WO2010107307A1 - Kit of parts comprising l-glutamine and egcg - Google Patents

Kit of parts comprising l-glutamine and egcg Download PDF

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Publication number
WO2010107307A1
WO2010107307A1 PCT/NL2010/000050 NL2010000050W WO2010107307A1 WO 2010107307 A1 WO2010107307 A1 WO 2010107307A1 NL 2010000050 W NL2010000050 W NL 2010000050W WO 2010107307 A1 WO2010107307 A1 WO 2010107307A1
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WO
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Prior art keywords
kit
glutamine
parts
egcg
application
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PCT/NL2010/000050
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French (fr)
Inventor
Gijsbert Klaasjan Roozendaal
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Glnp (Generic Life Quality Enhancing Niche Products) Holding B.V.
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Priority to EP10710923A priority Critical patent/EP2408320A1/en
Publication of WO2010107307A1 publication Critical patent/WO2010107307A1/en

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Classifications

    • 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
    • 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

Definitions

  • the invention relates to a kit of parts for maintaining or improving the state of health, and the application of such a kit.
  • the invention further relates to a method for preparing such a kit of parts.
  • nutritional supplements generally deemed safe to be administered and used.
  • Two important groups of nutritional supplements are formed by on the one hand amino acids and on the other antioxidants, such as for instance polyphenols.
  • a group of polyphenols with strong antioxidant properties is formed by the catechins which occur in green tea, such as for instance (-)-epicatechin (EC), (-)-epigallocatechin gallate (EGCG), epigallocatechin (EGC) and epicatechin gallate (ECG).
  • the first health area relates to the favourable effect of natural amino acids and antioxidant polyphenols in reducing the risk of developing cardiovascular diseases, in particular arteriosclerosis and diabetes mellitus, in particular type-2.
  • diabetes mellitus type-2 DMT2
  • hypertension hypertension
  • overweight in addition to smoking and a lack of daily physical exercise, the most important risk factors for the development of cardiovascular disease due to arteriosclerosis.
  • diabetes mellitus type-2 insulin resistance and a reduced insulin secretion by the ⁇ -cells in the pancreas are the key pathogenic factors.
  • amino acids amino acids:
  • orally administered L-Glutamine also enhances, via incretin- dependent mechanisms, the secretion of GLP- 1 (glucagon-like peptide 1 ) by the
  • GDH glutamate dehydrogenase
  • the second health area relates to the favourable effect of natural amino acids and antioxidant polyphenols on bacterial inflammations and on autoimmune-mediated inflammations, such as for instance rheumatoid inflammations.
  • natural amino acids the natural amino acid L-Glutamine forms a fuel and nutrient for rapidly proliferating gut epithelial cells and immune cells around the gut and bronchial tree (15, 16 ,17, 18) and hereby supports the mucosal and immune barrier against attacking micro-organisms.
  • inflammation In the case of inflammations it also reduces the endogenous inflammation reaction by preventing the release of pro-inflammatory mediators (IL-8, IL-6,TNF- ⁇ ) from granulocytes and the production of metalloproteinase in for instance the postischemic gut (19) and enhancing the production of anti-inflammatory factors (IL-IO) by T-lymphocytes (20, 21, 22) as well as the cysteinyl-leukotriene generation (23, 24).
  • IL-8, IL-6,TNF- ⁇ pro-inflammatory mediators
  • IL-6 IL-6,TNF- ⁇
  • IL-IO anti-inflammatory factors
  • L-Glutamine also enhances the production of the glutathione involved in relief of oxidative stress (26) and of the heat shock proteins (27, 28, 29), and activation occurs of peroxisome proliferator activated receptor gamma, an anti-inflammatory transcription factor which protects the gut from damage by cytokines released during ischemia (52).
  • the antioxidant polyphenol catechin such as EGCG, has a local bactericidal, fungicidal and antiviral effect, such as in the gut, making use of its oxidative action in high local concentrations and has a systemic inhibiting effect on the activation of the pro-inflammatory infection cascade, inter alia by inhibiting the NFkB and HMGBl, countering TNF- ⁇ and IL-I ⁇ induced toxicity.
  • the antioxidant polyphenol catechin acts not only as antioxidant (30, 31) but also inhibits the metalloproteinase-2 activity induced by IL-I ⁇ and made possible by chemokines.
  • the antioxidant polyphenol EGCG in vitro also counters the autoantigen expression in normal human cellular components (33).
  • the third health area relates to the favourable effect of natural amino acids and antioxidant polyphenols on mucositis and peripheral polyneuropathy induced by chemotherapy and radiotherapy.
  • L-Glutamine forms an important fuel and nutrient for the epithelial and immune cells of the intestinal wall 1 (GALT) and for those of the bronchial tree (16).
  • GALT epithelial and immune cells of the intestinal wall 1
  • bronchial tree 16
  • a number of clinical studies are known which indicate that L- Glutamine can reduce the peripheral neurological side-effects of chemotherapy and radiotherapy (34, 35, 36 and 37).
  • L-Glutamine has a favourable effect on the occurrence of the mucositis often associated with chemotherapy and radiotherapy (38). A possible favourable effect in combatting multiple sclerosis has also been reported (49).
  • antioxidant polyphenols these nutritional supplements can also reduce the side-effects of chemotherapy and radiotherapy (39).
  • the fourth health area relates to the favourable effect of natural amino acids and antioxidant polyphenols for maintaining or improving fitness and sporting performance.
  • L-Glutamine compensates the increased use by the body, and in particular the increased absorption by the kidney, in an attempt to keep the acid base balance in equilibrium, and provides for the increased use of glutamine by liver and gastrointestinal tract for the gluconeogenesis.
  • a possible favourable effect of glutamine in combatting Duchenne muscular dystrophy has also been reported (50).
  • the effect of EGCG on fat-burning is dosage- dependent in laboratory animals and is associated with a lower respiration quotient and a higher fatty acid ⁇ -oxidation in the skeletal muscles.
  • the plasma lactate levels were lower in these animals after exertion. This is associated with an increase in the free fatty acid concentration. This indicates an increased use of lipids as energy source in the case of humans (41) and mice (42) fed with polyphenol EGCG.
  • the fifth health area relates to the favourable effect of natural amino acids and antioxidant polyphenols on virus infections, such as infection with influenza, HIV, HIV/AIDS, HCV, HBV, HSV and HPV.
  • natural amino acids there are publications which indicate that oral use of natural amino acid L-Glutamine is effective in the treatment of Influenza A (53) and in the treatment of chronic diarrhoea and/or "wasting" in the case of HIV/ AIDS patients, as with Cryptosporidium diarrhoea, resulting not only in a reduction of the symptoms but also in an improved resorption of the antiviral therapy (HAART) (43).
  • Use of the oral amino acid L-Glutamine is also expressed in enhanced lymphocyte proliferation, this being significant because a number of CD4+ lymphocytes above 200/ mm 3 has been found to be clinically significant in reducing the risk of opportunistic infections.
  • the antioxidant polyphenol EGCG is likewise effective in the case of Influenza A (54, 55) and in the case of HIV infection mitigates the neurotoxicity of the IFN-gamma-reinforced damage caused by HIV-I glycoprotein gpl20 and Tat, both in vitro and in vivo (46).
  • the antioxidant polyphenol EGCG binds to the CD4+ T-cells in a manner such that the calculated binding of gpl20 to the CD4-EGCG complex is negligible (48).
  • the favourable binding of EGCG to the CD4 can thus effectively block the gpl20-CD4.
  • EGCG has a protective effect in respect of HIV -induced dementia (56) and the infection itself (57).
  • the 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 ⁇ -carotene to be delivered parenterally to a critically ill patient.
