NL1036746C2 - KIT OF PARTS CONTAINING L-GLUTAMINE AND EGCG. - Google Patents
KIT OF PARTS CONTAINING L-GLUTAMINE AND EGCG. Download PDFInfo
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- NL1036746C2 NL1036746C2 NL1036746A NL1036746A NL1036746C2 NL 1036746 C2 NL1036746 C2 NL 1036746C2 NL 1036746 A NL1036746 A NL 1036746A NL 1036746 A NL1036746 A NL 1036746A NL 1036746 C2 NL1036746 C2 NL 1036746C2
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- glutamine
- egcg
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT 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
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Polymers & Plastics (AREA)
- Pharmacology & Pharmacy (AREA)
- Mycology (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nutrition Science (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Botany (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Kit van onderdelen bevattende L-Glutamine en EGCGKit of parts containing L-Glutamine and EGCG
De uitvinding heeft betrekking op een kit van onderdelen ter bestendiging of 5 verbetering van de gezondheidstoestand en de toepassing van een dergelijke kit. De uitvinding heeft verder betrekking op een werkwijze ter bereiding van een dergelijke kit van onderdelen.The invention relates to a kit of parts for perpetuating or improving the health condition and the use of such a kit. The invention further relates to a method for preparing such a kit of parts.
Er is een voortdurende grote behoefte aan stoffen die gunstig zijn voor de gezondheidstoestand. Daarbij staan in het bijzonder voedingssupplementen in de 10 belangstelling die in het algemeen worden beschouwd als veilig om toe te dienen en te gebruiken. Twee belangrijke groepen voedingssupplementen worden gevormd door aan de ene kant aminozuren en aan de andere kant antioxidanten zoals bij voorbeeld polifenolen. Een groep van polifenolen met sterke antioxidatieve eigenschappen wordt gevormd door de catechinen die in groene thee voorkomen zoals bij voorbeeld (-)-15 epicatechine (EC), (-)-epigallocatechine gallaat (EGCG), epigallocatechine (EGC) en epicatechine gallaat (ECG).There is a continuing high need for substances that are beneficial to health status. Special attention is given to nutritional supplements that are generally considered to be safe for administration and use. Two important groups of dietary supplements are formed on the one hand by amino acids and on the other by antioxidants such as polyphenols. A group of polyphenols with strong anti-oxidative properties is formed by the catechins that occur in green tea such as (-) - epicatechin (EC), (-) - epigallocatechin gallate (EGCG), epigallocatechin (EGC) and epicatechin gallate (ECG) ).
Zowel uit prospectief, placebo gecontroleerd, gerandomiseerd klinisch vergelijkend onderzoek alsook uit dierexperimenteel en in vitro onderzoek gebruikmakend van het kweken van specifieke cellijnen blijkt dat natuurlijke 20 aminozuren en de daarvan totaal verschillende antioxidatieve polifenolen beiden een werking hebben op een aantal voor bestendiging of verbetering van de gezondheidstoestand belangrijke indicatiegebieden.Prospective, placebo-controlled, randomized clinical comparative studies as well as animal experimental and in vitro studies using specific cell lines show that natural amino acids and their totally different antioxidative polyphenols both have an effect on a number for sustaining or improving the health status important indication areas.
Het eerste indicatiegebied betreft de gunstige invloed van natuurlijke aminozuren en antioxidatieve polifenolen op de vermindering van de kans op het 25 krijgen van hart- en vaatziekten met name van arteriosclerose en diabetes mellitus, met name type-2. Een dyslipidemie zich uitend in een verhoogd cholesterol, verhoging van het LDL cholesterol en verlaging van het HDL cholesterol met verhoging van de triglyceriden, diabetes mellitus type-2, hypertensie en overgewicht zijn naast roken en een tekort aan dagelijkse lichamelijke inspanning de belangrijkste risico factoren op het 30 krijgen van hart-en vaatziekten door arteriosclerose. In geval van diabetes mellitus type-2 vormen insuline resistentie en een verminderde insuline secretie door de β-cellen in het pancreas pathogene sleutelfactoren.The first indication area concerns the beneficial influence of natural amino acids and antioxidative polyphenols on the reduction of the risk of developing cardiovascular diseases, in particular of arteriosclerosis and diabetes mellitus, in particular type-2. In addition to smoking and a lack of daily physical exertion, a dyslipidemia manifested in elevated cholesterol, elevation of LDL cholesterol and reduction of HDL cholesterol with elevation of triglycerides, type 2 diabetes mellitus, hypertension and overweight are the most important risk factors. getting heart disease from arteriosclerosis. In case of type 2 diabetes mellitus, insulin resistance and reduced insulin secretion by the β cells in the pancreas form pathogenic key factors.
Wat natuurlijke aminozuren betreft: 1 0 3 67 46 2 - Er zijn klinische trials die laten zien dat de parenterale suppletie van het aminozuur L-glutamine in de vorm van een di-peptide de glucose tolerantie verhoogt door: 1- vermindering van de insuline resistentie (1), waardoor het glucose verbruik 5 door het lichaam verbetert (2) en 2- verhoging van de insuline plasma spiegel (3).With regard to natural amino acids: 1 0 3 67 46 2 - There are clinical trials that show that parenteral supplementation of the amino acid L-glutamine in the form of a di-peptide increases glucose tolerance by: 1- reduction in insulin resistance (1), which improves glucose consumption by the body (2) and 2 increases insulin plasma levels (3).
