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    • 专利摘要:
    The invention relates to a nutritional or therapeutic agent comprising a mixture of molecules obtained from Vitis vinifera and Vaccinium angustifolium, comprising: at least 1% of catechins and epicatechins, the percentage being given by weight relative to the total weight of the mixture preferably at least 5%, and at least 5 ppm (parts per million in the mixture) of ferulic acid, preferably at least 10 ppm. The invention also relates to the use of this agent for its effects on cognitive functions in particular.
    公开号:FR3042712A1
    申请号:FR1560263
    申请日:2015-10-27
    公开日:2017-04-28
    发明作者:David Gaudout；Stephane Rey；Benoit Lemaire；Julien Bensalem；Anne Lepoudere；Delphine Lethuillier；Marie-Eve Paradis；Stephanie Dudonne；Yves Desjardins；Frederic Calon；Alexandre Dal-Pan；Charles Ramassamy
    申请人:Inst Nat de la Rech Scient (inrs)；Universite Laval；Institut National de La Recherche Scientifique INRS；ACTIV'INSIDE；Specialites Pet Food SAS；
    IPC主号:
    专利说明:

    SPECIAL NUTRITIONAL OR THERAPEUTIC AGENT COMPRISING A MIXTURE OF GRAPE AND BLUEBERRY
    The present invention relates to a mixture of specific polyphenols having a synergistic action including cognitive functions and executive functions in humans and animals. The invention also aims to use this mixture to improve cognitive functions and executive functions, delay cognitive decline and prevent and combat pathologies associated with cognitive decline in humans and animals.
    We know that old age is associated with cognitive disorders and neurodegenerative deficiencies such as Alzheimer's disease and Parkinson's disease. As the elderly population increases, there is a prevalence of these age-related disorders. It is therefore important to develop solutions to prevent or minimize age-related cognitive decline and delay the onset of associated pathologies. To this end, nutrition-based prevention has been suggested in recent years to prevent or delay progression to dementia and thus maintain stable cognitive status and well-being in the elderly. Research into understanding the relationship between nutrition and "healthy aging" has intensified, and among the foods studied, polyphenol-rich fruits and vegetables have been identified as capable of delaying physiological and functional deficits. age-related and protect humans or animals from associated degenerative diseases (as described for example in: JA Joseph, Shukitt-Hale B, Casadesus G. "reversing the deleterious effects of aging on communication and Neuronal Behavior: Beneficial Properties of Polyphenolic Fruit Compounds "from the American Journal of Clinical Nutrition 2005; 81 (Suppl 1): 313S-6S.). Indeed, polyphenols, especially flavonoids, are known for their ability to improve learning and memory processes and are now widely studied for their potential in the prevention of age-related cognitive decline in both men and women. animals only in humans. Although the mechanisms of action of flavonoids are not clearly identified, it is known that they are capable of modulating the cellular and molecular processes involved in learning and memory.
    Among the fruits containing polyphenols studied for their effect on the cognitive decain linked to the age, one can notably mention the berries and in particular the blueberry, the strawberries and the grapes. Among the various polyphenols present in berries, those that have been particularly studied for their effect on brain functions are resveratrol and flavonoids, particularly flavanols and anthocyanins.
    Blueberries are known to contain a large amount of polyphenols and have a greater antioxidant capacity than other fruits and vegetables. Many studies suggest that blueberry consumption delays age-related functional and physiological deficits. For example, daily consumption of blueberry juice for 12 weeks increases the performance of episodic memory in the elderly (Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, et al. "Blueberry supplementation improves memory in older adults." Journal of Agricultural and Food Chemistry, 2010; 58 (7): 3996-4000).
    The strawberry has a strong antioxidant and anti-inflammatory power capable of preventing age-related neurochemical and behavioral alterations.
    The grape is particularly rich in flavonoids (catechins, epicatechins, proanthocyanidic oligomers, procyanidic polymers, and anthocyanins) known for their powerful antioxidant capacities. The nutritional properties of grapes as the source of polyphenols in wine are therefore also the subject of many studies. Similar to the results obtained with blueberry juice, the consumption of grape juice for 12 weeks leads to an improvement in memory performance in older humans (Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA "Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment." The British Journal of Nutrition, 2010; 103 (5): 730-4).
    In addition, specific extracts of grapes (grape seed extract, for example) are now used as a nutritional supplement for their high concentration of polyphenols, especially flavanols, anthocyanins and resveratrol. These extracts are suitable for nutritional supplementation because they contain a higher concentration of polyphenols than fruits or juices, which facilitates the identification of their effects and the study of the underlying neurobiological mechanisms. The use of berries, juices or berry extracts to retard age-related cognitive decline and improve brain function is therefore known. However, when individuals or animals consume existing berries, juices or berry extracts, the bioavailability of the polyphenols contained in these products is not satisfactory and the effect on cognitive and functional functions is not sufficient.
    Also, the objective of the invention is to overcome these disadvantages by proposing a product containing polyphenols having improved bioavailability and greater effectiveness in combating cognitive decline. For this purpose, the invention provides a nutritional or therapeutic agent comprising a mixture of molecules obtained from Vitis vinifera and Vaccinium angustifolium, comprising: at least 1% of catechin and / or epicatechin, the percentage being given by weight per relative to the total weight of the mixture, preferably at least 5%, and at least 5 ppm (parts per million in the mixture) of ferulic acid, preferably at least 10 ppm. The agent according to the invention contains flavanols, in particular catechins and / or epicatechins, known for their effect on cognitive performance, as described in particular in Endeiro C, Vauzour D, Rattray M, Waffo-Teguo P, Merillon JM, Butler LT, et al. "Dietary levels of pure flavonoids improve spatial performance performance and increase hippocampal brain-derived neurotrophic factor" PloS on 2013; 8 (5): e63535, as well as in Van Praag H, Lucero MJ, Yeo GW, Stecker K, Heivand N, Zhao C, et al., "Plant-derived flavanol (-) epicatechin enhances angiogenesis and retention of spatial memory in mi ce" The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007; 27 (22): 5869-78.
    Similarly, ferulic acid is known for its effects on the neuronal system, in particular for protecting neuronal cells from cerebral ischemia-induced cell death as described in particular in Cheng CYS, S.Y .; Tang, N.Y .; Ho, T.Y .; Chiang, S.Y .; Hsieh, C.L. "Ferulic acid provides neuroprotection against oxidative stress-related apoptosis after cerebral ischemia / reperfusion injury by inhibiting ICAM-1 mRNA expression in rats. Brain Res., "2008; 1209: 136-50. Moreover, its antioxidant activity has been tested in Alzheimer's disease (Sgarbossa A, Giacomazza D, Di Carlo M." Ferulic Acid: A Hope for Alzheimer's Disease Therapy from Plants Nutrients, "2015; 7 (7): 5764-82), and its long-term administration appears to protect against memory and learning deficits (Yan JJC, JY, Kim, HS, Kim, KL, Jung, JS; Huh, SO, Suh, HW, Kim, YH, Song, DK, "Protection against 6-amyloid peptide in vivo toxicity with long-term administration offerulic acid." Br J Pharmacol., 2001; 133: 89-96.)
