WO2009156991A2 - Glycerophospholipids for the improvement of cognitive functions - Google Patents
Glycerophospholipids for the improvement of cognitive functions Download PDFInfo
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- WO2009156991A2 WO2009156991A2 PCT/IL2009/000626 IL2009000626W WO2009156991A2 WO 2009156991 A2 WO2009156991 A2 WO 2009156991A2 IL 2009000626 W IL2009000626 W IL 2009000626W WO 2009156991 A2 WO2009156991 A2 WO 2009156991A2
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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
- 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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- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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Definitions
- the present invention relates to serine glycerophospholipid preparations and their use in the improvement of cognitive functions.
- Glycerophospholipids also referred to as phospholipids, are ubiquitous in nature, are key components of the lipid bilayer of cells, and are involved in cell metabolism and signaling.
- the hydroxyl groups of the glycerol backbone of phospholipids are substituted by a hydrophilic phosphate head and hydrophobic tail composed of non- polar fatty acids.
- Glycerophospholipids may be subdivided into distinct classes, based on the nature of the polar headgroup such as for example: phosphatidylcholine (also known as PC or lecithin), phosphatidylethanolamine (PE) and phosphatidylserine (PS).
- phosphatidylcholine also known as PC or lecithin
- PE phosphatidylethanolamine
- PS phosphatidylserine
- glycerophospholipids such as phosphatidylinositols and phosphatidic acids are either precursors of, or are themselves, membrane-derived second messengers.
- Animal studies have shown that PS enhances neuronal membrane function and hence slows cognitive decline, especially in the elderly [McDaniel MA et al. Nutrition 19: 957-75 (2003) and Jorissen BL et at Nutr Neurosci. 4(2):121-34 (2001)].
- PUFA polyunsaturated fatty acids
- PUFA polyunsaturated fatty acids
- PUFA polyunsaturated fatty acids
- DHA Docosahexaenoic acid
- Studies showed an improvement in the elderly brain function as blood levels of DHA increased.
- DHA may have importance in the field of brain function enhancement, baby formula fortification, diabetics and cancer.
- the human body does not adequately synthesize DHA. Therefore it is necessary to obtain it from the diet. Humans obtain DHA from their diets, initially through the placenta, then from breast milk, and later through dietary sources, such as fish, red meat, animal organ meat and eggs.
- LA Linoleic acid
- ALA ⁇ -linolenic acid
- EFA essential fatty acids
- the body cannot synthesize them de novo, and they must therefore be obtained through food sources providing them "ready-made”.
- LA and ALA are needed for optimal growth and good health.
- Both LA and ALA are precursors of the ⁇ -3 and ⁇ -6 PUFA.
- LA is required for the synthesis of arachidonic acid (AA) (C20:4, ⁇ -6), a key intermediate in the synthesis of eicosanoids, whereas ALA is used partly as a source of energy, and partly as a precursor for metabolites and longer chain PUFA.
- AA arachidonic acid
- ALA is used partly as a source of energy, and partly as a precursor for metabolites and longer chain PUFA.
- LA and ALA can be elongated and desaturated to other more unsaturated fatty acids, principally AA and DHA (C22:6, ⁇ -3), respectively.
- Soybeans, egg yolk, bovine brain and fish are the major natural sources for obtaining and producing phospholipids, especially PS.
- the type of fatty acyl residues at the sn ⁇ and sn-2 positions in natural phospholipids vary, and their proportion in general depends on their source. For example, soybean is rich with LA fatty acid (about 54%) whereas fish derived lecithin is abundant with DHA fatty acid residue.
- the PS extracted from animal brain tissues, similar to human brain PS, has a fatty acid content which is characterized by relatively high levels of omega-3 moieties, compared to the levels of omega-3 found in plants, such as soy phospholipids.
- the bio-functionality of soybean PS in the improvement of cognitive function has been shown to be different from that of human brain PS [WO 2005/037848].
- the present invention provides alternative, enhanced, and cheaper methods of improving cognitive functions in a subject using a lipid preparation conjugated with omega-3 and omega-6 fatty acids, with specific amounts and specific conjugation patterns of LA, linolenic acid (alpha-linolenic acid, gamma-linolenic acid), DHLA. and eicosapentaenoyl (EPA), e.g. utilizing different sources of lipids.
