EP2531184A1 - Docosahexaenoic acid ethyl esters and/or its derivatives for prevention and/or treatment of age-related macular degeneration - Google Patents

Docosahexaenoic acid ethyl esters and/or its derivatives for prevention and/or treatment of age-related macular degeneration

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Publication number
EP2531184A1
EP2531184A1 EP10714963A EP10714963A EP2531184A1 EP 2531184 A1 EP2531184 A1 EP 2531184A1 EP 10714963 A EP10714963 A EP 10714963A EP 10714963 A EP10714963 A EP 10714963A EP 2531184 A1 EP2531184 A1 EP 2531184A1
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EP
European Patent Office
Prior art keywords
macular degeneration
age
related macular
treatment
amd
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10714963A
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German (de)
French (fr)
Inventor
Fernando Moreno Egea
Ángeles CUBILLO DE DIOS
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Soluciones Extractivas Alimentarias SL
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Soluciones Extractivas Alimentarias SL
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Filing date
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Application filed by Soluciones Extractivas Alimentarias SL filed Critical Soluciones Extractivas Alimentarias SL
Publication of EP2531184A1 publication Critical patent/EP2531184A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the retina has one of the highest concentrations of omega-3 fatty acids in the body.
  • the macula is an oval-shaped highly pigmented yellow spot (its Latin definition means spot or stain) roughly in the center of the retina of the human eye. It has a diameter of less than 10 mm and is often histologically defined as having two or more layers of ganglion cells.
  • the macula allows us to appreciate details and perform tasks that require central vision like reading.
  • Macular degeneration is a medical condition usually of older adults which results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It occurs in “dry” and "wet” forms. Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life.
  • AMD age-related macular degeneration
  • AMD AMD 90 percent of AMD patients and usually begins with the formation of tiny yellow deposits called drusen in the macula. Drusen usually do not cause serious loss of vision, but can cause distortion of vision. However, sometimes drusen will cause the macula to thin and break down, slowly leading to vision loss.
  • the wet form of AMD occurs in about 10 percent of AMD patients. It is caused by the growth of abnormal blood vessels beneath the macula that can leak fluid and blood. The wet form of AMD typically causes significant vision problems in the affected eye and can progress very rapidly, causing permanent central vision loss. The exact cause of AMD is not known, although AMD may be hereditary. Currently, there is no effective therapy that is capable of significantly slowing the degenerative progression of macular degeneration.
  • Oxidative processes have been proposed to play at least a contributing role in a steadily growing number of diseases, such as neurodegenerative disorders, cataract, and age-related macular degeneration (AMD).
  • ALD age-related macular degeneration
  • oxidative stress free radicals
  • oxygen which is necessary for life in providing aerobic respiration, may also be toxic.
  • the outer retina and, in particular, the outer segments of photoreceptors contain high concentrations of polyunsaturated fatty acids (PUFAs) in the membranes. This region is also exposed to a relatively high oxygen tension which is close to that found in arterial blood.
  • PUFAs polyunsaturated fatty acids
  • ROP is a disease of the eyes of prematurely born infants in which the retinal blood vessels increase in number and branch excessively, sometimes leading to bleeding or scarring. Infants who progress to a severe form of ROP are in danger of becoming permanently blind.
  • diabetic retinopathy a disease in which blood vessels swell and leak fluid or grow abnormally on the surface of the retina
  • AMD age-related macular degeneration
  • Omega-3 fatty acids create chemical compounds known as bioactive mediators, which protect against the growth of abnormal blood vessels, a condition that characterizes some forms of retinopathy. In part, this occurs because these mediators suppress a type of inflammatory protein called tumor necrosis factor alpha (TNF-alpha). TNF-alpha is found in one type of cell, called microglia, that can be closely associated with retinal blood vessels.
