WO2006116755A2 - Effets synergiques de l'acide docosahexaenoique (dha) et de l'absorbtion de carotenoides sur les fonctions cognitives - Google Patents

Effets synergiques de l'acide docosahexaenoique (dha) et de l'absorbtion de carotenoides sur les fonctions cognitives Download PDF

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WO2006116755A2
WO2006116755A2 PCT/US2006/016506 US2006016506W WO2006116755A2 WO 2006116755 A2 WO2006116755 A2 WO 2006116755A2 US 2006016506 W US2006016506 W US 2006016506W WO 2006116755 A2 WO2006116755 A2 WO 2006116755A2
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lutein
dha
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memory
day
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WO2006116755A3 (fr
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Elizabeth J. Johnson
Donald Max Snodderly
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Trustees Of Tufts College
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    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Memory loss is characteristic of the normal aging process as well as of many neurological disorders. Shockingly, approximately 80% of people over 30 complain of some degree of memory loss. Dementia, a structurally-caused, permanent or progressive decline of intellectual function, is one of the most serious disorders facing the elderly population. Dementia, which normally results in a loss of short-term and/or long-term memory, interferes substantially with social as well as economic activities. The risk of dementia is correlated with age and doubles every five years after the age of 60. Studies report that up to 50% of people over the age of 85 are afflicted with this disorder. An estimated 60-80% of elderly nursing home residents are affected by this disease.
  • Alzheimer-type dementia has been attributed to specific cellular and histological degenerative processes resulting in brain atrophy and the loss of cells from the basal forebrain, cerebral cortex, and other brain areas. Stroke, head trauma, and epilepsy can also lead to memory impairment.
  • Epilepsy a brain disorder in which neurons signal abnormally, can cause strange sensations, emotions, and behavior, or sometimes convulsions, muscle spasms, and loss of consciousness.
  • Existing medications for neurological disorders and memory weaknesses are not always well tolerated, nor have they been proven effective in alleviating symptoms of dementia and memory loss.
  • drugs such as anti-epileptic drugs
  • oral contraceptives can interfere with the effectiveness of other medications, such as oral contraceptives.
  • gingko biloba, piracetam, and various other "smart drugs” are being actively marketed, no proven memory-enhancing drug exists.
  • the present invention provides compositions and methods for increasing the absorption of dietary carotenoids in humans.
  • the invention can be used to slow, reduce, or prevent the onset of neurological or memory disorders, to improve learning and cognition, and to improve memory retention and acquisition.
  • the methods and compositions of the invention can used to increase the concentration of retinal lutein and zeaxanthin, thereby preventing the onset and/or slowing the progression of macular degeneration.
  • Pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of a lutein and docosahexaenoic acid (DHA) are disclosed.
  • DHA docosahexaenoic acid
  • the invention is based, in part, on the synergistic effect between docosahexaenoic acid (DHA) and carotenoids.
  • DHA docosahexaenoic acid
  • the plasma carotenoid concentration attributed to a dietary supplement is statistically higher than when taken without DHA.
  • Alpha-carotene, ⁇ -carotene, lycopene, lutein, ⁇ - cryptoxanthin, and zeaxanthin are the predominant carotenoids found in plasma. Lutein and zeaxanthin are the predominant carotenoids found in the macula of the human eye.
  • the invention provides a method for enhancing transport of lutein to a subject's brain comprising administering synergistic amounts of lutein and docosahexanaenoic acid (DHA) to a subject, such that the administration produces an improvement in cognitive function.
  • DHA docosahexanaenoic acid
  • administration can occur prior to onset of cognitive impairment. However, administration can also occur following signs of cognitive impairment.
  • the improvement in cognitive function can include decreases memory acquisition time and/or increases memory retention time.
  • the invention provides a method of modulating cognitive function in a subject, comprising administering to the subject therapeutically effective amounts of lutein and docosahexanaenoic acid (DHA), such that the administration produces an improvement in cognitive function.
  • the invention provides a method for preventing or delaying the onset of a memory disorder in a subject, the method comprising administering to the subject a prophylactically effective amounts of lutein and docosahexanaenoic acid (DHA), in a pharmaceutically acceptable carrier.
  • the invention also discloses a nutritional supplement composition for improving memory and cognitive abilities in mammals comprising, as active ingredients: docosahexanaenoic acid (DHA) and lutein, wherein the active ingredients comprise about 500 to 1500 mg/day of DHA and about 6 to 24 mg/day of lutein.
  • DHA docosahexanaenoic acid
  • the invention provides a method for increasing transport of lutein into a subject's brain, comprising administering DHA in sufficient quantity to increase HDL and HDL subtractions of blood, and administering lutein, wherein the coadministration of DHA increases transport of lutein into the brain.
  • the invention provides a method for enhancing carotenoid absorption in a subject comprising co-administering synergistic amounts of at least one carotenoid and docosahexanaenoic acid (DHA) to a subject, such that the administration produces increased absorption of the carotenoid.
  • the at least one carotenoid can be selected from the group consisting of lutein, ⁇ -carotene, ⁇ -carotene, lycopene, ⁇ - cryptoxanthin, and zeaxanthin.
  • Co-administration can increase serum carotenoid concentration levels between about 100 nmol/L to about l ⁇ mol/L compared to serum carotenoid concentrations levels in the absence of DHA.
  • the co-administration can increase transport of carotenoids, such as lutein, to a subject's brain.
  • the methods of this invention can be used to increase memory in the subject.
  • the methods can be used to decrease acquisition time and/or increase memory retention time.
  • the method comprises administering 500 to 1500 mg/day of DHA and about 6 to 24 mg/day of lutein, or more preferably administering about 700 to 1000 mg/day of DHA and about 10 to 15 mg/day of lutein.
  • the methods of the invention can provide neuroprotective effects, reduce risk of developing neurodegenerative disorders, and/ or increase memory and cognitive function. DHA and lutein act synergistically to improving cognitive performance.
  • apartment test which required subjects to remember objects after only one learning opportunity but with control of how they organized and remembered items, subjects in the DHA and lutein supplementation group recalled significantly more objects after supplementation.