Dit laatste verloopt waarschijnlijk door een relatief zwakke stimulatie van de insuline afgifte door β-cellen via stimulatie van de gamma-glutamyl cyclus gemedieerde glutathion productie en de productie van ATP door mitochondriale oxidatie. Bij deze 10 stimulatie van de insuline secretie speelt het natuurlijk aminozuur glutamine waarschijnlijk een signaaloverdragende rol (4,48).The latter is probably due to relatively weak stimulation of the insulin release by β-cells via stimulation of the gamma-glutamyl cycle mediated glutathione production and the production of ATP by mitochondrial oxidation. In this stimulation of insulin secretion, the natural amino acid glutamine probably plays a signal-transmitting role (4.48).
- Oraal toegediend L-Glutamine bevordert tevens via incretine afhankelijke mechanismen de afgifte van GLP-1 (glucagons-like peptide 1) door de L-cellen van de darmwand dat de secretie van insuline doet toenemen zowel bij magere 15 als dikke patiënten met type-2 diabetic mellitus (5).- Orally administered L-Glutamine also promotes the release of GLP-1 (glucagons-like peptide 1) through the L-cells of the intestinal wall through incretin-dependent mechanisms, which increases insulin secretion in both lean and overweight patients with type 1 2 diabetic mellitus (5).
Wat antioxidatieve polifenolen betreft: - deze hebben een regulerende invloed op de insuline secretie door β-cellen in het pancreas door een allosterische remming van het glutamaat dehydrogenase (GDH). EGCG heeft een positieve invloed op de glucose tolerantie / diabetes type-2, van 20 knaagdieren (7) en waarschijnlijk op de diabetische retinopathie bij de mens (8); - deze verbeteren de glucose tolerantie door vermindering van de insuline resistentie bij de mens en verhogen de vetoxidatie bij matig intensieve lichamelijke inspanning (9); - deze hebben daarnaast in diermodellen, vermoedelijk als anti-oxidant, een gunstige invloed op de ontwikkeling van arteriosclerose, de bloeddruk, obesitas/overgewicht 25 (10). Het polifenol EGCG verlaagt ook bij de mens het cholesterol (t 1) en gaat de stijging van de triglyceriden na de maaltijd tegen (12). Ook is een gunstig resultaat ter preventie van diabetes mellitus type 2 beschreven bij volwassenen (13).With regard to antioxidative polyphenols: - these have a regulating influence on the insulin secretion by β-cells in the pancreas through an allosteric inhibition of the glutamate dehydrogenase (GDH). EGCG has a positive influence on glucose tolerance / type 2 diabetes, of 20 rodents (7) and probably on diabetic retinopathy in humans (8); - these improve glucose tolerance by reducing insulin resistance in humans and increase fat oxidation with moderately intensive physical exertion (9); - these also have a favorable influence on the development of arteriosclerosis, blood pressure, obesity / overweight in animal models, presumably as an antioxidant (10). The polyphenol EGCG also lowers cholesterol (t 1) in humans and counteracts the rise in triglycerides after meals (12). A favorable result for the prevention of type 2 diabetes mellitus has also been described in adults (13).
De dagelijkse consumptie van de anti-oxidatieve polifenol catechinen gedurende 12 weken verminderde het lichaamsvet/overgewicht en het gehalte van het geoxideerd 30 LDL (14).The daily consumption of the anti-oxidative polyphenol catechins for 12 weeks reduced the body fat / overweight and the content of the oxidized LDL (14).
Het tweede indicatiegebied betreft de gunstige invloed van natuurlijke aminozuren en antioxidatief polifenolen op bacteriële ontstekingen en op auto-immuun 3 gemediëerde ontstekingen zoals bij voorbeeld reumatoïde-ontstekingen.The second indication area concerns the beneficial influence of natural amino acids and antioxidative polyphenols on bacterial inflammations and on autoimmune mediated inflammations such as, for example, rheumatoid inflammations.
Wat natuurlijke aminozuren betreft: Het natuurlijk aminozuur L-Glutamine vormt een brand- en bouwstof voor snel prolifererende darm epitheel cellen en afweercellen rond de darm en bronchiaalboom (15, 16,17,18) en ondersteunt hierdoor 5 de mucosa- en immuun barrière tegen aanvallende microorganismen. Tevens vermindert het in geval van ontstekingen de endogene ontstekingsreactie door het vrijkomen van pro-inflammatoire mediatoren (IL-8, IL-6,TNF-a) uit granulocyten en de productie van metalloproteinase bij voorbeeld in de postischemische darm (19) tegen te gaan en de aanmaak van anti-inflammatoire factoren (IL-10) door T-lymfocyten (20,21,22) te 10 bevorderen alsook de cysteinyl-leukotriene stofwisseling (23,24). Het L-Glutamine beïnvloedt de ontstekingsreactie door afremming van de NFk-B activering (25). Ook bevordert het natuurlijk aminozuur L-Glutamine de aanmaak van het, bij de opvang van oxidatieve stress betrokken, glutathion (26) en van de heat shock proteïnen (27,28,29).With regard to natural amino acids: The natural amino acid L-Glutamine forms a fuel and building material for rapidly proliferating intestinal epithelial cells and immune cells around the intestine and bronchial tree (15, 16, 17, 18) and thereby supports the mucosa and immune barrier against attacking microorganisms. In the case of inflammation, it also reduces the endogenous inflammatory response by preventing the release of pro-inflammatory mediators (IL-8, IL-6, TNF-a) from granulocytes and the production of metalloproteinase in the postischemic gut (19), for example. and the production of anti-inflammatory factors (IL-10) by promoting T lymphocytes (20, 21, 22) as well as the cysteinyl leukotriene metabolism (23, 24). The L-Glutamine influences the inflammatory response by inhibiting the NFk-B activation (25). The natural amino acid L-Glutamine also promotes the production of glutathione (26) and heat shock proteins (27.28,29) involved in oxidative stress relief.
