EP3046552A1 - Zusammensetzung zur regulierung von energiezyklus-, entzündungs- und insulinresistenzfunktionsstörungen und verwendung davon insbesondere in herz-kreislauf-erkrankungen - Google Patents

Zusammensetzung zur regulierung von energiezyklus-, entzündungs- und insulinresistenzfunktionsstörungen und verwendung davon insbesondere in herz-kreislauf-erkrankungen

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Publication number
EP3046552A1
EP3046552A1 EP14744782.5A EP14744782A EP3046552A1 EP 3046552 A1 EP3046552 A1 EP 3046552A1 EP 14744782 A EP14744782 A EP 14744782A EP 3046552 A1 EP3046552 A1 EP 3046552A1
Authority
EP
European Patent Office
Prior art keywords
composition
composition according
vitamin
ampk
excipients
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP14744782.5A
Other languages
English (en)
French (fr)
Inventor
Claude Vincent
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
International Nutrition Research Co SRL
Original Assignee
International Nutrition Research Co SRL
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR1356448A external-priority patent/FR3007986A1/fr
Priority claimed from FR1356446A external-priority patent/FR3007985A1/fr
Priority claimed from FR1356444A external-priority patent/FR3007984A1/fr
Priority claimed from FR1356450A external-priority patent/FR3007987A1/fr
Application filed by International Nutrition Research Co SRL filed Critical International Nutrition Research Co SRL
Publication of EP3046552A1 publication Critical patent/EP3046552A1/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • A—HUMAN NECESSITIES
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    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
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    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Definitions

  • the present invention relates to a specific composition and its use as a health product especially for the prevention of cardiometabolic risk, for the prevention and treatment of cardiometabolic diseases, and for the prevention and treatment of infertility and / or -fertility of overweight people.
  • Metabolic syndrome refers to the presence in an individual of several clinical and biological signs that indicate the onset of heart disease and type II diabetes, although these signs are not necessarily felt by the person affected. It is characterized by the association of several manifestations, in particular an important abdominal perimeter and / or a high level of triglycerides in the blood and / or an increase in glucose intolerance (high blood sugar) and / or insulin resistance and / or or decreased arterial hypertension and / or HDL and / or increased fibrinogen and / or inflammatory adipocytokines: TNFa ("Tumor Necrosis Factor a" tumor necrosis factor a), IL6 (Interleukin 6), PAI-1 (“Plasminogen activator inhibitor-1” activator inhibitor plasminogen-1), CRP (“C-reactive protein C-reactive protein) ultrasensitive, which cause a decrease in adiponectin and serotonin which are central hormones in this type of dysfunction.
  • TNFa Tumor Necrosis Factor
  • This chronic inflammation is responsible for the formation of fatty plaques in the vessels, which are deposited on the walls (angina pectoris and arteritis of the lower limbs) and eventually rupture (infarction and stroke) by the action of one of the adipocytokines of inflammation the CRPus (ultra-sensitive reactive protein C).
  • CRPus ultra-sensitive reactive protein C
  • free radicals by the formation of their waste, interfere with the exchanges at the level of the cells causing intolerance to glucose, an insulin resistance and diabetes by a matrix remodeling of the cell.
  • the liver is particularly sensitive to the metabolic syndrome since it is the first place of deposit of triglycerides and with the increase in storage occurs a fatty liver that can evolve into NAFLD (Nonalcoholic Fatty Liver Disease non-alcoholic fatty liver disease ), NASH ("nonalcoholic steatohepatitis” nonalcoholic steatohepatitis) with fibrosis more or less important and progressive to cirrhosis and cancer.
  • NAFLD Nonalcoholic Fatty Liver Disease non-alcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • nonalcoholic steatohepatitis nonalcoholic steatohepatitis
  • the objective of the present invention is to propose a different solution acting on specific pathways of the metabolic syndrome, easy to use and effective, which is capable of preventing cardiometabolic risk, preventing fatty liver and treating pre-diabetes, but also to treat cardiovascular diseases in general and to prevent and treat infertility and sub-fertility in men and women.
  • the present invention proposes to act both on the adiponectin and serotonin levels and to provide amino acids and small active biopeptides, with an action at the cellular level on the cycle of the AMP (adenosine monophosphate) and ATP (adenosine triphosphate) energy through AMP-activated protein kinase (AMPK), MAPK ("mitogen-activated protein kinase"), PPAR ("peroxisome proliferator activated receptors”) and SIRT1 (sirtuin 1), and on the cycles of inflammation and insulin resistance.
  • AMPK AMP-activated protein kinase
  • MAPK mitogen-activated protein kinase
  • PPAR peroxisome proliferator activated receptors
  • SIRT1 sinuin 1
  • the invention provides a composition suitable for use as an oral health product, in particular as a medical or medicinal product, comprising a mixture of active ingredients consisting of at least:
  • whey hydrolyzate with a molecular weight of between 200 and 5,000 daltons
  • At least one regulator of the AMPK and / or MAPK and / or PPAR ⁇ and ⁇ and / or SIRT1 cycles in particular a thiazolinedione mimetic or agonist, chosen from the family of tocopherols and vitamin B6 and leucine and the family of branched amino acids, and
  • such a composition makes it possible to reduce visceral fat, liver fat and deep subcutaneous fat, in particular by allowing an increase in adiponectin and serotonin levels. It can be used as a health product, particularly in the prevention of cardiometabolic risk and / or hepatic steatosis and / or in the prevention and / or treatment of pre-diabetes (avoiding the transition from pre-diabetes to type II diabetes), diabetes type II, cardiovascular disease and / or infertility and / or subfertility in overweight men or women. It is involved in the regulation of the dysfunction of energy cycles, inflammation and insulin resistance.
  • it is used in addition to a life-style change involving, in particular, a particular diet, a caloric restriction, the practice of a physical activity, the management of chronic stress and the management of an anxiety state requiring a therapeutic education of the patient. patient.