    Surprisingly, the combination and the specific amount of polyphenols present in the agent exhibit a synergistic effect and increase the bioavailability of the polyphenols when administered to humans or animals in comparison with the bioavailability of these same polyphenols when they are administered alone or via existing berry extracts or when grapes or blueberries are consumed.
    This effect is further increased when the agent also comprises: at least 200 ppm resveratrol, and / or at least 50 ppm quercetin and / or quercetin glycosides, and / or at least 500 ppm anthocyanidins.
    These molecules are also known for their effect on cognitive functions.
    Resveratrol is particularly known to be present in grapes. It has many activities beneficial to humans or animals, including improved working memory, learning and spatial memory, spontaneous motor activity (Abraham J, Johnson RW.) "Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice "Rejuvenation research., 2009; 12 (6): 445-53; Dal-Pan A, Pifferi F, Marchai J, Picq JL, Aujard F." Cognitive performance is selectively enhanced during chronic calorie restriction or resveratrol supplementation in a primate. "PloS., 2011; 6 (l): el6581.)
    Quercetin also has significant neuroprotective activity (Dajas F, Andres AC, Florencia A, Carolina E, Felicia RM.) "Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features." Central nervous system agents in medicinal chemistry. 13 (l): 30-5.) And it is also known that the consumption of foods rich in anthocyanidins makes it possible to prevent memory deficits and to improve cognitive performance (Barros D, Amaral OB, Izquierdo I, Geracitano L , Carmo Bassols Raseira M, Henriques AT, et al., "Behavioral and Genoprotective Effects of Vaccinium Berries, intake in mice", Pharmacology, Biochemistry, and Behavior, 2006; 84 (2): 229-34; Cho J, Kang JS, Long PH, Jing J, Y Back, Chung KS. "Antioxidant and memory enhancing effects of purple sweet potato anthocyanin and cordyceps mushroom extract." 2003; 26 (10): 821-5; Ramirez MR, Izquierdo I , do Carmo Bassols Raseira M, Zuanazzi JA, Barros D, Henriques AT. "Effect of lyophilized Vaccinium berries on memory, anxiety and locomotion in adult rats. Here again, the combination and the specific amount of polyphenols present in the agent according to the invention makes it possible to obtain the effects of polyphenols alone or at different concentrations in existing products, the molecules of the mixture and therefore the agent according to the invention have in particular a synergistic antioxidant effect. and / or on the improvement of cognitive and / or executive functions in humans or animals, the agent according to the invention is therefore particularly useful especially as a medicine in humans or animals, and specifically to prevent and / or fight against pathologies associated with cognitive decline.
    Similarly, the invention also relates to the use of such an agent for nutritional applications in humans or healthy animals, in particular to improve cognitive and / or executive functions. The invention is now described in detail with reference to the appended figures in which:
    FIG. 1 represents the differences in the bioavailability of polyphenols in mouse plasma, between acute administration and chronic administration of an extract of Vitis vinifera, an extract of Vaccinium angustifolium or an agent according to the invention;
    FIG. 2 represents the hierarchical ascending classification (CAH) of phenolic metabolites found in mouse plasma before and after treatment with chronic ingestion of an extract of Vitis vinifera, an extract of Vaccinium angustifolium or an agent according to US Pat. invention;
    FIG. 3 represents the hierarchical ascending classification (CAH) of phenolic metabolites found in the excrements of mice before and after treatment by chronic ingestion of an extract of Vitis vinifera, an extract of Vaccinium angustifolium or an agent according to US Pat. invention;
    Figure 4A shows the effects of ferulic acid alone on protection of neuronal cells after acute treatment;
    Figure 4B shows the effects of catechin alone on protection of neuronal cells after acute treatment;
    Figure 4C shows the effects of epicatechin alone on the protection of neuronal cells after acute treatment;
    Figure 4D shows the effects of the agent according to the invention on the protection of neuronal cells after acute treatment;
    Figure 5A shows the effects of ferulic acid alone, catechin alone and epicatechin alone, on protection of neuronal cells after three cumulative treatments (cell survival);
    Figures 5B, 5C, 5D, 5E show the effects of the agent according to the invention on the protection of neuronal cells after three cumulative treatments at different concentrations (cell survival);
    Figure 5F shows the effects of the agent according to the invention on the protection of neuronal cells after three cumulative treatments (production of ROS);
    Figure 6 shows the total antioxidant status (TAS) of adult dogs having been treated with the agent according to the invention, an extract of Vitis vinifera, an extract of Vaccinium ongustifolium, and a control;
    Figure 7 shows the effect on the cognitive functions of dogs of an agent according to the invention at different doses compared to a placebo. The subject of the invention is therefore a nutritional or therapeutic agent comprising at least one mixture of molecules obtained from Vitis vinifera and Vaccinium ongustifolium, said mixture comprising: at least 1% of catechin and / or epicatechin, the percentage given by weight relative to the total weight of the mixture, preferably at least 5%, and - at least 5 ppm (parts per million in the mixture) of ferulic acid, preferably at least 10 ppm.
    For the purposes of the invention, the term "nutritional agent" is intended to mean a nutritional food ingredient used alone or in combination with other ingredients or food additives in food formulas, including food supplements intended for humans or animals. .
    For the purposes of the invention, the term "therapeutic agent" is intended to mean an active ingredient used for therapeutic purposes alone or in combination with other active or non-active substances in drug formulations, including phytotherapy, intended for humans or the animal.
    By "at least X% of catechins and / or epicatechins" is meant at least X% of catechins if there are no epicatechins in the mixture, or at least X% of epicatechins if it is not There are no catechins in the mixture, ie at least X% of the mixture of catechins and epicatechins if both catechins and epicatechins are present in the mixture. Preferably, at least X% of the mixture of catechins and epicatechins is meant. By "ppm" is meant parts per million in the mixture.
    Preferably, in addition to the at least 1% of catechin and / or epicatechin, and at least 5 ppm of ferulic acid, the mixture of molecules according to the invention also comprises: at least 200 ppm of resveratrol, and / or at least minus 50 ppm quercetin and / or quercetin glycosides, and / or - at least 500 ppm anthocyanidins.
    According to a first embodiment, the mixture of molecules is a mixture consisting of an extract of Vitis vinifera and an extract of Vaccinium angustifolium.
    According to a second embodiment, the mixture of molecules is a mixture consisting of an extract obtained from a mixture of Vitis vinifera and Vaccinium angustifolium. According to a third embodiment, the mixture of molecules is a mixture consisting of: an extract of Vitis vinifera and / or an extract of Vaccinium angustifolium, and an extract obtained from a mixture of Vitis vinifera and Vaccinium angustifolium.
    For Vitis vinifera extract within the meaning of the invention is meant at least one molecule, preferably a set of molecules, obtained (s) from Vitis vinifera. The raw material may be the leaves and / or the fruits and / or the seeds and / or the woods, preferentially the raw material is the aerial part of the plant, that is to say the whole of the leaves, fruits, pelicle, seeds and wood, even more preferentially skin and seeds. Preferably, the extract of Vitis vinifera is an extract having a flavanol polymer content of less than 0.5% by weight of the total weight of the polyphenols of the extract, more preferably a content of less than 0.1%. By "flavanol polymer" is meant a flavanol having a degree of polymerization greater than 10.
    For Vaccinium angustifolium extract within the meaning of the invention is meant at least one molecule, preferably a set of molecules, obtained (s) from Vaccinium angustifolium. The raw material can be the leaves and / or the fruits, preferably the raw material is the whole of the leaves and fruits of the plant.