  • a formulation of an extract of green tea with a large number of other ingredients such as vitamins, minerals and amino acids and components which in solution provide an effervescent effect is described in the international application WO 01/00038.
  • the European patent EP 1572175B which patent corresponds to the Canadian patent application CA 2499006, describes a formulation comprising an extract of green tea comprising 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 which reduces the risk of postoperative complications.
  • Compositions with nutritional supplements comprising many ingredients are also described in a large number of other publications, such as in
  • German patent application DE 102006038224 in addition to glutamine and EGCG the compositions also comprise at least Tyrosine and Taurine, and these compositions are suitable for treating neuroendocrine health problems,
  • a lolly which comprises, in addition to an extract of green tea and glutamine, at least six other ingredients,
  • compositions for instance comprising antioxidants, wherein many are mentioned, such as for instance tea extract and amino acids with branched carbon chains, many of which are mentioned, such as for instance glutamine,
  • a large number of dietary supplements are described for removing heavy metals from the body, wherein a composition comprises, in addition to about 20 other ingredients, an extract of green tea and glutamine,
  • the present invention has for its object to provide a composition which is very effective in respect of improving the state of health and in maintaining the state of health in many areas.
  • the invention provides a kit of parts of the type stated in the preamble, substantially comprising a) L-Glutamine and b) (-)- epigallocatechin gallate (EGCG), preferably consisting only of a) L-Glutamine and b) EGCG.
  • EGCG epigallocatechin gallate
  • a) L-Glutamine and b) EGCG are preferably packed together in a double sachet, both a) L-Glutamine and b) EGCG more are preferably present independently of each other in the form chosen from the group of powder and capsule. Both components will generally be used in this form, although the ingestion of at least one of the components in dissolved form also forms part of the invention.
  • the kit of parts according to the invention preferably comprises about 1 - 6O g active L-Glutamine, more preferably about 5 - 3O g active L-Glutamine, in particular about 9 g active L- Glutamine and about 50 - 1500 mg EGCG, more preferably about 100 - 400 mg EGCG, in particular about 150 mg EGCG.
  • Generally recommended as daily dosage is a dosage no higher than 3 x the content of the double sachet according to the invention.
  • the kit of parts according to the invention is preferably applied in oral manner, although all other known and suitable administering methods, such as for instance parenteral, subcutaneous, intramuscular or intravenous, also form part of the invention.
  • an application of such a kit of parts is provided for the purpose of enhancing sporting performance.
  • an application of such a kit of parts is provided as means of preventing or reducing the risk of developing a physical disorder.
  • the application of such a kit of parts serves particularly to increase the activity of the immune system.
  • kit of parts particularly prevents or reduces the risk of developing one or more of the following physical disorders: cardiovascular disease, more particularly on the basis of arteriosclerosis diabetes mellitus, in particular type-2 high blood pressure obesity / overweight - neurological mucous membrane disorders, hair cell disorders, cardiac disorders and peripheral nerve disorders, also as side-effects of chemotherapy and radiotherapy, bacterial and viral infections rheumatic inflammations burns
  • Duchenne muscular dystrophy In these cases increased oxidative stress plays an important pathogenetic role which is targeted by the application.
  • a virus from the group consisting of influenza, HIV, HIV/AIDS, HCV, HBV, HSV and HPV one or more neurological disorders as caused by one or more of the diseases of the group consisting of those of Alzheimer, Parkinson and Huntington and multiple sclerosis or
  • 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, preferably in the form of a double sachet, in particular chosen independently of each other from the group of powder and capsule. Desired adjuvants are co-packaged in a manner known to the skilled person.
  • glutamate as dipeptides it is possible to envisage the two dipeptides Alanine-Glutamine and Glycine-Gutamine, Ala-Gin and Gly-Gln respectively.
  • a weight of active L-Glutamine is understood to mean a weight of derivative corresponding in number of MoI to the weight of L-Glutamine per se.
  • the term 'substantially' indicates that, in addition to the stated active ingredients, other ingredients can be present which are not active, or hardly so, such as adjuvants, without this detracting from the scope of protection of the invention.
  • kits of parts with both products packed in a double sachet specifically referred to as 2-Prepare For Optimal Care ® .
  • the use of the separate components a) L-Glutamine and EGCG together within an appropriate period of time of preferably no longer than one to two hours must also be deemed as forming part of the invention.
  • EGCG can be extracted from green tea, for instance as described in the European patent EP 1767097, and is also commercially available from for instance DSM Nutritional Products AG as Teavigo ® , 200 mg in a gelatin-free capsule.
  • the EGCG component of the kit is understood to mean a composition with an EGCG content of at least 90%, generally of at least about 95%. Since this compound is extracted from green tea, this purity is obtained here.
  • Both active parts of the kit are particularly used as powder or capsule as preferably applied in the double sachet.
  • the formulation of the capsule has the advantage that the bitter taste of EGCG is eliminated.
  • Other formulations such as pills, tablets, effervescent tablets, film tablets, which can also be packed in a double sachet, will of course also fall within the scope of protection of the invention.
  • Adjuvants known to the skilled person can also be present in all formulations in addition to the active ingredients.
  • Both active components are otherwise generally separated from each other in the double sachet, particularly by means of a closure. Separate packaging has the advantage that EGCG, which in high concentration acts locally as an oxidative substance, does not adversely affect (the action of) L-glutamine.
  • the present invention provides such a combination, with the combination of a) L-Glutamine, a conditionally essential amino acid, as first component, which amino acid increases the activity of the immune system and improves the muscle condition of persons with a poor nutritional level, in the case of burns and prior to and during heavy muscular exertion as in endurance sports.
  • the second component is a caffeine- free antioxidant which appears to mitigate complications from infections/inflammations, reduces cholesterol content, triglycerides and blood sugar, slows down the development and progression of Alzheimer and Parkinson disease and, by shifting the ratio of carbohydrate/fact burning in favour fat burning, improves stamina during great physical exertion by postponing excessive lactic acid production (acidification).
  • Glutamine decreases interleukin-8 and interleukin-6 but not nitric oxide and postaglandins E(2) production by human gut in vitro Cytokine2002; 18:92-97 21-Wilmore D. W, Role of glutamine in immunologic responses Nutrition.l998;14(7/8):618-626

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Abstract

The invention relates to a kit of parts for maintaining or improving the state of health, consisting of L-Glutamine, optionally as component of a dipeptide, and the green tea extract (-)-epigallocatechin gallate (EGCG). L-Glutamine and EGCG are particularly packed together in a double sachet. The invention also relates to the application of such a kit of parts for the purpose of enhancing sporting performance and as means of preventing or reducing the risk of developing a physical disorder. The kit of parts is applied in particularly advantageous manner for the purpose of increasing the activity of the immune system and in the case of cardiovascular diseases, diabetes mellitus, in particular type-2, high blood pressure, obesity and overweight, neurological mucous membrane disorders, hair cell disorders, cardiac disorders and peripheral nerve disorders, bacterial and viral infections, rheumatic inflammations and burns.