- the subject invention thus provides a preparation comprising a non-mammalian derived mixture of serine glycerophospholipid conjugates wherein the mixture comprises (a) linoleic acid (Cl 8:2) conjugated to PS and (b) DHA conjugated to PS wherein the w/w% of (a) / the w/w% of (b) is from about 0.09 to about 3.6.
- the invention provides a method of improving a condition in a subject suffering from a cognitive disease or disorder comprising administering to a subject in need thereof a preparation of the invention.
- the invention provides a use of a preparation of the invention for the manufacture of a nutritional, pharmaceutical or nutraceutical composition or a functional food.
- the invention provides a preparation of the invention for use in a nutritional, pharmaceutical or nutraceutical composition or a functional food.
- the invention further provides a nutritional, pharmaceutical or nutraceutical composition or a functional food comprising a preparation of the invention.
- the invention provides a preparation of the invention for use in improving a condition in a subject suffering from a cognitive disease or disorder.
- Figure 1 shows a diagram depicting the spatial short-term memory, memory recall and memory recognition in adults upon administration of lipid preparation A of the invention in comparison to administration of placebo.
- a preparation comprising a non-mammalian derived mixture of serine glycerophospholipid conjugates wherein the mixture comprises (a) linoleic acid (Cl 8:2) conjugated to PS and (b) DHA conjugated to PS wherein the w/w% of (a) / the w/w% of (b) is from about 0.09 to about 3.6.
- lipid as used herein should be understood to encompass fats and fatlike compounds, which are essentially insoluble in water and which include, but are not limited to, triglycerides, sterols, fatty acids, and so forth.
- glycophospholipid and “phospholipids” used interchangeably, should be understood to encompass a lipid of the general formula:
- R 1 substituted on position sn-Y
- R 2 substituted on position sn-2
- R 1 substituted on position sn-Y
- R 2 substituted on position sn-2
- X is serine, i.e. -CH I CH(COOH)NH 2
- the phospholipid is referred to as serine glycerophospholipid (PS).
- the sn ⁇ and sn-2 positions as used herein and as indicated in above formula, refer to the respective carbon atoms on the glycerol backbone wherein R 1 and R 2 , are substituted on the corresponding acyl groups.
- the terms "substituted” and its lingual equivalents and the term “conjugated' and its lingual equivalents are interchangeably used and should be understood to encompass a fatty acid acyl covalently attached to the glycerophospholipid backbone of a serine glycerophospholipid of the invention.
- the fatty acid may be attached to the sn-l and/or sn-2 positions.
- fatty acid should be understood to encompass a carboxylic acid with a long unbranched aliphatic tail (chain), which is either saturated or unsaturated having one unsaturated bond (mono-unsaturated fatty acids) or two or more unsaturated bonds (poly-unsaturated fatty acids).
- Non-limiting examples of saturated fatty acids include: Butyric acid (Butanoic acid, C4:0), Caproicacid (Hexanoic acid, C6:0), Caprylic acid (Octanoic acid, C8:0), Capric acid (Decanoic acid, C10:0), Why acid (Dodecanoic acid, C12:0), Myristic acid (Tetradecanoic acid, C14:0), Palmitic acid (Hexadecanoic acid, C16:0), Stearic acid (Octadecanoic acid, Cl 8:0), Arachidic acid (Eicosanoic acid, C20:0), Behenic acid (Docosanoic acid C22:0).
- Non-limiting examples of unsaturated fatty acids include: Myristoleic acid (C14:l, ⁇ -5), Pahnitoleic acid (C16:l, ⁇ -7), Oleic acid (C18:l, ⁇ -9), Linoleic acid (Cl 8:2, ⁇ -6), Linolenic acid (C18:3) [Alpha-linolenic acid (C18:3, ⁇ -3), Gamma-linolenic acid (C18:3, ⁇ -6)], Eicosenoic acid (C20:l, ⁇ -9), Arachidonic acid (C20:4, ⁇ -6), Eicosapentaenoic acid (C20:5 5 ⁇ -3), Erucic acid (C22:l, ⁇ -9), Docosapentanoic acid (C22:5, ⁇ -3) and Docosahexaenoic acid (C22:6, ⁇ -3), Nervonic acid (C24:l, ⁇ -9).
- a fatty acid acyl is conjugated at position sn-l and/or position sn-2 of the phospholipid backbone (through the glycerol oxygen atom).
- a fatty acid is conjugated at position sn- 1
- position sn-2 is either unsubstituted (e.g. having a hydrogen atom on the glycerol oxygen) or substituted with an acyl group selected from saturated, mono-unsaturated and polyunsaturated fatty acids, which may be the same or different from the substitution on position sn-l.