    By extract obtained from a mixture of Vitis vinifera and Vaccinium angustifolium is meant a set of molecules obtained from a mixture of Vitis vinifera and Vaccinium angustifolium. The raw material of Vitis vinifera can be the leaves and / or the fruits and / or the seeds and / or the woods, preferentially the raw material of Vitis vinifera is the aerial part of the plant, that is to say the whole leaves, fruits, pelicle, seeds and wood. The raw material of Vaccinium angustifolium may be the leaves and / or the fruits, preferentially the raw material of Vaccinium angustifolium is the whole of the leaves and fruits of the plant.
    The extracts according to the invention may be obtained by any process making it possible to obtain a mixture comprising at least 1% catechin and / or epicatechin by weight relative to the total weight of the mixture, preferably at least 5%, and at least 5 ppm. ferulic acid, preferably at least 10 ppm.
    Preferably, the extracts according to the invention are obtained by any process making it possible to obtain at least 1% of catechin and / or epicatechin, at least 5 ppm of ferulic acid, and: at least 200 ppm of resveratrol, and / or at least 50 ppm quercetin and / or quercetin glycosides, and / or at least 500 ppm anthocyanidins.
    A particularly suitable process is a process comprising the following steps: obtaining an extract of Vitis vinifera: o extraction with water and / or ethanol of Vitis vinifera, preferably all of the leaves, fruits, pellicle, pips and wood of Vitis vinifera,
    The amount of solvent (30% v / v to 96% V / V) used is between 2 and 10 times the mass of material used. The duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20 ° C and 80 ° C. The raw materials used may be in dry, fresh, or frozen forms whole or crushed; separating the water and / or ethanol solution from the solid material, for example by centrifugal decantation or by pressing and filtration; evaporation of the ethanol by evaporation under vacuum at a temperature preferably below 60 ° C. and at a pressure of less than 100 mbar; o Membrane separation of the previously desolvated extract so as to preferentially select the proanthocyanidic monomers and oligomers (having a degree of polymerization of between 2 and 10 inclusive) and to eliminate the flavanol polymers (> to the decamers), to obtain a extract characterized by a flavanol polymer content of less than 0.5% and more preferably less than 0.1% by weight relative to the total weight of the polyphenols of the extract. This step can be carried out using a filtration membrane having a cutoff threshold of less than 15,000 daltons and more preferably less than 3,000 daltons; obtaining an extract of Vaccinium angustifolium: o extraction with water and / or ethanol of Vaccinium angustifolium, preferably all the leaves and fruits of Vaccinium angustifolium, the amount of solvent (30% v / v to 96% V / V) implementation is between 2 and 10 times the mass of material used. The duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20 ° C and 80 ° C. The raw materials used may be in dry, fresh, or frozen form; separating the water and / or ethanol solution from the solid material by centrifugal decantation or by pressing and filtration; evaporation of the ethanol by evaporation under vacuum at a temperature preferably below 60 ° C. and a pressure of less than 100 mbar; drying the extracts by atomization, vacuum oven or lyophilization with or without a support such as a maltodextrin; mixture of Vitis vinifera extract and Vaccinium angustifolium before or after the drying step.
    According to one variant, the process consists in the implementation of the following steps: mixture of Vitis vinifera and Vaccinium angustifolium with water and / or ethanol extraction of Vaccinium angustifolium, preferably all the leaves and The amount of solvent (30% v / v to 96% V / V) used is between 2 and 10 times the mass of material used. The duration of the extraction can be between 30 minutes and 24 hours and the extraction temperature between 20 ° C and 80 ° C. The raw materials used may be in dry, fresh, or frozen form; o separation of the water and / or ethanol solution from the solid matter by centrifugal decantation or by pressing and filtration; evaporation of the ethanol by evaporation under vacuum at a temperature preferably below 60 ° C and a pressure of less than 100 mbar; drying the extract by spray or sublimation with or without a carrier such as maltodextrin.
    Whatever the variant of the process, before the drying step, the process may comprise the following steps: loading on a resin mixed or non-mixed extracts solutions, rinsing the resin with water, - application of an eluent solution of water / ethanol on the resin, recovery of the purified eluate, - evaporation of the ethanol of said eluate, - concentration of said eluate - drying of said purified aqueous extract. The nutritional or therapeutic agent according to the invention may consist exclusively of the mixture of molecules, that is to say extracts, or comprise other constituents. Preferentially, in addition to the mixture of molecules, the nutritional or therapeutic agent according to the invention contains other constituents, in particular excipients or coating agents, such as maltodextrin, microcrystalline cellulose, cyclodextrins, starch, soluble or insoluble fiber. The agent may be in any form suitable for a nutritional or therapeutic application, preferably in powder form. The agent according to the invention may be incorporated into a composition, in particular in a nutritional or therapeutic composition (medicament) in a form chosen from tablets, capsules, capsules, powders, solutions, microcapsules, suspensions, emulsions, food supplements, beverages, and food for humans or animals.
    It may be a nutritional composition intended for humans such as, for example, food supplements, bars, dairy products, swallowing or rehydrating powders, gels, jams, sweets, soft drinks or no, dry drinks to rehydrate, compotes.
    It may also be a medicine intended for humans, for example tablets or capsules.
    It can also be a nutritional or therapeutic composition for the animal. The term "animal" means any animal that can receive a nutritional or therapeutic agent according to the invention, for example but not limited to a pet, a poultry, a pig, a ruminant, a goat, or a mouse. Preferably, the animal is a pet, such as the cat or the dog. More preferably, the animal is a dog.
    It can also be a nutritional composition for the animal such as dry foods, such as croquettes (extruded, co-extruded or freeze-dried), treats, snacks, wet foods. or semi-moist such as pieces in sauce, jelly pieces, drinks, or food supplements. Preferably, the agent is incorporated in dry foods such as croquettes.
    Finally, it may be a medicinal product intended for the animal, or a veterinary product, such as, for example, tablets, capsules, sprays, or liquids administered by drops. Advantageously, the agent intended for the animal may be included in a composition, in particular in a nutritional or therapeutic composition, in inclusion, that is to say by adding it to the mass of the composition, for example by impregnation or mixing, or by coating, that is, that is to say by applying it to the surface of the composition, by spraying or by dusting, for example by premixing it with one or more ingredients such as at least one palatability factor. The nutritional or therapeutic agent can be used in particular to act on the cognitive and executive functions in an individual or a healthy animal but also in sick subjects.