Description

KIT OF PARTS COMPRISING L-GLUTAMINE AND EGCG
The invention relates to a kit of parts for maintaining or improving the state of health, and the application of such a kit. The invention further relates to a method for preparing such a kit of parts.
There continues to be a great need for substances which favourably affect the state of health. There is particular interest in nutritional supplements generally deemed safe to be administered and used. Two important groups of nutritional supplements are formed by on the one hand amino acids and on the other antioxidants, such as for instance polyphenols. A group of polyphenols with strong antioxidant properties is formed by the catechins which occur in green tea, such as for instance (-)-epicatechin (EC), (-)-epigallocatechin gallate (EGCG), epigallocatechin (EGC) and epicatechin gallate (ECG). Both prospective, placebo-controlled, randomized clinical comparative research and animal experiment research and in vitro research making use of the culture of specific cell lines show that natural amino acids and the antioxidant polyphenols which completely differ therefrom both have an effect in a number of health areas important for maintaining or improving the state of health. The first health area relates to the favourable effect of natural amino acids and antioxidant polyphenols in reducing the risk of developing cardiovascular diseases, in particular arteriosclerosis and diabetes mellitus, in particular type-2. A dyslipidemia manifesting itself in an increased cholesterol, increase in the LDL cholesterol and decrease in the HDL cholesterol with increase in the triglycerides, diabetes mellitus type-2 (DMT2), hypertension and overweight are, in addition to smoking and a lack of daily physical exercise, the most important risk factors for the development of cardiovascular disease due to arteriosclerosis. In the case of diabetes mellitus type-2 insulin resistance and a reduced insulin secretion by the β-cells in the pancreas are the key pathogenic factors. In respect of amino acids:
- There are clinical trials which show that the parenteral supplementation of the amino acid L-glutamine in the form of a dipeptide increases the glucose tolerance by: 1- reducing the insulin resistance (1), whereby the glucose ingestion by the body improves (2) and
2- increasing the insulin plasma level (3).
This latter probably progresses on the one hand due to a relatively weak stimulation of the insulin secretion by β-cells via stimulation of the gamma-glutamyl cycle-mediated glutathione production and of the production of ATP by mitochondrial oxidation. The natural amino acid glutamine probably has a signal-transmitting role (4, 48) in this stimulation of the insulin secretion.
- On the other hand, orally administered L-Glutamine also enhances, via incretin- dependent mechanisms, the secretion of GLP- 1 (glucagon-like peptide 1 ) by the
L-cells of the intestinal wall, which increases the secretion of insulin in lean and obese patients with type-2 diabetic mellitus (5). In respect of antioxidant polyphenols:
- these have a regulating effect on the insulin secretion by β-cells in the pancreas through an allosteric inhibition of the glutamate dehydrogenase (GDH). EGCG has a positive effect on the glucose tolerance / diabetes type-2, of rodents (7) and probably on the diabetic retinopathy in humans (8);
- they improve the glucose tolerance by reducing the insulin resistance in humans and increase the fat oxidation during moderately intensive physical exertion (9); - in animal models they have in addition, probably as antioxidant, a favourable effect on the development of arteriosclerosis, blood pressure, obesity/overweight (10). The polyphenol EGCG also reduces cholesterol in humans (11) and counters postprandial increase of the triglycerides (12). A favourable result in preventing diabetes mellitus type 2 in adults has also been described (13). The daily ingestion of the antioxidant polyphenol catechins for 12 weeks reduced body fat/overweight and the content of the oxidized LDL (14).
The second health area relates to the favourable effect of natural amino acids and antioxidant polyphenols on bacterial inflammations and on autoimmune-mediated inflammations, such as for instance rheumatoid inflammations. In respect of natural amino acids: the natural amino acid L-Glutamine forms a fuel and nutrient for rapidly proliferating gut epithelial cells and immune cells around the gut and bronchial tree (15, 16 ,17, 18) and hereby supports the mucosal and immune barrier against attacking micro-organisms. In the case of inflammations it also reduces the endogenous inflammation reaction by preventing the release of pro-inflammatory mediators (IL-8, IL-6,TNF-α) from granulocytes and the production of metalloproteinase in for instance the postischemic gut (19) and enhancing the production of anti-inflammatory factors (IL-IO) by T-lymphocytes (20, 21, 22) as well as the cysteinyl-leukotriene generation (23, 24). The L-Glutamine affects the inflammation reaction by attenuating the NFk-B activation (25). The natural amino acid L-Glutamine also enhances the production of the glutathione involved in relief of oxidative stress (26) and of the heat shock proteins (27, 28, 29), and activation occurs of peroxisome proliferator activated receptor gamma, an anti-inflammatory transcription factor which protects the gut from damage by cytokines released during ischemia (52). In respect of antioxidant polyphenols: The antioxidant polyphenol catechin, such as EGCG, has a local bactericidal, fungicidal and antiviral effect, such as in the gut, making use of its oxidative action in high local concentrations and has a systemic inhibiting effect on the activation of the pro-inflammatory infection cascade, inter alia by inhibiting the NFkB and HMGBl, countering TNF- α and IL-I β induced toxicity. In the case of severe inflammations the antioxidant polyphenol catechin acts not only as antioxidant (30, 31) but also inhibits the metalloproteinase-2 activity induced by IL-I β and made possible by chemokines. Evaluation of the signal transmission paths showed that EGCG preferentially blocked the phosphorylation of PKCdelta and inhibited the activation and translocation to the cell nucleus of the NF-kappa β in synovial fibroblasts treated with IL-I β in rheumatoid arthritis patients (32). The antioxidant polyphenol EGCG in vitro also counters the autoantigen expression in normal human cellular components (33). The third health area relates to the favourable effect of natural amino acids and antioxidant polyphenols on mucositis and peripheral polyneuropathy induced by chemotherapy and radiotherapy.
In respect of natural amino acids: L-Glutamine forms an important fuel and nutrient for the epithelial and immune cells of the intestinal wall 1 (GALT) and for those of the bronchial tree (16). A number of clinical studies are known which indicate that L- Glutamine can reduce the peripheral neurological side-effects of chemotherapy and radiotherapy (34, 35, 36 and 37). L-Glutamine has a favourable effect on the occurrence of the mucositis often associated with chemotherapy and radiotherapy (38). A possible favourable effect in combatting multiple sclerosis has also been reported (49).
In respect of antioxidant polyphenols: these nutritional supplements can also reduce the side-effects of chemotherapy and radiotherapy (39). The fourth health area relates to the favourable effect of natural amino acids and antioxidant polyphenols for maintaining or improving fitness and sporting performance.
In respect of natural amino acids: there are many publications about supplementing the normal level of natural amino acids for the above stated indications. Exertion initially induces an increase in the plasma glutamine level, but with continued exertion the plasma glutamine falls below the normal lower limit value. This fall in the glutamine level is however seen as a potential cause of exertion-induced immune incompetence which is linked to an observed increased susceptibility to infection among athletes (40, 51). After prolonged exertion, hunger and physical stress the body has an increased need for glutamine, which justifies oral use thereof at that moment. The administration of L-Glutamine compensates the increased use by the body, and in particular the increased absorption by the kidney, in an attempt to keep the acid base balance in equilibrium, and provides for the increased use of glutamine by liver and gastrointestinal tract for the gluconeogenesis. A possible favourable effect of glutamine in combatting Duchenne muscular dystrophy has also been reported (50). In respect of antioxidant polyphenols: by stimulating fat-burning the use hereof is favourable in improving stamina. The effect of EGCG on fat-burning is dosage- dependent in laboratory animals 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 associated with an increase in the free fatty acid concentration. This indicates an increased use of lipids as energy source in the case of humans (41) and mice (42) fed with polyphenol EGCG.
The fifth health area relates to the favourable effect of natural amino acids and antioxidant polyphenols on virus infections, such as infection with influenza, HIV, HIV/AIDS, HCV, HBV, HSV and HPV. In respect of natural amino acids: there are publications which indicate that oral use of natural amino acid L-Glutamine is effective in the treatment of Influenza A (53) and in the treatment of chronic diarrhoea and/or "wasting" in the case of HIV/ AIDS patients, as with Cryptosporidium diarrhoea, resulting not only in a reduction of the symptoms but also in an improved resorption of the antiviral therapy (HAART) (43). Use of the oral amino acid L-Glutamine is also expressed in enhanced lymphocyte proliferation, this being significant because a number of CD4+ lymphocytes above 200/ mm3 has been found to be clinically significant in reducing the risk of opportunistic infections.