  • the invention therefore relates to a composition adapted for use as an oral health product, comprising a mixture of active ingredients consisting of at least:
  • whey hydrolyzate with a molecular weight of between 200 and 5,000 daltons
  • At least one regulator of the AMPK and / or MAPK and / or PPAR ⁇ and ⁇ and / or SIRT1 cycles chosen from the tocopherol family, vitamin B6, leucine and the branched amino acid family, and
  • the composition may also contain at least one active pharmaceutical ingredient that regulates AMPK and / or MAPK cycles and / or PPARs ⁇ and ⁇ and / or
  • SIRT1 selected from metformin and statins.
  • health product within the meaning of the invention is meant any product acting in favor of human health, including a drug or a medical nutrition product.
  • medical nutrition product within the meaning of the invention is meant a therapeutic food for prevention or treatment, used alone or in combination with other therapies.
  • composition according to the invention is particularly suitable for persons wishing to lose visceral fat, hepatic fat and / or subcutaneous fat, in particular for medical reasons of primary or secondary or tertiary prevention of diseases.
  • pre diabetes pre-type II diabetes and these terms are used interchangeably to describe the present invention.
  • diabetes is defined as type II diabetes and these terms are used interchangeably to describe the present invention.
  • Cardiometabolic risk is defined as a syndrome that includes at least 3 risk factors such as waist circumference, blood glucose and blood pressure, HDL cholesterol, smoking and heredity.
  • This metabolic syndrome leads to several pathologies that are in particular: type II diabetes, atherosclerosis, ischemic coronary artery disease, cerebrovascular dementia, stroke, arterial occlusive disease of the lower limbs, metabolic infertility, liver diseases: steatosis, fibrosis, cirrhosis.
  • Whey hydrolyzate within the meaning of the invention is understood to mean any molecule or mixture of molecules obtained from whey, in particular whey hydrolysed by a process comprising a chemical hydrolysis or enzymatic hydrolysis step.
  • whey hydrolyzate In a particularly suitable way, it is a peptide hydrolyzate. It preferably comprises at least 75% of proteins or peptides, by weight of the hydrolyzate.
  • the whey hydrolyzate has a molecular weight of between 200 and 5000 daltons. Preferably at least 55% of the total molecules of the whey hydrolyzate has a molecular weight less than or equal to 1000 daltons.
  • the whey hydrolyzate consists essentially of small peptides, in particular bi and tri-peptides.
  • the size of the molecules in the hydrolyzate can be modulated by microfiltration.
  • the hydrolyzate is obtained with a hydrolysis whose level is between 15 and 35%.
  • the rate can not be higher, for the moment, at 35% because above 35% the bitterness is so pronounced that it can not be controlled and in addition the composition would have more free amino acids than active biopeptides which could cause loss of effectiveness and control of treatment.
  • Alpha lactalbumin is a nutritional active component of whey particularly rich in tryptophan and branched amino acids.
  • Milk calcium is a calcium extracted from milk and retains a therapeutic action superior to synthetic calcium due to the residual presence of small bioactive peptides.
  • AMPK and / or MAPK and / or PPAR cycle regulator a and ⁇ and / or SIRT1 means any molecule or mixture of molecules acting on at least one of the AMPK and / or MAPK and / or PPAR cycles a and y and / or or SIRT1. It could be :
  • the composition may contain one or more tocopherol (s), or vitamin B6, or leucine, or one or more acid (s) amino (s) plugged (s), or a mixture of at least two of these molecules
  • the composition may comprise metformin, or one or more statins, or a mixture of metformin and statin (s).
  • the regulator AMPK cycles and / or MAPK and / or PPAR and y and / or SIRT1 is preferably a mimetic or agonist thiazolinediones.
  • thiazolinediones mimetic is meant a molecule or mixture of molecules that fully copies the mode of action of thiazolinediones because of its similar chemical structure, but as much as possible without the disadvantages.
  • thiazolinediones means a molecule or mixture of molecules which acts in the same way as the thiazolinediones, but as much as possible without the disadvantages.
  • Thiazolinediones have the advantage of acting in particular as a regulator with a powerful action of PPARy and AMPK cycles and indirectly on SIRT1. This action mimics a caloric restriction accompanied by a physical activity.
  • the thiazolinediones mimetic or agonist is chosen from the family of tocopherols or vitamin B6 or leucine or from the family of branched amino acids. If it is tocopherol, it should preferably be a mixture of ⁇ and ⁇ tocopherol, even more preferably in proportions of 75% for ⁇ and 25% for ⁇ .
  • composition according to the invention may optionally contain one or more active pharmaceutical ingredient (s) activator (s) AMPK cycles and / or MAPK and / or PPAR a and ⁇ and / or SIRTl, chosen from the metformin and statins, including simvastatin because of its workability, but also atorvastatin, pravastatin, rosuvastatin, fluvastatin or lovastatin or a mixture of at least two of these statins.
  • active pharmaceutical ingredient s
  • activator s
  • AMPK cycles and / or MAPK and / or PPAR a and ⁇ and / or SIRTl
  • metformin and statins including simvastatin because of its workability, but also atorvastatin, pravastatin, rosuvastatin, fluvastatin or lovastatin or a mixture of at least two of these statins.
  • the amount of active pharmaceutical ingredient (s) regulator (s) AMPK cycles and / or MAPK and / or PPAR and Y and / or SIRTl is 200 to 700 mg for metformin and 2.5 to 10 mg for statins, for between 20 and 40 g of composition without excipients.
  • the different constituents of the composition act in synergy for a very effective action.
  • composition according to the invention is in particular capable of acting on the level of adiponectin.
  • Adiponectin is a molecule produced in particular by adipocytes of visceral adipose tissue. It acts at the peripheral level by two receivers through which it regulates the AMPK, MAPK, PPARa, PPARy, SIRT1 cycles and inhibits the N FKB signal.