  • lutein uptake in the brain is facilitated by DHA through an increase in HDL subfractions.
  • the present invention also provides a method of slowing the effects of aging by . administering a synergistic combination of carotenoids and DHA to the subject, wherein the synergistic combination increases the absorption of the carotenoid.
  • the present composition can slow the effects of the aging process, resulting in improved cognitive function and eyesight.
  • Figure 1 is a bar graph of the results of the verbal fluency test demonstrating the difference in the number of instances recalled for subjects given either lutein, DHA, lutein and DHA, or a placebo. For each group, significant difference from 1 st trial (p ⁇ ): a, 0.03, b, 0.00;
  • Figure 2 is a bar graph of the results of the shopping list memory test demonstrating the difference in the number of trials to learn the complete shopping list for subjects given either lutein, DHA, lutein and DHA, or a placebo. For each group, difference from 1 st trial (p ⁇ ): a, 0.07;
  • Figure 3 is a bar graph of the results of the word list memory test demonstrating the difference in the number of trials to learn the complete list for subjects given either lutein, DHA, lutein and DHA, or a placebo. For each group, difference from 1 st trial (p ⁇ ): a, 0.07;
  • Figure 4 is a bar graph of the results of the MIR apartment memory test demonstrating the difference in the number of items recalled after a delay for subjects given either lutein, DHA, lutein and DHA, or a placebo. For each group, significant difference from 1 st trial (p ⁇ ): a, 0.02;
  • Figure 5 is a graph of serum lutein concentrations in controls and subjects supplemented with lutein and/or docosahexaenoic acid (DHA), nmol/L (change from baseline), mean + se. "significantly different than baseline (p ⁇ 0.05) within a group. At 2 mos, the lutein+DHA group had significantly greater increases in serum lutein all other groups (p ⁇ 0.05);
  • DHA docosahexaenoic acid
  • Figure 6 is a graph of serum DHA concentrations in controls and subjects supplemented with lutein and/or docosahexaenoic acid (DHA), nmol/L (change from baseline), mean + se. a significantly different than baseline (p O.0001) within a group;
  • DHA docosahexaenoic acid
  • Figure 7 is a bar graph of total macular pigment optical density (MPOD, 4 month change from baseline) in controls and subjects supplemented with lutein and/or docosahexaenoic acid (DHA), mean + se.
  • DHA docosahexaenoic acid
  • Figure 8 is a graph of macular pigment optical density (MPOD) distribution (4 month change from baseline) in controls and subjects supplemented with lutein and/or docosahexaenoic acid (DHA), mean + se.
  • Figure 9 is a graph of serum concentrations of HDL subtractions in subjects supplemented with lutein and/or docosahexaenoic acid (DHA (12 and 800 mg, respectively), mean + se. Significantly different than baseline within a group: a, p ⁇ 0.013; b, p ⁇ 0.025; c, p ⁇ 0.010);
  • Figure 10 is a bar graph of serum concentrations of LDL subtractions in subjects supplemented with lutein and/or docosahexaenoic acid (DHA) (12 and 800 mg, respectively), mean + se. Significantly different than baseline within a group: a, p ⁇ 0.006; b, p ⁇ 0.014; and
  • Figure 11 is a bar graph of serum concentration of VLDL subtractions in subjects supplemented with lutein and/or docosahexaenoic acid (DHA) (12 and 800 mg, respectively), mean + se. Significantly different than baseline within a group: a, p ⁇ 0.035.
  • DHA docosahexaenoic acid
  • the present invention provides compositions and methods for increasing the absorption of dietary carotenoids in humans.
  • the invention can be used to slow, reduce, or prevent the onset of neurological or memory disorders, to improve learning and cognition, and to improve memory retention and acquisition.
  • the methods and compositions of the invention can used to increase the concentration of retinal lutein and zeaxanthin, thereby preventing the onset and/or slowing the progression of macular degeneration.
  • Pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of a lutein and docosahexaenoic acid (DHA) are disclosed.
  • DHA docosahexaenoic acid
  • neurodegeneration which causes morphological and/or functional abnormality of a neural cell or a population of neural cells.
  • Non-limiting examples of morphological and functional abnormalities include physical deterioration and/or death of neural cells, abnormal growth patterns of neural cells, abnormalities in the physical connection between neural cells, under- or over production of a substance or substances, e.g., a neurotransmitter, by neural cells, failure of neural cells to produce a substance or substances which it normally produces, production of substances, e.g., neurotransmitters, and/or transmission of electrical impulses in abnormal patterns or at abnormal times.
  • Neurological disorders include, but are not limited to, head injury, spinal cord injury, seizures, stroke, dementia, memory loss, attention deficit disorder (ADD), epilepsy, and ischemia. Neurological disorders also include neurodegenerative diseases. Neurodegeneration can occur in any area of the brain of a subject and is seen with many disorders including, but not limited to, Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease.
  • ALS Amyotrophic Lateral Sclerosis
  • Parkinson's disease Parkinson's
  • Further neurological disorders include CNS (central nervous system) damage resulting from infectious diseases such as viral encephalitis, bacterial or viral meningitis and CNS damage from tumors.
  • CNS central nervous system
  • the neuroprotective and/or neural regenerative strategy of the present invention can be also be used to improve the cell-based replacement therapies used to treat or prevent various demyelinating and dysmyelinating disorders, such as Pelizaeus-Merzbacher disease, multiple sclerosis, various leukodystrophies, post-traumatic demyelination, and cerebrovasuclar accidents.
  • Disorders of the central nervous system further include mental disorders such as mood disorders (i.e., depression, bipolar disorder), anxiety disorders, memory disorders and schizophrenic disorders.
  • the present invention may also find use in enhancing the cell- based therapies used to repair damaged spinal cord tissue following a spinal cord injury.
  • memory disorder refers to a diminished mental registration, retention or recall of past experiences, knowledge, ideas, sensations, thoughts or impressions. Memory disorder may affect short and/or long-term information retention, facility with spatial relationships, memory (rehearsal) strategies, and verbal retrieval and production.
