WO2001084961A2 - Preparation for the prevention and/or treatment of vascular disorders - Google Patents

Preparation for the prevention and/or treatment of vascular disorders Download PDF

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Publication number
WO2001084961A2
WO2001084961A2 PCT/NL2001/000347 NL0100347W WO0184961A2 WO 2001084961 A2 WO2001084961 A2 WO 2001084961A2 NL 0100347 W NL0100347 W NL 0100347W WO 0184961 A2 WO0184961 A2 WO 0184961A2
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Prior art keywords
fraction
preparation according
vitamin
acid
phospholipids
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PCT/NL2001/000347
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French (fr)
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WO2001084961A3 (en
Inventor
Amanda Johanne Kiliaan
Robert Johan Joseph Hageman
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Nutricia NV
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Nutricia NV
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Priority to HK03104859.9A priority Critical patent/HK1052439B/en
Priority to EP01928256A priority patent/EP1282365B1/en
Priority to AU2001255114A priority patent/AU2001255114A1/en
Priority to DE60132081T priority patent/DE60132081T2/en
Priority to DK01928256T priority patent/DK1282365T3/en
Application filed by Nutricia NV filed Critical Nutricia NV
Priority to CA2408032A priority patent/CA2408032C/en
Priority to DK07120681T priority patent/DK1911442T3/en
Priority to EP09156648.9A priority patent/EP2070519B3/en
Publication of WO2001084961A2 publication Critical patent/WO2001084961A2/en
Publication of WO2001084961A3 publication Critical patent/WO2001084961A3/en
Anticipated expiration legal-status Critical
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
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    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
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    • 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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
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    • 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
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    • 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
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to preparations suitable for the prevention andor treatment of vascular disorders.
  • the invention also relates to the use of these preparations for the prevention and/or treatment of diseases that find their main cause in vascular problems, in particular dementia syndromes.
  • the vascular system in the human body is well described in the art.
  • An important part of the system are the blood vessels, that generally are divided in arteries and veins, dependent whether they transport blood to or from the heart. They vary in size from large (e.g. the aorta) to very small (capillaries). From an anatomical point of view larger blood vessels in general comprise as observed from the lumen side:
  • tunica intima that consists of a smooth (mono)layer of endothelial cells and a subendothelial layer that consists of a loose layer of connective tissue
  • tunica media which consists of a layer of (innervated) smooth muscle cells and elastic fibers
  • tunica adventitia which is composed of loosely woven collagen fibers, which are infiltrated by tiny lymphatic and blood vessels.
  • the endothelial cells in the tunica intima are in direct contact with blood and have a barrier function for the underlying tissue.
  • This barrier function includes selective transport of components from blood to the underlying tissue and vice versa, and protection of the underlying tissue.
  • Endothelial cells get easily damaged due to a wide variety of causes like mechanic forces or interaction with stressor components such as classic anaphylatoxins, and components that may occur in the blood, such as homocysteine or components that result from treatment with certain types of drugs (e.g. chemotherapeutics).
  • Vascular permeability can further be increased by a wide variety of humoral- and cell-derived mediators. Endothelial dysfunction can result in a wide range of disorders.
  • Damage to the endothelial layer can disturb the physiological functions thereof such as transport properties and expose the underlying tissue to stressors.
  • Monocytes may migrate to these damaged spots, get caught by adhesion molecules, differentiate into macrophages, which, when activated, may start up an inflammatory reaction. Due to this reaction cytokines may be released, which may trigger the release of reactive oxygen species, or change coagulation behaviour of blood components. This may result in occurrence of plaques in the arteries, which may ultimately result in hypertension, atherosclerosis and (later) arteriosclerosis.
  • Atherosclerosis may lead to an impaired blood supply to tissue, which may then become ischaemic. This may lead to damage to cells and even apoptose of the cells that depend on the oxygen and nutrient supply via these blood vessels. Tissue that has become ischaemic may thus lose functional capacity.
  • Dementia syndromes are characterised by an abnormal high and progressive loss of functional capacity of the brain. This process may start relatively early in life, like the dementias that are associated with some forms of epileptics, encephalitis, Huntington's disease, the dementias that can be observed after intoxication by (chronic) alcohol or drug abuse and the dementias due to cerebrovascular accidents and some genetic forms of dementias (early onset dementias). It may also start relatively late in life such as in Alzheimer's disease (presenile dementia), in senile dementia and in atherosclerotic dementia. Dementias may develop suddenly, e.g. after an apoplectic event, or develop very slowly such as in senile dementia.
  • Alzheimer's disease is characterised by an early step of excision of the amyloid-beta peptide (AB) from the precursor protein (APP) that is present in the endosomes of neurons or other cells of the central nervous system.
  • AB amyloid-beta peptide
  • APP precursor protein
  • BACE beta- secretase
  • the AB peptide produced by beta- secretase (BACE) may diffuse outside the cell and polymerise into amyloid filaments, which in turn may develop into mature amyloid plaques, especially when chaperone molecules like protease inhibitors are present.
  • the inflammatory response to the deposits of AB polymers and/or amyloid plaque may eventually lead to neuronal cell death and loss of cerebral function.
  • Dementia syndromes occur relatively frequently; about 10 % of the elderly population in the Netherlands suffer from this disease and still no cure has been found to prevent or treat dementias.
  • Treatment with drugs that increase brain levels of neurotransmitters like acetylcholine, serotonin or (nor)adrenaline are ineffective in the long term and the relatively high doses that often are administered could lead to undesirable side effects.
  • vascular disorders For the prevention and treatment of vascular disorders no suitable therapy is available either.
  • Vascular disorders and the consequences thereof are a major cause of death in the Western countries.
  • At present vascular disorders are treated by prescribing specific diets that are restricted in cholesterol, saturated fatty acids and in some cases sodium content and by administering drugs that are designed to lower blood pressure (e.g. diuretics), and plasma levels of cholesterol e.g. statins (or other compounds that are able to inhibit the activity of HMG-CoA reductase).
  • drugs that are designed to lower blood pressure (e.g. diuretics), and plasma levels of cholesterol e.g. statins (or other compounds that are able to inhibit the activity of HMG-CoA reductase).
  • Cholesterol appears to be important for the cell membrane. It decreases the fluidity of the outer cell membrane. It also is able to capture some radicals and is claimed to stop self-propagating radical chain reactions in the cell membrane. It is currently thought that vascular disorders should be treated with cholesterol lowering diets. However, it is not recognised that some forms of cholesterol, in particular plasma cholesterol, could be important in the repair mechanisms associated with vascular damage.
  • WO 99/11625 discloses the use of specific derivatives of huperzine A for inhibiting acetylcholine esterase for example in the treatment of Alzheimer's dementia and myasthemia gravis.
  • EP 0213724 discloses the use of phosphatidylcholine and phosphatidylethanolamine for membrane fluidisation.
  • Citric acid and/or citrates are widely used in food manufacture as taste modifier, acidifier and product stabiliser.
  • US 5,234,702 and 5,077,069 disclose the use of citric acid as a synergetic component for the antioxidant action of ascorbyl palmitate, beta-carotene and tocopherol.
  • WO 99/21565 discloses the use of any Kreb's cycle intermediate selected from citric acid, aconitic acid, isocitric acid, ⁇ -ketoglutaric acid, succinic acid, fumaric acid, malic acid and oxaloacetate or precursors thereof for treating disorders that are characterised by a decreased level of oxidative metabolism (page 5, line 25), in particular disorders of the nervous system but also of cardiovascular diseases. In particular precursors of oxaloacetate are preferred (page 7, line 10). No reference is made to beneficial effects of administration of these components on vasoendothelial cells, nor to additional effects that could be obtained by including phopholipids or LC-PUFA's in the composition.
  • EP 0 711 559 describes the use of phosphatidylserines for the manufacture of a medicament for improving cerebration, in particular for the treatment of Parkinson' s disease and dementia such as Alzheimer' s disease.
  • the preparation according to this document contains phophatidyl-L-serine which has a structural fatty acid chain derived from at least one raw material lecithin as the effective ingredient.
  • PCT/US88/01693 describes the use of phosphoethanolamine and related compounds for the use in the treatment of Alzheimer's disease.
  • the present inventors have now found a preparation for the treatment of vascular disorders that is effective because it provides activity on the function of the tunica intima and endothelial cells in general, which is important for influencing the aetiology and development of a wide range of vascular disorders and several other secondary disorders, in particular dementia syndromes.
  • the present invention provides a preparation suitable for the prevention and/or treatment of vascular disorders, comprising the following fractions: a) long chain polyunsaturated fatty acids; b) phospholipids, which fraction contains at least two different phospholipids selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. c) compounds which are a factor in methionine metabolism, which fraction contains at least one member selected from the group consisting of folic acid, vitamin
  • the preparation of the invention can be a pharmaceutical, dietetic as well as a nutritional preparation.
  • the products can have the form of a liquid, powder, bar, cookie, sweetie, concentrate, paste, sauce, gel, emulsion, tablet, capsule, etc. to provide the daily dose of the bioactive components either as a single or in multiple doses.
  • the products can be packaged by applying methods known in the art, to keep the product fresh during shelf life and allow easy use or administration.
  • Fraction a) contains long chain polyunsaturated fatty acids, preferably ⁇ -3 and/or ⁇ -6 fatty acids.
  • the fatty acids can be free fatty acids, but are preferably bound to a suitable backbone, for instance a triglyceride. They can also be in the form of phopholipids as will be described later.
  • fraction a The function of fraction a) is to modulate inflammatory processes that may occur in vessel walls and cerebral tissue, to normalise plasma cholesterol levels, especially LDL- cholesterol levels and revert the atherosclerotic process and to increase fluidity of neuronal, erythrocyte and blood vessel membranes. It was found that especially a mixture of ⁇ -3 and ⁇ -6 long chain polyunsaturated fatty acids (LCPUFA's) should be included in a ratio of ⁇ -3 fatty acids to ⁇ -6 fatty acids of about 2.5 to 5.5 wt/wt.