- a fatty acid is conjugated at position sn-2 and position sn-l is either unsubstituted (e.g. having a hydrogen atom on the glycerol oxygen) or substituted with an acyl group selected from saturated, mono-unsaturated and polyunsaturated fatty acids, which may be the same or different from the substitution on position sn-2.
- a preparation of the invention typically comprises a mixture of two or more serine glycerophospholipid conjugates of the invention, having fatty acid conjugation patterns as disclosed herein.
- w/w% of a fatty acid conjugated to PS in a preparation of the invention it should be understood that the w/w% of said fatty acid which is conjugated to PS is calculated relative to the weight of the total fatty acids conjugated to PS in the preparation.
- the mixture of serine glycerophospholipid conjugates constitutes at least 10% w/w of the preparation. In another embodiment the mixture of serine glycerophospholipid conjugates constitutes at least 20% w/w of the preparation. In a further embodiment the mixture of serine glycerophospholipid conjugates constitutes at least 40% w/w of the preparation. In yet another embodiment the mixture of serine glycerophospholipid conjugates constitutes at least 50% w/w of the preparation. In a further embodiment the mixture of serine glycerophospholipid conjugates constitutes at least 54% w/w of the preparation.
- the preparation of the invention may also comprise other phospholipids, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidyl-inositol (PI), phosphatidylglycerol (PG) and phosphatidic acid (PA), to which fatty acid acyls are covalently attached (bonded) at either or both of the sn-l or sn-2 positions of the glycerol moiety of the phospholipid.
- the fatty acid conjugation profile of any of the above-noted polar lipids may be the same as, or different from, the fatty acid conjugation profile of PS, as disclosed herein.
- [PSJ fatty acid conjugation pattern” and “[PS] fatty acid conjugation profile” are interchangeably used herein and refer to a particular content of specific fatty acids conjugated to PS and their position of substitution on the PS glycerol backbone.
- a preparation of the invention further comprises (c) linolenic acid (C18:3) conjugated to PS and (d) DHA conjugated to PS wherein the w/w% of (c) / w/w% of (d) is from about 0.01 to about 0.3.
- a preparation of the invention further comprises (e) linoleic acid (C18:2) conjugated to PS and (f) EPA conjugated to PS wherein the w/w% of (e) / w/w% of (f) is from about 0.23 to about 9.4.
- a preparation of the invention further comprises (g) linolenic acid (Cl 8:3) conjugated to PS and (h) EPA conjugated to PS wherein the w/w% of (g) / w/w% of (h) is from about 0.02 to about 0.8.
- PS can be enriched with omega-3 or omega-6 fatty acids by enzymatic processes, e.g. enrichment of a natural phospholipid/lecithin with omega-3/omega-6 fatty acids by enzymatic transesterification/esterification followed by transformation of the head group to serine (using PLD enzymes) to obtain a PS-omega-3/omega-6 conjugate.
- Another enzymatic pathway is to obtain a phospholipid source which is naturally rich in omega-3 acids, such as marine-derived lecithin (e.g. krill, fish or algae) or eggs phospholipids, and transform their head groups to serine.
- omega-3 acids such as marine-derived lecithin (e.g. krill, fish or algae) or eggs phospholipids
- the PS preparation of the present invention can also be prepared by chemical transesterification/esterification methods that will enrich the sn- ⁇ and 2 positions with omega-3 or omega-6 acyl residues. Such methods of preparation of PS-omega-3 and PS-omega-6 have been described in WO 2005/038037.
- the PS preparation of the present invention can be prepared by GMO (genetically modified. organisms)/biotechnology methods, for example, providing phospholipids-producing organisms with omega-3 or omega-6 fatty acids to obtain phospholipids enriched with omega-3 or omega-6 PS. It may be preferred to use genetically engineered plants or microorganisms, to avoid use of animal sources.
- GMO genetically modified. organisms
- biotechnology methods for example, providing phospholipids-producing organisms with omega-3 or omega-6 fatty acids to obtain phospholipids enriched with omega-3 or omega-6 PS. It may be preferred to use genetically engineered plants or microorganisms, to avoid use of animal sources.
- a mixture of serine glycerophospholipid conjugates of the invention is prepared from a natural, synthetic or semi-synthetic source or any combinations thereof.