In respect of antioxidant polyphenols: the antioxidant polyphenol EGCG is likewise effective in the case of Influenza A (54, 55) and in the case of HIV infection mitigates the neurotoxicity of the IFN-gamma-reinforced damage caused by HIV-I 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 impedes the binding of gpl20 to the CD4+ T-cells in humans (47). EGCG binds to the CD4+ T-cells in a manner such that the calculated binding of gpl20 to the CD4-EGCG complex is negligible (48). The favourable binding of EGCG to the CD4 can thus effectively block the gpl20-CD4. EGCG has a protective effect in respect of HIV -induced dementia (56) and the infection itself (57).
The 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 delivered parenterally to a critically ill patient. A formulation of an extract of green tea with a large number of other ingredients such as vitamins, minerals and amino acids and components which in solution provide an effervescent effect is described in the international application WO 01/00038. The European patent EP 1572175B, which patent corresponds to the Canadian patent application CA 2499006, describes a formulation comprising an extract of green tea comprising 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 which reduces the risk of postoperative complications. Compositions with nutritional supplements comprising many ingredients are also described in a large number of other publications, such as in
German patent application DE 102006038224: in addition to glutamine and EGCG the compositions also comprise at least Tyrosine and Taurine, and these compositions are suitable for treating neuroendocrine health problems,
US patent 5,904,924: this patent describes a nutritional composition which is a mixture of about 60 natural products and herbs,
- US patent application US 2004/0071681 : described herein is a lolly which comprises, in addition to an extract of green tea and glutamine, at least six other ingredients,
International patent application WO 2007/135766: describes an ointment for leukoplakia or oral cancer comprising a green tea extract and alginic acid, European patent application EP 2025248: a large number of compositions are described for the treatment of cachexia and/or anorexia, such as for instance a composition comprising eicosapentaenoic acid, a phytochemical compound such as green tea and glutamine,
- International patent application WO 2006/020131 : described herein are a large number of compositions, for instance comprising antioxidants, wherein many are mentioned, such as for instance tea extract and amino acids with branched carbon chains, many of which are mentioned, such as for instance glutamine,
- US patent application 2009/0011048: a large number of dietary supplements are described for removing heavy metals from the body, wherein a composition comprises, in addition to about 20 other ingredients, an extract of green tea and glutamine,
- European patent application EP 2095727 corresponding to WO 2008/082582: described here are packed beverages comprising a large number of possible catechins, amino acids and also sweeteners.
In view of the abundance of described possible beneficial compositions, wherein different fields of application are indicated in each case, there is a demand for one simple composition with multiple activity. There is a great need for one safe nutritional supplement which reduces the risk of developing a disease and/or complications thereof, such as by reducing the risk 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 a poor nutritional level.
The present invention has for its object to provide a composition which is very effective in respect of improving the state of health and in maintaining the state of health in many areas.
In order to achieve the stated object, the invention provides a kit of parts of the type stated in the preamble, substantially comprising a) L-Glutamine and b) (-)- epigallocatechin gallate (EGCG), preferably consisting only of a) L-Glutamine and b) EGCG. a) L-Glutamine and b) EGCG are preferably packed together in a double sachet, both a) L-Glutamine and b) EGCG more are preferably present independently of each other in the form chosen from the group of powder and capsule. Both components will generally be used in this form, although the ingestion of at least one of the components in dissolved form also forms part of the invention. The kit of parts according to the invention preferably comprises about 1 - 6O g active L-Glutamine, more preferably about 5 - 3O g active L-Glutamine, in particular about 9 g active L- Glutamine and about 50 - 1500 mg EGCG, more preferably about 100 - 400 mg EGCG, in particular about 150 mg EGCG. Generally recommended as daily dosage is a dosage no higher than 3 x the content of the double sachet according to the invention. The kit of parts according to the invention is preferably applied in oral manner, although all other known and suitable administering methods, such as for instance parenteral, subcutaneous, intramuscular or intravenous, also form part of the invention.
According to another aspect of the invention, an application of such a kit of parts is provided for the purpose of enhancing sporting performance. According to yet another aspect of the invention, an application of such a kit of parts is provided as means of preventing or reducing the risk of developing a physical disorder. The application of such a kit of parts serves particularly to increase the activity of the immune system.
The application of a kit of parts particularly prevents or reduces the risk of developing one or more of the following physical disorders: cardiovascular disease, more particularly on the basis of arteriosclerosis diabetes mellitus, in particular type-2 high blood pressure obesity / overweight - neurological mucous membrane disorders, hair cell disorders, cardiac disorders and peripheral nerve disorders, also as side-effects of chemotherapy and radiotherapy, bacterial and viral infections rheumatic inflammations burns
Duchenne muscular dystrophy. In these cases increased oxidative stress plays an important pathogenetic role which is targeted by the application.
The kit of parts according to the invention is applied particularly effectively in the case of
- one or more of the infections with a virus from the group consisting of influenza, HIV, HIV/AIDS, HCV, HBV, HSV and HPV one or more neurological disorders as caused by one or more of the diseases of the group consisting of those of Alzheimer, Parkinson and Huntington and multiple sclerosis or
- a salivary/lacrimal and mucous membrane disorder as caused by Sjogren's disease.
The application of substantially a) L-Glutamine and b) EGCG together for the above described indications within an appropriate period of time also forms part of the present invention.
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, preferably in the form of a double sachet, in particular chosen independently of each other from the group of powder and capsule. Desired adjuvants are co-packaged in a manner known to the skilled person.
The invention will be further elucidated hereinbelow. Combining the action of two products as the result of a consciously chosen selection of that of the conditionally essential natural amino acid a) L-Glutamine and, as exogenous antioxidant, the most active component of the natural product green tea: b) (-)-epigallocatechin gallate (EGCG), belonging to the group of anti-oxidant polyphenols, has a greater efficacy than may be anticipated from merely bringing together two random nutritional supplements. The part of the kit a) L-Glutamine is understood in this patent document to mean
L-Glutamine or a derivative thereof, as well as L-Glutamine as part of a dipeptide. As derivative it is possible to envisage glutamate, as dipeptides it is possible to envisage the two dipeptides Alanine-Glutamine and Glycine-Gutamine, Ala-Gin and Gly-Gln respectively. A weight of active L-Glutamine is understood to mean a weight of derivative corresponding in number of MoI to the weight of L-Glutamine per se. The term 'substantially' indicates that, in addition to the stated active ingredients, other ingredients can be present which are not active, or hardly so, such as adjuvants, without this detracting from the scope of protection of the invention.
Particularly favourable is the application of a kit of parts with both products packed in a double sachet specifically referred to as 2-Prepare For Optimal Care®. However, the use of the separate components a) L-Glutamine and EGCG together within an appropriate period of time of preferably no longer than one to two hours must also be deemed as forming part of the invention.
The naturally occurring amino acid L-Glutamine is commercially available. EGCG can be extracted from green tea, for instance as described in the European patent EP 1767097, and is also commercially available from for instance DSM Nutritional Products AG as Teavigo®, 200 mg in a gelatin-free capsule.
The EGCG component of the kit is understood to mean a composition with an EGCG content of at least 90%, generally of at least about 95%. Since this compound is extracted from green tea, this purity is obtained here.