    Cognitive decline is characterized by an age-related decline in cognitive and executive functions, particularly concentration, work, long-term memory, reasoning, judgment, problem-solving, and speed of thinking. information processing. These impairments can lead to decreased self-esteem and quality of life. Age-related cognitive decline is the term used to describe the non-pathological form of impaired memory and cognitive function that results from the aging process within normal limits, given the age of a person. It is a complex process, with early signs emerging in humans between 35 and 65 years old, without specific neurodegenerative lesions. Progressive cognitive decline is perceptible by the appearance of minor cognitive problems that affect 15 to 20% of the population aged 65 or older, but who are in an unstable state. However, some pathological forms may occur in addition to this "normal" cognitive decline. Among these pathologies, Alzheimer's disease is the most common cause of dementia, affecting more than 24 million people worldwide. It is irreversible in our current state of knowledge, the only available treatments being purely symptomatic. In animals, these conditions can be very similar. In dogs, for example, cognitive dysfunction syndrome (CDD) is a widespread pathology characterized by spatiotemporal disorientation, a loss of elementary learning that often leads to uncleanliness, impaired sleep-wake alteration of social interactions. The agent according to the invention is capable of improving the cognitive and executive functions in humans or animals. The combination of the two raw materials and the specificity of the extracts according to the invention comprising polyphenols combined in particular quantities, produces a synergistic effect in comparison with the polyphenols taken alone or with the existing extracts comprising these polyphenols in different proportions and quantities. The synergy relates to the antioxidant effect and / or the improvement of cognitive and / or executive functions in humans or animals.
    The polyphenols present in the agent according to the invention, when they are administered to humans or animals, also have an improved bioavailability in comparison with the polyphenols taken alone or with the existing extracts comprising these polyphenols in different proportions and amounts. . The agent according to the invention used in humans or animals, thus makes it possible to improve the bioavailability of the polyphenols contained in said agent. The agent according to the invention can be used as a medicine for humans or animals.
    In particular, the invention relates to the use of the therapeutic or nutritional agent in the treatment or prevention in humans or animals of Alzheimer's disease and / or Parkinson's disease and / or Huntington's disease and / or pathological cognitive decline and / or dementia and / or depression and / or diabetes and / or schizophrenia and / or mental retardation and / or condition-related disorders. post menopause in women and / or cognitive dysfunction syndrome (CDS). The agent according to the invention can also be used in human or healthy animals, to improve cognitive functions and / or executive functions, and / or to limit age-related non-pathological cognitive decline, preferentially in a nutritional composition or a dietary supplement. It can especially be used in humans or healthy animals to improve memory and / or attention and / or concentration and / or liveliness and / or learning and / or intelligence and / or language and / or mood and / or stress and / or anxiety and / or vision and / or sleep.
    According to a particular embodiment of the invention, the man or the animal is old. Preferably, the human or the aged animal is a human or an animal that has reached at least 50% of the average life span associated with its species.
    Preferably, the therapeutic or nutritional agent is used at a dose which makes it possible to provide the human or the animal with: at least 100 μg per kg of body weight of catechin and / or epicatechin, and at least 0.05 μg per kg of body weight of ferulic acid.
    Even more preferably, the therapeutic or nutritional agent is used at a dose which makes it possible to provide the human or the animal with: preferably at least 100 μg per kg of body weight of catechin and / or epicatechin, and preferably at least 0.05 μg per kg body weight of ferulic acid, and - at least 10 μg per kg of body weight of resveratrol, and / or - not less than 0.2 μg per kg of body weight of quercetin and / or glycosides quercetin, and / or - at least 1 μg per kg of body weight of anthocyanidins. The invention is now illustrated by means of examples and results of tests demonstrating the synergistic antioxidant effect and on the cognitive and executive functions, and the improvement of the bioavailability of the therapeutic or nutritional agent which is the subject of the present application. Examples
    Example 1 Therapeutic or nutritional agent according to the invention
    This first example of a mixture according to the invention is obtained by implementing the method as described below.
    The raw materials used are: - the skin and seeds (seeds) of Vitis vinifera fruits, by-products of the wine industry, - frozen berries of Vaccinium angustifolium. 400 g of frozen berries of Vaccinium angustifolium are crushed and mixed with a solution of 2000 ml of ethanol 80% (V / V) with a content of 0.1% by weight of HCl. The mixture is kept at room temperature (20 ° C.) for 24 hours. The ethanolic solution is then separated from the pulp by filtration and concentrated under vacuum with a rotary evaporator at 20% dry matter. Part of this extract is kept for testing, the other part is kept for mixing with Vitis vinifera extract. 500 g of pellicle and Vitis vinifera seeds are mixed with 2500 ml of 80% ethanol (V / V) with a content of 0.1% by weight of HCl at 40 ° C. for 5 hours. The ethanolic solution is then separated from the pulp by filtration. The ethanol is then removed under vacuum with a rotary evaporator at a temperature of 50 ° C. under 60mbars. The aqueous solution is then diluted to a dry matter of 5% and filtered on a membrane of 5000 daltons. The permeate obtained is then loaded onto a column of resin (C18) at 1 BV / hour. The resin is then rinsed a first time with 3BV of distilled water at 2BV / hour, and then eluted with 5BV of an 80% (V / V) ethanol solution at 1 BV / hour. Part of the extracted solution is retained for testing and characterization (Table la). The polyphenols shown in this table were measured by high speed liquid chromatography with a fluorescence detector.
    Table la: Flavanol content of Vitis vinifera extract
    The other part is then mixed with the extract of Vaccinium angustifolium to form the mixture according to the invention and a maltodextrin is added to the mixture until a solution having a solids content of 30% is obtained.
    The solution is then spray-dried with an inlet temperature of 160 ° C.
    The product obtained is a purple powder containing the polyphenols shown in Table 1b. The polyphenols shown in this table were measured by high speed liquid chromatography UPLC-MS / MS.
    Table Ib: Polyphenol Content of the Agent According to the Invention of Example 1
    Example 2 Therapeutic or nutritional agent according to the invention
    This second example of a mixture according to the invention is obtained by carrying out the process as described below.
    The raw materials used are: - pips and skin of Vitis vinifera, - berries of Voccinium angustifolium. 1000g of frozen marc of Vaccinium angustifolium are ground and mixed with a solution of 5000ml of ethanol 60% (V / V) with a content of 0.1% by weight of HCl. The mixture is kept at room temperature (20 ° C.) for 24 hours. The ethanolic solution is then separated from the pulp by filtration and concentrated under vacuum with a rotary evaporator at 20% dry matter. 400 g of selected Vitis vinifera skin and pips are mixed with 1500 ml of 80% (V / V) ethanol at 60 ° C for 5 hours. The ethanolic solution is then separated from the pulp by filtration. The ethanol is then removed under vacuum with a rotary evaporator at a temperature of 50 ° C. under 60mbars. The aqueous solution is then diluted to a dry matter of 5% and filtered on a membrane of 5000 daltons. The permeate obtained is then loaded onto a column of resin (C18) at 1 BV / hour. The resin is then rinsed a first time with 3BV of distilled water at 2BV / hour, and then eluted with 5BV of an 80% (V / V) ethanol solution at 1 BV / hour.
    Part of the extracted solution is stored for testing and characterization (Table 2a), Table 2a: Flavanol content of Vitis vinifera extract
    The product obtained is a purple powder containing the polyphenols shown in Table 2b. The polyphenols shown in this table were measured by high speed liquid chromatography UPLC-MS / MS.
    Table 2b: polyphenol content of the agent according to the invention of Example 2
    Example 3: Therapeutic or nutritional agent according to the invention 19.980 kg of the agent of Example 1 is mixed with 0.020 kg of colloidal silica. The composition is obtained by mixing the constituents under the conventional conditions known to those skilled in the art. The agent is packaged in a PET bag itself packaged in a carton.