Wat antioxidatieve polifenolen betreft: Het antioxidatief polifenol catechine 15 werkt bij heftige ontstekingen niet alleen als antioxidant (30,31) maar remt ook de door IL-1 β geïnduceerde en de door chemokinen mogelijk gemaakte metalloproteinase -2 activiteit. Evaluatie van de signaal transmissie trajecten liet zien, dat EGCG preferentieel de fosforylering van PKCdelta blokkeerde en de activering en translocatie naar de celkern afremde van het NF-kappa β in met IL-1 β behandelde synovia 20 fïbroblasten van reumatoïde artritis patiënten (32). Ook gaat het antioxidatieve polifenol EGCG in vitro de auto-antigeen expressie tegen van normale menselijke cellulaire componenten (33).With regard to antioxidative polyphenols: The antioxidant polyphenol catechin not only acts as an antioxidant (30.31) in the case of severe inflammation, but also inhibits IL-1 β-induced and metalloproteinase -2 activity made possible by chemokines. Evaluation of the signal transmission pathways showed that EGCG preferentially blocked the phosphorylation of PKC delta and inhibited activation and translocation to the cell nucleus from the NF-kappa β in synovia treated synovia 20 of rheumatoid arthritis patients (32). The anti-oxidative polyphenol EGCG also inhibits the autoantigen expression of normal human cellular components in vitro (33).
Het derde indicatiegebied betreft de gunstige invloed van natuurlijke aminozuren en antioxidatieve polifenolen op de door chemo- en radiotherapie 25 geïnduceerde mucositis en perifere polyneuropathie.The third indication area concerns the beneficial influence of natural amino acids and antioxidative polyphenols on the mucositis and peripheral polyneuropathy induced by chemo- and radiotherapy.
Wat natuurlijke aminozuren betreft: Het L-Glutamine vormt een belangrijke brand- en bouwstof voor de epitheliale- en immuuncellen van de maagdarm wand (GALT) en voor die van de bronchiaal boom (16). Er zijn meerdere klinische studies bekend die aangeven dat L-Glutamine de perifere neurologische bijwerkingen van 30 chemo- en radiotherapie kan verminderen (34, 35, 36 en 37). L-Glutamine heeft een gunstig effect op het ontstaan van de vaak met chemo-en radiotherapie gepaard gaande mucositis (38). Ook een mogelijk gunstig effect op het bestrijden van multipele 4 sclerose (49) is gemeldWith regard to natural amino acids: L-Glutamine is an important fuel and building material for the epithelial and immune cells of the gastrointestinal wall (GALT) and for those of the bronchial tree (16). Several clinical studies are known to indicate that L-Glutamine can reduce the peripheral neurological side effects of chemotherapy and radiotherapy (34, 35, 36 and 37). L-Glutamine has a beneficial effect on the development of the mucositis often associated with chemotherapy and radiotherapy (38). A possible beneficial effect on combating multiple sclerosis (49) has also been reported
Wat antioxidatieve polifenolen betreft: deze voedingssupplementen kunnen de bijwerkingen van chemo- en radiotherapie verminderen (39).With regard to antioxidative polyphenols: these dietary supplements can reduce the side effects of chemotherapy and radiotherapy (39).
Het vierde indicatiegebied betreft de gunstige invloed van natuurlijke 5 aminozuren en antioxidatieve polifenolen voor het op peil houden of verbeteren van de conditie en sportprestaties.The fourth indication area concerns the beneficial influence of natural 5 amino acids and antioxidative polyphenols for maintaining or improving fitness and sports performance.
Wat natuurlijke aminozuren betreft: er zijn vele publicaties over aanvulling van het normale niveau van natuurlijke aminozuren voor bovenvermelde indicaties. Inspanning induceert initieel een verhoging van de plasma glutamine spiegel, maar bij 10 voortgezette inspanning daalt het plasma glutamine tot onder de normale ondergrenswaarde. Deze daling van de glutamine spiegel is wel als een potentiële oorzaak van de inspanning geïnduceerde immuun incompetentie gezien die in een oorzakelijk verband wordt gebracht met een geconstateerde verhoogde gevoeligheid voor infecties van de atleten (40). Na langdurige inspanning, hongeren en fysieke stress 15 heeft het lichaam een verhoogde behoefte aan glutamine wat het gebruik ervan op dat moment rechtvaardigt. De toediening van L-Glutamine compenseert het verhoogde gebruik door het lichaam en in het bijzonder de verhoogde opname door de nier in een poging de zuur-base balans in evenwicht te houden en het voorziet in het verhoogde gebruik van glutamine door lever en maagdarmkanaal voor de gluconeogenese. Ook een 20 mogelijk gunstig effect op het bestrijden van de ziekte van Duchenne (50) is gemeld.Regarding natural amino acids: there are many publications on supplementing the normal level of natural amino acids for the above indications. Exercise initially induces an increase in the plasma glutamine level, but with continued exercise, the plasma glutamine falls below the normal lower limit value. This decrease in glutamine levels has been seen as a potential cause of exercise-induced immune incompetence, which is brought into a causal relationship with an observed increased susceptibility to athletes' infections (40). After prolonged exertion, hunger and physical stress, the body has an increased need for glutamine, which justifies its use at that time. The administration of L-Glutamine compensates for increased use by the body and in particular for increased uptake by the kidney in an attempt to balance the acid-base balance and provides for increased use of glutamine by the liver and gastrointestinal tract for gluconeogenesis. A possible beneficial effect on combating Duchenne's disease (50) has also been reported.