Both active parts of the kit are particularly used as powder or capsule as preferably applied in the double sachet. The formulation of the capsule has the advantage that the bitter taste of EGCG is eliminated. Other formulations such as pills, tablets, effervescent tablets, film tablets, which can also be packed in a double sachet, will of course also fall within the scope of protection of the invention. Adjuvants known to the skilled person can also be present in all formulations in addition to the active ingredients. Both active components are otherwise generally separated from each other in the double sachet, particularly by means of a closure. Separate packaging has the advantage that EGCG, which in high concentration acts locally as an oxidative substance, does not adversely affect (the action of) L-glutamine.
There is a great need for safe nutritional supplements or combinations thereof which reduce the risk of developing a disease, as is also apparent from the number of articles and patent documents appearing in this field. The present invention provides such a combination, with the combination of a) L-Glutamine, a conditionally essential amino acid, as first component, which amino acid increases the activity of the immune system and improves the muscle condition of persons with a poor nutritional level, in the case of burns and prior to and during heavy muscular exertion as in endurance sports. The second component, the component of green tea extract EGCG, is a caffeine- free antioxidant which appears to mitigate complications from infections/inflammations, reduces cholesterol content, triglycerides and blood sugar, slows down the development and progression of Alzheimer and Parkinson disease and, by shifting the ratio of carbohydrate/fact burning in favour fat burning, improves stamina during great physical exertion by postponing excessive lactic acid production (acidification). The action of the two reliable nutritional supplements, i.e. the natural amino acid a) L-Glutamine and the antioxidant polyphenol b) EGCG, each forming part of a group of compounds with a different mechanism of action, support each other advantageously in a great number of areas, in particular those stated above.
Although the invention is elucidated above on the basis of a large number of different applications of the kit of parts, it will be apparent that the invention is by no means limited thereto. On the contrary, many variations are still possible within the scope of the invention for a person with ordinary skill in the art.
References:
1- Coeffier M,et al Parenteral glutamine in critically ill patients: effects on complication rate and glucose homeostasis. Clinical Nutrition Supplements.2004;l :33- 36
2- Bakalar B et al Parenterally administered dipeptide alanyL-Glutamine prevents worsening of insulin sensitivity in multiple-trauma patients. Crit Care
Med.2006;34(2):381-386
3- Coeffier M, e.a. Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa. Am J Physiology Gastrointest Liver Physiol 2003;285:G266-G273 4- Newsholme P e.a. Amino acid metabolism, insulin secretion and diabetesBiochemical Society Transactions 2007;35 part 5:1180-1186 5- Greenfield JR et al. Oral glutamine increases circulating glucagon-like pepetide-1, glucagon and insulin concentrations in lean, obese and type 2 diabetic subjects Am J
Clin Nutr 2009;89: 106-113
6- Li CGreen tea polyfenols modulate insulin secretion by inhibiting glutamate dehydrogenase. The J of Biological Chemistry2006;281(15):10214-10221 7- Wolfram S e.a. Epigallocatechin gallate supplementation alleviates diabetes in rodentsJ Nutr 2006;136(10):2512-8
8- Skopinski P e.a. Suppression of angiogenic activity of sera from diabetic patients with non-proliferative rethinopathy by compounds of herbal origin and sulindac sulfonelnt J MoI Med 2004;14(4):707-l 1 9- Venables M et al. Green tea extract ingestion, fat oxidation and glucose tolerance in healthy humans Am J Clin Nutr 2008;87:778-84
10- Wu LY Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model Eur J Nutr 2004;43:l 16-124
11- Kono S et alGreen tea consumption and serum lipid profiles: a cross-sectional study in Northern Kyushu Japan. Preventive Med 1992;21 :526-531
12- Unno T et al. Effect of tea catechins on postprandial plasma lipid responses in human subjects British Journal of Nutrition 2005;93:543-547
13- Iso H, et al. The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med 2006;144:554- 562
14- Nagao T et al. Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modified LDL in men Am J Clin Nutr 2005;81 : 122-129
15- Newsholme PMetabolism of glucose, glutamine, long chain fatty acids and ketone bodies by murine macrophages. Biochem J 1986;239: 121-5 16- O'Riordain MG,et al. Glutamine-supplemented total parenteral nutrition enhances T-lymphocytes response in surgical patients undergoing colorectal resection Ann Surg 1994;220:212
17- Houdijk A.P.J et al. Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet.1998;352 sept:772-776. 18- Oehler R, Roth E. Regulative capacity of glutamine. Curr Opin Clin Nutr Metab Care.2002;6:277-282 19- Robinson EKDifferential effects of luminal arginine and glutamine on metalloproteinase production in the postischemic gut. JPEN 2008;32(4):433-438 20- Coeffier Me.a. Glutamine decreases interleukin-8 and interleukin-6 but not nitric oxide and postaglandins E(2) production by human gut in vitro Cytokine2002; 18:92-97 21-Wilmore D. W, Role of glutamine in immunologic responses Nutrition.l998;14(7/8):618-626
22- O'Riordain MG,et al. Glutamine-supplemented total parenteral nutrition enhances T-lymphocytes response in surgical patients undergoing colorectal resection Ann Surg 1994;220:212
23-Kδller M e.a. Generation of leukotrienes from human polymorphonuclear granulocytes of severely burned patients, J Trauma 1988;28:733-40
24- Morlion BJ, e.a. Cysteinyl-leukotriene generation as a biomarker for survival in the critically ill. Crit Care Med.2000;28(l l):3655-3658
25- Singleton D D et al, Glutamine attenuates inflammation and NFkB activation via Cullin-1 deneddylation Biochemical and Biophysical Research Communications 2008;373:445-449.
26- Roth E, e.a Regulative potential of glutamine-relation to glutathione metabolism 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 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 and prevents phospholipid hydroperoxidation in plasma of humansJ Agic.Food Chem 1999;47:3967-3973
32- Ahmed S et al. Regulation of Interleukin-1-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
33- Hsu S e.a. Inhibition of autoantigen expression by (-)-epigallocatechin-3 -gal late (the major constituent of green tea) in normal human cells J Pharmacol Exp Ther 2005;315(2):805-l l
34- Vahdat L et al. Reduction of Paclitaxel-induced peripheral neuropathy with glutamine. Clinical Cancer Research.2001;7:l 192-1197 35- Stubblefield MD, et al. Glutamine as a neuroprotective agent in high-dose paclitaxel -induced peripheral neuropathy: a clinical and electrophysiologic study. Clinical 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
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
40- Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise and sport training J.Nutr.2008;138:2045S-2049S
41- Moon HS et al. Proposed mechanisms of (-)-epigallocatechin-3-gallate for anti- obesity Chemico-Biological Interactions 2007; 167:85-98
42- Murase T et al. Tea catechin ingestion combined with habitual exercise suppresses the aging associated decline in physical performance in senescence-accelerated miceAm J Physiol Regul Integr Comp Physiology 2008;295:R281-R289
43- Bushen OYDiarrea and reduced levels of antiretro viral drugs: improvement with glutamine or alanyL-Glutamine in a randomized controlled trial in Northeast
BrazilClinical Infectious Diseases 2004;38: 1764-70
44- Giunta B. EGCG mitigates neurotoxicity mediated by HIV-I proteins gpl20 and 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-I therapy. J Allergy Clin Immunol 2006;118(6):1369-1374 46- Hamza A e.a. How can (-)-epigallocatechin gallate from green tea prevent HIV-I infection? Mechanistic insights from computational modeling and the implication for 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 SNl and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion. Biochemical and Biophysical Research Communications 21 February 2009.
49- Aktas O 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
50- Hankard R et al Is glutamine a conditionally essential amino acid in Duchenne muscular dystrophy? Clin Nutr.l999;18(6):365-369
51- Castell LM, Newsholme EA. The effects of oral glutamine supplementation on athletes after prolonged, exhaustive exercise. Nutrition 1997; 13(7/8)738-742
52- Ban K, Kozar RA. Enteral glutamine: a novel mediator of PP ARy in the post ischemic gut. J of Leukocyte Biology.2008;84:595-599
53-Li J e.a. Glycyl-L-glutamine-enriched total parenteral nutrition maintains small intestine gut-associated lymphoid tissue and upper respiratory tract immunity. JPEN.1998;22(1):31-36
54-Song JM e.a. Antiviral effect of catechins in green tea on influenza virus. Antiviral
Research.2005;68(2)66-74. Epub 2005 Aug 9
55-Nakayama M e.a. Inhibition of the infectivity of influenza virus by tea polyphenols.
Antiviral Research. 1993 Aug;21(4):289-99 56-Giunta B, Obregon D, Hou H, Zeng J, Sun N, Nikolic V, Ehrhart J, Shytle D,
Fernandez F, Tan J. EGCG mitigates neurotoxicity mediated by HIV-I proteins gpl20 and Tat in the presence of IFN-γ: role of JAK/STAT1 signaling and implications for
HIV-associated dementia. Brain Research 2006; 1123:216-225
57-Hamza A, Zhan CG. How can (-)-epigallocatechin gallate from green tea prevent HIV-I infection? Mechanistic insights from computational modeling and the implication for rational design of anti-HIV-1 entry. Phys Chem B. 2006 Feb 16;110(6):2910-7.