  • LCPUFA's long chain polyunsaturated fatty acids
  • Preferred ⁇ -3 LCPUFA's are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Best results are obtained when DHA and EPA are included in about equimolar amounts, for example a ratio of DHA to EPA of 0.5 to 2 wt/wt.
  • Preferred ⁇ -6 LCPUFA's are dihomogammalinolenic acid (DHGLA) and arachidonic acid (AA). These should be included in an amount of about one fourth of the amount of EPA and DHA, for example a ratio of [DHA + EPA] to [DHGLA + AA] of 2.5 to 5.5, preferably 3.3-4.7 wt/wt.
  • the daily dosage of the total of EPA+DHA+DHGLA+AA is preferably at least 120 mg, more preferably at least 350 mg.
  • the preparation in particular contains 20 to 2000 mg, preferably 50 to 1000 mg EPA, 50 to 2000 mg, preferably 200 to 1000 mg DHA and 50 to 2000 mg, preferably 100 to 1000 mg DHGLA.
  • LCPUFA's that can be present are linoleic and ⁇ -linoleic acid.
  • the ratio of the total amount of EPA+DHA+DHGLA+AA to the total amount of linoleic and ⁇ - linoleic acid should be larger than 0.1 wt/wt, preferably larger than 0.2, most preferably larger than 0.4.
  • fraction b) contains at least two different phospholipids selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine.
  • this fraction contains phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine.
  • this fraction is to provide a direct source of neuronal and endothelial cell phospholipids. It is highly preferred to include a mixture of phospholipids, especially with regard to the choline/ethanolamine moiety couple on the one hand, and the serine/inositol moiety couple on the other hand. For best results the ratio of (phosphatidylcholine and/or phosphatidylethanolamine) to (phosphatidylserine and/or phosphatidylinositol) is 0.5-20 (wt wt). Per daily dose at least 0.2 g and preferably more than 1 g phospholipids should be administered, for example 4 g. When the product is meant to be used by patients suffering from dementia syndromes, the amount of phosphatidylserine per daily dose product should be at least 0.1 g for best results and preferably more than 0.5 g.
  • LCPUFA LCPUFA moiety
  • phospholipids which provide the LCPUFA's as described above for fraction a). They can for example be prepared by applying interesterification methods known in the art using for example raw phospholipid mixtures and ingredients that are rich in the particular LCPUFA's. Use of these specific phospholipids ensures a high activity next to a relatively stable product. In preparations for oral use it is not required to use higher organised lipid fractions such as sphingomyelines due to the high metabolic rates of this type of compound in the gut, gut epithelial cells and liver.
  • lipids that are essentially free from DHA, EPA, DHGLA or AA, such as neutral triglycerides are preferably not included in the phospholipid fraction or in relatively low amounts, e.g. less than 40 % and in particular less than 5 % of the lipid fraction.
  • Phospholipids can originate from egg yolk or soy, and can be isolated by applying methods that are known in the art, for example acetone extraction and optionally applying subsequent chromatographic techniques or adsorption methods.
  • the phospholipid fraction can also consist, where required, of mixtures of synthetic phospholipids and (extracts of) phospholipids of natural origin.
  • TMM Total methionine metabolism
  • Fraction c consists of compounds which are a factor in methionine metabolism and contains at least one member selected from the group consisting of folic acid, vitamin B12, vitamin B6, magnesium and zinc.
  • this fraction contains at least folic acid, in particular in an amount of at least 200 ⁇ g and most preferably more than 400 ⁇ g per daily dose.
  • Folic acid is also meant to include physiological equivalents thereof such as pharmaceutically acceptable salts thereof, 5-methyltetrahydrofolate and polyglutamate forms thereof as occur naturally. It is most preferred that at least folic acid and vitamin B6 are included, while the largest part of the population will benefit if these components are simultaneously included.
  • Vitamin B6 should be included in an amount of more than 2 mg, in particular more than 2.5 mg per daily dose.
  • fraction c comprises zinc and copper, the weight ratio of zinc to copper is between 5 to 12. Choline and/or betaine can be included.
  • the preparation according to the invention can contain a further fraction d) that contains citrate.
  • Citrate is also meant to include citric acid.
  • the products according to the invention should have a pH between 3.0 and 7.5 and preferably between 5 and 7. Citrate should be administered in an amount of 0.5 to 30 g, preferably 1.5 to 10 g per daily dose, for example more than 2.4 g.
  • citric acid as well as some other compounds, provides reducing equivalents to the cytosol and participates in the "Krebs cycle", thus yielding NADH and energy in the mitochondriae. It is also known for a long time that citric acid helps regulate glycolyses by feedback inhibition of the phosphofructokinase reaction.
  • huperzine A or functional analogues thereof (fraction e), especially in those products that are designed to be used for the prevention and treatment of dementia syndromes, especially in those phases of the disease where acetylcholine metabolism is severely impaired.
  • Huperzine A should be included in amounts of 0.04 to 2, preferably 0.07 to 1, most preferably 0.08 to 0.5 mg per daily dose.
  • an analogue also an extract of certain herbs such as Huperzia serrata can be used, when standardised on huperzine A content and purity. An amount of 0.04 to 20 mg, preferably 0.07 to 2 mg per daily dose of such an extract can be used.
  • lipophilic derivatives of huperzine A can be used, e.g. those obtained by modification of the primary and/or secondary amino groups.
  • preparations that comprise a fraction a), a fraction b) and a fraction c) as described above together with huperzine and/or citrate are highly preferred since they have in some patients an unexpected higher activity than a product that comprises fraction a, b and c without huperzine and/or citrate.
  • the preparation preferably further contains a fraction f) one or more of carnitine, vitamin Bl, vitamin B5 and coenzyme Q10 or functional analogues thereof.
  • carnitine can be mentioned pharmaceutically acceptable salts thereof or alkanoyl and acyl carnitines [acetyl-L-carnitine], which are particularly useful, or mixtures thereof.
  • Carnitine is advantageously included in products that are meant to be used for patients suffering from dementia syndromes. In these products preferably a lipophilic derivative is used as carnitine source. It is most preferred to use acetyl-L- carnitine. This component provides acetyl groups in the brain for biosynthetic purposes.
  • Carnitine should be included in an amount of 0.1 to 3 g, preferably 0.2 to 1 g per daily dose.
  • Vitamin B5 can be included for instance as calcium pantothenate or other stable form.
  • Preferred dosages are 8 to 80 mg, preferably 12 to 40 mg per daily dose product.
  • a lipophylic thiamine source such as benfothiamine, allithiamine, fursulthiamine or octothiamine.
  • a degeneration of cerebral function as is observed during Parkinson's and Huntington's disease can be retarded by the product according to the invention.
  • products for these types of patients it is advantageous to include also respectively taurine and gamma-amino butyric acid or derivatives thereof such as piracetam. If coenzym Q10 is included the amount can be 0.8 to 200 mg and preferably 5 to 70 mg. The amounts can be that low because of the beneficial effect of the phospholipids on the membrane function.
  • fraction g) can be present that provides anti-oxidant properties.
  • Fraction g) contains antioxidants selected from vitamin C, vitamin E, lipoic acid, selenium salts and carotenoids.
  • a fraction h) contains an extract of gingko biloba. This extract is obtained from the leaves and is enriched in flavonoids and especially terpenoids, in particular ginkgolides. It appears for example that an extract that comprises at least 4 % ginkgolides is effective.
  • the preparation preferably contains the above components of the different fractions in an amount above the recommended daily intake.
  • Per daily dose the preparation of the invention preferably comprises : at least 120 mg long chain polyunsaturated fatty acids; at least 200 mg phospholipids; at least 200 ⁇ g folic acid; and at least 0.5 g citrate.
  • the preparation comprises per daily dose: at least 20 mg, preferably at least 50 mg eicosapentaenoic acid at least 50 mg, preferably at least 200 mg docosahexaenoic acid at least 50, mg preferably at least 100 mg arachidonic acid at least 200 mg, preferably at least 1000 mg phosphatidylserine, at least 200 ⁇ g, preferably at least 400 ⁇ g folic acid at least 100 mg, preferably at least 200 mg magnesium at least 5 mg, preferably at least 10 mg zinc at least 2 mg, preferably at least 2.5 mg vitamin B6 at least 2 ⁇ g, preferably at least 4 ⁇ g vitamin B 12 at least 1.0 g, preferably at least 1.5 g citrate.
  • the preparations according to the invention can be used in the treatment and/or prevention of vascular, cardio- and cerebrovascular disorders and a selected range of secondary problems.
  • the nature and impact of the latter depends on the time pattern and degree of decrease of the blood flow and the function of the organ/ tissue that is involved. Damage to the endothelial cells may also lead to loss of elasticity and even a local lesion of the blood vessel.
  • Examples of problems of the cardiovascular system are atherosclerosis obliterans, angina pectoris, myocard infarct, cerebral vascular accidents, thrombosis, M. Burger, varices, thrombo-phlebitis and the syndrome of Raynaud. Damage to endothelial cells may also lead to a localized vasoconstriction. When damage to the endothelial cells has a more systemic nature this may lead to increased blood pressure.
  • vascular disorders that could be treated with the product are atherosclerosis, arteriosclerosis, hyper- cholesterolaemia, hyperlipidaemia, elevated blood pressure, angina pectoris, cerebro- vasular accidents, temporary disorders associated with ischaemia, vene thrombose, postpartum thrombose, myocard infarct, varicose veins (varices), thrombo angiitis obliterans and atheroslecrosis obliterans.
  • Secondary problems that are treatable with the product are some problems that occur after mechanic traumata, such as those that occur in accidents, during or after labor and during surgery.
  • Other examples of treatable secondary problems are problems with hearing loss (especially that associated with chemotherapy or ageing), with improper functioning of liver, stomach, kidneys, legs, lung, or prostate and sudden (cerebrovascular incident) or chronic decrease of cerebral functions.
  • An especially preferred use is in the prevention of cognitive degeneration in persons at risk for Alzheimer's disease or vascular dementia.
  • An effective blood supply would provide sufficient amounts of nutrients to the brain, which supports anti-inflammatory response to deposits of AB peptide polymer and helps degrade plaques.
  • An adequate blood supply further can help prevent the degenerative oxidative processes that are observed in many neurological disorders such as in Parkinson's disease (in the substantia nigra) and supports biosynthesis and metabolism of neurotransmitters such as gamma-amino butryric acid and dopamine.
  • the capsule is prepared using methods known in the art and comprises as active components: DHA 50 mg
  • the pudding is based on cow's milk, starch, sugar and flavourings prepared by methods known in the art and comprises as active ingredients per serving of 200 ml: phospholipids from egg 4 g
  • phosphatidylserine 100 mg encapsulated fish oil 0.3 g
  • Example 3 Powdered concentrate that consists of the active components as given in example 2 and further 0.1 g orange flavouring and maltodextrine to make up a total mass of 10 g. This amount is packed in a sachet and can be used to be reconstituted in any drink (milk, fruit juice, etc.).
  • Gingko biloba extract 200 mg calcium sulphate 300 mg vitamin D 10 ⁇ g
  • the bar is coated with a layer of chocolate.