  • the term memory disorder is intended to include dementia, slow learning and the inability to concentrate. Common causes of a memory disorder are age, severe head trauma, brain anoxia or ischemia, alcoholic-nutritional diseases, drug intoxications, and neurodegenerative diseases. For example, a memory disorder is a common feature of neurodegenerative diseases, such as Alzheimer's disease
  • Alzheimer-type dementia Memory disorders also occur with other kinds of dementia such as AIDS Dementia; Wernicke-Korsakoff s related dementia (alcohol induced dementia); age related dementia, multi-infarct dementia, a senile dementia caused by cerebrovascular deficiency, and the Lewy-body variant of Alzheimer's disease with or without association with Parkinson's disease. Creutzfeldt-Jakob disease, a spongiform encephalopathy caused by the prion protein, is a rare dementia with which memory disorder is associated. Loss of memory is also a common feature of braindamaged patients.
  • Non-limiting examples of causes of brain damage which may result in a memory disorder include stroke, seizure, an anaesthetic accident, ischemia, anoxia, hypoxia, cerebral edema, arteriosclerosis, hematoma or epilepsy; spinal cord cell loss; and peripheral neuropathy, head trauma, hypoglycemia, carbon monoxide poisoning, lithium intoxication, vitamin (Bl, thiamine and B12) deficiency, or excessive alcohol use.
  • Korsakoff s amnesic psychosis is a rare disorder characterized by profound memory loss and confabulation, whereby the patient invents stories to conceal his or her memory loss. It is frequently associated with excessive alcohol intake.
  • Memory disorder may furthermore be age-associated; the ability to recall information such as names, places and words seems to decrease with increasing age. Transient memory loss may also occur in patients, suffering from a major depressive disorder, after electro-convulsive therapy.
  • the term "therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the supplement may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the pharmacological agent to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the pharmacological agent are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • DHLA docosahexaenoic acid
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • ALA ⁇ -linolenic acid
  • DPA docosapentaenoic acid
  • Eicosapentaenoic acid a long-chain polyunsaturated fatty acid of the n-3 or omega-3 type, is a major component of fish oil.
  • EPA is an all cis polyunsaturated fatty acid containing 20 carbons and 5 double bonds.
  • EPA is also known as EPA; C20: 5n-3 and cis-5, 8, 11, 14,17-eicosapentaenoic acid.
  • EPA is a precursor of the series-3 prostaglandins, the series-5 leukotrienes and the series-3 thromboxanes, which are anti-artherogenic and antithrombogenic.
  • TAGs triacylglycerols
  • DHA a long-chain polyunsaturated fatty acid (LCPUFA) of the n-3 or omega-3 type
  • LCPUFA long-chain polyunsaturated fatty acid
  • DHA is an all cis polyunsaturated fatty acid containing 22 carbon atoms and 6 double bonds. DHA is also known as DHA; C22: 6n-3 and cis-4, 7, 10, 13, 16, 19- docosahexaenoic acid.
  • DHA is a vital component of the phospholipids of human cellular membranes, especially those in the brain and retina. DHA occurs naturally in the form of triacylglycerols (TAGs).
  • TAGs triacylglycerols
  • DHA Docosahexaenoic acid
  • DHA and EPA occur at high levels in fish oil and usually exist in the triglyceride form
  • DHA as used throughout this specification means not only DHA or EPA as such but also the corresponding glycerin ester (e.g. triglyceride), alkyl ester (e.g. ethyl ester), or other derivatives, and analogs thereof.
  • glycerin ester e.g. triglyceride
  • alkyl ester e.g. ethyl ester
  • subject refers to any living organism capable of eliciting an immune response.
  • subject includes, but is not limited to, humans, nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like.
  • farm animals such as cattle, sheep, pigs, goats and horses
  • domestic mammals such as dogs and cats
  • laboratory animals including rodents such as mice, rats and guinea pigs, and the like.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • free radical refers to molecules containing at least one unpaired electron. Most molecules contain even numbers of electrons, and their covalent bonds normally consist of shared electron pairs. Cleavage of such bonds produces two separate free radicals, each with an unpaired electron (in addition to any paired electrons). They may be electrically charged or neutral and are highly reactive and usually short-lived. They combine with one another or with atoms that have unpaired electrons. In reactions with intact molecules, they abstract a part to complete their own electronic structure, generating new radicals, which go on to react with other molecules. Such chain reactions are particularly important in decomposition of substances at high temperatures and in polymerization. In the body, oxidized free radicals can damage tissues. Antioxidant may reduce these effects.
  • Free radicals are generated as a secondary effect of oxidative metabolism. An excess of free radicals can overwhelm the natural protective enzymes such as superoxide dismutase, catalase, and peroxidase. Free radicals such as hydrogen peroxide (H 2 O 2 ), hydroxyl radical (HO*), singlet oxygen ( 1 O 2 ), superoxide anion radical (0* 2 " ), nitric oxide radical (NO*), peroxyl radical (ROO*), peroxynitrite (ONOO " ) can be in either the lipid or compartments.
  • ATD Age-related macular degeneration
  • Age-related losses in visual function are major health concerns in the U.S.
  • Age-related macular degeneration (AMD) is a leading cause of blindness.
  • AMD Age-related macular degeneration
  • Some epidemiologic reports suggest that intake of foods rich in lutein protects against AMD.
  • Lutein, along with its stereoisomer, zeaxanthin selectively accumulate in the retina and are particularly dense in the foveal region, or macula, where they are the main components of the macular pigment (MP).
  • the macula is located in the posterior portion of the retina and possesses the highest concentration of cone photoreceptors responsible for central vision and high resolution visual acuity.
  • Lutein is known to function as an antioxidant and blue light filter and thereby may protect the macula from light-initiated oxidative damage to the retina and retinal pigment epithelium. Oxidative stress is high in the eye due to the intense light exposure and the high rate of oxidative metabolism in the retina. It is generally believed that cumulative oxidative damage is responsible for aging and therefore, may play an important role in the pathogenesis of AMD. The appearance of oxidation products of lutein and zeaxanthin within the retina is consistent with the idea that these pigments can function as antioxidants in vivo.
