group by the end of the study period. In addition, in the treated group only 1 out of 48 cases (2%) while in the placebo group 9 out of 53 (17%) showed clinically significant (>2.0 dB) worsening in VFMD (p = 0.006, odds ratio: 10.93). Decrease in drusen-covered area of treated eyes was also statistically significant as compared to placebo when either the most affected eyes (p = 0.045) or the less affected eyes (p = 0.017) were considered. These findings strongly suggested that an appropriate combination of compounds which affect mitochondrial lipid metabolism, may improve and subsequently stabilize visual functions, and it may also improve fundus alterations in patients affected by early AMD.

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          Most cited references 34

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          A role for local inflammation in the formation of drusen in the aging eye.

          The accumulation of numerous or confluent drusen, especially in the macula, is a significant risk factor for the development of age-related macular degeneration (AMD). Identifying the origin and molecular composition of these deposits, therefore, has been an important, yet elusive, objective for many decades. Recently, a more complete profile of the molecular composition of drusen has emerged. In this focused review, we discuss these new findings and their implications for the pathogenic events that give rise to drusen and AMD. Tissue specimens from one or both eyes of more than 400 human donors were examined by light, confocal or electron microscopy, in conjunction with antibodies to specific drusen-associated proteins, to help characterize the transitional events in drusen biogenesis. Quantification of messenger RNA from the retinal pigment epithelium (RPE)/choroid of donor eyes was used to determine if local ocular sources for drusen-associated molecules exist. The results indicate that cellular remnants and debris derived from degenerate RPE cells become sequestered between the RPE basal lamina and Bruch's membrane. We propose that this cellular debris constitutes a chronic inflammatory stimulus, and a potential "nucleation" site for drusen formation. The entrapped cellular debris then becomes the target of encapsulation by a variety of inflammatory mediators, some of which are contributed by the RPE and, perhaps, other local cell types; and some of which are extravasated from the choroidal circulation. The results support a role for local inflammation in drusen biogenesis, and suggest that it is analogous to the process that occurs in other age-related diseases, such as Alzheimer's disease and atherosclerosis, where accumulation of extracellular plaques and deposits elicits a local chronic inflammatory response that exacerbates the effects of primary pathogenic stimuli.
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            Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration.

            Oxidative stress is believed to contribute to the pathogenesis of many diseases, including age-related macular degeneration (AMD). Although the vision loss of AMD results from photoreceptor damage in the central retina, the initial pathogenesis involves degeneration of RPE cells. Evidence from a variety of studies suggests that RPE cells are susceptible to oxidative damage. Mitochondrial DNA (mtDNA) is particularly prone to oxidative damage compared to nuclear DNA (nDNA). Using the quantitative PCR assay, a powerful tool to measure oxidative DNA damage and repair, we have shown that human RPE cells treated with H(2)O(2) or rod outer segments resulted in preferential damage to mtDNA, but not nDNA; and damaged mtDNA is not efficiently repaired, leading to compromised mitochondrial redox function as indicated by the MTT assay. Thus, the susceptibility of mtDNA to oxidative damage in human RPE cells, together with the age-related decrease of cellular anti-oxidant system, provides the rationale for a mitochondria-based model of AMD.
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              A potential role for immune complex pathogenesis in drusen formation.

              Drusen are abnormal extracellular deposits that accumulate between the retinal pigmented epithelium and Bruch's membrane and are commonly associated with age-related macular degeneration. Our recent work has identified a number of plasma proteins as molecular components of drusen. Of interest is the fact that many of these drusen-associated molecules are acute phase reactant proteins and some have established roles in mediating immune responsiveness. As immune and inflammatory responses appear to play a role in the formation of other pathologic age-related deposits, we examined the distribution of immunoglobulin molecules and terminal complement complexes at sites of drusen deposition. Here, we report that concentrations of immunoglobulin G and terminal C5b-9 complement complexes are present in drusen. In addition, we observe that retinal pigmented epithelial cells overlying or directly adjacent to drusen, as well as some within apparently normal epithelia, exhibit cytoplasmic immunoreactivity for immunoglobulin and the C5 component of complement. Taken together, these results suggest that drusen biogenesis may be a byproduct of immune responsiveness, and they implicate immune complex-mediated pathogenesis involving retinal pigmented epithelial cells as an initiating event in drusen formation.
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                Author and article information

                Journal
                OPH
                Ophthalmologica
                10.1159/issn.0030-3755
                Ophthalmologica
                S. Karger AG
                0030-3755
                1423-0267
                2005
                June 2005
                08 June 2005
                : 219
                : 3
                : 154-166
                Affiliations
                Ophthalmic Neuroscience Program, aDepartment of Ophthalmology, University of Rome ‘La Sapienza’, Rome, Italy; bDepartment of Ophthalmology, University of Pecs, Pecs, and cSecond Department of Ophthalmology, Semmelweis University, Budapest, Hungary
                Article
                85248 Ophthalmologica 2005;219:154–166
                10.1159/000085248
                15947501
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 3, Tables: 4, References: 68, Pages: 13
                Categories
                Original Paper

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