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Abstract

The present invention relates to a preparation suitable for the prevention and/or treatment of vascular disorders, comprising the following fractions: fraction a) long chain polyunsaturated fatty acids; fraction b) phospholipids, which fraction contains at least two different phospholipids selected from the group consisting of phosphatidylserine; phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. fraction c) compounds which are a factor in methionine metabolism, which fraction contains at least one member selected from the group consisting of folic acid, vitamin B12, vitamin B6, magnesium and zinc.

Description

Preparation for the prevention and/or treatment of vascular disorders
Background of the invention The present invention relates to preparations suitable for the prevention andor treatment of vascular disorders. The invention also relates to the use of these preparations for the prevention and/or treatment of diseases that find their main cause in vascular problems, in particular dementia syndromes.
The vascular system in the human body is well described in the art. An important part of the system are the blood vessels, that generally are divided in arteries and veins, dependent whether they transport blood to or from the heart. They vary in size from large (e.g. the aorta) to very small (capillaries). From an anatomical point of view larger blood vessels in general comprise as observed from the lumen side:
1. the tunica intima, that consists of a smooth (mono)layer of endothelial cells and a subendothelial layer that consists of a loose layer of connective tissue,
2. the tunica media, which consists of a layer of (innervated) smooth muscle cells and elastic fibers, and 3. the tunica adventitia which is composed of loosely woven collagen fibers, which are infiltrated by tiny lymphatic and blood vessels.
The endothelial cells in the tunica intima are in direct contact with blood and have a barrier function for the underlying tissue. This barrier function includes selective transport of components from blood to the underlying tissue and vice versa, and protection of the underlying tissue. Endothelial cells get easily damaged due to a wide variety of causes like mechanic forces or interaction with stressor components such as classic anaphylatoxins, and components that may occur in the blood, such as homocysteine or components that result from treatment with certain types of drugs (e.g. chemotherapeutics). Vascular permeability can further be increased by a wide variety of humoral- and cell-derived mediators. Endothelial dysfunction can result in a wide range of disorders. Damage to the endothelial layer can disturb the physiological functions thereof such as transport properties and expose the underlying tissue to stressors. Monocytes may migrate to these damaged spots, get caught by adhesion molecules, differentiate into macrophages, which, when activated, may start up an inflammatory reaction. Due to this reaction cytokines may be released, which may trigger the release of reactive oxygen species, or change coagulation behaviour of blood components. This may result in occurrence of plaques in the arteries, which may ultimately result in hypertension, atherosclerosis and (later) arteriosclerosis.
Atherosclerosis may lead to an impaired blood supply to tissue, which may then become ischaemic. This may lead to damage to cells and even apoptose of the cells that depend on the oxygen and nutrient supply via these blood vessels. Tissue that has become ischaemic may thus lose functional capacity.
Dementia syndromes are characterised by an abnormal high and progressive loss of functional capacity of the brain. This process may start relatively early in life, like the dementias that are associated with some forms of epileptics, encephalitis, Huntington's disease, the dementias that can be observed after intoxication by (chronic) alcohol or drug abuse and the dementias due to cerebrovascular accidents and some genetic forms of dementias (early onset dementias). It may also start relatively late in life such as in Alzheimer's disease (presenile dementia), in senile dementia and in atherosclerotic dementia. Dementias may develop suddenly, e.g. after an apoplectic event, or develop very slowly such as in senile dementia.
Alzheimer's disease is characterised by an early step of excision of the amyloid-beta peptide (AB) from the precursor protein (APP) that is present in the endosomes of neurons or other cells of the central nervous system. The AB peptide produced by beta- secretase (BACE) may diffuse outside the cell and polymerise into amyloid filaments, which in turn may develop into mature amyloid plaques, especially when chaperone molecules like protease inhibitors are present. The inflammatory response to the deposits of AB polymers and/or amyloid plaque may eventually lead to neuronal cell death and loss of cerebral function.
Dementia syndromes occur relatively frequently; about 10 % of the elderly population in the Netherlands suffer from this disease and still no cure has been found to prevent or treat dementias. Treatment with drugs that increase brain levels of neurotransmitters like acetylcholine, serotonin or (nor)adrenaline are ineffective in the long term and the relatively high doses that often are administered could lead to undesirable side effects.
For the prevention and treatment of vascular disorders no suitable therapy is available either. Vascular disorders and the consequences thereof are a major cause of death in the Western countries. At present vascular disorders are treated by prescribing specific diets that are restricted in cholesterol, saturated fatty acids and in some cases sodium content and by administering drugs that are designed to lower blood pressure (e.g. diuretics), and plasma levels of cholesterol e.g. statins (or other compounds that are able to inhibit the activity of HMG-CoA reductase).
Though some of the treatments are indeed effective in treating part of the phenomena associated with vascular problems, the treatments are not 100% effective in solving the real problem (the cause) and they may demonstrate undesired systemic side effects.
Prior art Vascular endothelial cells and their function in the blood vessel have been studied for a long time. Many details about biochemical processes that occur in these cells have been published as well.
Recently Chang published in vitro data about the effect of pyridoxal-5-phosphate on human umbilical vein endothelial cells that "suggested that vitamin B6 protects endothe- lial cells by enhancing the beneficial function and preventing cell injury which are responsible for the initiation and the disease process of atherosclerosis". See Chang S.J. Nutrition Research, 1999, 19 (11), 1613-1624; "Vitamin B6 protects vascular endothelial injury by activated platelets".
Much literature has appeared about the aetiology of vascular diseases and dementia syn- dromes. Associations have been made between consumption of fruit on plasma levels of homocysteine or cholesterol and the presence of cardiovascular diseases.
The structure of cell membranes has been studied; many different components appear to be part of the membrane, such as lipids, proteins and cholesterol. Cholesterol appears to be important for the cell membrane. It decreases the fluidity of the outer cell membrane. It also is able to capture some radicals and is claimed to stop self-propagating radical chain reactions in the cell membrane. It is currently thought that vascular disorders should be treated with cholesterol lowering diets. However, it is not recognised that some forms of cholesterol, in particular plasma cholesterol, could be important in the repair mechanisms associated with vascular damage.
WO 99/11625 discloses the use of specific derivatives of huperzine A for inhibiting acetylcholine esterase for example in the treatment of Alzheimer's dementia and myasthemia gravis.
EP 0213724 discloses the use of phosphatidylcholine and phosphatidylethanolamine for membrane fluidisation.
Citric acid and/or citrates are widely used in food manufacture as taste modifier, acidifier and product stabiliser. US 5,234,702 and 5,077,069 disclose the use of citric acid as a synergetic component for the antioxidant action of ascorbyl palmitate, beta-carotene and tocopherol.
WO 99/21565 discloses the use of any Kreb's cycle intermediate selected from citric acid, aconitic acid, isocitric acid, α-ketoglutaric acid, succinic acid, fumaric acid, malic acid and oxaloacetate or precursors thereof for treating disorders that are characterised by a decreased level of oxidative metabolism (page 5, line 25), in particular disorders of the nervous system but also of cardiovascular diseases. In particular precursors of oxaloacetate are preferred (page 7, line 10). No reference is made to beneficial effects of administration of these components on vasoendothelial cells, nor to additional effects that could be obtained by including phopholipids or LC-PUFA's in the composition.
EP 0 711 559 describes the use of phosphatidylserines for the manufacture of a medicament for improving cerebration, in particular for the treatment of Parkinson' s disease and dementia such as Alzheimer' s disease. The preparation according to this document contains phophatidyl-L-serine which has a structural fatty acid chain derived from at least one raw material lecithin as the effective ingredient. PCT/US88/01693 describes the use of phosphoethanolamine and related compounds for the use in the treatment of Alzheimer's disease.
Summary of the invention The present inventors have now found a preparation for the treatment of vascular disorders that is effective because it provides activity on the function of the tunica intima and endothelial cells in general, which is important for influencing the aetiology and development of a wide range of vascular disorders and several other secondary disorders, in particular dementia syndromes.
Thus, the present invention provides a preparation suitable for the prevention and/or treatment of vascular disorders, comprising the following fractions: a) long chain polyunsaturated fatty acids; b) phospholipids, which fraction contains at least two different phospholipids selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. c) compounds which are a factor in methionine metabolism, which fraction contains at least one member selected from the group consisting of folic acid, vitamin
B 12, vitamin B6, magnesium and zinc or equivalents thereof. The preparation of the invention can be a pharmaceutical, dietetic as well as a nutritional preparation. The products can have the form of a liquid, powder, bar, cookie, sweetie, concentrate, paste, sauce, gel, emulsion, tablet, capsule, etc. to provide the daily dose of the bioactive components either as a single or in multiple doses. The products can be packaged by applying methods known in the art, to keep the product fresh during shelf life and allow easy use or administration.
Detailed description of the invention The combined administration of these fractions results in the treatment and prevention of vascular disorders on different levels, in particular on the level of the tunica intima and endothelial cells in general. Fraction a) contains long chain polyunsaturated fatty acids, preferably Ω-3 and/or Ω-6 fatty acids. The fatty acids can be free fatty acids, but are preferably bound to a suitable backbone, for instance a triglyceride. They can also be in the form of phopholipids as will be described later.
The function of fraction a) is to modulate inflammatory processes that may occur in vessel walls and cerebral tissue, to normalise plasma cholesterol levels, especially LDL- cholesterol levels and revert the atherosclerotic process and to increase fluidity of neuronal, erythrocyte and blood vessel membranes. It was found that especially a mixture of Ω-3 and Ω-6 long chain polyunsaturated fatty acids (LCPUFA's) should be included in a ratio of Ω-3 fatty acids to Ω-6 fatty acids of about 2.5 to 5.5 wt/wt.
Preferred Ω-3 LCPUFA's are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Best results are obtained when DHA and EPA are included in about equimolar amounts, for example a ratio of DHA to EPA of 0.5 to 2 wt/wt. Preferred Ω-6 LCPUFA's are dihomogammalinolenic acid (DHGLA) and arachidonic acid (AA). These should be included in an amount of about one fourth of the amount of EPA and DHA, for example a ratio of [DHA + EPA] to [DHGLA + AA] of 2.5 to 5.5, preferably 3.3-4.7 wt/wt. The daily dosage of the total of EPA+DHA+DHGLA+AA is preferably at least 120 mg, more preferably at least 350 mg. Per daily dose the preparation in particular contains 20 to 2000 mg, preferably 50 to 1000 mg EPA, 50 to 2000 mg, preferably 200 to 1000 mg DHA and 50 to 2000 mg, preferably 100 to 1000 mg DHGLA.
Further LCPUFA's that can be present are linoleic and α-linoleic acid. However, the ratio of the total amount of EPA+DHA+DHGLA+AA to the total amount of linoleic and α- linoleic acid should be larger than 0.1 wt/wt, preferably larger than 0.2, most preferably larger than 0.4.
As described above fraction b) contains at least two different phospholipids selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. Preferably this fraction contains phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine.