  • TNF-alpha tumor necrosis factor alpha
  • AREDS Age-Related Eye Disease Study
  • DHA docosahexaenoic acid
  • AREDS 2 is a multi-center randomized trial designed to assess the effects of oral supplementation of high doses of macular xanthophylls (lutein and zeaxanthin) and/or omega -3 LCPUFAs (DHA and EPA) for the treatment of AMD and cataract.
  • macular xanthophylls lutein and zeaxanthin
  • omega -3 LCPUFAs DHA and EPA
  • beta-carotene may be supplemented to a patient using 110 a commercially available form of beta-carotene, suggesting one such product sold by Hoffman-LaRoche under the trademark "Solatene.”
  • Synthetic beta- carotene consists of one molecule called “bans beta carotene.”
  • synthetic beta-carotene may cause an increased risk of lung cancer and disease of the blood vessels.
  • This invention describes a method to prevent the onset or to slow down the
  • DHA is a ligand for the Peroxisome Proliferator Activated Receptor gamma (PPARy), which is expressed in the retinal pigment epithelium (RPE), a pigmented cell layer that nourishes retinal visual cells and is involved in the phagocytosis of the outer segments of
  • RPE retinal pigment epithelium
  • PPARs Peroxisome Proliferator-activated Receptors
  • PPARs are a group of nuclear receptors proteins that work as transcription factors regulating the expression of genes. PPARs are involved, among others, in lipid and glucidic metabolism and 130 accordingly to these functions synthetic agonists (thiazolidinediones and fibrates) have been marketed for years for treatment of type 2 diabetes or hypercholesterolemia.
  • PPARs in general are members of a superfamily of ligand-activated transcription factors and as stated above, DHA is one of their naturally occurring ligands, 135 specifically for the subtype PPARy.
  • PPARy play an important role in lipid degeneration, in regulation of reactive oxygen species and in the regulation of the chemical signal named "vascular endothelial growth factor” (VEGF). All of these molecules have been referred as related to the pathogenesis of age related macular degeneration.
  • VEGF vascular endothelial growth factor
  • RPE retinal pigment epithelium
  • ROS reactive oxygen species
  • PPARy upregulates the expression of antioxidant genes such as glutamate cysteine ligase and heme-oxidase-1.
  • those antioxidants work through 165 MAPK kinase patways to curb ROS (S. Qin, A. P. McLaughlin, and G. W. De Vries,
  • hypoxia increases the secretion of vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • PPARy has an antagonistic relationship with VEGF, inhibiting therefore the neovascularization typical of the wet form of macular degeneration (T.Murata et al., "Peroxisome 175 proliferator-activated receptor-)/ ligands inhibit choroidal neovascularization,”/ni e5i/ ' gai/Ve Ophthalmology and Visual Science, vol. 41, no. 8, pp. 2309-2317, 2000).
  • one aspect of the invention is related to high concentrates of docosahexaenoic acid (DHA) ethyl esters in order to maintain the levels of DHA in 180 the photoreceptor cells and thus improving the retinal pigment, known as rhodopsine, regeneration, preserving the ability of the retina to process images.
  • DHA docosahexaenoic acid
  • compositions comprising a therapeutically effective amount of zeaxanthine and docosahexaenoic acid (DHA) 185 are disclosed.
  • the invention is based, in part, on the synergistic effect between docosahexaenoic acid (DHA) and carotenoids.
  • Lutein and zeaxanthin belong to the xanthophyll class of carotenoids, also known as oxycarotenoids, which are natural fat-soluble yellowish pigments.
  • Zeaxanthin is derived exclusively from dietary sources, such as dark green leafy vegetables 190 and oranges. Zeaxanthin is believed to rebuild the ocular pigment density of the macula, thereby protecting against radiation damage of the retina, in the same way as protects plants from solar radiation.
  • Lutein and zeaxanthin are transported within the blood primarily on the surface of HDL (about 53%), but also on LDL (about 31%) and VLDL (about 16%).
  • zeaxanthin and DHA appear to alter the lipoprotein profile, resulting in increase zeaxanthin concentration in the macula.
  • supplemental zeaxanthin and DHA can be used to prevent or slow the progression of AMD.
  • the composition should contain at least 2mg per dose.
  • Table 1 presents the minimum contains in the formulation:
  • Vitamin E tocopherols 0,4 mg