- said natural source is derived from any one of plant (such as for example soy and algae), non-mammalian animal (such as for example krill, fish (such as for example Herring and blue Whiting)), or microorganism (such as for example bacteria) source or any combinations thereof.
- PS from different sources have different fatty acid conjugation patterns. For example, soy lecithin contains higher levels of linoleic acid conjugated to PS as compared with marine lecithin which contains higher levels of DHA conjugated to PS.
- the production of said lipid preparation involves an enzymatic catalysis.
- BC-PS bovine cortex
- SB-PS soybean
- this difference in efficacy was attributed to the different fatty acid composition of the two PS sources. While BC-PS has a relatively high DHA content and low LA content, SB-PS is enriched with LA and has no DHA attached to its backbone. It is thus assumed that the PS compositions with low ratio of LA/DHA will serve as better cognitive enhancers.
- the present invention surprisingly provides specific preparations of PS with LA/DHA ratios of 0.09-3.6 which are as effective, and in some cases even more effective, than PS preparations with lower LA/DHA ratios (more DHA), in their ability to enhance cognitive functions.
- the subject invention envisages that the use of a preparation of the invention comprising a mixture of serine glycerophospholipids with specific fatty acid conjugation patterns, which may be derived from distinct sources or may be prepared synthetically, results in similar or improved cognitive functions as compared to lipid preparations derived from a single source or prepared to mimic the fatty acid content of a lipid preparation derived from a single source.
- a lipid preparation comprising PS conjugated with more LA than purely marine-derived lipid preparations, have a similar or improved effect on cognitive functions as compared to either plant derived (such as soy) lipids on the one hand or marine derived (such as fish) lipids on the other.
- Such lipid preparations, derived from more than one source or prepared synthetically to mimic the fatty acid content of lipid preparations derived from more than one source are also cheaper to prepare than purely marine derived lipid preparations.
- the preparation of the invention may be in the form of fluid oil, powder, granules, wax, paste, oil or aqueous emulsion, and any other form that will enable its use in the target applications.
- the invention provides a use of a preparation of the invention, for the manufacture of a nutritional, pharmaceutical or nutraceutical composition or a functional food.
- the invention provides a preparation of the invention, for use in a nutritional, pharmaceutical or nutraceutical composition or a functional food.
- the invention provides a nutritional, pharmaceutical or nutraceutical composition or a functional food comprising a preparation of the invention.
- a nutritional composition as used herein can be any nutritional composition including, but not limited to, human milk fat substitute, infant formula, dairy product, milk 6
- infant formula encompasses infant formulas (for newborn to 6 months old infants), follow-up formulas (for 6-12 months old babies) and growing up formulas (for 1-3 years old children).
- a functional food as used herein can be any functional food, including, but not limited to, dairy product, ice-cream, biscuit, soy product, bakery, pastry, cakes and bread, instant product, sauce, soup, prepared food, frozen food, condiment, confectionary, oils and fat, margarine, spread, filling, cereal, instant product, drinks and shake, infant food, bar, snack, candy and chocolate product.
- a nutraceutical composition as used herein can be any nutraceutical, which can be any substance that may be considered a food or part of a food and provides medical or health benefits, including the prevention and treatment of diseases or disorders.
- nutraceutical compositions include, but are not limited to, a food additive, a food supplement, a dietary supplement, genetically engineered foods such as for example vegetables, herbal products, and processed foods such as cereals, soups and beverages and stimulant functional food, medical food and pharmafood.
- Dietary supplements may be delivered in the form of soft gel capsules, tablets, syrups, and other known dietary supplement delivery systems. .
- the pharmaceutical or nutraceutical compositions are in a dosage delivery form.
- Suitable routes of administration for the compositions of the subject invention are oral, buccal, sublingual administration, administration via a feeding tube, topical, transdermal, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, hi one embodiment, the compounds are administered orally.
- the exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic effect to be achieved (e.g. improving a condition in a subject suffering from a cognitive disease or disorder) and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.
- the present invention thus also provides pharmaceutical compositions of the invention in admixture with (pharmaceutically) acceptable auxiliaries, and optionally other therapeutic agents.
- the auxiliaries must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
- a pharmaceutical composition of the invention further comprises at least one pharmaceutically active agent.
- the pharmaceutical and nutraceutical compositions may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing in association the ingredients with any auxiliary agent.
- auxiliary agent(s), also named accessory ingredient(s) include those conventional in the art, such as carriers, fillers, binders, diluents, dessicants, disintegrants, lubricants, colorants, flavoring agents, antioxidants, and wetting agents.