    Example 4 Example of a Nutritional Composition for Man Example 4 is a 400 mg capsule consisting of:
    Therapeutic Agent of Example 1: 300mg - Vitamin C: 80mg Maltodextrin: 20mg
    The composition is obtained by mixing the constituents under the conventional conditions known to those skilled in the art, and put in a capsule according to the conventional conditions also.
    The recommended dosage is 1 to 2 capsules per day.
    Example 5: Example of a medicinal product intended for humans Example 5 is a tablet of 3,000 mg, consisting of:
    Therapeutic Agent of Example 1: 1500mg Sorbitol: 1400mg - Red fruit aroma: 47mg Magnesium stearate: 30mg
    Brilliant blue dye FCF lacquer E133: 20mg - Acesulfame K (E950): l, 5mg
    Saccharin sodium (E954): 1.5mg
    The composition is obtained by mixing the constituents under the conventional conditions known to those skilled in the art.
    The recommended dosage is 1 to 2 tablets per day.
    Example 6 Example of Animal Nutritional Composition The agent according to the invention of Example 2 was added to an extruded dog dry kibble complying with AFCO standards and comprising animal meal, fat, fiber , cereals and preservatives and antioxidants. The addition of the agent to the kibble has been done according to several embodiments, in particular by coating and by inclusion.
    Coating tests were carried out by adding the agent according to the invention to a liquid poultry appetite factor D'Tech (SPF, Elven, France). A first layer of poultry fat (6% relative to the weight of the kibble) was added in coating on the kibble, followed by a layer of mixture between the palatability factor (1%, 2% or 3%, the% being based on the weight of the kibble) and the agent according to the invention (0.02%, 0.04% or 0.1%, the% being based on the weight of the kibble).
    Inclusion tests were carried out by adding the agent according to the invention (0.02%, 0.04% or 0.1%, the% being relative to the weight of the kibble) in the raw material (also called premix) before extrusion.
    Example 7: Example of a veterinary product
    Gelatin capsules were prepared in a standard manner, adding an agent according to the invention of Example 2 and a maltodextrin (Control, Glucidexl2 lot # 421A323532, Roquette, Lestrem Cedex, France).
    Evaluation of the Efficacy and Biodisquency of the Agent According to the Invention Test 1: Effect on the Bioavailability in Mice The objective of this test is to compare the bioavailability of the polyphenols contained in the therapeutic or nutritional agent according to the invention (mixture of Example 1) with the bioavailability of the polyphenols contained in an extract of Vitis viniferaVitis vinifera and those contained in an extract of Vaccinium angustifolium (those described in Example 1), after acute oral administration (1 day) and chronic (15 days) to mice.
    Seventy-two male and female 4-month-old mice were divided into two groups to perform the acute study and the chronic study separately. In each group, three subgroups of 10 were created, each subgroup receiving a different treatment: Vitis vinifera extract, Vaccinium angustifolium extract and mixture of Example 1, and a fourth subgroup of 6 treated mice. with water (control group). The treatments are administered orally by gavage. The mixture was administered at a dose of 500 mg / kg body weight, and Vitis vinifera extract and Vaccinium angustifolium extract were administered at a dose equivalent to their amount in the mixing dose. - acute study: blood samples are taken for each group, before force-feeding then 30 minutes after force-feeding for each treatment. The animals are then sacrificed and blood samples are also taken. - chronic study: blood samples are collected before supplementation (day 0). The animals then receive their respective treatments every day for 15 days. On the last day of the study (day 15), 30 minutes after gavage, the animals are sacrificed and blood samples are collected. Feces are collected for each mouse before and during the supplementation period (day 0 and days 1 to 15 respectively).
    Phenolic metabolites are extracted from plasma samples and dry excreta by solid phase extraction (pSPE) and characterized by UHPLC-MS / MS (High Speed Liquid Chromatography). Plasma concentrations of phenolic metabolites after acute and chronic administration of the different treatments were compared using the Welch statistical test (Unequal Variance Correction) when the data were assumed to be normally distributed, or when this was not the case. using the Mann-Whitney test, with the GraphPad Prism 6.05 software. Similarly, the effects of treatments on circulating phenolic metabolite concentrations and accumulated excreta concentrations were analyzed for pairwise comparison using the Welch statistical test for normal data and the otherwise Mann-Whitney test. .
    Multiple comparisons were performed using an analysis of variance (ANOVA) or the non-parametric Kruskal-Wallis test, a test based on data in a normal distribution or not. The differences were considered significant at p <0.05.
    The hierarchical ascending classification (CAH) of phenol metabolites detected in plasma and mouse excrements was performed using MetaboAnalyst 3.0.
    The results are shown in Figures 1 to 3.
    Figure 1 shows the differences in bioavailability of phenolic compounds between acute and chronic administration of treatments. The results are given as mean ± SEM. *** P <0.005 versus acute supplementation. The term "ns" in the figure means not significant.
    It can be seen in this FIG. 1 that no difference is observed in the concentrations of circulating phenolic metabolites between acute supplementation and chronic supplementation for treatments with Vitis vinifera extract (grape) and with Vaccinium extract. angustifolium (blueberry).
    On the other hand, the repeated supplementation according to the invention, ie extract of Vitis vinifera and extract of Vaccinium angustifolium, for 15 days is associated with an increase in the concentration of phenolic compounds in the plasma (by 2.1 times, p = 0, 0033) compared to mice receiving only a single dose.
    Figure 2 represents the hierarchical ascending classification (CAFI) of phenolic metabolites analyzed in mice before (day 0) and after (day 15) chronic ingestion of the three treatments.
    Each line corresponds to a detected metabolite and each column to a studied animal. Grayscale cells indicate the intensity of plasma metabolite concentration relative to the average of all samples. The boxed graphs represent the phenolic metabolites of the extract of Vaccinium angustifolium, the concentration of which in the plasma has been significantly increased with the treatment according to the invention. The data is displayed as mean ± SEM. ** P <0.01 and p * <0.05 vs Vaccinium angustifolium B extract: extract of Vaccinium angustifolium. G: Vitis vinifera extract, N: Agent according to the invention.
    As seen on the map (heat map), it is found that there is no difference in the concentration of circulating phenolic metabolites from Vitis vinifera between a supplementation with Vitis vinifera extract (grape) and a supplementation with the agent according to the invention, whereas the phenolic metabolites derived from Vaccinium angustifolium were found more significantly in the plasma of the mice during the supplementation with the agent according to the invention than during the supplementation with the extract of Vaccinium angustifolium (blueberry). Indeed, as can be observed on the boxes, while the same amount of Vaccinium angustifolium extract is administered in both cases, with the agent according to the invention there is an increase in the absorption phenolic compounds of Vaccinium angustifolium 3.0 to 5.5 times. This increase, although lower (2.3 to 2.8 times), was also observed after the acute supplementation with agent according to the invention versus Vaccinium angustifolium extract.
    FIG. 3 represents the CAH heat map of the phenolic metabolites analyzed in the excrements of mice before (day 0) and after (days 1 to 15) the chronic ingestion of extract of Vaccinium angustifolium (blueberry), of extract Vitis vinifera (grape), and the agent according to the invention.