Wat antioxidatieve polifenolen betreft: Het gebruik daarvan is door stimulatie van de vetverbranding gunstig om het uithoudingsvermogen te verbeteren. Het effect op de vetverbranding van EGCG is bij proefdieren dosis afhankelijk en gaat gepaard met een lagere respiratie quotiënt en een hoger vetzuur β-oxidatie in de skeletspieren. De 25 plasma lactaat spiegels waren bij deze dieren lager na inspanning. Dit gaat gepaard met een toename van de vrije vetzuren concentratie. Dit duidt op een toegenomen gebruik van lipiden als energie bron bij met het polifenol EGCG gevoede mensen (41) en muizen (42).Regarding antioxidative polyphenols: Their use is beneficial by promoting fat burning to improve endurance. The effect on fat burning of EGCG in dose animals is dose dependent and is associated with a lower respiration quotient and a higher fatty acid β-oxidation in the skeletal muscles. The plasma lactate levels were lower in these animals after exertion. This is accompanied by an increase in the free fatty acid concentration. This indicates an increased use of lipids as an energy source in poliphenol EGCG-fed humans (41) and mice (42).
Het vijfde indicatiegebied betreft de gunstige invloed van natuurlijke 30 aminozuren en antioxidatieve polifenolen op virusinfecties zoals een infectie met influenza, HIV/AIDS, HIV, HCV, HBV, HSV of HPV.The fifth indication area concerns the beneficial influence of natural amino acids and antioxidative polyphenols on virus infections such as an infection with influenza, HIV / AIDS, HIV, HCV, HBV, HSV or HPV.
Wat natuurlijke aminozuren betreft:Er zijn publicaties die aangeven dat het oraal 5 gebruik van natuurlijk aminozuur L-Glutamine effectief is bij de behandeling van chronische diarree/en of “wasting” bij HIV/AIDS patiënten zoals bij Cryptosporidium diarree, niet alleen resulterend in een vermindering van de symptomen maar ook in een verbeterde resorptie van de antivirale therapie (HAART) (43). Het gebruik van het oraal 5 aminozuur L-Glutamine uit zich ook in een bevordering van de lymfocyten proliferatie. Een aantal CD4+ lymfocyten boven de 200/ mm3 is klinisch belangrijk gebleken om het risico op opportunistische infecties te verminderen.Regarding natural amino acids: There are publications indicating that the oral use of natural amino acid L-Glutamine is effective in the treatment of chronic diarrhea / and or "wasting" in HIV / AIDS patients such as Cryptosporidium diarrhea, not only resulting in an reduction of symptoms but also in improved resorption of antiviral therapy (HAART) (43). The use of the oral 5 amino acid L-Glutamine is also expressed in a promotion of lymphocyte proliferation. A number of CD4 + lymphocytes above 200 / mm3 have been shown to be clinically important to reduce the risk of opportunistic infections.
Wat antioxidatieve polifenolen betreft: het antioxidatieve polifenol EGCG vermindert de neurotoxiciteit van de door IFN-gamma versterkte schade door HIV-1 10 glycoproteïne gpl20 en Tat, zowel in vitro als in vivo (46). Er is een duidelijk bewijs voor een zeer sterke binding van EGCG aan het CD4 molecuul waardoor de binding van gpl20 aan de CD4+ T-cellen van de mens wordt belemmerd (47). EGCG bindt zich op een zodanige wijze aan de CD4+ T-cellen dat de berekende binding van gpl20 met het CD4-EGCG complex verwaarloosbaar is (48). De gunstige binding van EGCG aan het 15 CD4 kan dus effectief de gp 120-CD4 blokkeren.With regard to antioxidative polyphenols: the anti-oxidative polyphenol EGCG reduces the neurotoxicity of the IFN-gamma enhanced damage by HIV-1 glycoprotein gpl20 and Tat, both in vitro and in vivo (46). There is clear evidence of a very strong binding of EGCG to the CD4 molecule, which hinders the binding of gp120 to human CD4 + T cells (47). EGCG binds to the CD4 + T cells in such a way that the calculated binding of gp120 to the CD4-EGCG complex is negligible (48). The favorable binding of EGCG to the CD4 can thus effectively block the gp 120-CD4.
In de US octrooiaanvrage 2008/0131525 wordt een oplossing van het natuurlijk aminozuur glutamine en een aantal specifieke anti-oxidanten zoals selenium, zinc, vitamine C, vitamine E en β-caroteen beschreven om parenteraal aan een ernstig zieke patiënt toe te dienen. Een formulering van een extract van groene thee met een groot 20 aantal andere stoffen zoals vitaminen, mineralen en aminozuren en componenten die in oplossing een bruisend effect geven wordt beschreven in de internationale aanvrage WO 01/00038. In het Europees octrooi EP 1572175B wordt een formulering beschreven bevattende een extract van groene thee waaronder het polifenol (-)-epigallocatechine gallaat (EGCG) en een stikstofoxide donor zoals aminozuren als glutamine, specifiek 25 voor de preoperatieve gastro-intestinale toediening van een middel dat het risico op postoperatieve complicaties verkleint.US patent application 2008/0131525 describes a solution of the natural amino acid glutamine and a number of specific antioxidants such as selenium, zinc, vitamin C, vitamin E and β-carotene to be administered parenterally to a seriously ill patient. A formulation of an extract of green tea with a large number of other substances such as vitamins, minerals and amino acids and components that give an effervescent effect in solution is described in the international application WO 01/00038. European patent EP 1572175B describes a formulation containing an extract of green tea including the polyphenol (-) - epigallocatechin gallate (EGCG) and a nitrogen oxide donor such as amino acids such as glutamine, specifically for the preoperative gastrointestinal administration of an agent that reduces the risk of postoperative complications.
Er is een grote behoefte aan veilige voedingssupplementen of combinaties daarvan die de kans op het krijgen van een ziekte en/of complicaties daarvan verminderen zoals door het verminderen van de kans op arteriosclerose en diabetes 30 mellitus type-2, het verhogen van de activiteit van het immuunsysteem tegen oxidatieve stress of door het verbeteren van de spierconditie van personen met een slechte voedingstoestand.There is a great need for safe nutritional supplements or combinations thereof that reduce the chance of getting a disease and / or complications thereof such as by reducing the chance of arteriosclerosis and diabetes mellitus type-2, increasing the activity of the immune system against oxidative stress or by improving the muscle condition of people with poor nutritional status.