- compositions of the invention may further comprise edible fibers, aroma, taste ingredients, and ingredients that control physical and organoleptic properties.
- compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, pellets, dragees, or capsules, or as a powder or granules, or as a solution, suspension or elixir.
- compositions include aqueous and non-aqueous sterile injection.
- the compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use.
- sterile liquid carrier for example water
- transdermal administration e.g. gels, patches or sprays can be contemplated.
- compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use.
- sterile liquid carrier for example water
- the invention further provides a commercial package and/or kit for preparing a composition of the invention such as an edible fat source or food article in accordance with the invention comprising (a) a fat source; (b) optionally at least one of edible physiologically acceptable protein, carbohydrate, vitamin, mineral, amino acid, nucleotide and active or non-active additive; (c) optionally at least one edible physiologically acceptable carrier or diluent for carrying the constituent/s defined in (a) and (b); (d) means and receptacles for admixing the constituents defined in (a), (b) and/or (c); and (e) instructions for use such as, but not limited to terms of storage, instructions for preparation of the fat source or food article for administration, required dilutions, dosages, frequency of administration and the like.
- a commercial package or kit in accordance with the invention may also contain a fat source of the invention in a ready-to-use form, together with instructions for use. Dosages are usually determined according to age, weight, sex and condition of the subject, in accordance with good medical practice known to the attending physician and other medical personnel.
- the invention provides a method of improving a condition in a subject suffering from a cognitive disease or disorder comprising administering to a subject in need thereof a preparation of the invention.
- the invention further provides a use of a preparation of the invention for the manufacture of a nutritional, pharmaceutical or nutraceutical composition or a functional food for improving a condition in a subject suffering from a cognitive disease or disorder.
- the invention provides a preparation of the invention for use in improving a condition in a subject suffering from a cognitive disease or disorder.
- cognitive disease or disorder should be understood to encompass any cognitive disease or disorder.
- Non-limiting examples of such a cognitive disease or disorder are Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), dyslexia, age-associated memory impairment and learning disorders, amnesia, mild cognitive impairment, cognitively impaired non- demented, pre-Alzheimer's disease, Alzheimer's disease, Parkinson's disease, pre- dementia syndrome, dementia, age related cognitive decline, cognitive deterioration, moderate mental impairment, mental deterioration as a result of aging, conditions that influence the intensity of brain waves and/or brain glucose utilization, stress, anxiety, depression, behavior disorders, concentration and attention impairment, mood deterioration, general cognitive and mental well being, neurodegenerative disorders, hormonal disorders or any combinations thereof.
- the cognitive disorder is memory impairment.
- the term "improving a condition in a subject suffering from a cognitive disease or a cognitive disorder” as used herein should be understood to encompass: ameliorating undesired symptoms associated with a disease, disorder, or pathological condition; preventing manifestation of symptoms before they occur; slowing down progression of a disease or disorder; slowing down deterioration of a disease or disorder; slowing down irreversible damage caused in a progressive (or chronic) stage of a disease or disorder; delaying onset of a (progressive) disease or disorder; reducing severity of a disease or disorder; curing a disease or disorder; preventing a disease or disorder from occurring altogether (for example in an individual generally prone to the disease) or a combination of any of the above.
- lipid preparation of the invention For example, in a subject suffering from memory impairment, for example as a result of Alzheimer's Disease, symptoms including deterioration of spatial short-term memory, memory recall and/or memory recognition, focused and sustained attention, learning, executive functions and/or mental flexibility are improved by use of a lipid preparation of the invention.
- a cognitive disease or disorder is selected from the group consisting of Attention Deficit Disorder, Attention Deficit Hyperactivity Disorder, dyslexia, age-associated memory impairment and learning disorders, amnesia, mild cognitive impairment, cognitively impaired non-demented, pre-Alzheimer's disease, Alzheimer's disease, Parkinson 1 disease, pre-dementia syndrome, dementia, age related cognitive decline, cognitive deterioration, moderate mental impairment, mental deterioration due to aging, conditions that influence the intensity of brain waves and/or brain glucose utilization, stress, anxiety, depression, behavior disorders, concentration and attention impairment, mood deterioration, general cognitive and mental well being, neurodegenerative disorders, hormonal disorders and any combinations thereof.
- compositions whether pharmaceutical, nutraceutical, nutritional, etc
- product e.g. functional food
- treatment methods known in the art (i.e., combination therapy).