  • the present invention provides a method of altering the level of MP in a subject's eye. As shown in the Examples, the invention demonstrates that the level of MP can be manipulated in the cone-rich fovea when a subject ingests the composition of the present invention.
  • Carotenoids naturally-occurring pigments which are synthesized by plants, algae, bacteria, and certain animals, such as birds and shellfish have antioxidant activities.
  • Carotenoids are a group of hydrocarbons (e.g., carotenes) and their oxygenated, alcoholic derivatives (e.g., xanthophylls), and include, for example, actinioerythrol, astaxanthin, bixin, canthaxanthin, capsanthin, capsorubin, ⁇ -8'-apo- carotenal (apo-carotenal), ⁇ -12'-apo-carotenal, ⁇ -carotene, ⁇ -carotene, "carotene” (a mixture of ⁇ - and ⁇ -carotenes), ⁇ - carotene, ⁇ -cryptoxanthin, lutein, lycopene, violerythrin, zeaxanthin, and esters of hydroxyl- or carboxyl-containing members thereof.
  • Lutein and zeaxanthin belong to the xanthophyll class of carotenoids, also known as oxycarotenoids, which are natural fat-soluble yellowish pigments. Lutein and zeaxanthin are are derived exclusively from dietary sources, such as dark green leafy vegetables and orange and yellow fruits and vegetables. Dietary sources of these dihydroxycarotenoids include corn, egg yolks, broccoli, green beans, green peas, brussel sprouts, cabbage, kale, collard greens, spinach, lettuce, kiwi and honeydew.
  • lutein and zeaxanthin contain hydroxyl groups, which makes them more polar than other carotenoids.
  • lutein and zeaxanthin have identical chemical formulas and are isomers, they are not stereoisomers. They are both polyisoprenoids containing 40 carbon atoms and cyclic structures at each end of their conjugated chains.
  • lutein is intended to include lutein and all its isomers, including zeaxanthin. They both occur naturally as all-trans (all-E) geometric isomers and the principal difference between them is in the location of a double bond in one of the end rings.
  • Lutein and zeaxanthin are concentrated in the macula of the human eye. While over 15 different dietary carotenoids are detectable in human serum, only lutein and zeaxanthin and their metabolites are found to any substantial extent in the retina. Zeaxanthin concentration is highest in the center of the fovea, whereas lutein is relatively abundant in the perifoveal region. The absorption spectra of lutein and zeaxanthin enable these macular pigments to absorb blue light, which the can damage the retina. Scattering and chromatic aberration of blue light can be minimized by these macular pigments. In addition, these carotenoids are also potent antioxidants.
  • the methods of this invention can be used to increase the absorption of dietary carotenoids, such as lutein and zeaxanthin. This increase in absorption can be used to increase the amount of lutein/zeaxanthin that can be transported to the macular.
  • the methods of the invention can be used to increase the absorption of carotenoids, such as lutein and zeaxanthin, which can lead to an increase of the concentration of serum carotenoids, which can lead to improvements in cognitive function.
  • 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%).
  • LDL about 36%
  • VLDL about 16%
  • lipoprotein receptors found at the surface of RPE and Muller retinal cells.
  • HDL apolipoprotein
  • ApoE can be synthesized directly within the retina (Muller cells) and binds to receptors on ganglion cells.
  • HDL-E The subspecies of HDL containing ApoE (HDL-E) supplies lipids and lipid-soluble lutein and zeaxanthin, to the retina.
  • HDL-E The subspecies of HDL containing ApoE
  • retinal lutein and zeaxanthin levels may be concomitantly increased.
  • DHA Docosahexaenoic acid
  • DHA Docosahexaenoic acid
  • the invention provides methods of increasing macular pigment (MP) via an increased transport of lutein into the retina when lutein is taken in conjunction with DHA.
  • MP macular pigment
  • DHA supplementation is combined with lutein supplementation.
  • the invention pertains to increasing MPOD through the administration of a combination of lutein and DHA.
  • the combination of lutein and DHA has a synergistic effect resulting in increasing MPOD and increasing cognitive function and memory.
  • the content can range from about 0.25 mg to 30 mg of lutein and from about 100 mg to
  • DHA 2 g of DHA, preferably from about 5 mg to 20 mg of lutein and from about 500 mg to 1.5 g of DHA, particular preferably from about 10 mg to 20 mg of lutein and from about 700 mg to 1.5 g of DHA, and more preferably from about 10 to 15 mg of lutein and from about 700 mg to 1000 mg of DHA.
  • the mixture of lutein and DHA is preferably given in a single dose.
  • lutein and DHA can be taken in separate capsules at the same time.
  • the single dose can be solid, liquid, applied topically or intravenous.
  • the lutein and DHA are contained in a solid preparation that can be taken orally.
  • the solid preparation may be combined with a lipophilic component.
  • the utilization of carotenoids, such as lutein, is facilitated when taken in combination with dietary fat.
  • the solid preparation can, for example, use a permissible oil, such as sesame seed oil, corn oil, cotton seed oil, flax seed oil, soybean oil or peanut oil, and esters of medium-chain plant fatty acids at a concentration of from 0 to 500% by weight, preferably from 10 to 300% by weight, particularly preferably from 20 to 100% by weight, based on the active compounds.
  • the solid preparation can also be taken with a meal containing a sufficient fat content (e.g. greater than 1 gram, preferably greater than 1O g, more preferably greater than 25 g) so that the substantially water immiscible carotenoids can be fully absorbed by the subject.
  • a sufficient fat content e.g. greater than 1 gram, preferably greater than 1O g, more preferably greater than 25 g
  • BBB blood-brain barrier
  • Brain endothelial cells (BEC) lining cerebral vessels are joined by continuous tight junctions that convert the endothelial cell layer into a highly selective interface separating the peripheral circulation from the brain.
  • the central nervous system (CNS) is dependent on essential lipids that are transported in association with peripheral lipoproteins. Delivery across the blood-brain barrier (BBB) employs specific lipoprotein receptor systems. Patients suffering HDL-deficiency suffer from severe neuropathologies, which illustrates the importance of functional high density lipoprotein (HDL) metabolism for the nervous system.
