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

Ophthalmologica

Volumn 219, Issue 3, 2005, Pages 154-166

  Feher, J ^a,d   Kovacs, B ^b   Kovacs, I ^b,c   Schvoller M ^b   Papale, A ^a   Balacco Gabrieli, C ^a  

^a SAPIENZA UNIVERSITY OF ROME   (Italy)

^b UNIVERSITY OF PÉCS   (Hungary)

^c SEMMELWEIS UNIVERSITY   (Hungary)

^d NONE   (Italy)

Author keywords

Acetyl L carnitine n 3 fatty acids; Age related macular degeneration; Clinical trial; Coenzyme Q10; Drusen; Mitochondria; Visual acuity; Visual field

Indexed keywords

LEVACECARNINE; OMEGA 3 FATTY ACID; PHOTOTROP; PLACEBO; UBIDECARENONE; ACETYLCARNITINE; DRUG DERIVATIVE; UBIQUINONE;

ADULT; AGE DISTRIBUTION; AGED; ARTICLE; CLINICAL TRIAL; COMPARATIVE STUDY; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DISEASE CLASSIFICATION; DRUG EFFICACY; EYE FUNDUS; FEMALE; HUMAN; LIPID METABOLISM; MAJOR CLINICAL STUDY; MALE; MITOCHONDRION; PERIMETRY; RANDOMIZED CONTROLLED TRIAL; RETINA MACULA DEGENERATION; RISK ASSESSMENT; SENSITIVITY ANALYSIS; STATISTICAL SIGNIFICANCE; VISION; VISUAL ACUITY; VISUAL FIELD DEFECT; DOUBLE BLIND PROCEDURE; DRUG COMBINATION; DRUG EFFECT; MIDDLE AGED; PATIENT COMPLIANCE; TREATMENT OUTCOME;

ACETYLCARNITINE; ADULT; AGED; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; FATTY ACIDS, OMEGA-3; FEMALE; FUNDUS OCULI; HUMANS; MACULAR DEGENERATION; MALE; MIDDLE AGED; PATIENT COMPLIANCE; PERIMETRY; TREATMENT OUTCOME; UBIQUINONE; VISUAL ACUITY;

EID: 20544448450     PISSN: 00303755     EISSN: None     Source Type: Journal    
DOI: 10.1159/000085248     Document Type: Article

References (68)