- treatment of cognitive diseases or disorders using a composition or product of the invention may be combined with conventional drugs for the treatment of cognitive diseases or disorders.
- Non limiting examples of drugs indicated for the treatment of cognitive diseases or disorders include Acetylcholine esterase inhibitors (such as for example aricept (donepezil), exelon (rivastigmine), reminyl (galantamine), N-methyl-D-aspartate (NMDA) receptor antagonists (such as for example AP5 (APV, R-2-amino-5- phosphonopentanoate), AP7 (2-amino-7-phosphonoheptanoic acid), CPPene (3-[(R)-2- carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid), Amantadine:
- Acetylcholine esterase inhibitors such as for example aricept (donepezil), exelon (rivastigmine), reminyl (galantamine), N-methyl-D-aspartate (NMDA) receptor antagonists (such as for example AP5 (APV, R-2-amino-5-
- a composition or product of the invention may also be administered in conjunction with other compounds, including, but not limited to folic acid, vitamins, minerals, amino acids, nucleotides, antioxidants and so forth.
- Lipid preparations A, Al, A2, C, D, F, G, H, I, J, K, L, M, and N are prepared as follows:
- Marine lecithin produced by an extraction process from biomass derived from fish was dissolved in organic solvents and allowed to react with an aqueous solution containing L-serine, CaCl 2 , phospholipase D (PLD) and acetate buffer at pH of 5.6.
- the resulting PS preparation was purified by removal of the water phase, evaporation of the organic solvents and further purification stages.
- the resulted powder contained 44% PS and 31% DHA from PS fatty acids.
- PC enriched soybean lecithin was reacted with aqueous medium containing L-serine, CaCl 2 , PLD and acetate buffer at pH of 5.6.
- the resulting PS preparation was washed from water soluble material (salts, serine etc.) and further purified.
- the resulting powder contained 67.4% PS.
- lipid preparations A, Al, A2, C, D, F, G, H, I, J, K, L, M, and N are prepared as follows:
- Lipid preparation B was prepared as follows: Marine lecithin produced by an extraction process from biomass derived from fish (mainly Herring and blue Whiting) was dissolved in organic solvents and allowed to react with an aqueous solution containing L-serine, CaCl 2 , phospholipase D (PLD) and acetate buffer at pH of 5.6. The resulting PS preparation was purified by removal of the water phase, evaporation of the organic solvents and further purification stages. The resulting powder contained 44% PS and 31% DHA from PS fatty acids.
- Lipid preparation E was prepared as follows: PC enriched soybean lecithin was reacted to PS in aqueous medium that containing L- serine, CaCl 2 , PLD and acetate buffer at pH of 5.6. The resulting PS was washed from water soluble material (salts, serine etc.) and further purified. The resulting powder contained 67% PS.
- Table 5 provides the fatty acid ratio and the source ratio of preparations A, B, C, D, E and F of the examples below.
- the fatty acid and phospholipid content of each of these lipid preparations is further specified in Tables 2 and 3 below.
- Lipid preparations A, Al and A2 are different batches of the same preparation.
- Lipid preparations A, Al and A2 have a ratio between linoleic acid (C 18:2) (LA) conjugated to PS (w/w%) and Docosahexaenoic acid (DHA) conjugated to PS (w/w%) of about 0.9-1.4; have a ratio between linolenic acid (18:3) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 0.08-0.13; have a ratio between LA (18:2) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of about 2.3-3.5; and have a ratio between linolenic acid (18:3) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of about 0.2-0.3, wherein the total DHA conjugated to PS constitutes about 19-22% w/w of total fatty acids conjugated to PS.
- Lipid preparation B (100% marine-derived) has a ratio between linoleic acid (LA)(Cl 8:2) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of at most about 0.02; has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%) and
- DHA conjugated to PS (w/w%) of at most about 0.02; has a ratio between LA (18:2) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of at most about 0.05; and has a ratio between linolenic acid (18:3) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of at most about 0.05; wherein the total DHA conjugated to PS constitutes about 31% w/w of total fatty acids conjugated to PS.
- Lipid preparation C has a ratio between linoleic acid (LA)(Cl 8:2) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 0.1; has a ratio between linolenic acid (18:3) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 0.01; has a ratio between LA (18:2) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of about 0.23; and has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of about 0.02; wherein the total DHA conjugated to PS constitutes about 30% w/w of total fatty acids conjugated to PS.