    Each line corresponds to the metabolite detected and each column to a studied animal. Grayscale cells indicate the concentration of phenolic metabolites in excreta relative to the average of the samples. The boxes represent the phenolic metabolites of Vaccinium angustifolium, the concentration of which in excrements was significantly decreased when the agent according to the invention was ingested versus the extract of Vaccinium angustifolium. The results were given on average ± SEM. *** p <0.005 and ** p <0.01 versus Vaccinium angustifolium B extract: extract of Vaccinium angustifolium. G: Vitis vinifera extract, N: Agent according to the invention. As observed in the blood samples, no difference was found for the phenolic metabolites of Vitis vinifera between supplementation with the agent according to the invention and supplementation with Vitis vinifera extract, whereas the phenol metabolites of Vaccinium angustifolium were found at significantly lower concentrations in mouse excrements supplemented with the agent according to the invention in comparison with supplementation with Vaccinium angustifolium extract. Indeed, as shown in the boxes, and in agreement with the previous observations showing an increase in the absorption of phenolic metabolites of Vaccinium angustifolium when supplementation with the agent according to the invention, it is also found here that such Supplementation is associated with a decrease in excretions of phenolic Vaccinium angustifolium compounds from 2.9 to 6.3 times.
    All these results demonstrate that there are synergistic interactions between extracts of Vaccinium angustifolium and Vitis vinifera leading to an increase in bioavailability.
    Trial 2: bioavailability in the mouse brain
    The purpose of this study is to determine whether polyphenols and their metabolic derivatives are able to access the central nervous system, to know if they have effects in the brain. To evaluate the presence of polyphenols in the brain, 6 control mice (3 adults and 3 elderly) and 20 supplemented mice (10 adults and 10 elderly) were fed a controlled diet free of polyphenols or with a diet enriched with the agent. according to the invention (example 1) for 6 weeks. The dose of the agent according to the invention was 500 mg / kg of body weight / day. The brains of the mice were recovered at the end of the experiment, dissected and stored at -80 ° C. Specific polyphenols and metabolites were measured by high speed liquid chromatography UPLC-MS / MS.
    The results are shown in Table 3 below, and in Figures 4A-4D.
    Table 3: Amount of Polyphenols Detected in Mouse Brain
    After 6 weeks of consumption of a diet enriched with the agent according to the invention, catechins and epicatechins and their metabolites (methyl-catechin-glucuronide, catechin-glucuronide) and ferulic acid have been found in the brains of mouse. Dimers of proanthocyanidins have also been found. These polyphenols were not found in the brains of control mice. No significant differences were found based on age. The polyphenols of the agent according to the invention, because of their particular combination and their specific amount can reach the brain directly to produce their neuroprotective effects.
    Test 3: property of polyphenols on a neuronal cell culture model
    As epicatechin, catechin and ferulic acid have been detected in the brain, the goal of this study is to test their ability to protect neuronal cells and their potential synergistic effect using different experimental models.
    For this, the SK-N-SH cells, a human neuroblast cell line, were maintained in MEM medium supplemented with 10% (V / V) FBS, 100 U / ml penicillin, 100 μg / ml streptomycin and 1% sodium pyruvate (1 mM) in a humidified incubator at 37 ° C with 5% CO2. Cells were grown to 80% confluency and then seeded in multi-well cell culture plates to perform different experimental designs. The neuroprotective effect of different compounds was analyzed by two different and complementary tests: the cell death quantification test and the cell survival test.
    The cell death test is a colorimetric test based on the measurement of lactate dehydrogenase (LDH) activity released by the cytosol of cells damaged in the supernatant. The cell survival test was performed by a Resazurin test. Resazurin is an oxidation-reduction indicator of the permeable cell that can be used to monitor the number of viable cells using the tetrazolium compounds. Viable cells with active metabolism can reduce resazurin to resorufin product that is pink and fluorescent.
    Neuronal SK-N-SH cells were subjected to a toxic concentration of hydrogen peroxide (250 μΜ) and co-treated with epicatechin, catechin or ferulic acid at 1 μΜ, lnM and lpM for 24 hours. At the end of the treatment, the cells were washed twice and cell death (LDH release) and survival (Resazurin test) were analyzed. The results showing the effects of the three polyphenols taken individually after this acute treatment are shown in Figure 5A. It is found that the polyphenols taken individually do not protect the cells against hydrogen peroxide.
    In order to study the synergistic effect of epicatechin, catechin and ferulic acid, neuronal SK-N-SH cells were subjected for 24 hours to a toxic concentration of hydrogen peroxide and co-treated with a mixture (Mix) comprising both epicatechin, catechin and ferulic acid, said mixture being tested at the different concentrations of ΙμΜ, lnM or lpM. At the end of the treatment, the cells were washed twice and cell death (LDH release) and survival (Resazurin test) were analyzed. The results showing the effects of the three polyphenols together after this acute treatment are shown in Figures 5B. It is found that the combination of the three polyphenols does not protect the cells against hydrogen peroxide.
    The neuroprotective effects of the three polyphenols, i.e. epicatechin, catechin and ferulic acid, with cumulative treatment were then studied. The SK-N-SH cells were cultured to 80% confluency and then seeded in multi-well cell culture plates. The following day, each of the three polyphenols separately was added to the medium at ΙμΜ, lnM and 1 μM for 3 consecutive days. On the third day, the cells are subjected to a toxic concentration of hydrogen peroxide (250 μΜ) and the protection was analyzed 24 hours later. At the end of the treatment, the cells were washed twice and cell survival (Resazurin test) was analyzed. Results showing the effects of the three individual polyphenols (Mix) after this cumulative treatment are shown in Figure 5C. It is found that the polyphenols taken individually do not protect the cells against hydrogen peroxide after 3 days of consecutive treatment.
    In order to study the synergistic effect of epicatechin, catechin and ferulic acid, SK-N-SH cells were cultured to 80% confluency and then seeded in multi-well plates. cellular culture. The next day, a mixture of the three polyphenols was added to the medium for 3 consecutive days, each polyphenol being present at a concentration of ΙμΜ, 1nM or 1μM in the mixture. On the third day, the cells were subjected to a toxic concentration of hydrogen peroxide (125 μΜ and 250 μΜ) and the protection was analyzed 24 hours later. At the end of the treatment, the cells were washed twice and cell survival (Resazurin test) was analyzed. Results showing the effects of mixing the three polyphenols (Mix) after this cumulative treatment are shown in Figure 5D. It is found that the mixture of epicatechin, catechin and ferulic acid at 1 μΜ or 1 nM or 1 μM protects the cells against hydrogen peroxide after 3 days of consecutive treatment.
    The same test was carried out with lower concentrations in the mixture of the three polyphenols: 10 15 M, 1018 M or 10 21 M of each polyphenol in the mixture (Mix). It is seen in Figure 5E that with these lower concentrations, the mixture does not protect the cells against toxic concentrations of hydrogen peroxide. This shows that the amount of the three specific polyphenols in the agent according to the invention is important to obtain the desired synergistic effect.
    As the mixture of the three polyphenols in a sufficient amount is able to protect the neuronal SK-N-SH cells after cumulative treatment, a study of the effect of the mixture on the intracellular production of ROS (reactive oxygen species) has then been carried out. For this, the cells were cultured to 80% confluency and then seeded in multi-well plates of cell culture. The following day, a mixture containing the three polyphenols, i.e. epicatechin, catechin and ferulic acid was added to the medium, each polyphenol being present at a concentration of ΙμΜ, 1nM or 1 μM in the mixture. On the third day, SK-N-SH cells were subjected to a toxic concentration of hydrogen peroxide (250 μΜ) and the level of ROS in the cells was measured using a DCFDA fluorescent probe. The results obtained shown in FIG. 5F show that the mixture of the three polyphenols (Mix) containing 1 μM, 1 nM or 1 μM of each of the polyphenols makes it possible to reduce the level of ROS in the presence of 250 μl of hydrogen peroxide.
