ANTIOXIDANTS IN AMD Free radicals Free radicals are chemically active atoms or molecular fragments...
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ANTIOXIDANTS IN AMD
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Free radicals
• Free radicals are chemically active atoms or molecular fragments that have a charge due to an excess or deficient number of electrons
• They scavenge body to grab or donate electrons, thereby damaging cell, proteins, and DNA
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Free radicals formation
• Endogenous: form as a result of normal aerobic respiration, metabolism, and inflammation
• Exogenous free radicals form from environmental factors such as sunlight, X-rays, smoking and alcohol.
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Free radicals Examples
• Examples: super oxide anion(O2-) ,
hydroxyl radical (OH-),hydrogen peroxide (H2O2), some metals such as iron and copper
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Free radicals mechanism
• Some of the reactive species leak out of their enzyme-binding sites and may damage other components of tissues such as proteins, membrane lipids, and DNA if not captured by detoxifying enzymes
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Mechanisms of Lipid Peroxidation
• auto-oxidation:Polyunsaturated fatty acids are susceptible to auto-oxidation because
their allelic hydrogen is easily removed by several types of initiating radicals.
• Photo-oxidation: is a process by which oxygen is activated electronically by light to form
singlet oxygen, which in turn reacts at a diffusion-controlled rate with unsaturated fatty acids or other cellular constituents
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Free radicals & Retina
• Retina is vulnerable to damage from lipid peroxidation because of:
• high content of polyunsaturated fatty acids It is well established that polyunsaturated fatty acids are sensitive to peroxidation in proportion to their number of double bonds
• very rich in mitochondria• Excellent oxygen supply retina and choroid showed at least a sevenfold
higher rate of oxygen consumption per milligram of protein compared with all other
tissues tested (except the adrenal gland)
• Light exposure may trigger photo-oxidative processes
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What Are Antioxidants ?
• antioxidants are substances that are capable of counteract damaging effects of the free radicals
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Types of Antioxidants
• nutrients (vitamins and minerals) (Vitamin E ,Vitamin C, Beta-carotene selenium, manganese and zinc
• enzymes (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx )
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Vitamin E
• Refers to all entities that exhibit biological activity of the isomer tocopherol
• Alpha-tocopherol, the most widely available isomer, has strongest effect in the body
• It is fat-soluble and is in a unique position to safeguard cell
membranes from damage by free radicals.
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VITAMIN E AND AMD
17 studies have assessed association between vit E and AMD
10 of the 17 studies found no significant results (Blumenkranz et al., 1986;Cardinault et al., 2005; Cho et al., 2004; Christen et al.,1999; EDCCS (Eye Disease Case Control Study), 1993;Mares-Perlman et al., 1995c, 1996a; Sanders et al., 1993; Seddon et al., 1994a; Smith et al., 1997; van Leeuwen et al.,2005).
7 studies found significantly protective effects under certain circumstances (Belda et al., 1999; Delcourt et al., 1999; Ishihara et al., 1997; Simonelli et al.,2002; van Leeuwen et al., 2005; VandenLangenberg et al.,1998; West et al., 1994)
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Vitamin C
• is a water-soluble vitamin. also known as ascorbic acid.
• it scavenges free radicals that are in an aqueous (watery) environment, such as inside cells
• Vitamin C works synergistically with vitamin E to quench free radicals.
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VITAMIN C AND AMD
26 studies have assessed the association between vitamin C intake or supplement use and risk for ARM (Blumenkranz et al., 1986; Cho et al., 2004; Christen et al., 1999; Delcourt et al., 1999; EDCCS (Eye Disease Case Control Study), 1993; Flood et al., 2002; Goldberg et al., 1988; Ishihara et al., 1997; Mares-Perlman et al., 1996a; Seddon et al., 1994a; Simonelli et al., 2002; van Leeuwen et al., 2005; VandenLangenberg et al., 1998; West et al., 1994).
12 studies did not find significant association (Blumenkranz et al., 1986; Cho et al., 2004; Christen et al., 1999; Delcourt et al., 1999; EDCCS (Eye Disease Case Control Study), 1993; Goldberg et al., 1988; Ishihara et al., 1997; Mares-Perlman et al., 1996a; Seddon et al., 1994a; van Leeuwen et al., 2005; VandenLangenberg et al., 1998; West et al., 1994)
2 studies found significant results, but in opposite direction (Flood et al., 2002; Simonelli et al., 2002).
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Carotenoids in retina
Activity: • carotenoids have been shown to make up the
yellow pigment in the macula• limiting chromatic aberration at the fovea• protect the macula against short-
wavelength visible light• quenching of free radicals• Beta Carotene is the precursor for vitamin A
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Carotenoids in retina
• A mixture of the two carotenoids lutein and zeaxanthin presents in the macula
• zeaxanthin is concentrated in the fovea • lutein is dispersed throughout the retina.• Little beta-carotene is present in the
human eye.• carotenoids are present only in the retina
and not at all in the RPE.