  • adiponectin is itself dependent on several factors, including AMPK, MAPK, PPAR and SIRT1: a dephosphorylation of ⁇ , MAPK, PPAR and / or SIRT1 leads to a decrease in the secretion of adiponectin.
  • AMPK AMPK
  • MAPK MAPK
  • PPAR PPAR
  • SIRT1 SIRT1
  • ROS reactive oxygen species
  • RNS reactive nitrogen species
  • LPS lipopolysaccharide
  • HDL high density lipoprotein
  • HMV High Molecular Weight
  • adiponectin is very low in people with cardiometabolic risk, but also in obese insulin resistance, diabetics, people with lipodystrophy, people with fatty liver, NAFLD, NASH, people with hypertension and people with coronary artery disease.
  • Adiponectin is deficient in particular because of the increase of inflammatory adipocytokines, in particular TNF ⁇ , which act negatively through the transcription, translation and turnover of AMPK, MAPK, PPAR and SIRT1, causing their decrease by dephosphorylation and therefore a decrease in the secretion of adiponectin.
  • composition according to the invention makes it possible to increase the rate of circulating adiponectin and / or to regulate its secretion in the long term.
  • the presence of at least one regulator of the AMPK and / or MAPK and / or PPAR ⁇ and ⁇ and / or SIRT1 cycles makes it possible to activate AMPK and / or MAPK and / or PPAR has and ⁇ and / or SIRT1 and therefore to increase the level of adiponectin.
  • Milk calcium also increases the level of adiponectin, especially adiponectin HMW.
  • composition according to the invention is capable of acting on the level of serotonin.
  • Serotonin is a hormone that acts in particular on mood and depression, stress, sleep, food intake and deviant eating behavior such as bulimia. It is mainly found in the intestine in the chromaffin cells, but also in the platelets and in the brain.
  • the precursor of serotonin is tryptophan, which is transformed into 5HTP and then into 5HT, serotonin. Its metabolites are 5-HIAA (5-hydroxy-indol-acetic), 5-HTOL (5-hydroxy-tryptophol) and its derivatives N-acetyl-5HT and melatonin.
  • Metabolic syndrome and abdominal overweight result in serotonin deficiency. It is the inflammation of adipocytokines that leads to the breakdown of serotonin into 5HIAA in the liver. In fact, inflammation favors the kynurenic pathway.
  • the composition according to the invention makes it possible to increase the level of serotonin, in particular thanks to the tryptophan provided in particular by the whey hydrolyzate and the alpha lactalbumin, but also by the reduction of the inflammation.
  • Tryptophan should preferably represent between 6 and 9%, more preferably approximately 7% by weight of the neutral amino acids present in the composition. This particular proportion ensures that an appropriate amount of tryptophan can cross the brain barrier to be converted to serotonin.
  • the daily tryptophan intake by the composition according to the invention is preferably, for people with metabolic syndrome or pre-diabetes stage, at least 0.5 g, preferably from 0.5 to 0.8 g.
  • composition according to the invention makes it possible to supply a large quantity of high quality amino acids, in particular leucine and isoleucine, in addition to the tryptophan already mentioned.
  • Leucine is particularly capable of acting on SIRT1, AMPK and PPARy and therefore allows an increase in adiponectin.
  • hydroxybutirate the active metabolite of leucine, regulates the ⁇ -oxidation of lipids through AMPK and SIRT1.
  • the leucine can come from whey hydrolyzate and alpha lactalbumin, and it can also be used alone, as a regulator of AMPK cycles and / or MAPK and / or PPAR a and ⁇ and / or SIRT1.
  • Isoleucine induces a decrease in blood glucose by increasing the use of glucose through AMPK in particular.
  • the ratio of the weight of leucine / total amino acids of the composition is preferably between 10 and 15%, the weight ratio of leucine / neutral amino acids of the composition is preferably between 30 and 40%, and the ratio by weight of leucine / branched acids of the composition is preferably between 45 and 55%.
  • the daily intake of leucine by the composition according to the invention is preferably at least 5 g.
  • the ratio by weight of isoleucine / total amino acids of the composition is preferably between 5 and 10%
  • the ratio by weight of isoleucine / neutral amino acids of the composition is preferably between 15 and 25%
  • the ratio by weight of isoleucine / branched acids of the composition is preferably between 20 and 30%.
  • the daily intake of isoleucine by the composition according to the invention is preferably at least 2.5 g.
  • Tryptophan, leucine and isoleucine are contained in the particular whey hydrolyzate used and in alpha lactalbumin.
  • the choice of these two compounds is essential for the effect of the composition.
  • dairy whey proteins are more suitable than plant proteins which have fewer branched amino acids or the fermentation amino acids of biotechnology which have a lower activity than the amino acids of whey because of the absence of active biopeptides.
  • the shape of the whey is important that digestibility and therefore the availability of amino acids is different and plays on the chronobiology of the intake according to whether one uses concentrate, isolate or hydrolyzate.
  • the best effects to meet the objective of the invention are obtained with a hydrolyzate containing small molecules, in particular bi and tri peptides which highlight whey biopeptides.
  • the molecules of the hydrolyzate must have a size of between 200 and 5000 daltons which represent the optimum presence of whey biopeptides which are disengaged from the macro peptides.
  • For still optimized efficiency at least 55% of the total molecules of the whey hydrolyzate has a molecular weight less than or equal to 1000 daltons which corresponds to a peptide of 6 amino acids maximum.
  • alpha lactalbumin is necessary in the composition according to the invention, because the use of a whey hydrolyzate alone, even of excellent quality, is not sufficient to provide the necessary proportions and amounts of certain amino acids, especially tryptophan, leucine and isoleucine.