    Test 4: Evaluation of the Synergistic Effect in the Dog of the Agent According to the Invention The objective of this test is to verify the effectiveness of an agent according to the invention (mixture of Example 2) on the Antioxidant status of adult dogs by comparing this efficacy to that of an extract of Vitis vinifera, an extract of Vaccinium angustifolium and a control.
    Nine Beagle dogs (6 males and 3 females, BCS (body condition score) 5/9, mean age 20 ± 0.9 months, mean weight 9.1 ± 0.4 kg) were fed a maintenance diet for maintain their body weight. The dogs diet was supplemented with gelatin capsules (Cooper, Melun Cedex, France) containing either: a maltodextrin (Placebo control; Glucidexl2 lot # 421A323532, Roquette, Lestrem Cedex, France), an extract of Vitis vinifera (Grape Neurogrape Inside PC PR120 BatchAI50288, Activ'lnside, Libourne, France), an extract of Vaccinium angustifolium (wild blueberry extract 0.4TP Lot # 294, Nutra Canada, Quebec, Canada), the mixture of Example 2 (4 mg / ml). kg of body weight / day). The experiment was designed according to a cross test where the dogs were fed experimental rations with the supplementation capsule for 28 days with a break week between each supplementation period. Each dog received each of the four supplements.
    Blood samples were taken from the jugular vein before and after each supplementation and held in ice. The plasma was recovered by centrifugation at 2124 g of the whole blood for 10 min at 40 ° C. Aliquots of plasma were incubated at 80 ° C.
    Oxidative status was assessed by measuring total antioxidant status (TAS). For this, a colorimetric test of the RANDOX laboratories (Ref: NX2332, Crumlin, County Antrim, UK) was used to evaluate the SAR. The method involves incubating 2,2'-azino-di- [3-ethylbenzthiazoline sulphonate] (ABTS) with a peroxidase (metmyoglobin) and hydrogen peroxide to produce the radical cation ABTS +. It has a relatively stable blue-green color, measured at 600 nm. The presence of antioxidants in the samples leads to the suppression of the production of this color to a degree proportional to their concentration. SAR is expressed in mmol / L.
    To compare the four regimens with each other, ATAS was determined by comparing the CAS before and after supplementation: ATAS = TAS Day 28 - TAS Baseline.
    ATAS was analyzed using a mixed model. This model includes the fixed effects of the Baseline, the treatment and the order of randomization. It has been implemented with SAS (v9.4), a mixed procedure with unstructured matrix correlation to model errors in animals. The parameters were estimated using the maximum likelihood method restricted with the Newton-Raphson algorithm. The denominator of degrees of freedom was estimated using the Satterthwaite approximation. All effects were assessed with a degree a = 0.10.
    The Wilcoxon test was used to compare changes in TAS value before and after supplementation.
    The results obtained are presented in Table 4 (mean, standard error and Wilcoxon test) and in Figure 6.
    Table 4: TAS (mmol / L) (mean ± SEM) for groups of adult dogs (n = 9) fed with different supplementation regimes: agent according to the invention (Invention), extract of Vitis vinifera (Vv). extract of Vaccinium anaustofolium (Va) or maltodextrin (Control) for 28 days
    It can be seen in the table and in FIG. 6 that the mixture according to the invention significantly and synergistically increases the TAS concentration in comparison with the Vitis vinifera extract or the Vaccinium angustofolium extract alone.
    In addition, the results of the Wilcoxon test show that the invention is the only supplementation that has significantly high SAR concentrations after supplementation. Supplementation with Vitis vinifera extracts or Vaccinium angustofolium extract alone does not alter the SAR concentration.
    Thus, the supplementation with a mixture of molecules derived from Vitis vinifera and Vaccinium angustofolium according to the invention has a synergistic effect on the total antioxidant status of the animals as compared to the supplements with an extract of Vitis vinifera and an extract of Vaccinium angustofolium alone .
    Test 5: Evaluation of the effect on the memory The objective of this study is to verify the effect of a mixture according to the invention (example 2) at two doses on the memory levels in dogs. The study is a blinded randomized preclinical study in which a longitudinal parallel group model was used. Thirty-five Beagle dogs (Vivocore Inc. colony, Toronto, Canada, 14 males and 21 females, aged between 8.0 to 14.5 years at baseline) were divided into three groups for the experiment three weeks prior to the start of the study. supplementation. The distribution of the dogs was done according to performance (cumulative scores) based on the DNMP scores ("delayed non-matching position"), so that each group had a total score substantially equivalent to the DNMP test.
    The three groups of dogs were then respectively fed with kibbles containing either 0 ppm (placebo) or 240 ppm of the mixture of Example 2, ie 480 ppm of the mixture of Example 2 (ppm relative to the weight croquette).
    The DNMP test was performed days - 27 to -16, and the analysis was performed on days 58 to 63. The DNMP test test comprises two phases: - Phase 1: the dog must move an object placed on one three possible positions on a food well. The block to move covers a reward. - Phase 2: after a wait of 20s to 90s, two objects identical to the first phase are presented to the dog. An object is located in the same position as in the first phase. Nevertheless the good object is placed at one of the two remaining positions (no match), and if the dog moves this object, he receives the reward.
    For this study, 12 DNPM test sessions were performed, with one test assignment per day for all subjects. The variable delay subtask was used. For each test assignment, delays of 20 and 90 seconds were equitably distributed across the 12 trials, allowing evaluation of the working memory. An inter-test interval of 30 seconds was applied. There were 6 sessions for the initial phase and six sessions for the treatment phase. Subjects were tested on each of the designated days regardless of the score. During all the test procedures, the animals were rewarded with Canned Dog Wet Food Purina Essential Care Adult Formula.
    In order to compare the three treatments on the DNMP results, the increase against the Baseline was analyzed using a Chi-squared test. The analysis was performed using SAS (v9.4) with a degree a = 0.05.
    The results are shown in Figure 7. A significant cognitive increase is observed when the dogs received a treatment according to the invention (Mix2) in comparison with the dogs that did not receive the treatment. In addition, the amount of treatment does not affect the number of dogs with a significant increase, which shows that in dogs the efficacy is independent of the treatment dose.
    Test 6: Evaluation of the effect on the tolerance of the dog
    The purpose of this test was to verify the food safety of the nutritional or therapeutic agent of the invention on the dog, by verifying certain renal biomarkers. Indeed, many publications have reported a toxicity of the grape on the dog, causing the latter kidney deficiencies whose symptoms result in vomiting, diarrhea, etc.. (Eubig P, Brady M, Gwaltney-Brant S, Khan S, Mazzaferro E, Morrow C (2005). "Renal failure in dogs after ingestion of grape or grapes: a retrospective evaluation of 43 dogs" (1992-2002).
