WO1998031377A1 - Utilisation de produits alimentaires pour la protection contre les radicaux - Google Patents

Utilisation de produits alimentaires pour la protection contre les radicaux Download PDF

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Publication number
WO1998031377A1
WO1998031377A1 PCT/NL1998/000034 NL9800034W WO9831377A1 WO 1998031377 A1 WO1998031377 A1 WO 1998031377A1 NL 9800034 W NL9800034 W NL 9800034W WO 9831377 A1 WO9831377 A1 WO 9831377A1
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WO
WIPO (PCT)
Prior art keywords
whey
radicals
products
diseases
antipyrine
Prior art date
Application number
PCT/NL1998/000034
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English (en)
Inventor
Mohammed Essaidi
Frederik Albert Huf
Original Assignee
Mohammed Essaidi
Frederik Albert Huf
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mohammed Essaidi, Frederik Albert Huf filed Critical Mohammed Essaidi
Publication of WO1998031377A1 publication Critical patent/WO1998031377A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C21/00—Whey; Whey preparations
    • A23C21/02—Whey; Whey preparations containing, or treated with, microorganisms or enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum

Definitions

  • SOD serotonin-degenerative disease
  • glutathione-peroxidase glutathione-peroxidase
  • Radicals are formed in larger concentrations under more excessive circumstances such as sport, stress, hypoxemia as in ischaemia followed by reperfusion, radiotherapy, chemotherapy, infection and inflammation, but also accompany or cause illnesses like diabetes, cancer, cardio- vascular disease, arthritis, neurodegenerative diseases, (auto)immune diseases and other diseases. More generally, radicals are regarded to be an important cause of ageing processes.
  • a connection with the increased permeability of the intestine can be made, caused by stress, physical strain, hypoxemia/reperfusion, alcohol, food metabolites, drugs, xenobiotics, aminoacid deficiency, infections and inflammation and therefore enabling translocation from the lumen of toxins, prions, viruses and micro-organisms or their fragments present in the intestine and the immuno-response of the host.
  • the normal radical removing system is thought not be fast enough to remove radicals in time. The remaining radicals can cause damage to e.g. DNA causing fast mutations, eventually leading to cancer, and can also result in other diseases as indicated above. Also in the ordinary metabolism it is assumed that upon growing older the removing system slows down, resulting in radical concentrations which can again cause damage.
  • the body is normally assisted in its struggle to keep the radical concentration within the body negligible, by natural compounds taken in with food and/or formed as metabolites.
  • radicals or radical forming compounds such as for example vitamins (E and C), carotenoids, flavonoids and polyphenols (B. Halliwall and J.M.C. Cutteridge, "Free Radicals in Biology and Medicine”, Clarendon Press, Oxford, 1996, p. 86-188 and p.416-494; ILSI Monograph, "Oxidants, Antioxidants and Disease Prevention", ILSI Press, Brussles, 1995, p. 13-23).
  • Foodstuffs known to contain substantial amounts of different types of scavenging molecules include soybeans, tea, coffee, red wine, rosemary, sage and other spices, citrus and other fruits, onions, olives, tomatoes, carrots, broccoli etc. In some cases combinations of food products may enhance the radical scavenging.
  • the invention pertains to the use of a combination of products which is effective in preventing the formation of radicals in the human and animal body and/or in scavenging such radicals.
  • the invention also provides a method which allows the measurement of radical levels both in vivo and in vitro.
  • the invention relates to the combined use of whey solids and products released through fermentation by microorganisms, for preparing a foodstuff or medicament for the protection of the human or animal body against the effect of radicals.