  • alpha lactalbumin like milk calcium, can reduce the bitterness of whey, especially in the case of hydrolysis with a rate of between 15% and 35% which increases this bitterness.
  • the alpha lactalbumin is, very preferably, present in a proportion less than or equal to 50% by weight relative to whey.
  • the ratio by weight of protein between alpha lactalbumin and the hydrolyzate is between 50/50 and 30/70.
  • the hydrolyzate mixture of lactoserum and alpha lactalbumin of the composition according to the invention should therefore preferably contain at least tryptophan, leucine and isoleucine. Even more preferentially it also contains glutamine and arginine.
  • the presence of glutamine or glutamic acid reduces the hyperpermeability of the intestinal barrier.
  • the hyperpermeability of the intestinal barrier through the passage of LPS, is involved in the activation of the N FKB signal and thus in the decrease of adiponectin and especially the increase of inflammatory adipocytokines like IL6 and TNFa.
  • the action of glutamine or glutamic acid is enhanced by the presence of leucine and arginine.
  • glutamine and / or glutamic acid represent more than 150% of the weight of the leucine present in the composition.
  • glutamine and / or glutamic acid preferably represent by weight at least 7 times arginine.
  • composition may also contain other amino acids such as valine, phenylalanine or tyrosine in particular.
  • the mixture of principles active ingredients of the composition according to the invention may comprise one or more elements added freely chosen in particular from vitamin B9 and vitamin D.
  • the composition may contain essential fatty acids, in particular omega 3s.
  • omega 3 of plant origin ALA (alpha-linolenic acid), with a high proportion of EPA (eicosapentaenoic acid). or directly from purified EPA.
  • metformin has the advantage of acting through AMPK to inhibit hepatic glycogenesis, and improves endothelial dysfunction, but is associated with many side effects that disrupt treatment such as nausea and vomiting and in the worst case lactic acidosis.
  • These intolerances can be caused in particular by a renal insufficiency but also by the mutation of the transporter gene OCT1 which causes a saturation of metformin with concentrations of 30 ⁇ 19 ng / ml whereas the daily doses of the drug were normal of 1 to 3g / day .
  • the presence of the other constituents of the composition according to the invention makes it possible to be able to lower the activator doses of the AMPK and / or MAPK and / or PPAR ⁇ and ⁇ and / or SIRT1 cycles, in particular of metformin while retaining the same activity. but without side effects.
  • the daily dose of metformin in the composition according to the invention is less than or equal to 1 g, preferably between 500 mg and 1 g.
  • the composition may also contain additional constituents known to improve the adaptation of the AMPK, MAPK, PPAR and SIRT1 cycles such as zinc, chromium, curcumin, SOD, catalase, glutathione, resveratrol and or anthocyanins.
  • Curcumin at a low dose so as not to reach its pro-oxidant threshold, reduces the hyperpermeability of the intestinal barrier such as glutamine.
  • SOD, catalase and glutathione by their powerful antioxidant role, attack the ROS and indirectly modulate the N FKB signal of inflammation and therefore participate in an increase in the secretion of adiponectin.
  • SOD also acts on the prevention of ⁇ -oxidation of LDL.
  • Resveratrol, anthocyanins and curcumin act at the level of PPAR and AM PK.
  • the various constituents of the composition according to the invention act in synergy to provide surprising effects particularly adapted to the prevention of cardiometabolic risk and hepatic steatosis and to the treatment of the state of pre-diabetes.
  • the mixture of active ingredients of the composition according to the invention comprises at least:
  • composition may also contain freely added elements, such as vitamins and minerals, in addition to the native components of the hydrolyzate, alpha lactalbumin, or the regulators of the AM PK and / or MAPK cycles and / or PPAR a and ⁇ and / or SI RT1.
  • freely added elements such as vitamins and minerals, in addition to the native components of the hydrolyzate, alpha lactalbumin, or the regulators of the AM PK and / or MAPK cycles and / or PPAR a and ⁇ and / or SI RT1.
  • composition according to the invention is preferably constituted by at least:
  • the percentages being given, by weight of dry matter, of all the active ingredients present in the composition (apart from any excipients), a part of the constituents originating from the hydrolyzate, alpha lactalbumin or AMPK cycle regulator (s). and / or MAPK and / or PPAR a and ⁇ and / or SIRT1 and milk calcium and the remainder being freely added in the form of vitamins, minerals and fatty acids.
  • the mixture of active ingredients of the composition according to the invention comprises at least:
  • SIRT1 chosen from the family of tocopherols, vitamin B6, leucine, the family of branched amino acids, for between 20 and 40 g of composition composition without excipients, and
  • composition may also contain freely added elements, such as vitamins and minerals, in addition to the native components of the hydrolyzate, alpha lactalbumin, AMPK and / or MAPK cycle regulator (s) and / or or PPAR a and ⁇ and / or SIRT1.
  • freely added elements such as vitamins and minerals, in addition to the native components of the hydrolyzate, alpha lactalbumin, AMPK and / or MAPK cycle regulator (s) and / or or PPAR a and ⁇ and / or SIRT1.
  • composition according to the invention may consist of at least:
  • the branched amino acids of the above variant compositions consist of leucine, isoleucine and valine, preferentially:
  • composition according to the invention can be obtained by a process as described below:
  • obtaining a first mixture by mixing the constituents in the following order: whey hydrolyzate, alpha lactalbumin and milk calcium; the pH should be around 7 and stabilized at this level,
  • composition may be supplemented with conventional excipients and fillers known to those skilled in the art.
  • a powder is thus obtained which can be converted into a tablet or liquid, or used in its powder form in sachets, sticks, cans or capsules, for example.
  • it is in the form of powder or granules packaged in a bag to be diluted in water. It can also be in the form of ready-to-use beverage, food bars or extruded bars.