  • HDL metabolism at the BBB can be used in the delivery of essential metabolites into the brain, protection of BBB-integrity during inflammatory conditions and shuttling of neurotoxic compounds from the brain back into the circulation.
  • the transport of carotenoids across the blood brain barrier can be increased when taken in combination with a synergistic dose or DHA.
  • the dose of DHA is taken in sufficient quantity to increase HDL and HDL subfractions, thereby improving the delivery of carotenoids into the brain.
  • Improved memory and/or cognition can be measured following supplementation through a battery of genitive tests for memory and processing speed, or attention.
  • Examples of such tests include verbal fluency, digit span forward and backward, shopping list task, work list memory test, MIR (memory in reality) test, NES2 pattern comparison test, and the stroop test, which are described further in the Examples section.
  • MIR memory in reality
  • NES2 pattern comparison test and the stroop test, which are described further in the Examples section.
  • commonly used tests to monitor dementia are the Wechsler Adult Intelligence Scale and the Cambridge Cognitive Test (CAMCOG). These tests have a number of different sections and test a variety of things, including the ability to learn new things and the ability to comprehend arithmetic and vocabulary.
  • regeneration of neurons and hence treatment of disease can be monitored by measuring specific neurotransmitters.
  • dopamine levels can be monitored using known methods following administration of the composition of the present invention.
  • a labeled tracer is administered to the subject. The detection of the label is indicative of dopamine activity.
  • the labeled tracer is one that can be viewed in vivo in the brain of a whole animal, for example, by positron emission tomograph (PET) scanning or other CNS imaging techniques. See, for example, U.S. Pat. No. 6,309,634 for methods of measuring dopamine content in vivo.
  • treatment of disease is meant the reduction or elimination of symptoms of the disease of interest, as well as the regeneration of neurons.
  • dopamine levels prior and subsequent to treatment can be compared as a measure of neuron regeneration.
  • compositions of the invention can be prepared in various manners well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semisolid, or liquid material that can serve as a vehicle or medium for the active ingredient.
  • Suitable carriers or excipients are well known in the art and include, but are not limited to saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical compositions may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, solutions, suspensions, powders, syrups, and the like.
  • the term "pharmaceutical carrier” may encompass one or more excipients.
  • care should be taken to ensure bioavailability of an effective amount of the agent. Suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington 's Pharmaceutical Sciences, Mack Publishing Co . , Easton, Pa.
  • compositions will comprise a sufficient combination of DHA and at least one carotenoid, such as lutein, to produce a therapeutically effective amount, i.e., an amount sufficient to reduce or ameliorate symptoms of the disease state in question or an amount sufficient to confer the desired benefit.
  • the compositions can contain a pharmaceutically acceptable carrier.
  • Such carriers include any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
  • Pharmaceutically acceptable carriers include, but are not limited to, sorbitol, any of the various TWEEN compounds, and liquids such as water, saline, glycerol and ethanol.
  • Pharmaceutically acceptable salts can be included therein, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like
  • organic acids such as acetates, propionates, malonates, benzoates, and the like
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances, and the like, may be present in such vehicles.
  • the compounds can be formulated into solid or liquid preparations, with or without inert diluents or edible carrier(s), such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions.
  • the tablets, pills, capsules, troches and the like also may contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose; disintegrating agents such as alsinic acid, PrimogelTM , corn starch and the like; lubricants such as stearic acid, magnesium stearate or SterotexTM ; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint, methyl salicylate or fruit flavoring.
  • binders such as microcrystalline cellulose, gum tragacanth or gelatin
  • excipients such as starch or lactose
  • disintegrating agents such as
  • the dosage unit form When the dosage unit form is a capsule, it also may contain a liquid carrier such as polyethylene glycol or fatty oil. Materials used should be pharmaceutically pure and non-toxic in the amounts use. These preparations should contain at least 0.05% by weight of the therapeutic agent, but may be varied depending upon the particular form and may conveniently be between 0.05% to about 90% of the weight of the unit. The amount of the therapeutic agent present in compositions is such that a unit dosage form suitable for administration will be obtained.
  • a liquid carrier such as polyethylene glycol or fatty oil.
  • the solutions or suspensions also may include one or more of the following adjuvants depending on the solubility and other properties of the therapeutic agent: sterile diluents such as water for injections, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of toxicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injections, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • antioxidants such as ascorbic acid or sodium bisulfite
  • a therapeutic of the invention that will be effective in the treatment of a particular disease or disorder will depend on a number of factors that can be readily determined by the attending diagnostician, as one of ordinarily skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • Factors significant in determining the dose include: the dose; the species, subject's size, age and general health; the specific disease involved, the degree of or involvement of the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances specific to the subject.
  • Effective doses optionally may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • an effective amount of the combination of DHA and lutein of the instant invention to be administered systemically on a daily basis is about 10-30 mg/kg DHA and 0.08-0.5 mg/kg lutein.
  • the composition of the invention may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • the composition (and other ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • the compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • dry powders that comprise the inventive carotenoid and DHA combinations to enrich milk products such as yogurt, flavored milk drinks or ice cream, or milk pudding powders, baking mixes and confectionery products, for example fruit gums.
  • the invention also relates to food supplements, animal feeds, foods and pharmaceutical and cosmetic preparations comprising the above-described preparations, in particular carotenoid formulations of mixtures lutein and DHA.
  • Food supplement preparations and pharmaceutical preparations that comprise the inventive dry powders include, but are not limited to, tablets, sugar-coated tablets and hard and soft gelatin capsules.
  • Preferred food supplement preparations are tablets into which the dry powders are co-incorporated, and soft gelatin capsules in which the carotenoid-containing multicore structures are present as oily suspension in the capsules.
  • the carotenoid content in these capsules is from 0.1 to 30 mg of lutein and 500 mg to 2 g of DHA, preferably from about 6 to 15 mg of lutein and from 700 mg to 1.5 g of DHA.
  • the composition of the present invention can be administered in a liquid form.