The function of this fraction is to provide a direct source of neuronal and endothelial cell phospholipids. It is highly preferred to include a mixture of phospholipids, especially with regard to the choline/ethanolamine moiety couple on the one hand, and the serine/inositol moiety couple on the other hand. For best results the ratio of (phosphatidylcholine and/or phosphatidylethanolamine) to (phosphatidylserine and/or phosphatidylinositol) is 0.5-20 (wt wt). Per daily dose at least 0.2 g and preferably more than 1 g phospholipids should be administered, for example 4 g. When the product is meant to be used by patients suffering from dementia syndromes, the amount of phosphatidylserine per daily dose product should be at least 0.1 g for best results and preferably more than 0.5 g.
Another preferred characteristic of the preferred phospholipids is the LCPUFA moiety. It is preferred to use phospholipids which provide the LCPUFA's as described above for fraction a). They can for example be prepared by applying interesterification methods known in the art using for example raw phospholipid mixtures and ingredients that are rich in the particular LCPUFA's. Use of these specific phospholipids ensures a high activity next to a relatively stable product. In preparations for oral use it is not required to use higher organised lipid fractions such as sphingomyelines due to the high metabolic rates of this type of compound in the gut, gut epithelial cells and liver. Also, other lipids, that are essentially free from DHA, EPA, DHGLA or AA, such as neutral triglycerides are preferably not included in the phospholipid fraction or in relatively low amounts, e.g. less than 40 % and in particular less than 5 % of the lipid fraction. Phospholipids can originate from egg yolk or soy, and can be isolated by applying methods that are known in the art, for example acetone extraction and optionally applying subsequent chromatographic techniques or adsorption methods. The phospholipid fraction can also consist, where required, of mixtures of synthetic phospholipids and (extracts of) phospholipids of natural origin.
Fraction c) contains compounds, which are a factor in methionine metabolism. Total methionine metabolism (TMM) has been described in EP 0 891 719. Though it is known that a proper functioning of TMM is mandatory for the endogenous biosynthesis of many crucial compounds such as S-adenosyl methionine (for creatine, carnitine, etc) and glutathion, and though one has found associations between the occurrence of vascular disorders with hyperhomocysteinaemia, the relevance of a proper functioning of total methionine metabolism for in particular the endothelial cell has not been recognised.
Fraction c consists of compounds which are a factor in methionine metabolism and contains at least one member selected from the group consisting of folic acid, vitamin B12, vitamin B6, magnesium and zinc. Preferably this fraction contains at least folic acid, in particular in an amount of at least 200 μg and most preferably more than 400 μg per daily dose. Folic acid is also meant to include physiological equivalents thereof such as pharmaceutically acceptable salts thereof, 5-methyltetrahydrofolate and polyglutamate forms thereof as occur naturally. It is most preferred that at least folic acid and vitamin B6 are included, while the largest part of the population will benefit if these components are simultaneously included. Vitamin B6 should be included in an amount of more than 2 mg, in particular more than 2.5 mg per daily dose. It is even more advantageous when this fraction contains all of the members of the above mentioned group. The fraction can further contain SAMe (S-adenosyl methionine), choline, betaine and/or copper. If fraction c) comprises zinc and copper, the weight ratio of zinc to copper is between 5 to 12. Choline and/or betaine can be included.
Besides the fractions a) to c) described above, the preparation according to the invention can contain a further fraction d) that contains citrate. Citrate is also meant to include citric acid. The products according to the invention should have a pH between 3.0 and 7.5 and preferably between 5 and 7. Citrate should be administered in an amount of 0.5 to 30 g, preferably 1.5 to 10 g per daily dose, for example more than 2.4 g.
In the biochemistry literature one can find that citric acid, as well as some other compounds, provides reducing equivalents to the cytosol and participates in the "Krebs cycle", thus yielding NADH and energy in the mitochondriae. It is also known for a long time that citric acid helps regulate glycolyses by feedback inhibition of the phosphofructokinase reaction.
However, it is not recognised that for a proper functioning of vascular endothelial cells it is important to have at the same time sufficient amounts of ATP and reducing equivalents in the form of NADPH available in the cytosol of these cells and that citrate can ensure this to occur, and more effectively than a functional analog like a Krebs cycle intermediate like oxaloacetate, malic acid or fumarate.
It is advantageous to include huperzine A or functional analogues thereof (fraction e), especially in those products that are designed to be used for the prevention and treatment of dementia syndromes, especially in those phases of the disease where acetylcholine metabolism is severely impaired. Huperzine A should be included in amounts of 0.04 to 2, preferably 0.07 to 1, most preferably 0.08 to 0.5 mg per daily dose. As an analogue also an extract of certain herbs such as Huperzia serrata can be used, when standardised on huperzine A content and purity. An amount of 0.04 to 20 mg, preferably 0.07 to 2 mg per daily dose of such an extract can be used. Also lipophilic derivatives of huperzine A can be used, e.g. those obtained by modification of the primary and/or secondary amino groups.
According to the invention preparations that comprise a fraction a), a fraction b) and a fraction c) as described above together with huperzine and/or citrate are highly preferred since they have in some patients an unexpected higher activity than a product that comprises fraction a, b and c without huperzine and/or citrate.
The preparation preferably further contains a fraction f) one or more of carnitine, vitamin Bl, vitamin B5 and coenzyme Q10 or functional analogues thereof. As functional equivalents of carnitine can be mentioned pharmaceutically acceptable salts thereof or alkanoyl and acyl carnitines [acetyl-L-carnitine], which are particularly useful, or mixtures thereof. Carnitine is advantageously included in products that are meant to be used for patients suffering from dementia syndromes. In these products preferably a lipophilic derivative is used as carnitine source. It is most preferred to use acetyl-L- carnitine. This component provides acetyl groups in the brain for biosynthetic purposes. Carnitine should be included in an amount of 0.1 to 3 g, preferably 0.2 to 1 g per daily dose. Vitamin B5 can be included for instance as calcium pantothenate or other stable form. Preferred dosages are 8 to 80 mg, preferably 12 to 40 mg per daily dose product.
For products that are meant to be used for treatment or prevention of further progression of dementia syndromes it is preferred to use a lipophylic thiamine source such as benfothiamine, allithiamine, fursulthiamine or octothiamine. A degeneration of cerebral function as is observed during Parkinson's and Huntington's disease can be retarded by the product according to the invention. In products for these types of patients it is advantageous to include also respectively taurine and gamma-amino butyric acid or derivatives thereof such as piracetam. If coenzym Q10 is included the amount can be 0.8 to 200 mg and preferably 5 to 70 mg. The amounts can be that low because of the beneficial effect of the phospholipids on the membrane function. Also a fraction g) can be present that provides anti-oxidant properties. Fraction g) contains antioxidants selected from vitamin C, vitamin E, lipoic acid, selenium salts and carotenoids. A fraction h) contains an extract of gingko biloba. This extract is obtained from the leaves and is enriched in flavonoids and especially terpenoids, in particular ginkgolides. It appears for example that an extract that comprises at least 4 % ginkgolides is effective.
The preparation preferably contains the above components of the different fractions in an amount above the recommended daily intake. Per daily dose the preparation of the invention preferably comprises : at least 120 mg long chain polyunsaturated fatty acids; at least 200 mg phospholipids; at least 200 μg folic acid; and at least 0.5 g citrate.
More preferably, the preparation comprises per daily dose: at least 20 mg, preferably at least 50 mg eicosapentaenoic acid at least 50 mg, preferably at least 200 mg docosahexaenoic acid at least 50, mg preferably at least 100 mg arachidonic acid at least 200 mg, preferably at least 1000 mg phosphatidylserine, at least 200 μg, preferably at least 400 μg folic acid at least 100 mg, preferably at least 200 mg magnesium at least 5 mg, preferably at least 10 mg zinc at least 2 mg, preferably at least 2.5 mg vitamin B6 at least 2 μg, preferably at least 4 μg vitamin B 12 at least 1.0 g, preferably at least 1.5 g citrate.
The preparations according to the invention can be used in the treatment and/or prevention of vascular, cardio- and cerebrovascular disorders and a selected range of secondary problems. The nature and impact of the latter depends on the time pattern and degree of decrease of the blood flow and the function of the organ/ tissue that is involved. Damage to the endothelial cells may also lead to loss of elasticity and even a local lesion of the blood vessel.
Examples of problems of the cardiovascular system are atherosclerosis obliterans, angina pectoris, myocard infarct, cerebral vascular accidents, thrombosis, M. Burger, varices, thrombo-phlebitis and the syndrome of Raynaud. Damage to endothelial cells may also lead to a localized vasoconstriction. When damage to the endothelial cells has a more systemic nature this may lead to increased blood pressure. Other vascular disorders that could be treated with the product are atherosclerosis, arteriosclerosis, hyper- cholesterolaemia, hyperlipidaemia, elevated blood pressure, angina pectoris, cerebro- vasular accidents, temporary disorders associated with ischaemia, vene thrombose, postpartum thrombose, myocard infarct, varicose veins (varices), thrombo angiitis obliterans and atheroslecrosis obliterans.
Secondary problems that are treatable with the product are some problems that occur after mechanic traumata, such as those that occur in accidents, during or after labor and during surgery. Other examples of treatable secondary problems are problems with hearing loss (especially that associated with chemotherapy or ageing), with improper functioning of liver, stomach, kidneys, legs, lung, or prostate and sudden (cerebrovascular incident) or chronic decrease of cerebral functions. An especially preferred use is in the prevention of cognitive degeneration in persons at risk for Alzheimer's disease or vascular dementia.
We believe that many of the dementia syndromes find their basic cause in cardiovascular disorders. An effective blood supply would provide sufficient amounts of nutrients to the brain, which supports anti-inflammatory response to deposits of AB peptide polymer and helps degrade plaques. An adequate blood supply further can help prevent the degenerative oxidative processes that are observed in many neurological disorders such as in Parkinson's disease (in the substantia nigra) and supports biosynthesis and metabolism of neurotransmitters such as gamma-amino butryric acid and dopamine. Example 1
Capsule for use by demented persons three times a day.
The capsule is prepared using methods known in the art and comprises as active components: DHA 50 mg
EPA 75 mg phospholipids* 250 mg folic acid 200 μg vitamin B 12 25 mg Huperzia serrata 100 ug vitamin Bl 100 mg coenzym Q10 10 mg vitamin E 200 mg
Gingko biloba 120 mg * phosphatidylcholine 130 mg, phosphatidylserine 120 mg (synthetic)
Example 2
Pudding for improvement of vascular conditions and secondary disorders such as dementia syndromes. The pudding is based on cow's milk, starch, sugar and flavourings prepared by methods known in the art and comprises as active ingredients per serving of 200 ml: phospholipids from egg 4 g
(provides about 20 mg DHA and 20 mg AA and phospholipids comprise about 77 % phosphatidylcholine and 16 % phosphatidylethanolamine) phosphatidylserine 100 mg encapsulated fish oil 0.3 g
(provides about 30 mg DHA and 30 mg EPA) Single cell oil (25 mg AA) 0.06 g folic acid (synthetic monoglutamate) 0.3 mg vitamin B6 (pyridoxine) 3 mg zinc (ZnSO4) 10 mg magnesium (MgO) 100 mg vitamin B12 (cyanocobalamine) 3 μg citrate/ citric acid 1.2 g thiamine HC1 2 mg vitamin E 20 mg manganese (MnO) 10 mg
Example 3 Powdered concentrate that consists of the active components as given in example 2 and further 0.1 g orange flavouring and maltodextrine to make up a total mass of 10 g. This amount is packed in a sachet and can be used to be reconstituted in any drink (milk, fruit juice, etc.).
Example 4
Powder for improvement of vasoendothelial function consisting of soylecithin* 3 g folic acid 400 μg vitamin B6 3 mg vitamin B 12 4 μg zinc 15 mg magnesium 150 mg citric acid/ citrate (pH of product 7.0) 2.2 g maltodextrines to make up a total weight of 10 g * phosphatidylcholine:phosphatidylethanolamine:phosphatidylinositol = 24:22: 15)
Example 5
Muesli-bar of about 25 g based on sugar, cereals and pieces of dried fruit that comprises as active components: soylecithin* 2 g encapsulated fish oil 0.6 g
SCO (AA) 0.3 g
Folic acid 400 μg pyridoxamine 3 mg cyanocobalamine 5 μg zinc oxide 30 mg magnesium oxide 200 mg citric acid/citrate pH 6.5 mixture 2 g
Huperzine serrata extract 150 μg
Gingko biloba extract 200 mg calcium sulphate 300 mg vitamin D 10 μg
* phosphatidylcholine:phosphatidylethanolamine:phosphatidylinositol = 45:26:14)
The bar is coated with a layer of chocolate.