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Met de onderhavige uitvinding wordt beoogd te voorzien in een samenstelling die zeer effectief is met betrekking tot het verbeteren van de gezondheidstoestand en vasthouden van de gezondheidstoestand op velerlei gebied.The present invention has for its object to provide a composition which is very effective with regard to improving the health status and maintaining the health status in many fields.
Om het beoogde doel te bereiken biedt de uitvinding een kit van onderdelen van 5 de in de aanhef genoemde soort in wezen bevattende a) L-Glutamine en b) (-)-epigallocatechine gallaat (EGCG). Bij voorkeur zijn a) L-Glutamine en b) EGCG gezamenlijk verpakt in een dubbelsachet, bij nadere voorkeur komen zowel a) L-Glutamine als b) EGCG onafhankelijk van elkaar voor in de vorm gekozen uit de groep poeder en capsule. In het algemeen zullen de beide componenten in deze vorm worden 10 gebruikt maar ook het innemen van tenminste één van de componenten in opgeloste vorm behoort tot de uitvinding. Bij voorkeur bevat de kit van onderdelen volgens de uitvinding ongeveer 1 - 60 g werkzaam L-Glutamine, bij nadere voorkeur ongeveer 5 -30 g werkzaam L-Glutamine, in het bijzonder ongeveer 9 g werkzaam L-Glutamine en ongeveer 50 - 1500 mg EGCG, bij nadere voorkeur ongeveer 100 - 400 mg EGCG, in 15 het bijzonder ongeveer 150 mg EGCG. Als dagdosis wordt in het algemeen een niet hogere dosis dan 3 x de inhoud van het dubbelsachet volgens de uitvinding aangeraden. Bij voorkeur wordt de kit van onderdelen volgens de uitvinding op orale wijze toegepast, maar ook alle andere bekende en geschikte toedieningswijzen zoals bij voorbeeld parenteraal, subcutaan, intramusculair of intraveneus behoren tot de 20 uitvinding.To achieve the intended object, the invention provides a kit of parts of the type mentioned in the preamble essentially containing a) L-Glutamine and b) (-) - epigallocatechin gallate (EGCG). Preferably a) L-Glutamine and b) EGCG are packed together in a double sachet, more preferably both a) L-Glutamine and b) EGCG occur independently of each other in the form selected from the group powder and capsule. In general, the two components will be used in this form, but also the ingestion of at least one of the components in dissolved form is part of the invention. The kit of parts according to the invention preferably contains about 1 - 60 g of active L-Glutamine, more preferably about 5 - 30 g of active L-Glutamine, in particular about 9 g of active L-Glutamine and about 50 - 1500 mg of EGCG , more preferably about 100 - 400 mg EGCG, in particular about 150 mg EGCG. A daily dose not higher than 3 x the content of the double sachet according to the invention is generally recommended as the daily dose. The kit of parts according to the invention is preferably used orally, but all other known and suitable methods of administration, such as, for example, parenterally, subcutaneously, intramuscularly or intravenously, also belong to the invention.
Volgens een ander aspect van de uitvinding wordt een toepassing van een dergelijke kit van onderdelen geboden ter verhoging van sportprestaties.According to another aspect of the invention, an application of such a kit of parts is provided for increasing sports performance.
Volgens nog een ander aspect van de uitvinding wordt een toepassing van een dergelijke kit van onderdelen geboden als middel ter voorkoming van of ter verkleining 25 van de kans op het krijgen van een lichamelijke aandoening. In het bijzonder dient de toepassing van een dergelijke kit van onderdelen ter verhoging van de activiteit van het immuunsysteem.According to yet another aspect of the invention, an application of such a kit of parts is provided as a means to prevent or reduce the chance of getting a physical disorder. In particular, the use of such a kit of parts serves to increase the activity of the immune system.
In het bijzonder voorkomt de toepassing van een kit van onderdelen, of verkleint de kans op het krijgen van één of meer van de volgende lichamelijke aandoeningen: 30 - hart en vaatziekten meer in het bijzonder op basis van arteriosclerose diabetes mellitus in het bijzonder type-2 hoge bloeddruk 7 obesitas /overgewicht neurologische en slijmvlies aandoeningen, ook als bijwerkingen van chemo en radiotherapie bacteriële en virus infecties 5 - reumatische ontstekingen ziekte van Duchenne brandwonden.In particular, the use of a kit of parts prevents or reduces the chance of getting one or more of the following physical disorders: cardiovascular disease more particularly based on arteriosclerosis diabetes mellitus in particular type-2 high blood pressure 7 obesity / overweight neurological and mucous membrane disorders, also as side effects of chemo and radiotherapy bacterial and virus infections 5 - rheumatic inflammation Duchenne disease burns.
In het bijzonder wordt de kit van onderdelen volgens de uitvinding effectief 10 toegepast bij één of meer van de infecties met een virus uit de groep van influenza, HIV, HCV, HBV, HSV en HPV; bij één of meer neurologische aandoeningen zoals veroorzaakt door één of meer van de ziektes uit de groep van Alzheimer, Parkinson en Huntington, Multipele sclerose of bij een speeksel/traanklier en slijmvliesaandoening zoals veroorzaakt door de ziekte van Sjögren.In particular, the kit of parts according to the invention is used effectively in one or more of the infections with a virus from the group of influenza, HIV, HCV, HBV, HSV and HPV; in one or more neurological disorders such as caused by one or more of the diseases from the Alzheimer, Parkinson's and Huntington's disease, Multiple sclerosis or in a saliva / lacrimal gland and mucous membrane disorder such as caused by Sjögren's disease.