  • the protection against the effect of radicals applies especially to ageing and diseases and side-effects of radiotherapy or chemotherapy, combination therapy in the treatment of AIDS, to intensive care or the treatment of post-operational conditions, in the treatment or prophylaxis of diabetes, migraine, neurodegenerative diseases, cancer and cardiovascular diseases, or to the treatment of stress conditions, slimming or excessive exercise as well as (auto)immune diseases caused by pathogenic agents as toxins, prions, micro-organism or their fragments, which can be translocated from the lumen because of a radical-mediated increase of permeability of the intestine, caused e.g. by infections, drugs, xenobiotics, alcohol, aminoacid deficiency, hypoxemia as in ischemia followed by reperfusion, stress or physical strain. Furthermore the conversion is improved in animal
  • the mechanism of the protective effect of the method of the invention is believed to be multiple. Firstly, the formation of radicals is decreased by the active components. The decomposition of water by radiolysis is increased by hydrogen peroxide, and the removal of hydrogen peroxide by enzymes such as peroxidases and catalases decreases the damage. Also the damage from superoxide ions resulting from the presence of oxygen and superoxide dismutase is decreased. Furthermore there is extinction of radiation by iron compounds. Superoxide anion and hydrogen peroxide production resulting from hypoxemia followed by reperfusion is decreased by enzymes supplied by the fermentation products. Production of radicals during immunoresponse is not decreased as there is less formation of fatty acid oxidation products, since the body cells are protected against membrane destruction (J.J. Dibner et al, Animal Feed Sc. Tech. 62 (1996) 1-13).
  • the whey solids preferably comprise whey proteins.
  • Whey may be used as such, or in a concentrated form or in a low-lactose form. An effect is already obtained at a daily dosage of about 100 mg, but the preferred level of whey solids, especially whey proteins, is from 200 mg to 60 g, in particular 1-30 g of whey solids per day.
  • the products released through fermentation by microorganisms comprise enzymes and other metabolic products or parts of the microorganisms.
  • the microorganisms may be bacteria, yeast and fungi, preferably food-grade.
  • the microorganisms are selected from lactic acid bacteria and yeasts.
  • Suitable lactic acid bacteria include the genera Lactobacillus, Lactococc s, Streptococcus, Pediococcus, Vagococcus, Leuconostoc, Carnobacterium, Weisselia, Oenococcus, Lactosphaera, Micrococcus, Bifidobacterium and Propionibacterium.
  • yeasts include the genera Saccharomyces (ellipsoides and other) and Kluyveromyces .
  • the microorganisms themselves may be present (preferably at least 10 6 cells per daily dosage up to about 10 10 cells per day) or their parts thereof or cell excretion products only.
  • Active enzymes include oxidoreductases such as SOD, catalase, peroxidase, cytochrome C oxidase, and others.
  • Other active compounds resulting from fermentation are iron-containing proteins and other ferrous compounds.
  • the fermentation products result from fermentation, mainly of carbohydrates, like glucose, fructose, galactose, mannose, xylose, and their homo- and hetero-oligomers, such as sucrose, maltose and especially lactose, but also of proteins.
  • carbohydrates and proteins may be present in common food products such as milk, fruits, corn, vegetables.
  • the fermented food products such as buttermilk, yoghurt, acido- philus milk, beer, wine, honey, sauerkraut, fermented whey etc. may also be used as such.
  • the amount of products released by microbial fermentation may be from 50 mg to 5 g of dry matter derived from microbial fermentation per daily dosage.
  • the total daily amount of whey solids and dry fermentation products is preferably 50 mg- 50 g, in particular 100 mg- 10 g.
  • the fermentation products are derived from non-whey products such as honey, white wine etc, their level can be related to the dry matter of these non-whey products, which are used then at levels of e.g. 50 mg to 20 g.
  • the effectiveness of the protective combinations can be determined using a monitoring compound.
  • the system developed allows the measurement of the actual activity of scavengers in vitro.
  • antipyrine or another aniline derivative is used as a probe, because it reacts sufficiently fast with radicals and gives unique detectable products upon reaction with a radical. Radicals are formed by gamma- irradiation of a solution with antipyrine.