Claims

Claims
1. Preparation suitable for the prevention and/or treatment of vascular disorders, comprising the following fractions: a) long chain polyunsaturated fatty acids; b) phospholipids, which fraction contains at least two different phospholipids selected from the group consisting of phosphatidylserine, phosphatidylinositol, phosphatidylcholine and phosphatidylethanolamine. c) compounds which are a factor in methionine metabolism, which fraction contains at least one member selected from the group consisting of folic acid, vitamin B12, vitamin B6, magnesium and zinc or equivalents thereof.
2. Preparation according to claim 1, further comprising a fraction d) citrate or citric acid.
3. Preparation according to claim 1 or 2, further comprising a fraction e) huperzine A or functional analogs thereof.
4. Preparation according to any of claims 1 to 3 , wherein fraction a) comprises Ω-3 and Ω-6 fatty acids.
5 Preparation according to claim 4, wherein the Ω-3 fatty acids are selected from the group consisting of eicosapentaenoic acid and docosahexaenoic acid and the Ω-6 fatty acids are selected from the group consisting of arachidonic acid and dihomogammalinolenic acid.
6. Preparation according to any of claims 1 to 5, wherein fraction b) comprises phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine.
7. Preparation according to any of claims 1 to 6, wherein fraction c) contains at least folic acid and vitamin B6.
8. Preparation according to any of claims 1 to 7, wherein fraction c) further contains SAMe, choline, betaine and/or copper.
9. Preparation according to claim 8, wherein fraction c) comprises zinc and copper, wherein the weight ratio of zinc to copper is between 5 to 12.
10. Preparation according to any of claims 1 to 9, which further contains a fraction f) one or more members selected from the group consisting of carnitine, vitamin Bl, vitamin B5 and coenzyme Q10 or functional analogues thereof.
11. Preparation according to any of claims 1 to 10, which further contains a fraction g) one or more antioxidants selected from vitamin C, vitamin E, lipoic acid, selenium salt and carotenoids.
12. Preparation according to any of claims 1 to 11, which further contains a fraction h) an extract of gingko biloba.
13. Preparation according to any of claims 1 to 12, which comprises per daily dose: at least 120 mg of long chain polyunsaturated fatty acids; at least 200 mg phospholipids; at least 200 μg folic acid; and at least 500 mg citrate.
14. Preparation according to claim 13, which comprises per daily dose: at least 20 mg, preferably at least 50 mg eicosapentaenoic acid at least 50 mg, preferably at least 200 mg docosahexaenoic acid at least 50 mg, preferably at least 100 mg arachidonic acid at least 200 mg, preferably at least 1000 mg phospholipids, at least 200 μg, preferably at least 400 μg folic acid at least 100 mg, preferably at least 200 mg magnesium at least 5 mg, preferably at least 10 mg zinc at least 2 mg, preferably at least 2.5 mg vitamin B6 at least 2 μg, preferably at least 4 μg vitamin B 12 at least 1.0 g, preferably at least 1.5 g citrate.
15. Use of a preparation according to any of claims 1 to 14 for the treatment and/or prevention of vascular disorders or secondary disorders associated therewith.
16. Use according to claim 15, wherein the vascular disorder is atherosclerosis, arteriosclerosis, hypercholesterolaemia, hyperlipidaemia, elevated blood pressure, angina pectoris, dementia syndromes, cerebrovasular accidents, temporary disorders associated with ischaemia, M. Raynaud, vene thrombose, postpartum thrombose, myocard infarct, varicose veins, thrombo angiitis obliterans and atheroslecrosis obliterans.
17. Use according to claim 15, wherein in the secondary vascular disorder is dementia syndromes, cognitive degeneration or hearing loss.
18. Preparation according to claim 1, which is a nutritional supplement.
PCT/NL2001/000347 2000-05-08 2001-05-08 Preparation for the prevention and/or treatment of vascular disorders Ceased WO2001084961A2 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP09156648.9A EP2070519B3 (en) 2000-05-08 2001-05-08 Preparation for the prevention and/or treatment of dementia syndromes
EP01928256A EP1282365B1 (en) 2000-05-08 2001-05-08 Preparation for the prevention and/or treatment of vascular disorders
AU2001255114A AU2001255114A1 (en) 2000-05-08 2001-05-08 Preparation for the prevention and/or treatment of vascular disorders
DE60132081T DE60132081T2 (en) 2000-05-08 2001-05-08 PREPARATION FOR THE PREVENTION AND TREATMENT OF VASCULAR DISEASES
DK01928256T DK1282365T3 (en) 2000-05-08 2001-05-08 Preparation for the prevention and / or treatment of vascular disorders
HK03104859.9A HK1052439B (en) 2000-05-08 2001-05-08 Preparation for the prevention and/or treatment of vascular disorders
CA2408032A CA2408032C (en) 2000-05-08 2001-05-08 Preparation for the prevention and/or treatment of vascular disorders
DK07120681T DK1911442T3 (en) 2000-05-08 2001-05-08 Preparation for the prevention and / or treatment of vascular disorders

Applications Claiming Priority (4)

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US56638600A 2000-05-08 2000-05-08
US09/566,386 2000-05-08
US09/703,798 US7226916B1 (en) 2000-05-08 2000-11-02 Preparation for the prevention and/or treatment of vascular disorders
US09/703,798 2000-11-02

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AT (2) ATE381894T1 (en)
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CA (1) CA2408032C (en)
CY (3) CY1107237T1 (en)
DE (2) DE60132081T2 (en)
DK (3) DK2070519T6 (en)
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HK (1) HK1052439B (en)
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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL1019368C2 (en) * 2001-11-14 2003-05-20 Nutricia Nv Preparation for improving receptor performance.
WO2003013549A3 (en) * 2001-08-09 2003-11-06 Degussa Bioactives Gmbh & Co K Formulation containing (lyso-) phosphatidylserine for the prevention and treatment of stress states in warm-blooded animals
WO2003092673A1 (en) * 2002-05-03 2003-11-13 Pronova Biocare As Use of epa and dha in secondary prevention
WO2003088765A3 (en) * 2002-04-19 2003-12-24 Degussa Bioactives Gmbh Functional foods containing a phospholipid-containing stable matrix
EP1275399A3 (en) * 2001-07-09 2004-01-07 N.V. Nutricia Method and preparation for preventing and/or treating vascular disorders and secondary disorders associated therewith
EP1388295A1 (en) * 2002-08-07 2004-02-11 Nestec S.A. Cereal based food product comprising DHA
FR2847472A1 (en) * 2002-11-22 2004-05-28 Synergia Pharmaceutical or dietetic compositions useful for protecting against artery and heart disease comprise B vitamins and vitamin C
WO2004068969A1 (en) * 2003-02-05 2004-08-19 N.V. Nutricia Enteral composition for the prevention and/or treatment of sepsis
WO2004091317A1 (en) * 2003-04-17 2004-10-28 Boehringer Ingelheim International Gmbh Multi-vitamin and mineral supplement for pregnant women
WO2003088949A3 (en) * 2002-04-19 2004-12-16 Bioghurt Biogarde Gmbh & Co Kg Matrix comprising a bioactive component containing phospholipid
WO2004112777A1 (en) * 2003-06-20 2004-12-29 Mochida Pharmaceutical Co., Ltd. Composition for prevention/treatment for varicose vein
EP1499204A2 (en) * 2002-04-19 2005-01-26 Bioghurt Biogarde GmbH & Co. KG. Physiologically compatible, phospholipid-containing, stable and hard matrix
WO2005006890A3 (en) * 2003-07-10 2005-07-14 Carl A Forest Foods, beverages, condiments, spices and salad dressings with specialized supplements
JP2005529903A (en) * 2002-05-03 2005-10-06 プロノバ バイオケア エイ エス Use of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for secondary brain disease events such as stroke
EP1645276A1 (en) * 2004-10-08 2006-04-12 Wageningen Centre for Food Sciences Treatment of neurodegenerative disorders
JP2007504197A (en) * 2003-09-04 2007-03-01 ビオグルト ビオガルデ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト Physiologically active composition of phosphatidylserine base
WO2007045407A3 (en) * 2005-10-18 2007-07-26 Artmed S R L Nutraceutical and pharmaceutical compositions containing choline as adiuvants for the prevention and treatment of retinopathies and glaucoma
JP2007533609A (en) * 2003-08-15 2007-11-22 ペーク，インコーポレイテッド． Enhanced magnesium intake in mammals
DE10250727B4 (en) * 2002-04-19 2008-07-10 Cargill, Incorporated, Wayzata Matrix with a bioactive phospholipid-containing component
WO2009022323A1 (en) * 2007-08-13 2009-02-19 Ben-Gurion University Of The Negev Research And Development Authority Over-production of dihomo gamma linolenic acid by a mutant strain of parietochloris incisa
EP1845999A4 (en) * 2005-01-24 2010-09-22 Pronova Biocare As Use of a fatty acid composition containing dha for the production of a medical product or a food stuff for the treatment of amyloidos-rerelated diseases
EP2283835A2 (en) 2002-06-19 2011-02-16 N.V. Nutricia Method and preparation for treating metabolic stress
US7935365B2 (en) 2003-10-22 2011-05-03 Enzymotec, Ltd. Glycerophospholipids for the improvement of cognitive functions
US7951845B2 (en) 2006-01-19 2011-05-31 The Regents Of The University Of Michigan Composition and method of treating hearing loss
US7968112B2 (en) 2003-10-22 2011-06-28 Enzymotec Ltd. Lipids containing omega-3 and omega-6 fatty acids
US8052992B2 (en) 2003-10-22 2011-11-08 Enzymotec Ltd. Glycerophospholipids containing omega-3 and omega-6 fatty acids and their use in the treatment and improvement of cognitive functions
WO2012049222A3 (en) * 2010-10-12 2012-06-28 Vifor Sa Novel omega-3 and omega-6 fatty acid compositions and uses thereof
US8324187B2 (en) * 2003-09-25 2012-12-04 Enzymotec Ltd. Stabilized formulations of phosphatidylserine
EP1888081A4 (en) * 2005-05-23 2012-12-05 Massachusetts Inst Technology COMPOSITIONS CONTAINING POLYUNSATURATED FATTY ACIDS AND METHODS OF USE
US8338397B2 (en) 2006-01-19 2012-12-25 The Regents Of The University Of Michigan Composition and method of treating side effects from antibiotic treatment
US8367729B2 (en) 2004-09-17 2013-02-05 Suntory Holdings Limited Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders
US8377912B2 (en) 2000-05-08 2013-02-19 N. V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US8383677B2 (en) 2006-12-28 2013-02-26 Suntory Holdings Limited Nerve-regenerating agent
US8703209B2 (en) 2003-06-17 2014-04-22 Edward Larry McCleary Composition and method for modulating hydrogen ion physiology
US8729124B2 (en) 2002-03-05 2014-05-20 Pronova Biopharma Norge As Use of EPA and DHA in secondary prevention
US8871808B2 (en) 2006-06-22 2014-10-28 Ben-Gurion University Of The Negev Research And Development Authority Et Al. Over-production of dihomo linolenic acid by a mutant strain of Parietochloris incisa
US8927528B2 (en) 2006-01-19 2015-01-06 The Regents Of The University Of Michigan Composition for treating hearing loss
WO2015140545A1 (en) * 2014-03-20 2015-09-24 Isis Innovation Limited Combination therapy comprising an omega-3 fatty acid, a folate species and a vitamin b12 species
US9168241B2 (en) 2005-06-30 2015-10-27 Suntory Holdings Limited Compositions ameliorating a reduced diurnal activity and/or depressive symptoms
USRE46372E1 (en) 2006-01-19 2017-04-25 The Regents Of The Univerity Of Michigan Method for treating hearing loss
US9770433B2 (en) 2006-01-19 2017-09-26 The Regents Of The University Of Michigan Composition and method for treating tinnitus
US9889156B2 (en) 2006-01-19 2018-02-13 The Regents Of The University Of Michigan Method for treating noise-induced hearing loss (NIHL)
US9919008B2 (en) 2006-01-19 2018-03-20 The Regents Of The University Of Michigan Method for treating age-related hearing loss (ARHL)
US10238599B2 (en) 2006-01-19 2019-03-26 The Regents Of The University Of Michigan Composition and method for treating congenital cytomegalovirus induced hearing loss
US20190105356A1 (en) * 2015-05-15 2019-04-11 P Tech, Llc Systems and methods for thrombosis prevention
US10744146B2 (en) 2001-08-02 2020-08-18 Suntory Holdings Limited Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction
WO2023041776A1 (en) 2021-09-17 2023-03-23 N.V. Nutricia Solid composition suitable as a nutritional composition or supplement for animals that suffer from brain related disorders, decline or diseases
IT202200010583A1 (en) * 2022-05-23 2023-11-23 Neilos S R L “Nutraceutical or pharmaceutical composition for male infertility”
WO2024003711A1 (en) * 2022-06-27 2024-01-04 Aker Biomarine Antarctic As Phospholipid compositions comprising epa and/or dha for ameliorating neurodegeneration and age-related neurodegenerative disorders