1. van Leeuwen R, Klaver CC, Vingerling JR, Hofman A, de Jong PT: The risk and natural course of age-related maculopathy: Follow-up at 6 1/2 years in the Rotterdam study. Arch Ophthalmol 2003;121:519-526.
2. Bird AC: The Bowman lecture: Towards an understanding of age-related macular disease. Eye 2003;17:457-466.
3. Delcourt C, Cristol JP, Tessier F, Leger CL, Descomps B, Papoz L: Age-related macular degeneration and antioxidant status in the POLA study. POLA Study Group. Pathologies Oculaires Liées à l'Age. Arch Ophthalmol 1999;117:1384-1390
4. Mares-Perlman JA, Brady WE, Klein R, Klein BE, Bowen P, Stacewicz-Sapuntzakis M, Palta M: Serum antioxidants and age-related macular degeneration in a population-based case-control study. Arch Ophthalmol 1995;113:1518-1523.
5. Seddon JM, Ajani UA, Sperduto RD, Hiller R, Blair N, Burton TC, Farber MD, Gragoudas ES, Haller J, Miller DT: Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group. JAMA 1994;272:1413-1420.
6. West S, Vitale S, Hallfrisch J, Munoz B, Muller D, Bressler S, Bressler NM: Are antioxidants or supplements protective for age-related macular degeneration? Arch Ophthalmol 1994;112:222-227
7. Mares-Perlman JA, Fisher AI, Klein R, Palta M, Block G, Millen AE, Wright JD: Lutein and zeaxanthin in the diet and serum and their relation to age-related maculopathy in the third national health and nutrition examination survey. Am J Epidemiol 2001;153:424-432.
8. Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report No. 8. Arch Ophthalmol 2001;119:1417-1436
9. Richer S, Stiles W, Statkute L, Pulido J, Frankowski J, Rudy D, Pei K, Tsipursky M, Nyland J: Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration. The Veterans LAST Study (Lutein Antioxidant Supplementation Trial). Optometry 2004;75:216-230.
10. Toescu EC, Myronova N, Verkhratsky A: Age-related structural and functional changes of brain mitochondria. Cell Calcium 2000;28:329-338.
11. James AM, Murphy MP: How mitochondrial damage affects cell function. J Biomed Sci 2002;9:475-487.
12. Schon EA, Manfredi G: Neuronal degeneration and mitochondrial dysfunction. J Clin Invest 2003;111:303-312.
13. Murphy MP, Smith RA: Drug delivery to mitochondria: The key to mitochondrial medicine. Adv Drug Deliv Rev 2000;41:235-250.
14. Binienda Z, Virmani A: The mitochondriotropic effects of L-carnitine and its esters in the central nervous system. Curr Med Chem Cent Nerv Syst Agents 2003;3:275-282.
15. Barron MJ, Johnson MA, Andrews RM, Clarke MP, Griffiths PG, Bristow E, He LP, Durham S, Turnbull DM: Mitochondrial abnormalities in ageing macular photoreceptors. Invest Ophthalmol Vis Sci 2001;42:3016-3022.
16. Liang FQ, Godley BF: Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: A possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res 2003;76:397-403.
17. Feher J, Papale A, Tomei M, Balacco Gabrieli C: Mitochondrial damage and protection in retinal dystrophies. ARVO abstract 1194. Invest Ophthalmol Vis Sci 1998;39:S570.
18. Ferdinandusse S, Denis S, Dacremont G, Wanders RJ: Studies on the metabolic fate of n-3 polyunsaturated fatty acids. J Lipid Res 2003;44:1992-1997.
19. Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP: Oxidative damage and protection of the RPE. Prog Retin Eye Res 2000;19:205-221.
20. Feher J, Papale A, Mannino G, Gualdi L, Balacco Gabrieli C: Mitotropic compounds for the treatment of age-related macular degeneration: The metabolic approach and a pilot study. Ophthalmologica 2003;217:351-357.
21. Kerner J, Hoppel C: Fatty acid import into mitochondria. Biochim Biophys Acta 2000;1486:1-17.
22. Levine J, Panchalingam K, McClure RJ, Gershon S, Pettegrew JW: Effects of acetyl-L-carnitine and myo-inositol on high-energy phosphate and membrane phospholipid metabolism in zebra fish: A 31P-NMR-spectroscopy study. Neurochem Res 2003;28:687-690.