    Twenty-four Beagle dogs (20 males and 4 females, BCS 5/9, mean age 31 ± 3 months, mean weight 11.4 ± 0.2 kg), were fed a maintenance diet (Royal Canin medium adult, France ) to maintain their optimal weight during the test. Four groups of 6 dogs thus each received supplements, ie capsules containing matlodextrin (placebo) or an agent according to the invention, ie the mix as prepared in Example 2 to 4 (Mix 1), (Mix 5), 40 (Mix 10) mg / kg body weight / day.
    Urine and blood samples were collected at the beginning of the trial (week 0), after 12 weeks and after 24 weeks.
    Cystatin C (CysC), clusterin and neutrophil gelatinase-associated lipocalin (NGAL) plasma and urine were analyzed in blood samples (Tvarijonaviciute A, Ceron JJ, Holden SL, Biourge V, Morris PJ, German AJ Effect of Weight Loss in Obese Dogs on Indicators of Renal Function or Disease, J. Vet Intern Med 2013; 27: 31-38.
    Garcia-Martinez JD, Tvarijonaviciute A, Ceron JJ, Calden M, martinez-Subierla S. Urinary Clusterin as a Renal Marker in Dogs. J. Vet. Diagn. Invest. 2012; 24: 301-306). Each parameter was analyzed using a mixed-effect model, evaluating the effects of baseline, day, treatment, and treatment day x (SAS v9.4; a = 0.05).
    As shown in Table 5, the biomarkers were found in amounts below the upper limit obtained with control and experimental treatments at week 0 (CysC plasma, urinary CysC / Crea ratio, urinary cluster / Creat ratio, NGAL plasma, NGAL urinary / creat respectively of 2.23 μg / mL, 156 ng / g, 443 ng / g, 47 ng / mL, 28.5 ng / g).
    Table 5
    Adult dogs consuming the agent according to the invention therefore show no clinical sign of intolerance, even at the maximum dose tested (10 times the normal dose).
    权利要求:
    Claims (13)
    [1" id="c-fr-0001]
    A nutritional or therapeutic agent comprising at least one mixture of molecules obtained from Vitis vinifera and Vaccinium angustifolium, comprising: at least 1% of catechins and / or epicatechins, the percentage being given by weight relative to the total weight of mixture, and - at least 5 ppm (parts per million in the mixture) of ferulic acid.
    [2" id="c-fr-0002]
    2. Agent according to claim 1, characterized in that the mixture of molecules comprises at least 5% of catechins and / or epicatechins, the percentage being given by weight relative to the total weight of the mixture,
    [3" id="c-fr-0003]
    3. Agent according to claim 1 or 2, characterized in that the mixture of molecules comprises at least 10 ppm (parts per million in the mixture) of ferulic acid.
    [4" id="c-fr-0004]
    4. Agent according to one of claims 1 to 3, characterized in that the mixture consists of an extract of Vitis vinifera and an extract of Vaccinium angustifolium.
    [5" id="c-fr-0005]
    5. Agent according to one of claims 1 to 3, characterized in that the mixture consists of an extract obtained from Vitis vinifera and Vaccinium angustifolium.
    [6" id="c-fr-0006]
    6. Agent according to one of claims 1 to 3, characterized in that the mixture consists of: - an extract of Vitis vinifera and / or an extract of Vaccinium angustifolium, and - an extract obtained from Vitis vinifera and Vaccinium angustifolium.
    [7" id="c-fr-0007]
    7. Agent according to one of the preceding claims, characterized in that the mixture of molecules also comprises: at least 200 ppm of resveratrol, and / or at least 50 ppm of quercetin and / or glycosides of quercetin, and / or at least 500 ppm of anthocyanidins.
    [8" id="c-fr-0008]
    8. Agent according to one of the preceding claims, for use as a medicine for humans or animals.
    [9" id="c-fr-0009]
    9. Agent according to one of claims 1 to 7, for use in the treatment or prevention in humans or animals of Alzheimer's disease and / or Parkinson's disease and / or disease of Huntington and / or pathological cognitive decline and / or dementia and / or depression and / or diabetes and / or schizophrenia and / or mental retardation and / or post-condition disorders menopause in women and / or cognitive dysfunction syndrome (CDS).
    [10" id="c-fr-0010]
    10. Agent according to one of claims 1 to 7, for its use in humans or healthy animals, to improve cognitive functions and / or executive functions, and / or to limit cognitive decline non-pathological related to age.
    [11" id="c-fr-0011]
    Agent for use according to claim 10 for improving memory and / or attention and / or concentration and / or liveliness and / or learning and / or intelligence and / or language and / or mood and / or stress and / or anxiety and / or vision and / or sleep.
    [12" id="c-fr-0012]
    12. Agent according to one of claims 1 to 7 for its use in humans or animals, to improve the bioavailability of the polyphenols contained in said agent.
    [13" id="c-fr-0013]
    13. Composition comprising a nutritional or therapeutic agent according to one of claims 1 to 7, characterized in that it is in a form selected from tablets, capsules, capsules, powders, solutions, microcapsules, suspensions, emulsions, food supplements, beverages, and food for humans or animals.
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    同族专利:
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    法律状态:
    2016-10-24| PLFP| Fee payment|Year of fee payment: 2 |
    2017-04-28| PLSC| Publication of the preliminary search report|Effective date: 20170428 |
    2017-10-26| PLFP| Fee payment|Year of fee payment: 3 |
    2018-10-25| PLFP| Fee payment|Year of fee payment: 4 |
    2019-10-28| PLFP| Fee payment|Year of fee payment: 5 |
    2020-10-27| PLFP| Fee payment|Year of fee payment: 6 |
    2021-10-27| PLFP| Fee payment|Year of fee payment: 7 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1560263|2015-10-27|
    FR1560263A|FR3042712B1|2015-10-27|2015-10-27|SPECIAL NUTRITIONAL OR THERAPEUTIC AGENT COMPRISING A MIXTURE OF GRAPE AND BLUEBERRY|FR1560263A| FR3042712B1|2015-10-27|2015-10-27|SPECIAL NUTRITIONAL OR THERAPEUTIC AGENT COMPRISING A MIXTURE OF GRAPE AND BLUEBERRY|
    KR1020187014968A| KR20180103836A|2015-10-27|2016-10-27|Special nutritional or therapeutic formulations containing a mixture of grapes and blueberries|
    CA3002753A| CA3002753A1|2015-10-27|2016-10-27|Specific nutritional or therapeutic agent including a mixture of grape and blueberry|
    EP16794958.5A| EP3368055A1|2015-10-27|2016-10-27|Specific nutritional or therapeutic agent including a mixture of grape and blueberry|
    JP2017515987A| JP2019500001A|2015-10-27|2016-10-27|Specific nutritional or therapeutic compositions comprising a mixture of grapes and blueberries|
    US15/771,328| US11266705B2|2015-10-27|2016-10-27|Specific nutritional or therapeutic agent including a mixture of grape and blueberry|
    AU2016344713A| AU2016344713B2|2015-10-27|2016-10-27|Specific nutritional or therapeutic agent including a mixture of grape and blueberry|
    PCT/EP2016/075905| WO2017072219A1|2015-10-27|2016-10-27|Specific nutritional or therapeutic agent including a mixture of grape and blueberry|
    SG11201803492TA| SG11201803492TA|2015-10-27|2016-10-27|Specific nutritional or therapeutic agent including a mixture of grape and blueberry|
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