  • the pharmacological agent of the present invention is freely soluble in a variety of solvents, such as for example, methanol, ethanol, and isopropanol.
  • the pharmacological agent is, however, highly lipophilic and, therefore, substantially insoluble in water.
  • a variety of methods are known in the art to improve the solubility of the pharmacological agent in water and other aqueous solutions. For example, U.S. Patent No. 6,008,192 to Al-Razzak et al.
  • composition of the invention can be coformulated with and/or coadministered with one or more additional carotenoid or antioxidant.
  • the composition can include a combination of DHA and lutein, together with Alpha-carotene, ⁇ -carotene, lycopene, ⁇ -cryptoxanthin, and zeaxanthin.
  • the composition of the invention is coformulated with and/or coadministered with one or more additional therapeutic agents that are useful for improving the pharmacokinetics of the pharmacological agent.
  • additional therapeutic agents that are useful for improving the pharmacokinetics of the pharmacological agent.
  • U.S. Patent No. 6,037,157 to Norbeck et al. discloses a method for improving the pharmacokinetics of the pharmacological agent by coadministration of the pharmacological agent and a drug that is metabolized by the cytochrome P450 monooxygenase, such as for example, the P450 3A4 isozyme.
  • composition of the present invention can be used alone or in combination to treat neurodegenerative disorders to produce a synergistic effect.
  • the pharmacological agent can be used alone or in combination with an additional agent, e.g., an agent which imparts a beneficial attribute to the therapeutic composition, e.g., an agent which effects the viscosity of the composition.
  • the combination can also include more than one additional agent, e.g., two or three additional agents if the combination is such that the formed composition can perform its intended function.
  • compositions of the invention may include a "therapeutically effective amount” or a “prophylactically effective amount” of a pharmacological agent of the invention.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the pharmacological agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the pharmacological agent to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the pharmacological agent are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of the composition of the invention is between 10-30 mg/kg body weight DHA and 0.08-0.5 mg/kg body weight of lutein.
  • administration of a therapeutically effective amount of DHA and lutein in a concentration of pharmacological agent in the bloodstream that is between about 30-1500 ⁇ M DHA and
  • the concentration of pharmacological agent in the blood is between about 100-1000 ⁇ M DHA and 1-10 ⁇ M lutein. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the methods of the present invention can be used to slow or prevent neurodegeneration.
  • the methods of the invention can be used to prevent and/or slow the progression of macular degeneration. Many of these diseases are associated with the normal aging process, and thus the supplement of the present invention can be take prophylatically to slow progression of the disease.
  • the methods of the present invention can be used to reduce, ameliorate, prevent, and/or treat disorders associated with antioxidant levels and excess free radicals.
  • Populations at risk can be identified through methods known in the art (See, for example, U.S. Publication No. US 2002-0182736 Al, US Patent Application No. 10/114,181 filed April 2, 2002, which describes a method that is accurate, quick, non-invasive, which can be easily adapted for high throughput usage and diagnostic procedures).
  • At risk populations or people who wish to reduce the risk of free-radical associated disorders can benefit from the methods of the present invention.
  • disorders that can be reduced, ameliorated, prevented, and/or treated using the methods of this invention include, but are not limited to, aging at a higher than normal rate, segmental progeria disorders, Down's syndrome; heart and cardiovascular diseases such as arteriosclerosis, adriamycin cardiotoxicity, alcohol cardiomyopathy; gastrointestinal tract disorders such as inflammatory & immune injury, diabetes, pancreatitis, halogenated hydrocarbon liver injury; eye disorders such as cataractogenesis, degenerative retinal damage, macular degeneration; kidney disorders such as autoimmune nephrotic syndromes and heavy metal nephrotoxicity; skin disorders such as solar radiation, thermal injury, porphyria: nervous system disorders such as hyperbaric oxygen, Parkinson's disease, neuronal ceroid lipofuscinoses, Alzheimer's disease, muscular dystrophy and multiple sclerosis; lung disorders such as lung cancer, oxidant pollutants (03,NO 2 ), emphysema, bronchopulmonary dysphasia, asbestos carcinogenicity; red blood cell disorder
  • the oral intake of the composition can be used either therapeutically or prophylactically to improve memory of a subject and reduce dementia.
  • Subjects Fifty non-smoking women (60-80 years) were recruited from the general population for a 4 month supplementation study. All subjects underwent a screening examination that includes a medical history, a physical examination, and a routine blood clinical chemistry profile. Volunteers with any history or biochemical evidence of lactose intolerance, liver, kidney, or pancreatic disease, anemia, active bowel disease or resection, insulin-dependent diabetes, easy bruising or bleeding, bleeding disorders, hyperglyceridemia, hyperlipidproteinemia, or alcoholism were excluded from the study. Moreover, individuals taking mineral oil or medications suspected of interfering with fat-soluble vitamin absorption were excluded. Subjects using steroids or non-steroid anti-inflammatory drugs, or antihistamine drugs were excluded.
  • Subjects who had a vaccination within 2 weeks of the study screening were be excluded. Subjects were excluded if they have taken any nutrient supplement for 2 months or more before admission into the study or carotene supplements 6 months or more before the study. Smoking was not permitted during the course of the study.
  • Supplementation Protocol Dietary supplements in capsule form were Lutein (12 mg/day) (Kemin Foods) and Docosahexaenoic Acid (DHASCO) (800 mg/day) (Martek Biological Sciences). Participants in each of the four supplementation groups were instructed to drink one can of a nutritional supplement daily (Boost Plus) (Mead Johnson) when taking their capsules. Subjects ingested their dietary supplements daily for a period of 4 months. Both the subjects and the experimenter were masked to the experimental groups.