15 Ook de toepassing van in wezen a) L-Glutamine en b) EGCG te samen binnen een geschikt tijdsbestek voor de hierboven beschreven indicaties behoort tot de huidige uitvinding.The use of essentially a) L-Glutamine and b) EGCG together within a suitable timeframe for the indications described above is also part of the present invention.
Tenslotte biedt de huidige uitvinding een werkwijze ter bereiding van een kit van onderdelen met het kenmerk dat a) L-Glutamine en b) EGCG samen in een kit 20 worden verpakt, bij voorkeur in de vorm van een dubbelsachet, in het bijzonder onafhankelijk van elkaar gekozen uit de groep van poeder en capsule. Gewenste hulpstoffen worden op voor de deskundige bekende wijze mee verpakt.Finally, the present invention provides a method for preparing a kit of parts, characterized in that a) L-Glutamine and b) EGCG are packaged together in a kit 20, preferably in the form of a double sachet, in particular independently of each other selected from the group of powder and capsule. Desired auxiliaries are also packaged in a manner known to the expert.
De uitvinding zal vervolgens nader worden toegelicht. Het combineren van de werking van twee producten, het conditioneel essentiële natuurlijke aminozuur a) L-25 Glutamine en de meest actieve component van het natuurlijk product groene thee: b) (-)-epigallocatechine gallaat (EGCG), behorend tot de groep van anti-oxidatieve polifenolen, heeft een grotere werkzaamheid dan verwacht mag worden van het louter samenvoegen van twee willekeurige voedingssupplementen.The invention will be explained in more detail below. Combining the action of two products, the conditionally essential natural amino acid a) L-25 Glutamine and the most active component of the natural product green tea: b) (-) - epigallocatechin gallate (EGCG), belonging to the group of anti -oxidative polyphenols, has a greater efficacy than might be expected from the mere joining of two random nutritional supplements.
Onder het onderdeel van de kit a) L-Glutamine wordt in dit octrooidocument L-30 Glutamine verstaan of een derivaat daarvan en ook L-Glutamine als onderdeel van een dipeptide. Bij derivaat kan gedacht worden aan glutamaat, bij dipeptiden aan de twee di-peptiden Alanine-Glutamine en Glycine-Gutamine, Ala-Gln respectievelijk Gly-Gln.The part of the kit a) L-Glutamine in this patent document is understood to mean L-30 Glutamine or a derivative thereof and also L-Glutamine as part of a dipeptide. In the case of a derivative, glutamate can be considered, in the case of dipeptides the two peptides Alanine-Glutamine and Glycine-Gutamine, Ala-Gln and Gly-Gln respectively.
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Onder een gewicht aan werkzaam L-Glutamine wordt een gewicht aan derivaat verstaan dat in aantal Mol overeenkomt met het gewicht aan L-Glutamine per se. Het begrip ‘in wezen’ geeft aan dat er naast de genoemde werkzame stoffen andere, niet of nauwelijks werkzame stoffen aanwezig kunnen zijn, zoals hulpstoffen, zonder dat dit afbreuk doet 5 aan de beschermingsomvang van de uitvinding.A weight of active L-Glutamine is understood to mean a weight of derivative that corresponds in number of Mol to the weight of L-Glutamine per se. The term "in essence" indicates that in addition to the active substances mentioned there may be other substances that are not or hardly active, such as excipients, without this affecting the scope of the invention.
In het bijzonder is het toepassen van een kit van onderdelen die beide producten in een dubbelsachet verpakt welke specifiek aangeduid wordt met 2-Prepare™ gunstig. Maar ook het te samen binnen een geschikt tijdsbestek van bij voorkeur niet langer dan één a twee uur gebruiken van de afzonderlijke componenten a) L-Glutamine en EGCG 10 dient onder de uitvinding te worden begrepen.In particular, the use of a kit of parts that packs both products in a double sachet which is specifically referred to as 2-Prepare ™ is beneficial. But also the use of the individual components a) L-Glutamine and EGCG 10 together within a suitable period of time, preferably no longer than one or two hours, is to be understood by the invention.
Het in de natuur voorkomend aminozuur L-Glutamine is commercieel verkrijgbaar. EGCG kan bij voorbeeld uit groene thee worden geëxtraheerd zoals beschreven in het Europees octrooischrift EP 1767097 en is ook commercieel verkrijgbaar bij voorbeeld bij DSM Nutritional Products AG als Teavigo®, 200 mg in 15 een gelatinevrij e capsule.The naturally occurring amino acid L-Glutamine is commercially available. EGCG can for example be extracted from green tea as described in the European patent EP 1767097 and is also commercially available for example from DSM Nutritional Products AG as Teavigo®, 200 mg in a gelatin-free capsule.
De beide werkzame onderdelen van de kit worden in het bijzonder als poeder of capsule zoals dit bij voorkeur wordt toegepast in het dubbelsachet. Uiteraard vallen ook andere formuleringen zoals pillen, tabletten, bruistabletten, fïlmtabletten die ook in een dubbelsachet verpakt kunnen worden onder de beschermingsomvang van de uitvinding. 20 Naast de werkzame stoffen kunnen er ook in alle formuleringen aan de deskundige bekende hulpstoffen aanwezig zijn. In het dubbelsachet zijn de beide werkzame onderdelen overigens in het algemeen van elkaar gescheiden, in het bijzonder door middel van een afsluiting.The two active parts of the kit are used in particular as a powder or capsule as it is preferably used in the double sachet. Of course, other formulations such as pills, tablets, effervescent tablets, film tablets which can also be packaged in a double sachet are included within the scope of the invention. In addition to the active substances, auxiliaries known to those skilled in the art can also be present in all formulations. In the double sachet, the two active parts are otherwise generally separated from each other, in particular by means of a closure.