- Lipid preparation D has a ratio between linoleic acid (LA) (C 18:2) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 3.6; has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 0.3; has a ratio between LA (18:2) conjugated to PS (w/w%) and EPA conjugated to PS
- DHA conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 0.8; wherein the total DHA conjugated to PS constitutes about 11% w/w of total fatty acids conjugated to PS.
- Lipid preparation E (100% soy-derived) has a ratio between linoleic acid (LA)(C18:2) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of above 100; has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of above 10; has a ratio between LA (18:2) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of above 100; and has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of above 10, with practically no DHA.
- Lipid preparation F has a ratio between linoleic acid (LA) (Cl 8:2) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 9; has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%)and DHA conjugated to PS (w/w%) of about 0.7; has a ratio between LA (18:2) conjugated to PS (w/w%) and EPA conjugated to PS (w/w%) of about 23; and has a ratio between Linolenic acid (18:3) conjugated to PS (w/w%) and DHA conjugated to PS (w/w%) of about 1.8; wherein the total DHA conjugated to PS constitutes about 5.6% w/w of total fatty acids conjugated to PS.
- omega-3 fatty acids In order to avoid hyper-inflammatory situations, it is preferable to supplement subjects with omega-3 fatty acids in a balanced ratio with omega-6 fatty acids.
- Omega 3 fatty acids increase bleeding time, decrease platelet aggregation, blood viscosity, and fibrinogen; and increase erythrocyte deformability; thus decreasing the tendency to thrombus formation.
- Table 8 shows the ratio between omega 6 and omega 3 fatty acids conjugated to PS and shows that preparations A 5 C and D have balanced ratios whereas a ratio of ⁇ 0.01 (as in preparation B) or >10 (as in preparation E) may be considered not balanced.
- preparations A, C and D are also envisaged.
- Other preparations (G-N) comprising for example 50%, 55%, 60%, 65%, 70%, 80% , 85%, and 90% marine material (i.e. 50%, 45%, 40%, 35%, 30%, 20%, 15%, and 10% soy material) are also envisaged (Table 9).
- 160 subjects were intended to be randomized following screening to one of two treatment groups, 80 subjects in each treatment group:
- the capsules containing lipid preparation A and the placebo capsules were of identical appearance, taste and smell. Memory functions of 15 subjects who received preparation A treatment and 18 subjects who received placebo capsules were tested using NexAde computerized neuropsychological assessment software (NexSig Neurological Examination Technologies Ltd, Israel) at baseline and following ⁇ 3 treatment months.
- the computerized neuropsychological assessment software consisted of seven separate tasks including: symbol spotting, pattern identification, pattern recall, digit-symbol substitution, digits span forward, digits span backward and delayed pattern recall.
- eight cognitive composite scores were calculated including focused attention (the ability to respond discretely to specific visual auditory or tactile stimuli), sustained attention (the ability to maintain a consistent behavioral response during continuous and repetitive activity), memory recognition (the ability to identify previously stored information), memory recall (involves digging into the memory and bringing back information on a stimulus/response basis), visuospatial learning, spatial short term memory (a memory system that stores spatial information for a few seconds so that it can be used in the service of ongoing cognitive tasks), executive functions and mental flexibility.
- Results Figure 1 indicates that lipid preparation A improved memory parameters following ⁇ 3 months treatment period.
- Figure 1 demonstrates three of the memory parameters that were tested: memory recall, memory recognition and spatial short term memory.
- Memory recall and recognition is a "process" used to get information back out of our memory. Memory recall involves digging into the memory and bringing back information on a stimulus/response basis, and memory recognition indicates the ability to identify previously stored information.
- Spatial short term memory is a memory system that stores spatial information for a few seconds so that it can be used in the service of ongoing cognitive tasks. The results presented in Figure 1 show that lipid preparation A improved cognitive performance of learning and memory abilities in comparison with placebo.
- lipid preparation A improved mild cognitive impairment and age-associated memory impairment.
- Table 1 indicates that lipid preparation A significantly improved the final score of the computerized cognitive assessment tool. This score is an adjusted calculation that sums the different composite scores. Table 1 demonstrates individual tests (digits recall forward and backward) and specific composite scores (focused attention, memory recall and memory recognition) that were significantly improved. It is concluded that lipid composition A significantly improved numerous cognitive parameters such as attention, memory and learning.
