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TREATMENT OF
MACULAR DEGENERATION
 
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Research Supporting the Role of Antioxidant Vitamins and Minerals in Preventing the Development of Age-Related Macular Degeneration
Age-related macular degeneration is the major cause of visual impairment and blindness in the Western World among people aged 65 years and over. (1-3) A recent study has shown that, in 2004, age-related macular degeneration affected more than 1.75 million people in the United States and it has been predicted that this could increase to approximately 3 million by the year 2020 as the life expectancy of the populations in the western world increases. (4)

Age-related macular degeneration is a degenerative condition where the macula, the light-gathering region of the retina responsible for central and detailed vision, becomes damaged resulting in loss of vision and blindness. Yellowish deposits of drusen form resulting in distortion and blurring of vision. There are two different types of age-related macular degeneration: the ‘dry’ or atrophic form which usually progresses slowly and causes central vision loss and the ‘wet’ or exudative form where retinal blood vessels leak blood. The wet form of age-related macular degeneration is rarer, more severe and may progress rapidly causing significant central vision loss.

Although there is currently no cure for this debilitating condition, some new treatments are now available including photodynamic therapy and macular surgery which may limit the extent of visual loss resulting from age-related macular degeneration. In addition, recent research has provided exciting evidence of some improvement in the vision of patients suffering from the wet form of age-related macular degeneration following treatment with medications injected into the eye including Avastin (bevacizumab), its derative Lucentis (ranibizumab) and Macugen (pegaptanib sodium). (5) These medications act by inhibiting the action of vascular endothelial growth factor (VEGF) which is known to stimulate the development of new blood vessels.

The precise cause of macular degeneration still remains unknown however, many scientists believe that heredity may play an important role and this theory is currently the subject of extensive scientific investigation. Other possible factors which have been implicated in causing age-related macular degeneration include UV light exposure and malnutrition. Scientific studies have shown that people who consume large amounts of fruit and vegetables are at a lower risk of developing age-related macular degeneration (6) and it was concluded that a diet rich in fruit and vegetables will contain high levels of antioxidant vitamins and beta-carotene. Furthermore, scientific evidence has suggested that cumulative oxidative damage to the retina may be a possible cause of the pathogenesis associated with developing age-related macular degeneration. (7)   The retina is known to be particularly susceptible to oxidative stress as its need for oxygen is large, it is exposed to high levels of light and its membranes have high levels of polyunsaturated fatty acids which are readily oxidised. Consequently, much interest has centred on studying the effects of antioxidants as a possible means of preventing the development of age-related macular degeneration. Results from one clinical trial, investigating the effects of zinc supplementation on the development of age-related macular degeneration showed a statistically significant reduction in loss of visual acuity in the group of patients treated with the zinc supplement. (8)  However, this trial was small and a larger-scale investigation was recommended before any beneficial effects of zinc supplementation could be definitively proven. Many studies subsequently investigated the effects of a range of antioxidant vitamins and minerals on the development of age-related macular degeneration but results were inconsistent. For example, while treatment with zinc was shown to reduce the loss of visual acuity in patients with age-related macular degeneration, (8) another study showed that treatment that vitamin E alone was unlikely to have a protective effect against age-related macular degeneration. (9)  Consequently, the National Eye Institute commissioned a large, randomized clinical trial as part of the Age-Related Eye Disease Study (AREDS) to definitively evaluate the effects of high doses of zinc and selected antioxidant vitamins on the development of advanced age-related macular degeneration in a cohort of older persons. (10) This study involved 3640 participants aged between 55 and 80 recruited from 11 centres across the United States. The participants presented with extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy or pigment abnormalities in one or both eyes, or advanced age-related macular degeneration or vision loss due to  age-related macular degeneration in one eye. At least one eye had best-corrected visual acuity of 20/32 or better. The participants were randomly assigned to one of four groups: Group 1 received antioxidants (vitamin C, 500mg; vitamin E, 400IU; beta carotene, 15mg), Group 2 received zinc and copper (zinc 80mg as zinc oxide; copper 2mg as cupric oxide), Group 3 received antioxidants plus zinc, Group 4 received a placebo. The results showed a statistically significant reduction in the odds of developing advanced age-related macular degeneration following treatment with antioxidants plus zinc. Exclusion of participants with extensive small drusen, nonextensive intermediate drusen or pigment abnormalities from the results showed that, in the remaining higher-risk group of participants, antioxidants plus zinc as well as zinc alone significantly reduced the chance of developing advanced age-related macular degeneration. Importantly, the study also found no statistically significant serious adverse effects following treatment with any of the formulations used in the study. The conclusion from this study was that patients with extensive intermediate size drusen, at least one large drusen, noncentral geographic atrophy in one or both eyes or advanced age-related macular degeneration or vision loss due to age-related macular degeneration should consider taking a high dose supplement of antioxidants (vitamin C, vitamin E and beta carotene) plus zinc.