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69904257T2 (en) * 1999-01-20 2003-04-17 N.V. Nutricia, Zoetermeer infant formula
PL2046312T3 (en) * 2006-07-14 2021-02-08 Kaydence Pharma As Pharmaceutical and nutraceutical products comprising vitamin k2
WO2009002145A1 (en) 2007-06-26 2008-12-31 N.V. Nutricia Lipid composition for improving function of brain functioning
WO2009002146A1 (en) 2007-06-26 2008-12-31 N.V. Nutricia Supporting activities of daily living
WO2009002166A1 (en) 2007-06-26 2008-12-31 N.V. Nutricia Improving memory in subjects with mini-mental state examination of 24-26
WO2009002148A1 (en) 2007-06-27 2008-12-31 N.V. Nutricia Food composition for prodromal dementia patients
DE102007042557A1 (en) * 2007-09-07 2009-03-19 Membramed Gmbh Preparation, useful against cognitive and/or physical inefficiency, stress symptoms, attention deficit syndrome and/or hyperactivity, comprises phospholipids, fruit preparation and active agents, nutrients and/or flavors
ES2748136T3 (en) 2007-10-15 2020-03-13 United Animal Health Inc Method to increase the performance of the young
US8343753B2 (en) 2007-11-01 2013-01-01 Wake Forest University School Of Medicine Compositions, methods, and kits for polyunsaturated fatty acids from microalgae
WO2009070589A1 (en) * 2007-11-30 2009-06-04 Jbs United, Inc. Method and composition for treating pulmonary hemorrhage
BRPI0822111B8 (en) 2007-12-20 2021-05-25 Nutricia Nv liquid makeup, and use of a liquid makeup
US9034399B2 (en) * 2008-01-03 2015-05-19 Melaleuca, Inc. Dietary compositions for promoting brain health
US20110052556A1 (en) 2008-02-29 2011-03-03 Biolab Sanus Farmaceutical Ltda Pharmaceutical composition comprising racetam and carnitine and process for its preparation
EP2172203A1 (en) * 2008-09-17 2010-04-07 Giuliani S.P.A. Pharmaceutical composition for the treatment of gastrointestinal irritation disorders
CA2777233A1 (en) * 2008-10-13 2010-04-22 Pregnant Princess & Co. Ltd. Compositions and methods for treating varicose veins
CN102438468B (en) * 2009-04-17 2014-06-04 纳塔克制药有限公司 Compositions rich in omega-3 fatty acids low in phytanic acid
WO2011066471A1 (en) 2009-11-25 2011-06-03 Loma Linda University Medical Center Chitosan-based hemostatic textile
US9481861B2 (en) 2011-07-12 2016-11-01 Foodchek Systems, Inc. Culture medium, method for culturing Salmonella and E. coli and method for detecting Salmonella and E. coli
RU2505290C2 (en) * 2011-10-31 2014-01-27 Общество С Ограниченной Ответственностью "Консорциум-Пик" Pharmaceutical composition possessing exhibiting property of endothelial dysfunction reduction accompanying cardiovascular diseases
WO2013138368A1 (en) * 2012-03-12 2013-09-19 Loma Linda University Medical Center Substances and methods for the treatment of cerebral amyloid angiopathy related conditions or diseases
EP3043658B1 (en) 2013-08-29 2019-11-20 Abbott Laboratories Nutritional composition having lipophilic compounds with improved solubility and bioavailability
CN103432156A (en) * 2013-08-30 2013-12-11 深圳奥萨医药有限公司 Medicinal composition of omega-3 fatty acid and B vitamin and application thereof
US9259357B2 (en) 2014-04-16 2016-02-16 Loma Linda University Composition, preparation, and use of chitosan shards for biomedical applications
DE202014102551U1 (en) * 2014-05-30 2015-02-26 Orthomol Pharmazeutische Vertriebs Gmbh Dietetic preparation in the form of a bar
ES2795836T3 (en) * 2015-07-29 2020-11-24 Abbott Lab Nutritional products with improved bioavailability and lipophilic solubility in an easy-to-mix form
CN105079009B (en) 2015-08-25 2018-05-01 厦门金达威生物科技有限公司 Prevention and/or the composition for the treatment of cardiovascular and cerebrovascular disease
CN107252089A (en) * 2017-04-05 2017-10-17 吉林省润生特膳食品科技开发有限公司 A kind of hawthorn peach kernel yam flour and preparation method thereof
AU2018390261B2 (en) 2017-12-21 2023-03-16 Nippon Zoki Pharmaceutical Co., Ltd. Agent for treatment of nervous system disease
CN110404049A (en) * 2019-07-23 2019-11-05 张明 Composition and the application of cardiovascular and cerebrovascular diseases and senile dementia are prevented and treated by Neulized inhalation
FR3099339B1 (en) * 2019-08-01 2022-06-17 Specialites Pet Food Protein hydrolyzate from blue fish
CN112843072B (en) * 2021-01-12 2026-07-10 山东省科学院生物研究所 Applications of phospholipids in regulating angiogenesis
CN113456640A (en) * 2021-08-26 2021-10-01 烟台大学 Application of huperzine A in preventing myocardial ischemia injury