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Ophthalmology & Optometry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a composition containing DHA ethyl esters with over 80% by weight purity for the prevention and treatment of age related macular degeneration, that uses peroxisome proliferator-activated receptor gamma (PPARƴ) as target.

Description

BACKGROUND OF THE INVENTION
The retina has one of the highest concentrations of omega-3 fatty acids in the body.
The macula is an oval-shaped highly pigmented yellow spot (its Latin definition means spot or stain) roughly in the center of the retina of the human eye. It has a diameter of less than 10 mm and is often histologically defined as having two or more layers of ganglion cells. The macula allows us to appreciate details and perform tasks that require central vision like reading. Macular degeneration is a medical condition usually of older adults which results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It occurs in "dry" and "wet" forms. Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life.
There are two types of age-related macular degeneration (AMD): the dry (atrophic) form and the wet (exudative) form. The dry form of AMD affects about
90 percent of AMD patients and usually begins with the formation of tiny yellow deposits called drusen in the macula. Drusen usually do not cause serious loss of vision, but can cause distortion of vision. However, sometimes drusen will cause the macula to thin and break down, slowly leading to vision loss. The wet form of AMD occurs in about 10 percent of AMD patients. It is caused by the growth of abnormal blood vessels beneath the macula that can leak fluid and blood. The wet form of AMD typically causes significant vision problems in the affected eye and can progress very rapidly, causing permanent central vision loss. The exact cause of AMD is not known, although AMD may be hereditary. Currently, there is no effective therapy that is capable of significantly slowing the degenerative progression of macular degeneration. Thus, today treatment is limited to invasive methods such as laser photocoagulation, which uses a high- energy laser beam to create small burns in areas of the retina with abnormal blood vessels, or photodynamic therapy, where a drug is injected into the bloodstream, concentrates in the abnormal blood vessels, and is then activated to close off the abnormal vessels.
Oxidative processes have been proposed to play at least a contributing role in a steadily growing number of diseases, such as neurodegenerative disorders, cataract, and age-related macular degeneration (AMD). Much has been made in recent years about oxidative stress, free radicals and how oxygen, which is necessary for life in providing aerobic respiration, may also be toxic. The outer retina and, in particular, the outer segments of photoreceptors contain high concentrations of polyunsaturated fatty acids (PUFAs) in the membranes. This region is also exposed to a relatively high oxygen tension which is close to that found in arterial blood. Given the well-known susceptibility of PUFAs to undergo oxidation in the presence of oxygen or oxygen-derived radical species, it is understandable why oxidative steps are thought to be involved in the pathogenesis of AMD.
There have already been studies claiming the positive effects of dietary Omega3 fatty acids and their protective role against retinopathy on prematurity (ROP)
(John Paul SanGiovanni et al. "The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina" Progress in Retinal and Eye Research, Volume 24, Issue 1, January 2005, Pages 87-138). The researchers studied the effect of the omega-3 fatty acids EPA and DHA, derived from fish, and the omega-6 fatty acid arachidonic acid on the loss of blood vessels, the re- growth of healthy vessels, and the growth of destructive abnormal vessels in a mouse model of oxygen-induced retinopathy. The retinopathy in the mouse shares many characteristics with retinopathy of prematurity (ROP) in humans. ROP is a disease of the eyes of prematurely born infants in which the retinal blood vessels increase in number and branch excessively, sometimes leading to bleeding or scarring. Infants who progress to a severe form of ROP are in danger of becoming permanently blind. There are also aspects of the disease process that may apply to diabetic retinopathy, a disease in which blood vessels swell and leak fluid or grow abnormally on the surface of the retina, and age-related macular degeneration (AMD), a disease of the macula, the part of the retina responsible for central vision, and a leading cause of vision loss in people over 60 years of age.
Upon the results of the above-mentioned study, Omega-3 fatty acids create chemical compounds known as bioactive mediators, which protect against the growth of abnormal blood vessels, a condition that characterizes some forms of retinopathy. In part, this occurs because these mediators suppress a type of inflammatory protein called tumor necrosis factor alpha (TNF-alpha). TNF-alpha is found in one type of cell, called microglia, that can be closely associated with retinal blood vessels. The above mentioned study only recommended healthy dietary habits, but did not presented any recommended daily intake of omega-3 fatty acids.
The Age-Related Eye Disease Study (AREDS) did not pay attention to such protective role of fatty acids, especially docosahexaenoic acid (DHA).The study and subsequent clinical trial found that taking high levels of antioxidants and zinc can reduce the risk of developing advanced age-related macular degeneration
(AMD) by about 25 percent.
This major clinical trial closely followed about 3,600 participants with varying stages of AMD. The results showed that the AREDS formulation, while not a cure for AMD, may play a key role in helping people at high risk for developing advanced AMD keep their remaining vision. However there are interactions with high intake of zinc which is part of the formulation proposed after clinical trial and it's not clear the bioavailability of that metal in human body.
AREDS 2 is a multi-center randomized trial designed to assess the effects of oral supplementation of high doses of macular xanthophylls (lutein and zeaxanthin) and/or omega -3 LCPUFAs (DHA and EPA) for the treatment of AMD and cataract.
Enrollment for the trial closed on June 2008 and 4000 participants aged between 50 and 85 years old were recruited. One of the goals of this new trial consists in reducing the amount of zinc or betacarotenes in the original AREDS formulation. Bartels et al., U. S. Patent #6,660,297 discloses a nutritional supplement to treat 100 macular degeneration. The essential ingredients disclosed in the Bartels application are Vitamin C, Vitamin E, beta-carotene, Zinc, and Copper. The Bartels patent suggests that at least 400 lUs of Vitamin E should be taken on a daily basis. However, studies have shown that doses of Vitamin E of 400 lUs and greater apparently lead to an increased risk of death in a study population (See 105 Miller et al.: High Dosage Vitamin E Supplementation May Increase All-I cause