While the AREDS report provided conclusive evidence that treatment with high doses of vitamins C, E, beta carotene and zinc reduced the risk of developing advanced age-related macular degeneration, unfortunately, these were the only antioxidants included in the study. Many more scientific studies have been carried out to investigate the effects of other antioxidants on the development of age-related macular degeneration. For example, the carotenoids lutein and zeaxanthin are antioxidants which were not included in the AREDs study as they were not commercially available at the time the AREDS study was planned. Carotenoids are phytochemicals commonly found in fruit and vegetables and provide the red, orange and yellow colours associated with these foods. Extensive research has shown that these antioxidants may protect the macula against short-wavelength visible light and that the oxidative-reductive pathways for lutein and zeaxanthin in the human retina may play an important role in the prevention of age-related macular degeneration. (11) Lutein is the primary dietary carotenoid xanthophyll pigment responsible for macular pigment optical density in primates and researchers have demonstrated  that low dietary intake of lutein  is indeed a major risk factor for advanced age-related macular degeneration.  (6) In addition, The Eye Disease Case Control Study (1993) reported that subjects with high fasting blood levels of lutein and zeaxanthin ( > 80th percentile) had a reduced risk of developing neovascular age-related macular degeneration. (12) Thus, evidence from these studies seemed to indicate that treatment with lutein could have a beneficial effect on reducing the risk of developing advanced age-related macular degeneration. In 2004 the LAST study (Lutein Antioxidant Supplementation Trial) was carried out in an attempt to conclusively evaluate the effect of lutein either alone or in combination with additional carotenoids, antioxidants and vitamins and minerals on the development of atrophic age-related macular degeneration. (13) This study was a prospective, 12 month, randomized, double-masked, placebo-controlled trial. It was also approved by the R&D and Human Subjects Committees at the Department of Veteran Affairs North Chicago and Hines Hospitals. The trial involved 90 subjects with atrophic age-related macular degeneration. The subjects were assigned to one of three groups: Group 1 received lutein only (10mg), Group 2 received a broad-spectrum supplementation formula containing lutein (10mg) as well as antioxidants, vitamins and minerals, Group 3 received a placebo. Results from the study showed that the subjects in Groups 1 and 2 demonstrated an increase in mean eye macular pigment optical density as well as an improvement in visual acuity, glare recovery and most measures of quality of vision improved for both groups also. This study, therefore, conclusively demonstrated that visual function is improved in patients with atrophic age-related macular degeneration following supplementation with either lutein alone or lutein in combination with antioxidants, vitamins and minerals.

A study in the UK investigating the relationship between plasma concentrations of lutein and zeaxanthin and age-related macular degeneration in a group of 380 patients aged between 66 and 75 years demonstrated that the risk of early or late age-related macular degeneration was significantly higher in patients with lower plasma concentrations of zeaxanthin. Thus, the results from this study support the view that zeaxanthin may protect against age-related macular degeneration. (14) Similarly, the Third National Health and Nutrition Examination Survey reported that higher intakes of lutein and zeaxanthin among people aged 40 to 59 years may be associated with a reduced risk of age-related macular degeneration. (15)  The recent CAREDS study (Catotenoids in Age-Related Eye Disease) evaluated the relationship between dietary lutein plus zeaxanthin and intermediate age-related macular degeneration in women aged between 50 and 79 years and concluded that diets rich in lutein plus zeaxanthin may protect against intermediate age-related macular degeneration in healthy women younger than 75 years of age. (16)

It has been suggested that zeaxanthin may play a much more important role in preventing or stabilizing macular degeneration than was previously thought. Macular pigment is primarily composed of lutein and zeaxanthin and protects the retina from damage caused by light exposure and oxidative damage. A high macular pigment density allows retention of visual sensitivity. This, therefore, links into and goes some way to explaining the findings of the LAST study, where lutein supplementation resulted in an increase in the density of macular pigment and improved visual function. Zeaxanthin, along with vitamin E, have both been shown to have a protective effect on the rod and cone photoreceptors in the retina and it is thought that they both have an important role to play in maintaining retinal health. (17)

Although a wealth of information exists relating to the benefits of lutein and zeaxanthin supplements on preventing the progression of age-related macular degeneration, a number of  studies have been carried out to investigate the effects of other antioxidants. For example,  bilberry and grape seed  are both anthocyanidin bioflavonoids which, as well as acting as antioxidants, have also been shown to have the additional benefit of being particularly effective in strengthening blood capillaries and preventing leakage from these small blood vessels. (18) In addition, they are essential for the proper absorption and use of vitamin C.