Claims

Claims
1. Kit of parts for maintaining or improving the state of health, substantially comprising a) L-Glutamine and b) (-)-epigallocatechin gallate (EGCG).
2. Kit of parts for maintaining or improving the state of health as claimed in claim 1, consisting only of a) L-Glutamine and b) (-)-epigallocatechin gallate (EGCG).
3. Kit of parts as claimed in one or more of the claims 1 or 2, wherein a) L- Glutamine and b) EGCG are packed together in a double sachet.
4. Kit of parts as claimed in one or more of the claims 1-3, wherein both a) L- Glutamine and b) EGCG are present independently of each other in the form chosen from the group of powder and capsule.
5. Kit of parts as claimed in one or more of the claims 1-4, comprising 1 - 6O g active a) L-Glutamine, preferably about 9 g, and 50 - 1500 mg active b) EGCG, preferably about 150 mg.
6. Application of a kit of parts as specified in one or more of the claims 1-5 in oral manner.
7. Application of a kit of parts as specified in one or more of the claims 1-6 for the purpose of enhancing sporting performance.
8. Application of a kit of parts as specified in one or more of the claims 1-6 as means of preventing or reducing the risk of developing a physical disorder.
9. Application of a kit of parts as claimed in claim 7 for the purpose of increasing the activity of the immune system.
10. Application of a kit of parts as claimed in claim 8 or 9, wherein the physical disorder is one or more of the following: cardiovascular disease, particularly on the basis of arteriosclerosis diabetes mellitus, in particular type-2 - high blood pressure obesity / overweight neurological mucous membrane disorders, hair cell disorders, cardiac disorders and peripheral nerve disorders, also as side-effects of chemotherapy and radiotherapy, - bacterial and viral infections rheumatic inflammations burns
Duchenne muscular dystrophy.
11. Application of a kit of parts as claimed in claim 10, wherein the virus infection relates to one or more of the infections with a virus from the group consisting of influenza, HIV, HIV/AIDS, HCV, HBV, HSV and HPV.
12. Application of a kit of parts as claimed in claim 10, wherein the neurological disorder relates to one or more of the diseases of the group consisting of those of
Alzheimer, Parkinson and Huntington and multiple sclerosis.
13. Application of a kit of parts as claimed in claim 10, wherein the mucous membrane disorder relates to Sjogren's disease.
14. Application of substantially a) L-Glutamine and b) EGCG together within an appropriate period of time for the indications described in one or more of the claims 7- 13.
15. Method for preparing a kit of parts as specified in one or more of the claims 1- 5, characterized in that a) L-Glutamine and b) EGCG are packaged together in a kit.
PCT/NL2010/000050 2009-03-20 2010-03-22 Kit of parts comprising l-glutamine and egcg WO2010107307A1 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012130893A1 (en) * 2011-03-28 2012-10-04 Centre National De La Recherche Scientifique (C.N.R.S) Use of epigallocatechin gallate as an antiviral agent against infections by the hepatitis c virus
WO2013077893A1 (en) * 2011-11-21 2013-05-30 Emmaus Medical, Inc. Methods and compositions for the treatment of diabetes and related symptoms
WO2013061161A3 (en) * 2011-10-28 2013-11-07 Anaxomics Biotech Sl New combination therapies for treating neurological disorders
CN103493694A (en) * 2013-09-18 2014-01-08 杭州市农业科学研究院 Method for increasing Longjing 43 tea tree EGCG content through exogenous induction