Mortality. Ann. Intern. Med., 2004, November 10). Baranowitz, U. S. Patent 5.310.764, also suggests the use of beta-carotene for treatment of age-related macular degeneration.
Baranowitz suggests that beta-carotene may be supplemented to a patient using 110 a commercially available form of beta-carotene, suggesting one such product sold by Hoffman-LaRoche under the trademark "Solatene." Synthetic beta- carotene consists of one molecule called "bans beta carotene." However, research has suggested that synthetic beta-carotene may cause an increased risk of lung cancer and disease of the blood vessels.
115
SUMMARY OF THE INVENTION:
Up to date, treatments around AMD have been focused in the supply of xantophiles or antioxidants that could prevent the readily oxidable area.
120 This invention describes a method to prevent the onset or to slow down the
AMD using solely docosahexaenoic acid, DHA as DHA is a ligand for the Peroxisome Proliferator Activated Receptor gamma (PPARy), which is expressed in the retinal pigment epithelium (RPE), a pigmented cell layer that nourishes retinal visual cells and is involved in the phagocytosis of the outer segments of
125 photoreceptor cells.
Peroxisome Proliferator-activated Receptors (PPARs) are a group of nuclear receptors proteins that work as transcription factors regulating the expression of genes. PPARs are involved, among others, in lipid and glucidic metabolism and 130 accordingly to these functions synthetic agonists (thiazolidinediones and fibrates) have been marketed for years for treatment of type 2 diabetes or hypercholesterolemia.
PPARs in general are members of a superfamily of ligand-activated transcription factors and as stated above, DHA is one of their naturally occurring ligands, 135 specifically for the subtype PPARy.
PPARy play an important role in lipid degeneration, in regulation of reactive oxygen species and in the regulation of the chemical signal named "vascular endothelial growth factor" (VEGF). All of these molecules have been referred as related to the pathogenesis of age related macular degeneration.
140
An abnormal retinal pigment epithelium (RPE) is crucial in the pathogenesis of both subtypes of AMD, dry and wet forms [De Jong PTVM . Age related macular degeneration, New England Journal of Medicine, 2006; 355(14): 1474-1485]. Being one of the main functions of RPE the phagocytosis of the outer segments
145 of the photoreceptors, metabolic waste can build up as the person ages. This waste accrues in Bruch's membrane, thickening the membrane and forming deposits referred to as drusen. When these deposits become large and soft, they compromise blood flow within RPE layer. These deposits in Bruch's membrane provoke chronic inflammation.
150 It is well known the anti inflammatory effect of long chain polyunsaturated acids in the state of the art.
The retina because of its high oxygen consumption and its composition of polyunsaturated fatty acids is an ideal environment for the generation of reactive oxygen species (ROS). The association of the chronic inflammation and ROS
155 generation promote the thinning or destruction of RPE seen in AM D and therefore the death of rods and cones as they are dependant on RPE for their nutrition. This translates in loss vision. (B. S. Winkler, M . E. Boulton, J. D. Gottsch, and P. Sternberg, "Oxidative damage and age-related macular degeneration," Molecular Vision, vol. 5, p. 32, 1999.).
160 ROS jeopardise the protecting function of DHA in the retina and because humans do not have the ability of synthesize de novo polyunsaturated fatty acids are dependant on dietary sources. Moreover, PPARy upregulates the expression of antioxidant genes such as glutamate cysteine ligase and heme-oxidase-1. Those antioxidants work through 165 MAPK kinase patways to curb ROS (S. Qin, A. P. McLaughlin, and G. W. De Vries,
"Protection of RPE cells from oxidative injury by 15-deoxy-A12,14-prostaglandin J2 by augmenting GSH and activating MAPK," Investigative Ophthalmology and Visual Science, vol. 47, no. 11, pp. 5098-5105, 2006).
If the blood supply to choriocapillaris is seriously compromised, hypoxia can take 170 place. Hypoxia increases the secretion of vascular endothelial growth factor
(VEGF) which provokes choroidal neovascularization. The small vessels are very weak and tend to leak, creating the exudative form of AMD. PPARy has an antagonistic relationship with VEGF, inhibiting therefore the neovascularization typical of the wet form of macular degeneration (T.Murata et al., "Peroxisome 175 proliferator-activated receptor-)/ ligands inhibit choroidal neovascularization,"/ni e5i/'gai/Ve Ophthalmology and Visual Science, vol. 41, no. 8, pp. 2309-2317, 2000).
Therefore, one aspect of the invention is related to high concentrates of docosahexaenoic acid (DHA) ethyl esters in order to maintain the levels of DHA in 180 the photoreceptor cells and thus improving the retinal pigment, known as rhodopsine, regeneration, preserving the ability of the retina to process images.
In another aspect of the invention, pharmaceutical compositions comprising a therapeutically effective amount of zeaxanthine and docosahexaenoic acid (DHA) 185 are disclosed. The invention is based, in part, on the synergistic effect between docosahexaenoic acid (DHA) and carotenoids.
Lutein and zeaxanthin belong to the xanthophyll class of carotenoids, also known as oxycarotenoids, which are natural fat-soluble yellowish pigments. Zeaxanthin is derived exclusively from dietary sources, such as dark green leafy vegetables 190 and oranges. Zeaxanthin is believed to rebuild the ocular pigment density of the macula, thereby protecting against radiation damage of the retina, in the same way as protects plants from solar radiation. Lutein and zeaxanthin are transported within the blood primarily on the surface of HDL (about 53%), but also on LDL (about 31%) and VLDL (about 16%). When
195 these lipoproteins reach retinal tissue, they are transferred to that tissue by means of lipoprotein receptors found at the surface of RPE and Muller retinal cells. Although the precise mechanism has not yet been established, there is increasing evidence suggesting that HDL might be the most significant carrier for the retina (Parker RS. Absorption, metabolism, and transport of carotenoids.
200 FASEB J. 1996;10:542-551).
In addition, the co-administration of zeaxanthin and DHA appears to alter the lipoprotein profile, resulting in increase zeaxanthin concentration in the macula. Thus, the combination of supplemental zeaxanthin and DHA can be used to prevent or slow the progression of AMD.
205 Since there is no presence of lutein in this invention zeaxanthin, the composition should contain at least 2mg per dose. Table 1 presents the minimum contains in the formulation:
TABLE
DHA ethyl ester 500mg DHA80 by weight
Zeaxanthin 2mg
Vitamin E tocopherols 0,4 mg