Alpha-lipoic acid has been shown to protect cells from age-associated oxidative damage (19) and studies on glutathione have demonstrated that it can also protect against oxidative injury. (20)

Selenium is a trace mineral which is incorporated into proteins to make antioxidant enzymes and it has been shown to help protect the body against the damaging effects of free radicals.  One study demonstrated that high doses of selenium appeared to slow the progression of macular degeneration (21) and interestingly, a more recent study demonstrated that selenium can down-regulate the production of VEGF (22) which may go someway to explaining the previously reported effect on decreasing the progression of age-related macular degeneration.

Results of the above-mentioned studies collectively support the view that high dietary levels of antioxidants, vitamins and minerals including vitamins E, C, B6, beta-carotene, zinc, cupric oxide, lutein, zeaxanthin, bilberry, alpha lipoic acid, grape seed extract, L-glutathione and selenium, that is, the ingredients of i-defense Gold Macular Formula, may protect against the development of age-related macular degeneration. Furthermore, supplements of antioxidants, vitamins and minerals resulted in patients with age-related macular degeneration showing a reduced risk of developing advanced age-related macular degeneration and an improvement in visual acuity.

However, it must also be mentioned that the studies all demonstrated that antioxidant and vitamin supplements do not reverse damage already present in the retina. The National Eye Institute now recommends that people who are at high risk of developing advanced AMD should consider taking the combination of nutrients used in the AREDS study. One note of caution is that some medical studies have demonstrated a link between beta-carotene and lung cancer in smokers and therefore, smokers should avoid taking a supplement containing beta-carotene. (23, 24)

The number of patients worldwide suffering from the debilitating and incapacitating effects of AMD is continuing to grow and although AMD has been extensively researched and studied, there is still no cure for the condition. Therefore, it is important to identify any intervention that decreases the progression of the disease and will allow the patient to enjoy a better quality of life.

REFERENCES

1. National Advisory Eye Council. Report of the Retinal Diseases Panel: Vision Research: A National Plan, 1994-1998. Bethesda, Md: United States Department of Health and Human Services: 1993. Publication NIH 93-3186.

2.   Klaver, C.C.W., Vingerling, J.R. and de Jong, P.T.V.M. (1998). Age-Specific Prevalence and Causes of Blindness and Visual Impairment in an Older Population. Archives of Ophthalmology. 116:  653-658.

3.   Attebo, K., Mitchell, P., and Smith W. (1996) Visual acuity and the causes of visual loss in Australia: the Blue Mountains Eye Study. Ophthalmology 103: 357-364

4.   Friedman, D.S., O’Colmain, B.J., Munoz, B., Tomany, S.C., McCarty, C., de Jong, P.T., Nemesure, B., Mitchell, P. and Kempen, J. (2004) Prevalence of age-related macular degeneration in the United States. Archives of  Ophthalmology 122(4): 564-572.

5.  Gragoudas, E.S., Adamis, A.P., Cunningham, E.T.Jr., Feinsod, M., Guyer, D.R. (2004) Pegaptanib for Neovascular Age-Related Macular Degeneration. New England Journal of Medicine  351: 2805 – 2816.

6.   Seddon, J.M., Ajani, U.A., Sperduto, R.D., Hiller, R., Blair, N., Burton, T.C., Farber, M.D., Gragoudas, E.S., Haller, J., Miller, D.T. et al. (1994) Dietary caroteoids, vitamins A, C and E and advanced age-related macular degeneration. Eye Disease Case-Control Study Group JAMA 272: 1413-1420

7.  Beatty, S., Koh, H-H, Henson, D. AND Boulton, M. (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Survey Ophthalmol 45: 115-134

8. Newsome, D.A., Swartz, M., Leone, N.C., Elston, R.C. and Miller, E. (1998) Oral zinc in macular degeneration. Archives of  Ophthalmology 106: 192-198.