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5904924A (en) * 1997-11-04 1999-05-18 Oncologics, Inc. Green nutritional powder composition
US20040071681A1 (en) * 2002-10-10 2004-04-15 Lydia Muller Method and composition for reducing cravings for a craved substance
CA2499006A1 (en) * 2002-12-09 2004-06-24 Fresenius Kabi Deutschland Gmbh Formulation which can be administered gastrointestinally, and the use thereof
WO2006020131A1 (en) * 2004-07-20 2006-02-23 Window Rock Enterprises, Inc. Methods and compositions for weight management and mood enhancement
WO2007135766A1 (en) * 2006-05-19 2007-11-29 Ito En, Ltd. Ointment for amelioration or treatment of oral tumor
DE102006038224A1 (en) * 2006-08-04 2008-02-07 Bieger, Wilfried P., Priv.-Doz. Dr.med.habil. Procedure for the determination of neuroendocrinal health disorders such as e.g. chronic fatigue syndrome, comprises measuring glucocorticoids, sex steroids and amino acids/neurotransmitter and/or their metabolites in body fluids
WO2008081582A1 (en) * 2006-12-27 2008-07-10 Kao Corporation Packed drink
US20090011048A1 (en) * 2002-04-16 2009-01-08 Coleman Henry D Dietary Supplement For Promoting Removal Of Heavy Metals From The Body
EP2025248A1 (en) * 2007-07-31 2009-02-18 Fresenius Kabi Deutschland GmbH Cachexia prevention supplement

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US20040071681A1 (en) * 2002-10-10 2004-04-15 Lydia Muller Method and composition for reducing cravings for a craved substance
CA2499006A1 (en) * 2002-12-09 2004-06-24 Fresenius Kabi Deutschland Gmbh Formulation which can be administered gastrointestinally, and the use thereof
WO2006020131A1 (en) * 2004-07-20 2006-02-23 Window Rock Enterprises, Inc. Methods and compositions for weight management and mood enhancement
WO2007135766A1 (en) * 2006-05-19 2007-11-29 Ito En, Ltd. Ointment for amelioration or treatment of oral tumor
DE102006038224A1 (en) * 2006-08-04 2008-02-07 Bieger, Wilfried P., Priv.-Doz. Dr.med.habil. Procedure for the determination of neuroendocrinal health disorders such as e.g. chronic fatigue syndrome, comprises measuring glucocorticoids, sex steroids and amino acids/neurotransmitter and/or their metabolites in body fluids
WO2008081582A1 (en) * 2006-12-27 2008-07-10 Kao Corporation Packed drink
EP2025248A1 (en) * 2007-07-31 2009-02-18 Fresenius Kabi Deutschland GmbH Cachexia prevention supplement

Non-Patent Citations (57)