Claims

CLAIMS:
1. Composition comprising on a daily dosage basis 500mg of DHA ethyl ester 80%
2. A composition of claim 1, wherein zeaxanthine is present
3. Composition described in the preceding claims where the DHA ethyl ester is 82% by weight
4. Composition described in claims 1 or 2, wherein the DHA ethyl ester is 84% by weight
5. Use of a composition in accordance to any of the preceding claims in the preparation of a nutritional or pharmaceutical product for the prevention and/or treatment of the age related macular degeneration.
6. The use as claimed in claims 1-5, wherein the drug is used for oral administration.
7. The use as claimed in claims 1-6, wherein the drug is used in soft gelatin capsules.
225
EP10714963A 2010-02-02 2010-02-02 Docosahexaenoic acid ethyl esters and/or its derivatives for prevention and/or treatment of age-related macular degeneration Withdrawn EP2531184A1 (en)

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EP4138779A4 (en) * 2020-04-21 2024-05-22 Univ Massachusetts Methods and compositions for treatment of age-related macular degeneration

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WO2005110375A1 (en) * 2004-05-08 2005-11-24 Paul Edward L Jr Nutritional supplement for treatment of ocular diseases
FR2883182B1 (en) * 2005-03-16 2008-02-15 Novartis Ag VITAMIN COMPOSITION USEFUL IN THE TREATMENT OF OCULAR DISEASES
WO2006116755A2 (en) * 2005-04-28 2006-11-02 Trustees Of Tufts College Synergitic effects of docosahexaenoic acid (dha) and carotenoid absorption of cognitive function

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