9.  Hall, N.F. and Gale, C. R. (2002) Prevention of age related macular degeneration. British Medical Journal 325: 1-2

10.   Age-related Eye Disease Study Group (2001) AREDS Report 8. A  Randomized, Palcebo-Controlled Clinical Trial of High-Dose Supplementation with Vitamins C and E, Beta Carotene and Zinc for Age-Related Macular Degeneration and Vision Loss. Archives of Ophthalmology 119: 1417-1436

11.  Khachik, F., Bernstein, P.S. and Garland, D.L. (1997) Identification of lutein and zeaxanthin oxidation products in human and monkey retinas. Investigative Ophthalmology and Visuals Science  38 (9): 1802-1811

12. EDCCS Eye Disease Case Control Study (1993) Antioxidant status and neovascular age-related macular degeneration. Eye Disease Case-Control Study Group Archives of Ophthalmology 111: 104-109

13.   Richer, S., Stiles, W., Statkute, L., Pulido, J., Frankowski, J., Rudy, D., Pei, K., Tsipursky, M. and Nyland, J. (2004) 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 75: 216-230

14.  Gale, C.R., Hall, N.F., Phillips, D.I.W. and Martyn, C. N. (2003) Lutein and Zeaxanthin Status and Risk of Age-Related Macular Degeneration. Investigative Ophthalmology and Visual Science 44: 2461-2465

15.   Mares-Perlman, J.A., Fisher, A.I., Klein, R., Palta, M., Block, G., Millen, A.E. and Wright, J.D. (2001)  Lutein and Zeaanthin in the Diet and Serum and Their Relation to Age-related Maculopathy in the Third National Health and Nutrition Examination Survey. American Journal of Ophthalmology 153 (5): 424-432

16.  Moeller, S.M., Parekh, N., Tinker, L., Ritenbaugh, C., Blodi, B., Wallace, R.B. and  Mares, J.A. (2006) Associations between Intermediate Age-related macular Degeneration and Lutein and Zeaxanthin in the Carotenoids in Age-Related Eye Disease Study (CAREDS) Archives of Ophthalmology 124: 1151-1162

17.  Thomson, L.R., Toyoda, Y., Delori, F.C., Garnett, K.M., Wong, Z-Y., Nichols, C.R., Cheng, K.M., Craft, N.E. and Dorey, C.K. (2002) Long Term Supplementation with Zeaxacthin Reduces Photoreceptor Death in Light-damaged Japanese Quail. Experimental Eye Research 75: 529-542

18.  Valensi, P.E., Behar, A., de Champvallins, M.M., Attalah, M., Boulakia, F.C. and Attali, J.R. (1996) Effects of Purified micronized Flavonoid Fraction on capillary Filtration in diabetic Patients. Diabetic Medicine 13: 882-888.

19. Voloboueva, L.A., Liu, J., Suh, J.H. Ames, B.N. and Miller, S.S. (2005) ( R) -aplha-lipoic acid protects retinal pigment epithelial cells from oxidative damage. Investigative Ophthalmology and Visual Science 46 (11): 4302-4310

20.  Sternberg, P. Jr., Davidson, P.C., Jones, D.P., Hagen, T.M., Reed, R.L. and Drews-Botsch, C. (1993) protection of retinal pigment epithelium from oxidative injury by glutathione and precursors. Investigative Ophthalmology and Visual Science  34 (13): 3661-3668.

21.  Crary, E.J. and McCarty, M.F. (1984) Potential applications for high-dose nutritional antioxidants. Medical Hypotheses 13 (1): 77-98.

22.  McCarty, M.F. (2005) The putative therapeutic value of high-dose selenium in proliferative retinopathies may reflect down-regulation of VEGF production by the hypoxic retina. Medical Hypotheses. 64 (1): 159-161.

23.  Albanes, D., Heinonen, O.P., Taylor, P.R., Virtamo, J., Edwards, B.K., Rautalahti, M., Hartman, A.M., Palmegren, J., Freedman, L.S., Haapakoski, J., Barrett, M.J., Pietinen, P., Malila, N., Tala, E., Lippo, K., Salomaa, E.R., Tangrea, J.A., Teppo, L., Askin, F.B., Taskinen, E., Erozan, Y., Greenwald, P. and Huttunen, J.K. (1996) Alpha-tocopherol, beta-carotene cancer prevention study: Effects of base-line characteristics and study compliance. Journal of National Cancer Institute 88: 1560-1570.

24.  Redlich, C.A., Blaner, W.S., Van Bennekum, A.M., Chung, J.S., Clever, S.L., Holm, C.T. and Cullen, M.R. (1998) Effect of supplementation with beta-carotene and vitamin A on lung nutrient levels. Cancer Epidemiological Biomarkers 7: 211-214.