Family Cites Families (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2824362A1 (en) 1978-06-01 1979-12-13 Josef Dipl Chem Dr Rer N Klosa Pharmaceuticals for treating depression and insomnia - contg. L-tryptophan with vegetable oil in soft gelatin capsules
IT1212900B (en) * 1983-11-17 1989-11-30 Valle Francesco Della THERAPEUTIC USE OF PHOSPHATIDYLSERINE IN DISEASES OF THE CENTRAL NERVOUS SYSTEM WITHOUT EFFECTS ON BLOOD COAGULATION
AU594066B2 (en) 1985-07-26 1990-03-01 Yeda Research And Development Co. Ltd. A special lipid mixture for membrane fluidization
US4897380A (en) 1985-08-30 1990-01-30 Pollack Robert L Method and composition for relieving dietary-related disorders
US5177082A (en) * 1985-11-05 1993-01-05 Yu Chao Mei Huperzines and analogs
GB8601915D0 (en) * 1986-01-27 1986-03-05 Efamol Ltd Pharmaceutical compositions
JPS63208524A (en) 1987-02-25 1988-08-30 Nippon Oil & Fats Co Ltd Sleep rhythm improver
IL86423A0 (en) 1987-05-19 1988-11-15 Baylor College Medicine Pharmaceutical compositions for the treatment of alzheimer's disease
WO1989002737A1 (en) 1987-09-30 1989-04-06 University Of Florida Treatment of hypertension by chronic administration of l-tryptophan or l-5-hydroxytryptophan
US4837219A (en) * 1987-11-05 1989-06-06 Jeffrey Hutterer Medication for Alzheimer's disease
US5004615A (en) * 1988-04-27 1991-04-02 Bionix Corporation Methods for diagnosing, monitoring and controlling the onset and progression of certain dementias and impeding memory loss or improving impairment of memory
JP2732109B2 (en) * 1989-02-10 1998-03-25 正樹 今川 Dementia treatment
JP2909508B2 (en) * 1989-02-14 1999-06-23 マルハ株式会社 Krill phospholipid fractionation method
US6294520B1 (en) 1989-03-27 2001-09-25 Albert T. Naito Material for passage through the blood-brain barrier
JPH02302732A (en) 1989-05-18 1990-12-14 Seiko Epson Corp liquid crystal display device
US5401730A (en) * 1990-07-06 1995-03-28 The Hope Heart Institute Method for reducing platelet aggregation
US5077069A (en) 1991-01-07 1991-12-31 Kabi Pharmacia Ab Composition of natural antioxidants for the stabilization of polyunsaturated oils
US5108767A (en) 1991-06-10 1992-04-28 Abbott Laboratories Liquid nutritional product for persons receiving renal dialysis
DE4309217A1 (en) * 1992-01-18 1994-07-28 Margarethe Rabien Combination product of pantothenic acid or dexpanthenol + alpha -lipoic acid + vitamin E (muscular dystrophy, polyneuropathy, muscle atrophy, ataxia, new indication ( alpha -lipoic acid + pantothenic acid) Alzheimer's disease
US5234702A (en) 1992-03-19 1993-08-10 Abbott Laboratories Antioxidant system for powdered nutritional products
US5223285A (en) 1992-03-31 1993-06-29 Abbott Laboratories Nutritional product for pulmonary patients
US5308832A (en) 1992-07-27 1994-05-03 Abbott Laboratories Nutritional product for persons having a neurological injury
JPH0717855A (en) 1992-09-02 1995-01-20 Maruha Corp Brain function improving composition, learning ability enhancer, memory enhancing agent, dementia preventive agent, dementia therapeutic agent, or functional food having a brain function improving effect
DE4304394A1 (en) 1993-02-13 1993-09-02 Fresenius Ag Prepn. for nourishment of oncological patients - comprises fats formulation contg. oleic acid, alpha-linolenic acid, etc., and opt. carbohydrate and proteins
WO1994027628A1 (en) 1993-05-28 1994-12-08 Abbott Laboratories Enteral nutritional product
WO1995015750A1 (en) * 1993-12-10 1995-06-15 Hashim Sami A Reducing likelihood of vascular disorders in susceptible patients
FR2714574B1 (en) 1993-12-31 1996-03-15 Inst Rech Biolog Sa New food supplements for the nutrition of very young children.
JPH07224142A (en) 1994-02-08 1995-08-22 Dai Ichi Kogyo Seiyaku Co Ltd Epoxy resin and epoxy resin composition
DE69525150T2 (en) 1994-04-01 2002-09-05 Abbott Laboratories, Abbott Park FOOD PRODUCT FOR THE TREATMENT OF ULCERATIVE KOLITIS AND USE THEREOF
CA2150741A1 (en) 1994-06-17 1995-12-18 Susan Trimbo Pediatric lipid emulsion
JP3053537B2 (en) 1994-11-08 2000-06-19 株式会社ヤクルト本社 Brain function improver
GB9423625D0 (en) * 1994-11-23 1995-01-11 Scotia Holdings Plc Fortified fruit juice
US5589468A (en) 1995-01-13 1996-12-31 Clintec Nutrition Co. Method for providing nutrition to elderly patients
EP0726073A3 (en) * 1995-02-10 1998-07-08 Eduardo Samuel Bleiweiss Pharmaceutical compositions containing at least one of haloperidol, imipramine or trifluoroperazine
JPH08252856A (en) 1995-03-16 1996-10-01 Asahi Glass Co Ltd Device for manufacturing window plate with resin frame
JPH0954212A (en) * 1995-08-11 1997-02-25 Sharp Corp Retardation film, manufacturing method thereof, and liquid crystal display device
JP3791951B2 (en) 1995-11-08 2006-06-28 株式会社ヤクルト本社 Method for producing oil and fat composition containing polyunsaturated fatty acid-containing phosphatidylserine
IT1277953B1 (en) * 1995-12-21 1997-11-12 Sigma Tau Ind Farmaceuti PHARMACEUTICAL COMPOSITION CONTAINING L-CARNITINE OR AN ALCANOYL L-CARNITINE AND A 3-OMEGA SERIES POLYUNSATURED ACID USEFUL
GB9606736D0 (en) * 1996-02-19 1996-06-05 Shire International Licensing Therapeutic method
AU2583397A (en) 1996-04-10 1997-10-29 Chronorx, Llc Unit dosage forms, containing magnesium, vitamin c, vitamin e, folate and selenium, for treatment of vasoconstriction and related conditions
WO1997039759A2 (en) 1996-04-24 1997-10-30 Brigham And Women's Hospital Omega-3 fatty acids and omega-3 phosphatidylcholine in the treatment of bipolar disorder
US6077828A (en) 1996-04-25 2000-06-20 Abbott Laboratories Method for the prevention and treatment of cachexia and anorexia
JP3664814B2 (en) * 1996-06-26 2005-06-29 旭化成ケミカルズ株式会社 Blood lipid improving agent and food additive
US6008221A (en) * 1996-11-06 1999-12-28 Bristol-Myers Squibb Company Method for treating Alzheimer's disease with folic acid
JPH10140919A (en) 1996-11-11 1998-05-26 Mika Oosawa Partition structure in the building space
ATE221324T1 (en) * 1996-11-20 2002-08-15 Nutricia Nv FAT-CONTAINING NUTRITIONAL COMPOSITION FOR THE TREATMENT OF METABOLIC SYNDROME
JPH10165119A (en) * 1996-12-10 1998-06-23 Seijiro Yanai Enriched rice added with gingko leave extract and its production
US6013273A (en) 1997-01-27 2000-01-11 Novartis Nutrition Ag Treatment of endotoxic shock
GB9701675D0 (en) 1997-01-28 1997-03-19 Bridgeman Keith Composition for the treatment of parkinson's disease
EP1021177A4 (en) 1997-02-04 2002-05-15 John V Kosbab Compositions and methods for prevention and treatment of vascular degenerative diseases
US5843469A (en) * 1997-04-11 1998-12-01 Mcentee; William J. Lipid soluble forms of thiamine for prevention and treatment of age-related cognitive impairment of the nervous system
US6344482B1 (en) 1997-04-23 2002-02-05 Andrew L. Stoll Omega-3 fatty acids in the treatment of bipolar disorder
US5820867A (en) 1997-04-24 1998-10-13 Bewicke; Calverly M. General anti-depressant composition for dietary supplement
AU7222598A (en) 1997-04-29 1998-11-24 Scotia Holdings Plc Treatment of depression and anxiety using docosahexaenoic acid or natural antioxidants
FR2762993B1 (en) 1997-05-06 1999-08-13 Inst Rech Biolog Sa NEW USE OF PHOSPHOLIPIDS OF ANIMAL ORIGIN IN THERAPEUTICS AND / OR DIETETICS
EP0891719A1 (en) 1997-07-14 1999-01-20 N.V. Nutricia Nutritional composition containing methionine
GB9715444D0 (en) 1997-07-22 1997-09-24 Scotia Holdings Plc Therapeutic and dietary compositions
AU8925998A (en) 1997-09-03 1999-03-22 Macro Hi-Tech Jv, Ltd. Huperzine a derivatives
US6537969B1 (en) 1997-10-24 2003-03-25 John P. Blass Nutritional supplement for cerebral metabolic insufficiencies
US5922704A (en) * 1997-12-24 1999-07-13 Feeling Fine Company Llc Optimal nutritional supplement for men
FR2773484B1 (en) * 1998-01-09 2001-03-30 Pierre Moreau NEW COMPOSITIONS WITH SYNERGISTIC EFFECT BETWEEN MICRONUTRIENTS AND SUBSTANCES OF LIVING ORIGIN
CN1288383A (en) 1998-01-13 2001-03-21 雷克索尔日落公司 St. John's wort and methyl donor composition and uses thereof
WO1999037155A1 (en) 1998-01-27 1999-07-29 Nutramax Laboratories, Inc. Combinations of tyrosine, methylating agents, phospholipids, fatty acids, and st. john's wort for the treatment of mental disturbances
GB9808579D0 (en) 1998-04-22 1998-06-24 Novartis Nutrition Ag Improvements in or relating to organic compounds
HUP0101890A2 (en) 1998-05-04 2001-10-28 Andreas Johannes Kesel Monomeric, oligomeric and polymeric knoevenagel condensation products
CN1235770A (en) * 1998-05-15 1999-11-24 武汉华凯保健品开发有限公司 Ginkgo tea
EP1085886A1 (en) 1998-06-11 2001-03-28 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Protecting neurons from ischemia
IT1299195B1 (en) 1998-06-25 2000-02-29 Sigma Tau Healthscience Spa COMPOSITION WITH NEUROPROTECTIVE ACTIVITY FOR THE PREVENTION AND TREATMENT OF STATE-RELATED NERVOUS AND BEHAVIORAL ALTERATIONS
CA2340223A1 (en) 1998-08-12 2000-02-24 Morinaga Milk Industry Co., Ltd. Nutritional compositions for preventing or treating hyperlipoproteinemia
JP2000148134A (en) 1998-11-13 2000-05-26 Seiko Epson Corp Image display method and image processing device
FR2788437B1 (en) 1999-01-14 2006-08-11 Inst Rech Biolog Sa NEW USE OF PLANT AND ANIMAL PHOSPHOLIPIDS IN NUTRITIONAL THERAPEUTICS
US6120814A (en) * 1999-02-22 2000-09-19 Nature's One, Inc. Organic nutritional formula
GB9916536D0 (en) 1999-07-14 1999-09-15 Scarista Limited Nutritional or pharmaceutical compositions
US7208180B2 (en) 2000-05-08 2007-04-24 N.V. Nutricia Method and preparation for the preventing and/or treating vascular disorders and secondary disorders associated therewith
US7226916B1 (en) 2000-05-08 2007-06-05 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
EP2632360A4 (en) 2010-10-29 2014-05-21 Bard Inc C R Bioimpedance-assisted placement of a medical device