  • composition according to the invention when it is administered orally in sufficient quantity, allows in particular:
  • composition according to the invention make it possible in particular to increase the secretion of adiponectin and serotonin, to reduce inflammatory adipocytokines and insulin resistance for an action on the loss of visceral fat, liver fat and fat under -cutaneous deep.
  • composition according to the invention acts as an appetite suppressant and provides a feeling of satiety thanks to the increase of the rate of serotonin, and by the action of branched amino acids and milk calcium.
  • the composition according to the invention also makes it possible to lose visceral fat for a long time, in particular by:
  • composition according to the invention is also capable of acting on many other factors of cardiometabolic risk.
  • it is able to reduce stress, normalize blood pressure, reduce IL6 inflammation, TNFa, PAI-1 and CRP ultrasensitive, limit clotting (fibrinogen), regulate cholesterol and triglycerides, to reduce blood glucose and postprandial glucose, insulinemia and, more generally, to regulate cell energy cycles by regulating the APM / TP ratio through the AMPK, MAPK, PPAR a and ⁇ cycles and SIRT1.
  • the invention therefore relates to the composition as described above for its application as a health product, in particular as a medicament or as an oral medical nutrition product for the prevention of cardiometabolic risk and / or for the prevention of hepatic steatosis and / or for the prevention and / or treatment of the state of type II pre-diabetes (and thus fight against the onset of type II diabetes), type II diabetes, cardiometabolic diseases and / or infertility and / or sub-fertility in humans.
  • composition according to the invention can be used as a health product to reduce visceral fat and deep subcutaneous fat in people overweight.
  • the health product can specifically be used to decrease visceral fat and deep subcutaneous fat in overweight and / or to reduce waist circumference and / or reduce stress and / or normalize blood pressure and / or or to limit the oxidation and / or decrease the ultrasensitive CRP inflammation and / or to limit coagulation and / or to regulate cholesterol and triglycerides and / or to lower blood glucose and blood sugar post prandial and / or insulinemia and / or decrease hypersensitivity of the intestinal barrier and / or rebalance the intestinal flora and / or fight against type II diabetes.
  • composition according to the invention is preferably between 40 and 80 g, more preferably in two doses of between 20 and 40 g distributed a time (usually 1 hour) before lunch and the other before dinner.
  • the bioavailability in the body of the amino acids, peptides and proteins present in the composition is between 10 and 30 minutes, which allows a rapid action to trigger satiety so as to limit the amount of food to be taken during the meal next .
  • the presence of milk calcium, with alpha lactalbumin improve the palatability of the dietary product according to the invention by masking in particular the bitter taste of the whey hydrolyzate, so that they participate in removing the risk that people will stop eating it for reasons of taste and abandon their diet before its end.
  • the combination of fatty acids, in particular EPA, with the milk calcium and the particular amino acid mixture according to the invention and the released biopeptides also makes it possible to slow down the transformation of the preadipocytes into visceral adipocytes by regulation of PCM. -1 ("Monocyte chemoattractant protein 1"), to limit the action of macrophages visceral adipose tissue and accelerate lipolysis of visceral adipocytes.
  • PCM. -1 Monocyte chemoattractant protein 1
  • the invention also allows:
  • composition can therefore be used as an oral health product, acting:
  • composition according to the invention in particular the variant containing metformin and / or statins, can be used in particular as a medicament for the treatment of metabolic syndrome and the prevention and / or treatment of cardiometabolic diseases.
  • a composition makes it possible to treat the metabolic syndrome by decreasing visceral fat, liver fat and deep subcutaneous fat, in particular by increasing the level of adiponectin and serotonin.
  • the combined presence of at least one activating pharmaceutical active ingredient of the AMPK, MAPK, PPAR ⁇ and ⁇ and / or SIRT1 cycles, and at least one nutritional regulator of the AMPK, MAPK, PPAR ⁇ and ⁇ cycles and or SIRT1 activates AMPK, MAPK, PPARa, PPARy and / or SIRT1 and thus increases the level of adiponectin.
  • composition according to the invention can be used as a health product, especially as a medicament for prevention and primary, secondary and tertiary treatment of cardiometabolic diseases.
  • a health product especially as a medicament for prevention and primary, secondary and tertiary treatment of cardiometabolic diseases.
  • it can be used to fight cardiometabolic risk factors but also cardiometabolic diseases including:
  • cardiovascular diseases such as hypertension, arteritis of the lower limbs, coronary heart disease, after-effects of infarction or cerebral stroke,
  • hyperlipidemia and in particular hyperlipidemia of type II diabetes
  • composition variant containing metformin and / or one or more statin (s) makes it possible to synergize the pharmacological effects of the active principle (s) active (s) pharmaceutical (s) and the same effects of the active ingredients nutritional such as amino acids and small active biopeptides contained in whey hydrolyzate and alpha lactalbumin as well as nutritional regulators of AMPK and / or MAPK and / or PPAR cycles a and ⁇ and / or SIRT1, and calcium of milk.
  • the composition according to the invention thus makes it possible to preserve and even increase the effectiveness of the treatment by reducing the doses of the pharmaceutical active ingredient (s) in order to minimize or cancel their undesirable side effects.
  • the activating pharmaceutical active ingredients of the AMPK, MAPK, PPAR ⁇ and ⁇ and / or SIRT1 cycles are known to increase the level of adiponectin, but at doses causing significant adverse effects, in particular myalgias. muscle for statins and manifestations ranging from simple stomach upset to lactic acidosis, which can be fatal, to nausea and vomiting for metformin.
  • composition according to the invention in particular the variant containing metformin and / or one or more statin (s), also makes it possible to improve fertility in overweight men and women, in particular in persons at risk.
  • cardiometabolic in particular increasing the rate of adiponectin, to decrease the inflammatory adipocytokines and the insulin resistance which are the triggering factors of this infertility and / or under fertility, in particular the syndrome of the polykistic ovaries in the woman and the quantity and quality of the sperm in the man.