- Table 2 indicates that lipid preparation A improved the different parameters of Rey- AVLT procedure, and thus further confirms the cognitive enhancement properties of the preparation. Specifically, lipid composition A significantly improved immediate and delayed memory recall, best learning, total learning and total immediate recall.
- lipid preparation A improved mild cognitive impairment and age- associated memory impairment.
- lipid preparation B prepared according to Example 1 above was investigated in a single-center, open label, ⁇ 3 months trial in 16 elderly (age>60) with impaired cognitive performance.
- Table 3 indicates that lipid preparation B improved the final score of the computerized cognitive assessment tool. Although the improvement did not reach statistical significance, its magnitude was comparable to that following lipid preparation A consumption (see Table 1). An improvement was also detected in individual tests (digits recall forward and backward) and specific composite scores (spatial short term memory, focused attention, memory recall and memory recognition) that were improved by lipid preparation B. Again, the magnitude of the effect was comparable to that following treatment with preparation A (see Table 1), but the improvement didn't always reach statistical significance. It is thus concluded that lipid preparation B improved several cognitive parameters similarly to lipid preparation A, however, since the improvement did not always reach statistical significance, it seems that lipid preparation A has an advantage over lipid preparation B in improving cognitive skills and treating mild cognitive impairment and age associated memory decline. These results are surprising since lipid preparation B has a lower LA/DHA ratio (more DHA) in comparison with lipid preparation A. Table 3: Effect of lipid preparation B on the computerized cognitive assessment tool parameters
- lipid preparation C The efficacy of lipid preparation C is investigated in a single-center, open label, ⁇ 3 months trial in 8 elderly with impaired cognitive performance.
- Lipid preparation C improves memory recall, memory recognition, attention, concentration, learning and spatial short term memory following ⁇ 3 months treatment period.
- the improvement of all parameters tested is similar to the improvement following ⁇ 3 treatment months with lipid preparation A (Example 2) and similar to, or better than, the improvement following ⁇ 3 treatment months with lipid preparation B .
- lipid preparation D The efficacy of lipid preparation D is investigated in a single-center, open label, ⁇ 3 months trial in 8 elderly with impaired cognitive performance.
- Lipid preparation D improves memory recall, memory recognition, attention, concentration, learning and spatial short term memory following ⁇ 3 months treatment period.
- the improvement of all parameters tested is similar to the improvement following ⁇ 3 treatment months with lipid preparation A (Example 2) and C, and similar to or better than the improvement following ⁇ 3 treatment months with lipid preparation B .
- lipid preparation E prepared according to Example 1 above was investigated in a single-center, open label, ⁇ 3 months trial in 24 elderly (age>60) with impaired cognitive performance.
- Lipid preparation E tends to improve memory recall, memory recognition, attention, concentration, learning and spatial short term memory only to a minor extent following ⁇ 3 months treatment period. The improvement of all parameters tested is lower than the improvement following ⁇ 3 treatment months with any of the lipid preparations A (Example 2), B, C and D.
- the efficacy of lipid preparation is investigated in a single-center, open label, ⁇ 3 months trial in 8 elderly with impaired cognitive performance.
- Lipid preparation F tends to improve memory recall, memory recognition, attention, concentration, learning and spatial short term memory only to a minor extent following ⁇ 3 months treatment period. The improvement of all parameters tested is lower than the improvement following ⁇ 3 treatment months with any of the lipid preparations A (Example 2), B, C and D.
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CA2728646A CA2728646C (en) | 2008-06-24 | 2009-06-24 | Serine glycerophospholipid conjugates and their use in the improvement of cognitive functions |
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CN2009801280098A CN102105173A (en) | 2008-06-24 | 2009-06-24 | Glycerophospholipids for the improvement of cognitive functions |
DK09769797.3T DK2307058T3 (en) | 2008-06-24 | 2009-06-24 | Glycerophospholipids to improve cognitive functions. |
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BRPI0910184A BRPI0910184B8 (en) | 2008-06-24 | 2009-06-24 | preparation of a non-mammalian-derived mixture of serum glycerophospholipid conjugates, method of ameliorating a condition in a patient suffering from cognitive disease or disorder, use of a preparation, nutritional, pharmaceutical or nutraceutical composition or functional food |
ES09769797.3T ES2651417T3 (en) | 2008-06-24 | 2009-06-24 | Glycerophospholipids for the improvement of cognitive functions |
EP09769797.3A EP2307058B1 (en) | 2008-06-24 | 2009-06-24 | Glycerophospholipids for the improvement of cognitive functions |
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