23. Villa RF, Turpeenoja L, Benzi G, Giuffrida Stella AM: Action of L-acetylcarnitine on age-dependent modifications of mitochondrial membrane proteins from rat cerebellum. Neurochem Res 1988;13:909-916
24. Leaf A, Xiao YF, Kang JX: Interactions of n-3 fatty acids with ion channels in excitable tissues. Prostaglandins Leukot Essent Fatty Acids 2002;67:113-120.
25. Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE: Essential fatty acids in visual and brain development. Lipids 2001;36:885-895.
26. Simopoulos AP: Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002;21:495-505.
27. Youdim KA, Martin A, Joseph JA: Essential fatty acids and the brain: Possible health implications. Int J Dev Neurosci 2000;18:383-399.
28. Clarke SD: Polyunsaturated fatty acid regulation of gene transcription: A molecular mechanism to improve the metabolic syndrome. J Nutr 2001;131:1129-1132.
29. Nakamura MT, Cho HP, Xu J, Tang Z, Clarke SD: Metabolism and functions of highly unsaturated fatty acids: An update. Lipids 2001;36:961-964.
30. Papucci L, Schiavone N, Witort E, Donnini M, Lapucci A, Tempestini A, Formigli L, Zecchi-Orlandini S, Orlandini G, Carella G, Brancato R, Capaccioli S: Coenzyme Q10 prevents apoptosis by inhibiting mitochondrial depolarization independently of its free radical scavenging property. J Biol Chem 2003;278:28220-28228.
31. Crane FL: Biochemical functions of coenzyme Q10. J Am Coll Nutr 2001;20:591-598.
32. Yamamura T, Otani H, Nakao Y, Hattori R, Osako M, Imamura H, Das DK: Dual involvement of coenzyme Q10 in redox signaling and inhibition of death signaling in the rat heart mitochondria. Antioxid Redox Signal 2001;3:103-112.
33. Barzanti V, Battino M, Baracca A, Cavazzoni M, Cocchi M, Noble R, Maranesi M, Turchetto E, Lenaz G: The effect of dietary lipid changes on the fatty acid composition and function of liver, heart and brain mitochondria in the rat at different ages. Br J Nutr 1994;71:193-202.
34. Pepe S: Mitochondrial function in ischaemia and reperfusion of the ageing heart. Clin Exp Pharmacol Physiol 2000;27:745-750.
35. Rodriguez de Turco EB, Parkins N, Ershov AV, Bazan NG: Selective retinal pigment epithelial cell lipid metabolism and remodeling conserves photoreceptor docosahexaenoic acid following phagocytosis. J Neurosci Res 1999;57:479-486.
36. Wang JY, Saito M: Dietary supplementation of n-3 fatty acids and hydroperoxide levels in rat retinas. Free Radic Res 2001;35:367-375.
37. Furuno T, Kanno T, Arita K, Asami M, Utsumi T, Doi Y, Inoue M, Utsumi K: Roles of long chain fatty acids and carnitine in mitochondrial membrane permeability transition. Biochem Pharmacol 2001;62:1037-1046.
38. Atamna H, Ames BN, Liu J: Delaying aging with mitochondrial micronutrients and antioxidants. Scientific World J 2001;1(1 suppl 3):81-82.
39. Seddon JM, Rosner B, Sperduto RD, Yannuzzi L, Haller JA, Blair NP, Willett W: Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol 2001;119:1191-1199.
40. Smith W, Mitchell P, Leeder SR: Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol 2000;118:401-404.
41. Midena E, Degli Angeli C, Blarzino MC, Valenti M, Segato T: Macular function impairment in eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 1997;38:469-477.
42. Hutchings N, Wild JM, Hussey MK, Flanagan JG, Trope GE: The long-term fluctuation of the visual field in stable glaucoma. Invest Ophthalmol Vis Sci 2000;41:3429-3436.
43. van Leeuwen R, Chakravarthy U, Vingerling JR, Brussee C, Hooghart AJ, Mulder PG, de Jong PT: Grading of age-related maculopathy for epidemiological studies: Is digital imaging as good as 35-mm film? Ophthalmology 2003;110:1540-1544.
44. Scholl HP, Dandekar SS, Peto T, Bunce C, Xing W, Jenkins S, Bird AC: What is lost by digitizing stereoscopic fundus color slides for macular grading in age-related maculopathy and degeneration? Ophthalmology 2004;111:125-132.
45. Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD, de Jong PT, Klaver CC, Klein BE, Klein R: An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995;39:367-374.
46. Bland JM, Altman DG: Multiple significance tests: The Bonferroni method. BMJ 1995;310:170-171.
47. Perneger TV: What's wrong with Bonferroni adjustments. BMJ 1998;316:1236-1238.
48. Li J, Tso MO, Lam TT: Reduced amplitude and delayed latency in foveal response of multifocal electroretinogram in early age related macular degeneration. Br J Ophthalmol 2001;85:287-290.
49. Haimovici R, Owens SL, Fitzke FW, Bird AC: Dark adaptation in age-related macular degeneration: Relationship to the fellow eye. Graefes Arch Clin Exp Ophthalmol 2002;240:90-95.
50. Tolentino MJ, Miller S, Gaudio AR, Sandberg MA: Visual field deficits in early age-related macular degeneration. Vision Res 1994;34:409-413.
51. Remky A, Lichtenberg K, Elsner AE, Arend O: Short wavelength automated perimetry in age related maculopathy. Br J Ophthalmol 2001;85:1432-1436.
52. Abdelsalam A, Del Priore L, Zarbin MA: Drusen in age-related macular degeneration: Pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol 1999;44:1-29.
53. Sunness JS, Johnson MA, Massof RW, Marcus S: Retinal sensitivity over drusen and nondrusen areas: A study using fundus perimetry. Arch Ophthalmol 1988;106:1081-1084.
54. Tolentino MJ, Miller S, Gaudio AR, Sandberg MA: Visual field deficits in early age-related macular degeneration. Vision Res 1994;34:409-413.
55. Feher J, Kovacs B, Schvöller M, Kovacs I, Balacco Gabrieli C: Improvement of fundus alterations in early AMD treated with combination of n-3 fatty acids, coenzyme Q10 and acetyl-L-carnitine (Phototrop™). ARVO 2004, abstract 3093.
56. Johnson PT, Lewis GP, Talaga KC, Brown MN, Kappel PJ, Fisher SK, Anderson DH, Johnson LV: Drusen-associated degeneration in the retina. Invest Ophthalmol Vis Sci 2003;44:4481-4488.
57. Demaison L, Sergiel JP, Moreau D, Grynberg A: Influence of the phospholipid n-6/n-3 polyunsaturated fatty acid ratio on the mitochondrial oxidative metabolism before and after myocardial ischemia. Biochim Biophys Acta 1994;1227:53-59.
58. 2+ activation of PDH. Am J Physiol 1999;276:H149-H158.
59. Aureli T, Di Cocco ME, Capuani G, Ricciolini R, Manetti C, Miccheli A, Conti F: Effect of long-term feeding with acetyl-L-carnitine on the age-related changes in rat brain lipid composition: A study by 31P NMR spectroscopy. Neurochem Res 2000;25:395-399.
60. Virmani MA, Caso V, Spadoni A, Rossi S, Russo F, Gaetani F: Action of acetyl-L-carnitine on the neurotoxicity evoked by amyloid fragments on primary rat cortical neurones. Ann NY Acad Sci 2001;939:162-178.
61. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF: An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 2001;20:705-732.
62. Rungger-Brandle E, Englert U, Leuenberger PM: Exocytic clearing of degraded membrane material from pigment epithelial cells in frog retina. Invest Ophthalmol Vis Sci 1987;28:2026-2037.
63. Spaide RF, Ho-Spaide WC, Browne RW, Armstrong D: Characterization of peroxidized lipids in Bruch's membrane. Retina 1999;19:141-147.
64. Holz FG, Sheraidah G, Pauleikhoff D, Bird AC: Analysis of lipid deposits extracted from human macular and peripheral Bruch's membrane. Arch Ophthalmol 1994;112:402-406.
65. Curcio CA, Millican CL, Bailey T, Kruth HS: Accumulation of cholesterol with age in human Bruch's membrane. Invest Ophthalmol Vis Sci 2001;42:265-274.
66. Anderson DH, Mullins RF, Hageman GS, Johnson LV: A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 2002;134:411-431.
67. Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH: A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 2000;70:441-449.
68. Anderson DH, Ozaki S, Nealon M, Neitz J, Mullins RF, Hageman GS, Johnson LV: Local cellular sources of apolipoprotein E in the human retina and retinal pigmented epithelium: Implications for the process of drusen formation. Am J Ophthalmol 2001;131:767-781.