  • composition allows the treatment of infertility and sub-fertility in general, in particular infertility or sub-fertility in men or women with a decrease in adiponectin and / or an increase in inflammatory adipocytokines and insulinemia.
  • the invention is specifically directed to the use of the composition as a medicament for the treatment of infertility or sub-fertility in men or women with: - a waist circumference outside the IDF 2005 standards (80/94 cm), and / or
  • composition can be used in particular:
  • composition according to the invention is particularly suitable for the treatment of metabolic infertility or metabolic sub-fertility.
  • metabolic infertility or metabolic sub-fertility means infertility or sub-fertility so the cause is a metabolic dysfunction that results in a metabolic syndrome in particular a waist circumference above international standards and / or insulin resistance or type II diabetes and / or dyslipidemia and / or hepatic steatosis and / or low grade chronic inflammation and / or an anxiety or depressive state.
  • This metabolic infertility is clinically translated by polykistic ovaries, endometriosis, anovulation, dysovulation, oligozoospermia, asthenozoospermia or erectile dysfunction.
  • compositions act in synergy for a very effective action on the improvement of fertility in men or women, in particular in men or women with a metabolic syndrome.
  • composition according to the invention is in particular capable of acting on the level of adiponectin, inflammation and insulinemia.
  • the level of adiponectin is generally very low in infertile persons whereas the CRPus and TNFa levels are elevated insulin levels, especially in people with polykistic ovaries, endometriosis, oligozoospermia, asthenozoospermia or erectile dysfunction.
  • the disruption of adiponectin levels or of its mechanism of action caused by inflammation is associated with a disturbance of fertility and fertility.
  • adipocytokines is essential for the maintenance of the integrity of the hypothalamic-pituitary-ovarian axis, ovulation, successful nesting and the course of pregnancy.
  • Adiponectin is positively bound with SHBG and negatively with testosterone and TNFa.
  • the reproductive system is coupled with energy balance.
  • AMPK and PPAR ⁇ and ⁇ play a major role in intervening in the regulation of ovarian function in women, since they regulate steroidogenesis of granulosa cells and oocyte maturation.
  • Some hormones involved in metabolism use AMPK as a signal molecule to transmit their central and ovarian effects on reproductive function. Disruption of this system is at the origin of pathologies such as polykistic ovary syndrome and endometriosis.
  • an action on testosterone a decrease in women in polykistic ovaries and an increase in men in sub-fertility or metabolic infertility.
  • composition according to the invention is capable of acting on the level of serotonin.
  • women with polykistic ovarian syndrome also have a low level of serotonin.
  • Men with infertility due to a metabolic syndrome or diabetes or who have continuous erectile dysfunction may have a low serotonin level of less than 80 ng / ml responsible for oligospermia.
  • composition according to the invention in particular the composition variant comprising metformin and / or one or more statin (s), can be used specifically as a health product, in particular as a medicament, for the prevention of atherosclerosis.
  • Atherosclerosis is characterized by a deposit of lipids on the intima of the arteries forming a nucleus which fills with fibers of lipid deposits, foam cells and finally macrophages that secrete adipocytokines.
  • the final phase is calcification of the atheroma plaque.
  • the genesis of atherosclerosis is the same as that of the metabolic syndrome; these include excess cholesterol, triglycerides, hypertension, abdominal obesity, type II diabetes, smoking, chronic stress, sedentary lifestyle, pollution, and family history. There is therefore a great similarity between atherosclerosis and the metabolic syndrome, although the consequence of atherosclerosis may be a single dyslipidemia related to inflammation.
  • Adiponectin The level of adiponectin is very low and the levels of inflammation and insulinemia are high in people with atherosclerosis. Adiponectin is deficient in particular because of the increase of inflammatory adipocytokines, in particular TNFa, which act negatively through the transcription, translation and turnover of AMPK, MAPK, PPAR and SIRT1, causing their decrease by dephosphorylation and therefore a decrease in the secretion of adiponectin.
  • composition according to the invention makes it possible to increase the rate of circulating adiponectin and / or to regulate its secretion in the long term.
  • composition according to the invention is capable of acting on the level of serotonin.
  • the invention also allows: to prevent the formation and rupture of atheroma plaques, in particular by significantly decreasing the secretion of inflammatory adipocytokines, in particular CRP us, so as to prevent cardiovascular events,
  • composition according to the invention can therefore be used as a health product for different therapeutic applications.
  • composition comprising a mixture of active ingredients consisting of at least:
  • whey hydrolyzate with a molecular weight of between 200 and 5,000 daltons
  • At least one regulator of the AMPK and / or MAPK and / or PPAR ⁇ and ⁇ and / or SIRT1 cycles chosen from the tocopherol family, vitamin B6, leucine and the branched amino acid family, and
  • ⁇ о ⁇ ение may be used preferentially to prevent cardiometabolic risk, to prevent hepatic steatosis and / or to treat pre-diabetes and type II diabetes, particularly as a medical nutrition product.
  • composition comprising a mixture of active ingredients consisting of at least:
  • whey hydrolyzate with a molecular weight of between 200 and 5,000 daltons
  • At least one regulator of the AMPK and / or MAPK and / or PPAR ⁇ and ⁇ and / or SIRT1 cycles may be used preferentially to prevent cardiometabolic risk, prevent and / or treat hepatic steatosis and / or prevent and / or treat pre-diabetes and type II diabetes, prevent and / or treat cardiovascular disease, prevent and / or treat infertility or sub-fertility, prevent atherosclerosis, especially as a drug.
  • the invention is now illustrated by non-limiting examples of compositions in the form of a 40 g powder (active ingredients and excipients) packaged in a bag, suitable for use as a health product.