Er is een grote behoefte aan veilige voedingssupplementen of combinaties 25 daarvan die de kans op het krijgen van een ziekte verminderen zoals ook blijkt uit de hoeveelheid artikelen en octrooidocumenten die op dit gebied verschijnen. De huidige uitvinding biedt een dergelijke combinatie met de combinatie van als eerste component a) L-Glutamine, een conditioneel essentieel aminozuur welk aminozuur de activiteit van het immuunsysteem verhoogt en de spierconditie verbetert van personen met een slechte 30 voedingstoestand, bij brandwonden en voorafgaand aan en tijdens zware spierinspanningen zoals bij duursporten. De tweede component, de component uit groene thee extract EGCG is een caffeine vrije anti-oxidant welke complicaties van 9 infecties/ontstekingen lijkt te verminderen, het gehalte aan cholesterol, triglyceriden en bloedsuiker verlaagt, het ontstaan en de progressie van de ziektes van Alzheimer en Parkinson vertraagt en door verschuiving in de verhouding koolhydraat / vet verbranding ten gunste van de vetverbranding het uithoudingsvermogen tijdens zware 5 lichamelijke inspanning verbetert door overmatige melkzuurproductie (verzuring) uit te stellen.There is a great need for safe nutritional supplements or combinations thereof that reduce the chance of getting a disease, as is also apparent from the amount of articles and patent documents that appear in this field. The present invention offers such a combination with the combination of as a first component a) L-Glutamine, a conditionally essential amino acid which amino acid increases the activity of the immune system and improves the muscle condition of persons with a poor nutritional status, in the case of burns and prior to and during heavy muscle exertion such as endurance sports. The second component, the component from green tea extract EGCG is a caffeine-free antioxidant which appears to reduce complications of 9 infections / inflammations, lowers the content of cholesterol, triglycerides and blood sugar, the development and progression of Alzheimer's diseases and Parkinson's slows down and due to a shift in the ratio of carbohydrate / fat burning in favor of fat burning, the endurance during heavy physical exertion is improved by postponing excessive lactic acid production (acidification).
De werking van de twee betrouwbare voedingssupplementen, namelijk het natuurlijk aminozuur a) L-Glutamine en het anti-oxidatieve polyfenol b) EGCG die elk tot een groep verbindingen behoren met een verschillend werkingsmechanisme, 10 ondersteunt elkaar gunstig op een groot aantal gebieden, in het bijzonder op de hierboven genoemde.The action of the two reliable dietary supplements, namely the natural amino acid a) L-Glutamine and the antioxidant polyphenol b) EGCG, each belonging to a group of compounds with a different mechanism of action, favorably supports each other in a large number of areas, in particular in particular to the above.
Hoewel de uitvinding hiervoor aan de hand van een groot aantal verschillende toepassingen van de kit van onderdelen is toegelicht, moge het duidelijk zijn dat de uitvinding daartoe geenszins is beperkt. Er zijn integendeel binnen het kader van de 15 uitvinding voor een gemiddelde vakman nog vele variaties mogelijk.Although the invention has been explained above with reference to a large number of different applications of the kit of parts, it will be clear that the invention is by no means limited thereto. On the contrary, many variations are still possible for a person skilled in the art within the scope of the invention.
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26- Roth E, e.a Regulative potential of glutamine-relation to glutathione metabolism 15 Nutrition.2002; 18:217-221 27- Cao Y e.a. Glutation enhances gut glutathion production JPEN 1998;22:224-7 28- Wischmeyer PE Glutamine and heat shock protein expression. Nutrition 2002;18:225-8 29- Singleton KD, e.a. Glutamine's protection against sepsis and lung injury is 20 dependent on heat shock 70 expression Am J Physiol Regul Integr Comp Physiol 2007;292:R1839-R1845 30- Henning SM, et al.Catechin content of 18 teas and a green tea extract supplement correlates with the antoxidant capacity Nutrition and Cancer 2003;45(2):226-235 31- Nakagawa KM, et al. Tea catechin supplementation increases antioxidant capacity 25 and prevents phospholipid hydroperoxidation in plasma of humansJ Agic.Food Chem 1999;47:3967-3973 32- Ahmed S et al. Regulation of Interleukin-Ι-β-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism 2006;54(8):2393-2401 30 33- Hsu S e.a. Inhibition of autoantigen expression by (-)-epigallocatechin-3-gallate (the major constituent of green tea) in normal human cells J Pharmacol Exp Ther 2005;315(2):805-11 12 34- Vahdat L et al. Reduction of Paclitaxel-induced peripheral neuropathy with glutamine. Clinical Cancer Research.2001 ;7:1192-1197 35- Stubblefield MD, et al. Glutamine as a neuroprotective agent in high-dose paclitaxel -induced peripheral neuropathy: a clinical and electrophysiologic study. Clinical 5 Oncology 2005;17:271-276 36- Wang WS, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients The Oncologist 2007;12:312-319 37- Amara S .Oral Glutamine for the prevention of chemotherapy-induced peripheral neuropathy. The Annals of Pharmacotherapy.2008;42:1481-1485 10 38- Anderson PMOral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 1998;83: 1433-1439 39- Yamamoto T et al. Protective effects of EGCG on salivary gland cells treated with gamma-radiation or cis-platinum(II)diamine dichloride Anticancer Research. 