* Cited by examiner, † Cited by third party
Title
AHMED S ET AL.: "Regulation of Interleukin-1-?-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts", ARTHRITIS AND RHEUMATISM, vol. 54, no. 8, 2006, pages 2393 - 2401
AKTAS 0 ET AL.: "Green tea epigalloocatechin-3- gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis", J IMMUNOL, vol. 173, no. 9, 2004, pages 5794 - 5800
AMARA S .: "Oral Glutamine for the prevention of chemotherapy-induced peripheral neuropathy", THE ANNALS OF PHARMACOTHERAPY, vol. 42, 2008, pages 1481 - 1485
ANDERSON PM: "Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy", CANCER, vol. 83, 1998, pages 1433 - 1439
BAKALAR B ET AL.: "Parenterally administered dipeptide alanyL-Glutamine prevents worsening of insulin sensitivity in multiple-trauma patients", CRIT CARE MED., vol. 34, no. 2, 2006, pages 381 - 386
BAN K; KOZAR RA: "Enteral glutamine: a novel mediator of PPARy in the post ischemic gut", J OF LEUKOCYTE BIOLOGY, vol. 84, 2008, pages 595 - 599
BUSHEN OY: "Diarrea and reduced levels of antiretroviral drugs: improvement with glutamine or alanyL-Glutamine in a randomized controlled trial", NORTHEAST BRAZILCLINICAL INFECTIOUS DISEASES, vol. 38, 2004, pages 1764 - 70
CAO Y E.A.: "Glutation enhances gut glutathion production", JPEN, vol. 22, 1998, pages 224 - 7
CASTELL LM; NEWSHOLME EA: "The effects of oral glutamine supplementation on athletes after prolonged, exhaustive exercise", NUTRITION, vol. 13, no. 7/8, 1997, pages 738 - 742
COEFFIER M: "Enteral glutamine stimulates protein synthesis and decreases ubiquitin mRNA level in human gut mucosa", AM J PHYSIOLOGY GASTROINTEST LIVER PHYSIOL, vol. 285, 2003, pages G266 - G273
COEFFIER M: "Parenteral glutamine in critically ill patients: effects on complication rate and glucose homeostasis", CLINICAL NUTRITION SUPPLEMENTS, vol. 1, 2004, pages 33 - 36
COEFFIER ME.A.: "Glutamine decreases interleukin-8 and interleukin-6 but not nitric oxide and postaglandins E(2) production by human gut in vitro", CYTOKINE, vol. 18, 2002, pages 92 - 97
GAMMELSAETER R ET AL.: "Complementary expression of SNl and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 21 February 2009 (2009-02-21)
GIUNTA B.: "EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-y: role of JAK/STAT1 signaling and implications for HIV-associated dementia", BRAIN RESEARCH, vol. 1123, 2006, pages 216 - 225
GIUNTA B; OBREGON D; HOU H; ZENG J; SUN N; NIKOLIC V; EHRHART J; SHYTLE D; FERNANDEZ F; TAN J.: "EGCG mitigates neurotoxicity mediated by HIV-1 proteins gp120 and Tat in the presence of IFN-y: role of JAK/STAT1 signaling and implications for HIV-associated dementia", BRAIN RESEARCH, vol. 123, 2006, pages 216 - 225
GLEESON M.: "Dosing and efficacy of glutamine supplementation in human exercise and sport training", J.NUTR., vol. 138, 2008, pages 2045S - 2049S
GREENFIELD JR ET AL.: "Oral glutamine increases circulating glucagon-like pepetide-1, glucagon and insulin concentrations in lean, obese and type 2 diabetic subjects", AM J CLIN NUTR, vol. 89, 2009, pages 106 - 113
HAMZA A E.A.: "How can (-)-epigallocatechin gallate from green tea prevent HIV-1 infection? Mechanistic insights from computational modeling and the implication for rational design of anti-HIV-1 entry inhibitors", PHYS CHEM B, vol. 110, no. 6, 2006, pages 2910 - 7
HAMZA A; ZHAN CG: "How can (-)-epigallocatechin gallate from green tea prevent HIV-1 infection?", MECHANISTIC INSIGHTS FROM COMPUTATIONAL MODELING AND THE IMPLICATION FOR RATIONAL DESIGN OF ANTI-HIV-1 ENTRY. PHYS CHEM B., vol. 110, no. 6, 16 February 2006 (2006-02-16), pages 2910 - 7
HANKARD R ET AL.: "Is glutamine a conditionally essential amino acid in Duchenne muscular dystrophy?", CLIN NUTR., vol. 18, no. 6, 1999, pages 365 - 369
HENNING SM ET AL.: "Catechin content of 18 teas and a green tea extract supplement correlates with the antoxidant capacity", NUTRITION AND CANCER, vol. 45, no. 2, 2003, pages 226 - 235
HOUDIJK A.P.J ET AL.: "Randomised trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma", LANCET, vol. 352, September 1998 (1998-09-01), pages 772 - 776
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, vol. 315, no. 2, 2005, pages 805 - 11
ISO H ET AL.: "The relationship between green tea and total caffeine intake and risk for self-reported type 2 diabetes among Japanese adults", ANN INTERN MED, vol. 144, 2006, pages 554 - 562
K61LER M E.A.: "Generation of leukotrienes from human polymorphonuclear granulocytes of severely burned patients", J TRAUMA, vol. 28, 1988, pages 733 - 40
KONO S ET AL.: "Green tea consumption and serum lipid profiles: a cross-sectional study in Northern Kyushu Japan", PREVENTIVE MED, vol. 21, 1992, pages 526 - 531
LI C: "Green tea polyfenols modulate insulin secretion by inhibiting glutamate dehydrogenase", THE J OF BIOLOGICAL CHEMISTRY, vol. 281, no. 15, 2006, pages 10214 - 10221
LI J E.A.: "Glycyl-L-glutamine-enriched total parenteral nutrition maintains small intestine gut-associated lymphoid tissue and upper respiratory tract immunity", JPEN, vol. 22, no. 1, 1998, pages 31 - 36
MITHIEUX G.: "New data and concepts on glutamine and glucose metabolism in the gut", CURR OPIN CLIN METAB CARE, vol. 4, no. 4, 2001, pages 267 - 271
MOK E. ET AL.: "Oral glutamine and amino acid supplementation inhibit whole-body protein degradation in children with Duchenne muscular dystrophy", AM. J. CLIN. NUTR., vol. 83, 2006, pages 823 - 828, XP002554314, Retrieved from the Internet <URL:www.ajcn.org> [retrieved on 20091106] *
MOON HS ET AL.: "Proposed mechanisms of (-)-epigallocatechin-3-gallate for anti-obesity", CHEMICO-BIOLOGICAL INTERACTIONS, vol. 167, 2007, pages 85 - 98
MORLION B.J, E.A.: "Cysteinyl-leukotriene generation as a biomarker for survival in the critically ill", CRIT CARE MED., vol. 28, no. 11, 2000, pages 3655 - 3658
MURASE T ET AL.: "Tea catechin ingestion combined with habitual exercise suppresses the aging associated decline in physical performance in senescence-accelerated mice", AM J PHYSIOL REGUL INTEGR COMP PHYSIOLOGY, vol. 295, 2008, pages R281 - R289
NAGAO T ET AL.: "Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modified LDL in men", AM J CLIN NUTR, vol. 81, 2005, pages 122 - 129
NAKAGAWA KM ET AL.: "Tea catechin supplementation increases antioxidant capacity and prevents phospholipid hydroperoxidation in plasma of humansJ Agic", FOOD CHEM, vol. 47, 1999, pages 3967 - 3973
NAKAYAMA M E.A.: "Inhibition of the infectivity of influenza virus by tea polyphenols", ANTIVIRAL RESEARCH., vol. 21, no. 4, August 1993 (1993-08-01), pages 289 - 99
NEWSHOLME P E.A.: "Amino acid metabolism, insulin secretion and diabetes", BIOCHEMICAL SOCIETY TRANSACTIONS, vol. 35, 2007, pages 1180 - 1186
NEWSHOLME P: "Metabolism of glucose, glutamine, long chain fatty acids and ketone bodies by murine macrophages", BIOCHEM J, vol. 239, 1986, pages 121 - 5
O'RIORDAIN MG: "Glutamine-supplemented total parenteral nutrition enhances T-lymphocytes response in surgical patients undergoing colorectal resection", ANN SURG, vol. 220, 1994, pages 212
ROBINSON EK: "Differential effects of luminal arginine and glutamine on metalloproteinase production in the postischemic gut", JPEN, vol. 32, no. 4, 2008, pages 433 - 438
ROTH E, E.A, REGULATIVE POTENTIAL OF GLUTAMINE-RELATION TO GLUTATHIONE METABOLISM NUTRITION, vol. 18, 2002, pages 217 - 221
SINGLETON D D ET AL.: "Glutamine attenuates inflammation and NFkB activation via Cullin-1 deneddylation", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 373, 2008, pages 445 - 449
SINGLETON KD, E.A.: "Glutamine's protection against sepsis and lung injury is dependent on heat shock 70 expression", AM J PHYSIOL REGUL INTEGR COMP PHYSIOL, vol. 292, 2007, pages R1839 - R1845
SKOPINSKI P E.A.: "Suppression of angiogenic activity of sera from diabetic patients with non-proliferative rethinopathy by compounds of herbal origin and sulindac sulfone", INT J MOL MED, vol. 14, no. 4, 2004, pages 707 - 11
SONG JM E.A.: "Antiviral effect of catechins in green tea on influenza virus", ANTIVIRAL RESEARCH, vol. 68, no. 2, 2005, pages 66 - 74
STUBBLEFIELD MD ET AL.: "Glutamine as a neuroprotective agent in high-dose paclitaxel -induced peripheral neuropathy: a clinical and electrophysiologic study", CLINICAL ONCOLOGY, vol. 17, 2005, pages 271 - 276
UNNO T ET AL.: "Effect of tea catechins on postprandial plasma lipid responses in human subjects British", JOURNAL OF NUTRITION, vol. 93, 2005, pages 543 - 547
VAHDAT L ET AL.: "Reduction of Paclitaxel-induced peripheral neuropathy with glutamine", CLINICAL CANCER RESEARCH, no. 7, 2001, pages 1192 - 1197
VENABLES M ET AL.: "Green tea extract ingestion, fat oxidation and glucose tolerance in healthy humans", AM J CLIN NUTR, vol. 87, 2008, pages 778 - 84
WANG WS ET AL.: "Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients", THE ONCOLOGIST, vol. 12, 2007, pages 312 - 319
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, vol. 18, no. 6, 2006, pages 1369 - 1374
WILMORE D.W, ROLE OF GLUTAMINE IN IMMUNOLOGIC RESPONSES NUTRITION, vol. 14, no. 7/8, 1998, pages 618 - 626
WISCHMEYER PE: "Glutamine and heat shock protein expression", NUTRITION, vol. 18, 2002, pages 225 - 8
WOLFRAM S E.A.: "Epigallocatechin gallate supplementation alleviates diabetes in rodents", J NUTR, vol. 136, no. 10, 2006, pages 2512 - 8
WU LY: "Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model", EUR J NUTR, vol. 43, 2004, pages 116 - 124
YAMAGUCHI K. ET AL.: "Inhibitory effects of (-)-epigallocatechin gallate on the life cycle of human immunodeficiency virus type 1 (HIV-1)", ANTIVIRAL RESEARCH, vol. 53, 2002, pages 19 - 34, XP002554315, Retrieved from the Internet <URL:www.elsevier.com/locate/antiviral> [retrieved on 20091106] *
YAMAMOTO T ET AL.: "Protective effects of EGCG on salivary gland cells treated with gamma-radiation or cis-platinum(II)diamine dichloride", ANTICANCER RESEARCH, vol. 24, no. 5A, 2004, pages 3065 - 3075

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