  • Boost Plus nutritional supplement daily
  • the battery of cognitive tests included tests of memory and processing speed or attention and a measure of self-reported mood. All of these tests or versions of them have been used in cognitive aging research and also have demonstrated sensitivity to drugs or other health variables in treatment or epidemiological studies (See, for example, Ferris, S. H, et al. (1986). Assessing cognitive impairment and evaluating treatment effects: Psychometric performance tests. In L. Poon (Ed.), Handbook for Clinical Memory Assessment of Older Adults (pp. 139-148). Washington, DC: American Psychological Association; Letz, R. (1991). NES2 User's Manual
  • Verbal Fluency Test Subjects name as many items from a category as possible during a one-minute period. (See, for example, Borkowski, J. G., Benton, A.L., & Spreen, O. (1967). Word fluency and brain damage. Neuropsychologic 5, 135-150).
  • Digit Span Forward and Backward Subjects are asked to repeat numbers in increasing spans in forward sequences, then in backward sequences. Protocol adapted from Wechsler, D. A. (1981). Manual for the Wechsler Adult Intelligence Scale - Revised. New York: Psychological Corporation.
  • Word List Memory Test Ten unassociated words are presented (at a rate of one word every two seconds) on a computer monitor in three serial trials. Verbal recall is tested immediately after each trial and after a delay. (Computer version of test described by
  • Alzheimer's disease The consortium to establish a registry for Alzheimer's disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology, 39, 1159-1165.)
  • MIR Memory in Reality Test
  • Subjects place 10 common household objects in 7 rooms of a model of an apartment. Verbal and visuospatial (location) recall is tested after a delay.
  • the MIR - Memory-in-Reality Test Psykologiforlaget AB, Sweden.
  • NES2 Pattern Comparison Test Subjects choose the odd pattern from three similar patterns displayed on a computer monitor. The scores are the number of correct responses (maximum 15) and the mean response latency for correct decisions. (See Letz, R. (1991). NES2 User's Manual (Version 4.4), Winchester, MA: Neurobehavioral
  • Stroop Test Subjects name words (subtask 1 - read words printed in black, and sub task 2 - read color name words printed in the same color) and colors (subtask 3 - name colors of rectangles, and subtask 4 - name colors in which color name words are printed, when colors are different from the color name) in this assessment of response time and the ability to inhibit non-salient information. This version is presented via computer. Protocol adapted from Stroop, J.R. (1935). Studies of interference in serial verbal reactions. Journal of Experimental Psychology, 18, 643-662.
  • NES2 Mood Scales Subjects rate their degree of tension, depression, anger, fatigue, and confusion over the previous seven days, using a computerized format.
  • the Mood Scales are adapted from the Profile of Mood States (POMS; McNair, Lorr, & Dropleman, 1971). For description, see Letz, R. (1991). NES2 User's Manual (Version 4.4), Winchester, MA: Neurobehavioral Systems, Inc.
  • Serum carotenoids were extracted and analyzed by HPLC using the method described by Yeum et al. (Yeum, K.J., et A., Am J Clin Nutr, 1996. 64(4): p. 594-602.).
  • the fatty acid composition of serum was determined following direct transesterification and gas-liquid chromatography by procedures similar to those previously described (Patton, G.M., et al., Methods in Enzymology, 1981. 72: p. 8-20.).
  • MPOD Macular Pigment Optical Density
  • the stimulus subtended 0.8 degrees of visual angle and was centrally fixated for measurements of peak MP density Additional measurements of macular pigment were obtained by having the subject look at a fixation point at 1.5°, 3°and 5° temporal retinal eccentricities.
  • the fixation point was produced by a small black dot on transparent glass in the path of the light that formed the background field.
  • the parafoveal reference was located at 7° temporal retinal eccentricity.
  • the subject's head position was stabilized with an adjustable bitebar and headrest apparatus.
  • a profile of MPOD in the temporal retina was obtained for each subject. Measurements were made in the right eye for all subjects. MPOD was measured in two baseline sessions on separate days and in two sessions on separate days at the end of 4 months of supplementation.
  • the NMR method employs the characteristic methyl group signals broadcast by lipoprotein subclasses of different size as the basis for their quantification.
  • Each measurement includes the concentrations of 5 subclasses of HDL (larger numbers denoting larger subclasses), 3 subclasses of LDL and 6 subclasses of VLDL (V1-V6).
  • Lipoprotein subclasses were grouped into large, intermediate and small subclasses. That is, large, intermediate, and small HDL were H5+H4, H3, and H2+H1, respectively. Large, intermediate and small LDL were L3, L2, and Ll, respectively. And large, intermediate and small VLDL were V6+V5, V4+V3, and V2+V1, respectively.
  • Results are expressed as mean + SE. Within each group, each subject was followed longitudinally and significant differences from baseline were measured using Student's paired t-test (Systat versionlO, Port Richmond, CA. Group differences were measured using ANOVA followed by the Bonferroni post hoc test (SystatlO).
  • the total MPOD was calculated as the area under the curve for the 5 loci at which optical densities were measured KaleidaGraph version 3.5, Synergy Software, Reading, PA). Within each group, each subject was followed longitudinally and significant differences from baseline were measured using Wilcoxan signed rank test. Group differences were measured using Kruskal Wallis analysis of variance followed by Mann- Whitney U test statistical analysis using SAS version 8 (SAS version 8, cary, NC, SAS Institute, Inc, 1999). Significance was considered when the p-value was less than 0.05.
  • Table 2 presents the means and standard deviations of test scores by subject group at baseline and after supplementation. The average performance of subjects was close to ceiling (the maximum score) for many cognitive tests, which suggests that older and less educated subjects in this study were generally very competent. U)
  • MPOD Macular Pigment Optical Density
  • MP Responders and Non Responders Two of 14 in the L group and three of 14 subjects in the LD group did not have increases in MPOD with lutein supplementation. Response not related to BMI, age, baseline concentrations of serum lutein.
  • Lipoprotein size is importance in evaluating disease risk.
  • Age-related macular degeneration and cardiovascular disease share many of the same risk factors.
  • a common lipoprotein profile designated atherogeneic lipoprotein phenotype is characterized by a predominance of small dense LDL particles. Multiple features of this phenotype, including increased levels of triglyceride rich lipoprotein remnants and LDLs, reduced levels of HDL and an association with insulin resistance, contribute to increased risk for coronary heart disease compared with individuals with a predominance of larger LDL.