  • composition is obtained from the following active ingredients:
  • alpha lactalbumin including 12 g of proteins / peptides
  • vitamin E preferably in the form of a mixture of tocopherol
  • composition comprises in whey and alpha lactalbumin:
  • the product When administered twice a day (one sachet before lunch and one packet before dinner) for at least 120 days in patients with signs of cardiometabolic risk, the product is administered twice daily. waist circumference of about 5% compared to the initial waistline, which is characterized by a significant decrease in fat and in particular visceral and subcutaneous fat. Administration for 200 to 240 days, allows a loss of 10% of the waist compared to the initial waist.
  • the loss of fat mass is usually greater than the total weight loss which implies a relative increase in lean mass because it does not fall with the invention because of the composition and in particular branched amino acids and leucine.
  • the composition according to the invention makes it possible in particular to reduce visceral fat between 5 and 10%, depending on the treatment time, of the total starting weight, this reduction being significant of the reduction of the risk of cardiometabolic diseases. It is reflected in particular by:
  • Example 2 of composition and use for the prevention / treatment of pre diabetes, diabetes and sub-fertility and metabolic infertility
  • composition is obtained from the following active ingredients:
  • alpha lactalbumin including 12 g of proteins / peptides
  • vitamin E preferably in the form of a mixture of tocopherol
  • This composition comprises:
  • composition 2 for Pre-diabetes and Diabetes
  • the composition makes it possible in particular to reduce the visceral fat between 5 and 10%, depending on the treatment time, of the total starting weight, this reduction being significant of the reduction of the risk of diabetic diseases. It is reflected in particular by:
  • composition 2 for the Prevention and / or Treatment of Infertility or Sub-Fertility:
  • Example 2 When the composition of Example 2 is administered twice daily (one sachet before breakfast and one sachet before dinner) for at least 120 days, in patients presenting with signs associated with cardiometabolic risk, particular mention is made of a decrease in waist circumference of around 5% compared to the initial waist circumference, which characterized by a significant decrease in fat and in particular visceral and subcutaneous deep fat. Administration for 200 to 240 days, allows a loss of 10% of the waist compared to the initial waist. Fat loss is usually greater than total weight loss which implies a relative increase in lean body mass.
  • composition according to the invention makes it possible in particular to reduce visceral fat between 5 and 10% (depending on the treatment time) of the total starting weight, this reduction being significant of the reduction of the risk of sub-fertility and infertility, in particular. subfertility and metabolic infertility, and cardiometabolic diseases. It is reflected in particular by:
  • LH leukinizing hormone
  • Composition Example 3 and its Use for Secondary and Tertiary Primary Prevention and Treatment of Cardiovascular Diseases and Atherosclerosis
  • composition is obtained from the following active ingredients:
  • alpha lactalbumin including 12 g of proteins / peptides, - 5 mg of simvastatin,
  • vitamin E preferably in the form of a mixture of tocopherol
  • This composition comprises:
  • Composition 3 for the Prevention and Treatment of Cardiovascular Diseases
  • composition 3 for the Prevention of Atherosclerosis
  • normalization of systolic and diastolic blood pressure improvement of homeostasis factors such as fibrinogen, matrix remodeling with improved membrane elasticity, normalization of CRP us and plasma and adipocyte markers of inflammation increased adipocyte adipocyte and plasma serotonin increase.
  • composition is obtained from the following active ingredients:
  • alpha lactalbumin including 12 g of proteins / peptides
  • vitamin E preferably in the form of a mixture of tocopherol
  • This composition comprises:
  • Example 2 When administering the composition of Example 2 in a course of treatment twice a day (a sachet before lunch and a sachet before dinner) for at least 120 days, in patients presenting signs associated with atherosclerosis and / or at the dysfunction of the metabolic survivalillisme, one notes a decrease in the circumference of the order of 5% compared to the initial waistline, which is characterized by a significant decrease in fat and in particular visceral and subcutaneous deep fat. Administration for 200 to 240 days, allows a loss of 10% of the waist compared to the initial waist. Fat loss is usually greater than total weight loss which implies a relative increase in lean body mass.
  • composition according to the invention makes it possible in particular to reduce the visceral fat between 5 and 10%, depending on the treatment time, of the total starting weight, this reduction being significant of the reduction of the risks related to diabetes especially associated with high triglycerides which according to prevalence studies are the most dangerous associations for a cardiovascular event. It is reflected in particular by:
  • adipocyte and plasma adiponectin increase
  • composition according to the invention is accompanied by a change in lifestyle to further enhance its effects. Indeed, in chronic diseases, the problem is more complicated than in the case of an acute disease where it is usually enough to make the diagnosis, to formulate the treatment, to inform the patient and to follow through analyzes the treatment results and adapt it if necessary.
  • the composition according to the invention is therefore preferably used as a health product in addition to a change in lifestyle to support the treatment in the context of the increase in adiponectin and serotonin, the decrease in insulinemia and inflammation in particular.
  • composition according to the invention is preferably used as a health product in addition to:
  • the diet should in particular include a consumption of carbohydrates with a low glycemic load (or glycemic index) in general of less than 20 and / or a consumption of soluble and insoluble fibers and / or a suppression of saturated fatty acids and the partial replacement of these acids.
  • the goal of such a diet is to limit postprandial blood glucose and related inflammation peaks that cause cardiovascular events, to limit the excessive oxidation of carbohydrates, to lower the inflammation of adipocytokines, to stop from the transformation of preadipocytes into adipocytes and the infiltration of macrophages and finally the lipolysis of visceral adipocytes.
  • the drastic limitation of the glycation products makes it possible to lower the inflammation, this requires a change that is often radical in the cooking methods, in particular fried foods.
  • the intake of omega 3 and non-fat animal protein from fish and white meat can also promote lipolysis especially in the liver. In addition, it significantly increases adiponectin.
  • caloric restriction it increases SIRT1 and therefore promotes an increase in adiponectin levels.