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Beta-carotene and AMD
Of the 13 studies that have tried to relate beta-
carotene to ARM 2 studies found significant results to support a protective role for beta-carotene on advanced AMD (Cardinault et al., 2005; Cho et al., 2004;
EDCCS (Eye Disease Case Control Study), 1993; Flood et al., 2002; Mares-Perlman et al., 1995c, 1996a; Sanders et al., 1993; Seddon et al., 1994a; Simonelli et al., 2002; Smith et al., 1997; van Leeuwen et al., 2005;
VandenLangenberg et al., 1998; West et al., 1994),
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VITAMIN A AND AMD
12 studies related vitamin A or retinol to
AMD, of these, only 3 studies found significant results (Blumenkranz et al., 1986; Cho et al., 2004; Delcourt et
al., 1999; Flood et al., 2002; Goldberg et al., 1988; Ishihara et al., 1997; Knekt et al., 1992; Sanders et al., 1993; Seddon et al., 1994a; Simonelli et al., 2002; Vanden Langenberg et al., 1998; West et al., 1994).
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Lutein / Zeaxanthin and AMD
14 studies have related lutein and zeaxanthin to ARM (Cardinault et al., 2005; Cho et al., 2004; EDCCS (Eye Disease Case Control Study),
1993; Flood et al., 2002;Gale et al., 2003; Mares-Perlman et al., 1995c, 1996a, 2001; Sanders et al., 1993; Seddon et al., 1994a; Simonelli et al., 2002; Snellen et al., 2002; van Leeuwen et al., 2005; Vanden- Langenberg et al., 1998).
5 studies indicated beneficial effects due to consuming higher level of lutein/zeaxanthin
9 studies, did not find significant results including four
prospective studies from the Beaver Dam Eye Study (VandenLangenberg et al., 1998), the Blue Mountain Eye Study (Flood et al., 2002), the Nurses’ Health Study, the Health Professionals Follow-up Study (Cho et al., 2004), and the Rotterdam Study
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ZINC
• Is the most abundant trace element in human eye
• It is a cofactor for several antioxidant enzymes including catalase & superoxide dismutase
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ZINC AND AMD
• 8 studies related zinc to AMD, Of
these 3 studies found significant results
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Vit E Cataract & AMD Trial (VECAT)
• Aim: to evaluate effects of VE in prevention of early AMD
• Design: C-C, n=1193, FU=4y, Vit E 500 IU/d • Result: no effect
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EYE DISEASE CASE DONTROL STUDY (EDCCS)
• Aim: to evaluate effects of dietary intake of antioxidant in decrease risk of AMD
• Design: C-C, n= 876, • Results: higher intake of carotenoids →
decrease risk for AMD
Intake of Vit E,C & A was not associated with risk of AMD
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BAEVER DAM EYE STUDY (BDES)
• Aim: to evaluate association between antioxidant & zinc and AMD
• Design: questionnaire(10 y) , n ≈ 5000 F/U=5y
• Results: modest inverse association between intake of pro Vit A & zinc and AMD
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PHYSICIAN’S HEALTH STUDY (PHS)
• Aim: to evaluate association between antioxidant and AMD
• Design: cohort, n= 21120, F/A> 12y, supplementary antioxidant & multivitamin
• Results: no association between use of antioxidants & multivitamin and reduce of AMD
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NHS & HPFS
• Aim: to evaluate effects of dietary intake of antioxidant in decrease risk of AMD
• Design: prospective F/U, n= 120,000, Results: consume of > 3 serving/d of fruits had significantly reduce risk of AMD did not find significant association between intake of vegetables, supplement antioxidants, multivitamin or carotenoids
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AGE RELATRD EYE DISEASE STUDY
(AREDS)
• Aim: to evaluate effects of vit C (500mg) vit E (400 IU) beta-carotene (15 mg) & zinc (80mg) /d in AMD
• Design: C-T, n ≈5000, in 4 groups, (no drusen, small, intermediate or large drusen) received antioxidant or zinc or both F/U>6y
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AREDS STUDY (contd.)
Patients divided into 4 categories:Category 1: little or no AMD -> randomized to antioxidants or placebo to determine any effect on lens changes
Category 2: early AMDCategory 3: intermediate AMDCategory 4: advanced AMD in one eye
Category 2, 3 and 4 randomized to receive :1. Placebo2. Antioxidants alone3. Zinc alone4. Antioxidants plus zinc
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AREDS STUDY (contd.)
Results
For category 2, only 13% of patients progressed to advanced AMD.
For categories 3 and 4 (who are at greater risk for developing advanced AMD), it was found that the combination of zinc and antioxidants were most effective in reducing the progression to advanced AMD.
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Recommendations of AREDS
• Persons >55y should have dilated eye examination• Those with Extensive intermediated size drusen At least one large drusen Non central geographic atrophy Visual loss due to AMD in one eye
Should consider take supplement of antioxidants and zinc
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Conclusions and considerations
• Oxidative stress and its sequelae are clearly involved in the etiology of AMD
• Data from the observational studies suggest beneficial effects of some specific antioxidants
• Data from the intervention trials are not totally consistent
• However, it is clear that good nutrition, coupled with healthy lifestyles which preclude known risk factors for eye diseases such as smoking, overweight, must be begun early in life in order to obtain the benefit of prolonged sight later in life
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