2004;24(5A):3065-3075 15 40- Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise26 - Roth E, et al. Regulative potential of glutamine relationship to glutathione metabolism Nutrition.2002; 18: 217-221 27- Cao Y et al. Glutation enhances gut glutathione production JPEN 1998; 22: 224-7 28- Wischmeyer PE Glutamine and heat shock protein expression. Nutrition 2002; 18: 225-8 29- Singleton KD, et al. Glutamine's protection against sepsis and lung injury is 20 dependent on heat shock 70 expression Am J Physiol Regul Integr Comp Physiol 2007; 292: R1839-R1845 30- Henning SM, et al .Catechin content of 18 teas and a green tea extract supplement correlates with the antoxidant capacity Nutrition and Cancer 2003; 45 (2): 226-235 31- Nakagawa KM, et al. Tea catechin supplementation increases antioxidant capacity 25 and prevents phospholipid hydroperoxidation in plasma of humans Agic.Food Chem 1999; 47: 3967-3973 32-Ahmed S et al. Regulation of Interleukin-β-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism 2006; 54 (8): 2393-2401 30 33- Hsu S et al. Inhibition of autoantigen expression by (-) - epigallocatechin-3-gallate (the major constituent of green tea) in normal human cells J Pharmacol Exp Ther 2005 315 (2): 805-11 12 34 - Vahdat L et al. Reduction or Paclitaxel-induced peripheral neuropathy with glutamine. Clinical Cancer Research.2001; 7: 1192-1197 35- Stubblefield MD, et al. Glutamine as a neuroprotective agent in high-dose paclitaxel -induced peripheral neuropathy: a clinical and electrophysiologic study. Clinical 5 Oncology 2005; 17: 271-276 36- Wang WS, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients The Oncologist 2007; 12: 312-319 37- Amara S. Oral Glutamine for the prevention of chemotherapy-induced peripheral neuropathy. The Annals of Pharmacotherapy.2008; 42: 1481-1485 10 38- Anderson PMOral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 1998; 83: 1433-1439 39 - Yamamoto T et al. Protective effects of EGCG on salivary gland cells treated with gamma-radiation or cis-platinum (II) diamine dichloride Anticancer Research. 2004; 24 (5A): 3065-3075 15 40- Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise
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Tat in the presence of IFN-γ: role of JAK/STAT1 signaling and implications for HIV-associated dementia. Brain Research 2006; 1123:216-225 45- Williamson MP e.a.Epigallocatechin gallate, the main polyfenol in green tea, binds to T-cell receptor, CD4: potential for HIV-1 therapy. J Allergy Clin Immunol 30 2006;118(6):1369-1374 46- Hamza A e.a. How can (-)-epigallocatechin gallate from green tea prevent HIV-1 infection? Mechanistic insights from computational modeling and the implication for 13 rational design of anti-HIV-1 entry inhibitors. Phys Chem B2006;l 10(6):2910-7 47- Mithieux G. New data and concepts on glutamine and glucose metabolism in the gut. Curr Opin Clin Metab Care.2001;4(4):267-271 48- Gammelsaeter R et al. Complementary expression of SN 1 and SAT2 in the islets of 5 Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion. Biochemical and Biophysical Research Communications 21 February 2009.Tat in the presence of IFN-γ: role of JAK / STAT1 signaling and implications for HIV-associated dementia. Brain Research 2006; 1123: 216-225 45- Williamson MP et al. Epigallocatechin gallate, the main polyphenol in green tea, binds to T-cell receptor, CD4: potential for HIV-1 therapy. J Allergy Clin Immunol 30 2006; 118 (6): 1369-1374 46- Hamza A et al. How can (-) - epigallocatechin gallate from green tea prevent HIV-1 infection? Mechanistic insights from computational modeling and the implication for 13 rational design of anti-HIV-1 entry inhibitors. Phys Chem B2006; 10 (6): 2910-7 47- Mithieux G. New data and concepts on glutamine and glucose metabolism in the gut. Curr Opin Clin Metab Care.2001; 4 (4): 267-271 48- Gammelsaeter R et al. Complementary expression of SN 1 and SAT2 in the islets or 5 Langerhans suggested concerted action or glutamine transport in the regulation of insulin secretion. Biochemical and Biophysical Research Communications 21 February 2009.
49- Aktas 0 et al. Green tea epigalloocatechin-3- gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 2004; 173(9):5794-5800 io 50- Hankard R et al Is glutamine a conditionally essential amino acid in Duchenne muscular dystrophy? Clin Nutr. 1999; 18(6):365-369 103674649- Aktas 0 et al. Green tea epigalloocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J. Immunol 2004; 173 (9): 5794-5800 io 50- Hankard R et al Is glutamine a conditionally essential amino acid in Duchenne muscular dystrophy? Clin Nutr. 1999; 18 (6): 365-369 1036746
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| PCT/NL2010/000050 WO2010107307A1 (en) | 2009-03-20 | 2010-03-22 | Kit of parts comprising l-glutamine and egcg |
| EP10710923A EP2408320A1 (en) | 2009-03-20 | 2010-03-22 | Kit of parts comprising l-glutamine and egcg |
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| WO2013061161A2 (en) * | 2011-10-28 | 2013-05-02 | Green Bcn Consulting Services Sl | New combination therapies for treating neurological disorders |
| EP2782588B1 (en) * | 2011-11-21 | 2020-04-15 | Emmaus Medical, Inc. | Methods and compositions for the treatment of diabetes and related symptoms |
| CN103493694B (en) * | 2013-09-18 | 2016-04-13 | 杭州市农业科学研究院 | A kind of external source abductive approach improving Dragon Well tea 43 tea tree breed EGCG content |
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-
2009
- 2009-03-20 NL NL1036746A patent/NL1036746C2/en active
-
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| US5904924A (en) * | 1997-11-04 | 1999-05-18 | Oncologics, Inc. | Green nutritional powder composition |
| US20090011048A1 (en) * | 2002-04-16 | 2009-01-08 | Coleman Henry D | Dietary Supplement For Promoting Removal Of Heavy Metals From The Body |
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| EP2408320A1 (en) | 2012-01-25 |
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