  • the management of chronic stress is preferably carried out by holistic methods or specific or general physical activities to lower the circulating cortisol. This chronic stress management has an impact on AMPK, MAPK, PPARy and SIRTl.
  • the management of the anxious or depressive tendency can be achieved by holistic methods or specific or general physical activities.
  • the intake of tryptophan and therefore serotonin can improve the anxiety or depressive background common to many overweight people.
  • the production of cerebral serotonin the quality of sleep is improved.
  • weight loss and fat mass sleep apnea often disappear.
  • Caloric restriction and increased physical activity act on the AMPK, PPAR and SIRT1 cycles in a significant way and conversely, the biochemical increase of AMPK, PPAR and SIRT1 mimics the action of caloric restriction and physical activity. This is why the combination of a composition capable of increasing AMPK, PPAR and SIRTl, and a caloric restriction associated with physical activity has an extremely favorable impact on the prevention of cardiometabolic and steatosis risk factors. hepatic and pre diabetes treatment.
  • composition supplemented by a change in lifestyle requires self-management of the patient which requires in particular a therapeutic education of the patient.
  • the use of the health product composition is accompanied by a process comprising in particular:
  • Therapeutic patient education requires two conditions:
  • Patient motivation in the health setting is difficult to implement when it comes to lifestyle change, especially if it is aimed at a change of more than 20% of habits that are rooted in the patient's personality (family, region, religion, social milieu, professional environment, etc.).
  • the use of the composition as a health product is also accompanied by the determination of a waistline reduction target.
  • the difficulty lies in the number of people concerned, since the metabolic syndrome affects 25 to 35% of the adult population is millions of people.
  • the medical and paramedical structures are not capable of forming such a mass of population. It is therefore preferable to use e-health in a personalized way but also standardized by phenotypes because the contact must be frequent, ideally every day.
  • the use of the composition as a health product is also accompanied by training the patient in a lifestyle change by example and by training effect.
  • the use of the composition as a health product can be accompanied by a therapeutic e-health teaching, in particular by the use of a medical video game in which an avatar of the patient evolves as his model.
  • the patient provides information on their medical data and evolutions, as well as information on the health product's intake, diet, caloric restriction, chronic stress, depressive tendency and pharmacological medication if necessary.
  • the avatar reacts like the patient who will then receive messages according to his positive or negative evolution. Each evolution of the avatar is explained with a teaching on the positive or negative points.
  • the invention therefore also relates to the use of the composition as a health product accompanied by a method of therapeutic education including in particular: - the motivation of the patient by the determination of a waistline reduction target, and / or

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EP14744782.5A 2013-07-02 2014-07-02 Zusammensetzung zur regulierung von energiezyklus-, entzündungs- und insulinresistenzfunktionsstörungen und verwendung davon insbesondere in herz-kreislauf-erkrankungen Withdrawn EP3046552A1 (de)

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FR1356448A FR3007986A1 (fr) 2013-07-02 2013-07-02 Medicament destine a lutter contre l'infertilite et la sous-fertilite en particulier dans le cadre d'une sous fertilite ou infertilite metabolique
FR1356446A FR3007985A1 (fr) 2013-07-02 2013-07-02 Medicament pour la prevention et le traitement des facteurs de risques cardiometaboliques, en particulier maladies cardiovasculaires, pre-diabete, diabete de type ii et steatose hepatique
FR1356444A FR3007984A1 (fr) 2013-07-02 2013-07-02 Produit de nutrition medicale destine a la prevention du risque cardiometabolique et de la steatose hepatique et au traitement du pre diabete
FR1356450A FR3007987A1 (fr) 2013-07-02 2013-07-02 Medicament pour la prevention et le traitement de l'atherosclerose et du survieillissement metabolique
PCT/EP2014/064110 WO2015000986A1 (fr) 2013-07-02 2014-07-02 Composition intervenant dans la regulation du dysfonctionnement des cycles de l'energie, de l'inflammation et de l'insulinoresistance et son utilisation notamment dans les maladies cardiometaboliques

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FR3032883B1 (fr) * 2015-02-24 2017-03-17 International Nutrition Res Company Composition pour la prevention et le traitement de la steatose et de la steatohepatite metaboliques
FR3079142B1 (fr) * 2018-03-23 2020-11-27 Matieres Premieres Int Composition veterinaire comprenant de la superoxyde dismutase et au moins un hydrolysat de proteines riche en peptides bioassimilables
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EP1339429A4 (de) * 2000-11-29 2007-03-14 Smithkline Beecham Corp Zusammensetzung enthaltend statine und calcium für verbesserte kardiovaskuläre gesundheit
US20120214771A1 (en) * 2001-07-27 2012-08-23 Fontini Sampalis Compositions for treatment of cardiometabolic disorders
WO2004022083A1 (en) * 2002-09-04 2004-03-18 Dsm Ip Assets B.V. A nutritional and therapeutic composition of an insulin sensitizer and a peptide fraction
CN101084004A (zh) * 2004-12-22 2007-12-05 帝斯曼知识产权资产管理有限公司 单个酶促步骤中的血压降低寡肽
WO2009115331A2 (en) * 2008-03-20 2009-09-24 University Of Limerick Protein product for modifying cardiovascular health
US8486922B2 (en) * 2010-04-28 2013-07-16 Chien-Hung Chen Composition
US20120177631A1 (en) * 2011-01-10 2012-07-12 Morteza Naghavi Composition for Health Promoting Compounds
US20150038589A1 (en) * 2011-07-22 2015-02-05 Karel Paul Bouter Nutritional Product Comprising a Biguanide
FR2981545B1 (fr) * 2011-10-25 2014-07-11 Internat Nutrition Res Company Produit dietetique destine a la diminution de la graisse viscerale en preoperatoire bariatrique
FR2981544B1 (fr) * 2011-10-25 2014-01-31 Internat Nutrition Res Company Produit dietetique destine a la prevention du risque cardiometabolique

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