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8865687B2 (en) 2000-05-08 2014-10-21 N.V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
US7208180B2 (en) 2000-05-08 2007-04-24 N.V. Nutricia Method and preparation for the preventing and/or treating vascular disorders and secondary disorders associated therewith
US8377912B2 (en) 2000-05-08 2013-02-19 N. V. Nutricia Preparation for the prevention and/or treatment of vascular disorders
EP1985307A3 (en) * 2001-07-09 2012-11-28 N.V. Nutricia Method and preparation for preventing and/or treating depression
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EP1275399A3 (en) * 2001-07-09 2004-01-07 N.V. Nutricia Method and preparation for preventing and/or treating vascular disorders and secondary disorders associated therewith
EP1985307A2 (en) 2001-07-09 2008-10-29 N.V. Nutricia Method and preparation for preventing and/or treating depression
EP2263695A2 (en) 2001-07-09 2010-12-22 N.V. Nutricia Method and preparation for treating depressions
US10744146B2 (en) 2001-08-02 2020-08-18 Suntory Holdings Limited Composition having effects of preventing or ameliorating conditions or diseases caused by brain hypofunction
WO2003013549A3 (en) * 2001-08-09 2003-11-06 Degussa Bioactives Gmbh & Co K Formulation containing (lyso-) phosphatidylserine for the prevention and treatment of stress states in warm-blooded animals
EP2340827A3 (en) * 2001-11-14 2012-11-14 N.V. Nutricia Method and preparation preventing and/or treating neurodegenerative or neurological disorders using a drug combination
EP2340825A3 (en) * 2001-11-14 2011-09-07 N.V. Nutricia Method and preparation preventing and/or treating neurodegenerative or neurological disorders using a neurotransmitter precursor
US8362078B2 (en) 2001-11-14 2013-01-29 N.V. Nutricia Method for reducing the severity of neurological disorders
EP2363125A1 (en) * 2001-11-14 2011-09-07 N.V. Nutricia Preparation for improving the sensitivity action of receptors
US7888391B2 (en) 2001-11-14 2011-02-15 N.V. Nutricia Method for reducing the severity of neurological disorders
EP2340824A3 (en) * 2001-11-14 2012-05-30 N.V. Nutricia Method and preparation for reducing the severity of ADHD and/or motor disorders
US9504712B2 (en) 2001-11-14 2016-11-29 N.V. Nutricia Preparation for improving the action of receptors
WO2003041701A3 (en) * 2001-11-14 2004-03-18 Nutricia Nv Preparation for improving the action of receptors
US7384981B2 (en) 2001-11-14 2008-06-10 N.V. Nutricia Preparation for improving the action of receptors
EP2340826A3 (en) * 2001-11-14 2012-09-12 N.V. Nutricia Method and preparation preventing and/or treating neurodegenerative or neurological disorders
US9844525B2 (en) 2001-11-14 2017-12-19 N.V. Nutricia Preparation for improving the action of receptors
NL1019368C2 (en) * 2001-11-14 2003-05-20 Nutricia Nv Preparation for improving receptor performance.
US8729124B2 (en) 2002-03-05 2014-05-20 Pronova Biopharma Norge As Use of EPA and DHA in secondary prevention
JP2005527208A (en) * 2002-04-19 2005-09-15 ビオグルト ビオガルデ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト Functional food containing a stable phospholipid-containing matrix
DE10250727B4 (en) * 2002-04-19 2008-07-10 Cargill, Incorporated, Wayzata Matrix with a bioactive phospholipid-containing component
JP2005527207A (en) * 2002-04-19 2005-09-15 ビオグルト ビオガルデ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト Physiologically acceptable, stable and rigid matrix containing phospholipids
WO2003088949A3 (en) * 2002-04-19 2004-12-16 Bioghurt Biogarde Gmbh & Co Kg Matrix comprising a bioactive component containing phospholipid
WO2003088765A3 (en) * 2002-04-19 2003-12-24 Degussa Bioactives Gmbh Functional foods containing a phospholipid-containing stable matrix
EP1499204A2 (en) * 2002-04-19 2005-01-26 Bioghurt Biogarde GmbH & Co. KG. Physiologically compatible, phospholipid-containing, stable and hard matrix
WO2003092673A1 (en) * 2002-05-03 2003-11-13 Pronova Biocare As Use of epa and dha in secondary prevention
JP2005529903A (en) * 2002-05-03 2005-10-06 プロノバ バイオケア エイ エス Use of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for secondary brain disease events such as stroke
AU2003229993B2 (en) * 2002-05-03 2008-07-24 Pronova Biopharma Norge As Use of EPA and DHA in secondary prevention
EP2283835A2 (en) 2002-06-19 2011-02-16 N.V. Nutricia Method and preparation for treating metabolic stress
EP3184107A1 (en) 2002-06-19 2017-06-28 N.V. Nutricia Method and preparation for treating metabolic stress
WO2004014151A1 (en) * 2002-08-07 2004-02-19 Nestec S.A. Cereal based food product comprising dha and/or epa
EP1388295A1 (en) * 2002-08-07 2004-02-11 Nestec S.A. Cereal based food product comprising DHA
WO2004047564A1 (en) * 2002-11-22 2004-06-10 Synergia Holding Novel pharmaceutical compositions in particular for preventing cardiovascular pathologies
FR2847472A1 (en) * 2002-11-22 2004-05-28 Synergia Pharmaceutical or dietetic compositions useful for protecting against artery and heart disease comprise B vitamins and vitamin C
WO2004068969A1 (en) * 2003-02-05 2004-08-19 N.V. Nutricia Enteral composition for the prevention and/or treatment of sepsis
WO2004091317A1 (en) * 2003-04-17 2004-10-28 Boehringer Ingelheim International Gmbh Multi-vitamin and mineral supplement for pregnant women
US8703209B2 (en) 2003-06-17 2014-04-22 Edward Larry McCleary Composition and method for modulating hydrogen ion physiology
JP4870430B2 (en) * 2003-06-20 2012-02-08 持田製薬株式会社 Composition for prevention and treatment of varicose veins
JPWO2004112777A1 (en) * 2003-06-20 2006-07-27 持田製薬株式会社 Composition for prevention and treatment of varicose veins
WO2004112777A1 (en) * 2003-06-20 2004-12-29 Mochida Pharmaceutical Co., Ltd. Composition for prevention/treatment for varicose vein
EP1637134A4 (en) * 2003-06-20 2010-01-27 Mochida Pharm Co Ltd Composition for prevention/treatment for varicose veins
WO2005006890A3 (en) * 2003-07-10 2005-07-14 Carl A Forest Foods, beverages, condiments, spices and salad dressings with specialized supplements
EP2606900A1 (en) * 2003-08-15 2013-06-26 Perque, Inc. Enhancement of magnesium uptake in mammals
AU2011201073B2 (en) * 2003-08-15 2012-01-19 Perque, Inc. Enhancement of magnesium uptake in mammals
US8017160B2 (en) 2003-08-15 2011-09-13 Russell Jaffe Enhancement of magnesium uptake in mammals
EP1660103A4 (en) * 2003-08-15 2009-07-08 Perque Inc Enhancement of magnesium uptake in mammals
JP2007533609A (en) * 2003-08-15 2007-11-22 ペーク，インコーポレイテッド． Enhanced magnesium intake in mammals
JP2007504197A (en) * 2003-09-04 2007-03-01 ビオグルト ビオガルデ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディートゲゼルシャフト Physiologically active composition of phosphatidylserine base
US8324187B2 (en) * 2003-09-25 2012-12-04 Enzymotec Ltd. Stabilized formulations of phosphatidylserine
US7968112B2 (en) 2003-10-22 2011-06-28 Enzymotec Ltd. Lipids containing omega-3 and omega-6 fatty acids
US7935365B2 (en) 2003-10-22 2011-05-03 Enzymotec, Ltd. Glycerophospholipids for the improvement of cognitive functions
US8052992B2 (en) 2003-10-22 2011-11-08 Enzymotec Ltd. Glycerophospholipids containing omega-3 and omega-6 fatty acids and their use in the treatment and improvement of cognitive functions
US8367729B2 (en) 2004-09-17 2013-02-05 Suntory Holdings Limited Composition with preventive or improvement effect on symptoms or diseases associated with stress-induced behavior disorders
EP1645276A1 (en) * 2004-10-08 2006-04-12 Wageningen Centre for Food Sciences Treatment of neurodegenerative disorders
EP1845999A4 (en) * 2005-01-24 2010-09-22 Pronova Biocare As Use of a fatty acid composition containing dha for the production of a medical product or a food stuff for the treatment of amyloidos-rerelated diseases
NO343234B1 (en) * 2005-01-24 2018-12-17 Pronova Biopharma Norge As Fatty acid composition containing DHA and EPA for the treatment and / or prevention of amyloidosis related diseases
US10525071B2 (en) 2005-05-23 2020-01-07 Massachusets Institue Of Technology Compositions containing PUFA and methods of use thereof
EP1888081A4 (en) * 2005-05-23 2012-12-05 Massachusetts Inst Technology COMPOSITIONS CONTAINING POLYUNSATURATED FATTY ACIDS AND METHODS OF USE
US10736912B2 (en) 2005-05-23 2020-08-11 Massachusetts Institute Of Technology Compositions containing PUFA and/or uridine and methods of use thereof
EP1909801A4 (en) * 2005-05-23 2012-12-05 Massachusetts Inst Technology COMPOSITIONS BASED ON POLYUNSATURATED FATTY ACIDS AND / OR URIDINE AND METHODS OF USE THEREOF
US9168241B2 (en) 2005-06-30 2015-10-27 Suntory Holdings Limited Compositions ameliorating a reduced diurnal activity and/or depressive symptoms
WO2007045407A3 (en) * 2005-10-18 2007-07-26 Artmed S R L Nutraceutical and pharmaceutical compositions containing choline as adiuvants for the prevention and treatment of retinopathies and glaucoma
US7951845B2 (en) 2006-01-19 2011-05-31 The Regents Of The University Of Michigan Composition and method of treating hearing loss
US8338397B2 (en) 2006-01-19 2012-12-25 The Regents Of The University Of Michigan Composition and method of treating side effects from antibiotic treatment
US9144565B2 (en) 2006-01-19 2015-09-29 The Regents Of The University Of Michigan Method for treating hearing loss
USRE46372E1 (en) 2006-01-19 2017-04-25 The Regents Of The Univerity Of Michigan Method for treating hearing loss
US10238599B2 (en) 2006-01-19 2019-03-26 The Regents Of The University Of Michigan Composition and method for treating congenital cytomegalovirus induced hearing loss
US9770433B2 (en) 2006-01-19 2017-09-26 The Regents Of The University Of Michigan Composition and method for treating tinnitus
US8927528B2 (en) 2006-01-19 2015-01-06 The Regents Of The University Of Michigan Composition for treating hearing loss
US9889156B2 (en) 2006-01-19 2018-02-13 The Regents Of The University Of Michigan Method for treating noise-induced hearing loss (NIHL)
US9919008B2 (en) 2006-01-19 2018-03-20 The Regents Of The University Of Michigan Method for treating age-related hearing loss (ARHL)
US8871808B2 (en) 2006-06-22 2014-10-28 Ben-Gurion University Of The Negev Research And Development Authority Et Al. Over-production of dihomo linolenic acid by a mutant strain of Parietochloris incisa
US8383677B2 (en) 2006-12-28 2013-02-26 Suntory Holdings Limited Nerve-regenerating agent
WO2009022323A1 (en) * 2007-08-13 2009-02-19 Ben-Gurion University Of The Negev Research And Development Authority Over-production of dihomo gamma linolenic acid by a mutant strain of parietochloris incisa
AU2011315532B2 (en) * 2010-10-12 2015-02-05 Vifor Sa Novel omega-3 and omega-6 fatty acid compositions and uses thereof
WO2012049222A3 (en) * 2010-10-12 2012-06-28 Vifor Sa Novel omega-3 and omega-6 fatty acid compositions and uses thereof
US12161616B2 (en) 2014-03-20 2024-12-10 Oxford University Innovation Limited Combination therapy comprising an omega-3 fatty acid, a folate species and a vitamin B12 species
WO2015140545A1 (en) * 2014-03-20 2015-09-24 Isis Innovation Limited Combination therapy comprising an omega-3 fatty acid, a folate species and a vitamin b12 species
US10966947B2 (en) 2014-03-20 2021-04-06 Oxford University Innovation Limited Combination therapy comprising an omega-3 fatty acid, a folate species and a vitamin B12 species
US20210052666A1 (en) * 2015-05-15 2021-02-25 P Tech, Llc Systems and methods for thrombosis prevention
US10828339B2 (en) * 2015-05-15 2020-11-10 P Tech, Llc Systems and methods for thrombosis prevention
US11607431B2 (en) 2015-05-15 2023-03-21 P Tech, Llc Systems and methods for thrombosis prevention
US12064456B2 (en) 2015-05-15 2024-08-20 P Tech, Llc Systems and methods for thrombosis prevention
US20190105356A1 (en) * 2015-05-15 2019-04-11 P Tech, Llc Systems and methods for thrombosis prevention
WO2023041776A1 (en) 2021-09-17 2023-03-23 N.V. Nutricia Solid composition suitable as a nutritional composition or supplement for animals that suffer from brain related disorders, decline or diseases
IT202200010583A1 (en) * 2022-05-23 2023-11-23 Neilos S R L “Nutraceutical or pharmaceutical composition for male infertility”
WO2024003711A1 (en) * 2022-06-27 2024-01-04 Aker Biomarine Antarctic As Phospholipid compositions comprising epa and/or dha for ameliorating neurodegeneration and age-related neurodegenerative disorders

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