  • Increased atherogenic potential of small dense LDL is suggested by greater propensity for transport into the sub endothelial space, increased binding to arterial proteoglycans, and susceptibility to oxidative modification.
  • LDL exhibits reduced LDL receptor affinity compared with intermediated sized LDL.
  • the Stanford Five City Project presented data indicating that LDL size is the strongest physiologic risk factor in conditional logistic regression analysis and is independent of BDDL cholesterol, non-HDL cholesterol, and nonfasting triglycerides but not of the ratio total cholesterol/HDL cholesterol.
  • the Quebec cardiovascular study reported that LDL particle size is an independent predictor of cardiovascular events that is independent of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, total cholesterol/HDL cholesterol, apo B, and body mass index.
  • the DHA and lutein (DL) group had the highest levels of large HDL and large LDL and lowest amount of small LDL at study end. Accordingly, the co-administration of at least one carotenoid, such as lutein, and DHA can be used to improve the cholesterol profile thereby reducing the risk of atherosclerosis and/or slowing or preventing the development of atherosclerosis, and reducing risk of heart attacks and strokes.
  • the invention can be used to reduce existing cholesterol plaques on the artery walls, and reduce formation of cholesterol plaques and reduce the risk of rupture of cholesterol plaques.
  • the LD group tended to have the largest differences from the C group.
  • the large HDL subclass was significantly greater (p ⁇ 0.013) and the intermediate HDL was significantly less in the LD group than the levels in the C group (p ⁇ 0.025) ( Figure 9).
  • the intermediate HDL was significantly greater in the L group than in the LD group (p ⁇ 0.010).
  • the large HDL subclass had the greatest concentrations.
  • the large LDL subclass was significantly greater in the LD group than in the control group (p 0.006).
  • the intermediate and small LDL were less in the LD group compared to the controls. However, this was only significant for the intermediate LDL (p ⁇ 0.014) ( Figure 10).
  • the large LDL subclass had the greatest concentrations.
  • the intermediate VLDL subclass was significantly greater (p ⁇ 0.035) in the LD group than in the C group ( Figure 10).
  • the intermediate VLDL subclass had the greatest concentrations.
  • Table 4 shows correlations between final test scores and possible covariates (age and education), DHA and lutein serum levels, and an endpoint, macular pigment ocular density (MPOD), from the primary vision study.
  • test scores that changed significantly after supplementation, Verbal Fluency and Trials to Learn Shopping List scores were the least subject to ceiling effects in the total sample of subjects.
  • subjects' scores on the Verbal Fluency test at baseline did not differ significantly by age, younger subjects recalled more instances of a category than older subjects at the end of the study.
  • variable lutein serum level at end of study was highly positively skewed, the variable was log-transformed to produce a more normal distribution. No significant relationship was found between final lutein serum levels, with or without log- transformation, and Verbal Fluency scores. Also, in juxtaposition to the findings for DHA, higher lutein serum levels were significantly associated with needing more trials to learn shopping lists. This result can be understood by looking at Figure 2, which shows that subjects in the Lutein supplementation group had some of the highest scores for the variable Trials to Learn Shopping List.
  • DHA supplementation group had less room to improve than the other treatment groups.
  • the subjects in this study although elderly, were competent at the tests, and some of the oldest subjects were among the most competent initially.
  • control subjects appear to have been among the strongest performers at baseline on span measures of memory, and similar to the DHA supplementation group, initially high scores might have reduced their ability to improve on some cognitive measures.
  • control subject scores were not among the highest at baseline on the Verbal Fluency test. The lack of significant change on the Verbal Fluency test by control group subjects suggests that lack of supplementation was likely associated with lack of improvement.
  • Fluency scores after 4 months (summarized in Table 5) of supplementation identifies a possible mechanism by which cognitive improvement in many of the subjects may have occurred. It should be noted that a similar relationship between final serum levels of lutein and Verbal Fluency scores was not found. There was also no significant relationship found between final Verbal Fluency scores and macular pigment ocular density, a significant dependent variable in the primary study of vision. The association of serum lutein levels with MPOD after supplementation provides strong corroboration that serum lutein increased MPOD. Lutein supplementation was associated with improvement in Verbal Fluency scores. As in the macula, among the carotenoids, there is a preference for lutein to accumulate in the brain. A facilitation of lutein uptake into the brain by DHA (via increases in HDL subfractions) may occur.
  • Example 4 Relations Between Serum Nutrient Levels and MPOD: The results of this study demonstrate that supplementation with daily oral doses of lutein (12 mg/d for 4 months) is effective in increasing circulating levels of lutein as well as MPOD. About 1/3 of subjects in L and LD groups did not have increases in MPOD with lutein supplementation. A MPOD response was not related to BMI, age, dietary intake of lutein or baseline serum and macular concentrations of lutein. The invention is based, in part, on the unexpected effects of DHA supplementation on serum lutein and MPOD. The increases from baseline in serum lutein at 2 month for the LD group were greater than that for the group supplemented with lutein alone (L group).
  • DHA fish oil
  • DHA status has been related to a decreased risk of AMD
  • the coadministration was shown to alter the lipoprotein profile, resulting in increase lutein concentration in the macula.
  • the combination of supplemental lutein and DHA can be used to prevent or slow the progression of AMD.
  • the study confirms that oral administration of the composition of the present invention is effective as a nutritional supplement, either therapeutically or prophylactically.

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Abstract

L'invention porte sur des préparations pharmaceutiques et des méthodes accroissant l'absorption de caroténoïdes diététiques par l'homme, et susceptibles de ralentir réduire ou prévenir l'apparition de troubles neurologiques ou de mémoire; et d'améliorer l'apprentissage, la cognition, et l'acquisition et la rétention d'éléments par la mémoire. Lesdites préparations pharmaceutiques consistent en doses à effet thérapeutique et/ou prophylactique de lutéine et d'acide docosahexaénoïque (DHA).
PCT/US2006/016506 2005-04-28 2006-04-28 Effets synergiques de l'acide docosahexaenoique (dha) et de l'absorbtion de carotenoides sur les fonctions cognitives WO2006116755A2 (fr)

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