  • the aniline compound has the general formula R ⁇ N- r , wherein R 1 and R 2 are each C,-C 6 alkyl, C,-C 6 alkenyl, C,-C 6 acyl or C,-C 6 alkylamino, or together with the nitrogen atom form a 5- or 6-membered ring which may contain one or more further nitrogen, oxygen or sulphur atoms.
  • R 1 represents an acyl group and more preferably R*R 2 N- represents an optionally substituted oxopyrrolyl, oxoimid- azolyl, oxopyrazolyl, oxo(is)oxazolyl, oxo(iso)thiazolyl, oxopyridyl, oxopyridazinyl or oxo-oxazinyl ring or di- or tetra-hydro analogue thereof.
  • the compound is antipyrine (R*R 2 N- is a l,5-dimethyl-3-oxo-2-pyrrazolinyl group).
  • Either the disappearance of antipyrine can be followed or the concentration of formed molecules/radicals can be measured by known techniques as chromatographic methods, for example micellar electrokinetic chromatography, HPLC, GLC, capillary chromatography, autoanalyser methods and direct radical measurements like electron spin resonance.
  • chromatographic methods for example micellar electrokinetic chromatography, HPLC, GLC, capillary chromatography, autoanalyser methods and direct radical measurements like electron spin resonance.
  • the nature of the o- and m-hydroxy derivatives can be established, if necessary, by spectrometric methods, such as NMR. Ligand assays or colour tests can be used as well.
  • a solution containing a potential scavenger is added, which is subsequently irradiated. If one measures the concentration of antipyrine, or the concentration of the degradation products, upon gamma-irradiation, it is found that the relative rate of degradation of antipyrine is slowed down by the scavenging power of the potential scavenger solution.
  • antipyrine however is that it is not present in food or the body (for in vivo and in vitro applications) and therefore no undefined basic level has to be subtracted as is the case for e.g. salicylic acid.
  • antipyrine passes all organs with an optimal concentration ratio to blood. The chosen concentrations are chosen for convenience of detection but can easily be adjusted to other values. Further experimental details are described by Coolen et al in /. Chromatography A, 788 (1997) 95-103.
  • the invention relates in particular to such a method for determining the risk of radical damage in a human or animal body, to be performed in conjunction with administering a physiologically acceptable aniline derivative, in particular antipyrine, to said body and taking a fluid sample from said body, said method comprising monitoring the level of said aniline derivative and its o-hydroxy and m-hydroxy substituted analogues in said fluid sample.
  • a physiologically acceptable aniline derivative in particular antipyrine
  • the aniline derivative is a derivative as described above, especially antipyrine.
  • the body fluid may be blood, serum, but especially urine.
  • the scavenging effect of whey when compared to milk or a solution of whey proteins, is surprisingly strong.
  • the effect of buttermilk, fermented whey or whey in combination with white wine (Elzas) is even stronger, in fact 100%.
  • the scavenger in whey does not occur in the raw milk, but has been formed during the (lactic acid) fermentation.
  • fermented milk products had a higher scavenging potency than the milk they were produced from. This may be due to special metabolites or active proteins like enzymes formed from the (lactic acid) fermentation.
  • the synergetic effect of whey and white wine cannot be explained by simple addition of effects and the same holds for the extremely effective protection of antipyrine by the whey combinations and buttermilk.
  • the mixtures of white wine or honey and whey or other fermented (milk) products or fermented vegetable products and/or products with a probiotic action based on microbial activity or the products in itself are acceptable as food products. It might however be necessary to purify, at least partially, the sources in case one would like to use the combined purified or concentrated fractions of scavengers in health applications such as clinical food, medical food and/or functional food.
  • Clinical foods containing whey or other fermented (milk) products and white wine or honey or their combined active fractions or similar combinations and their fractions, can be used in case of e.g. radiotherapy, chemotherapy, combination therapy for AIDS, intensive care and post-operative care. Blood cells are protected during combination therapy for AIDS by (fermented) whey, as observed ex vivo.
  • Medical foods containing whey or other fermented (milk) products and white wine or honey or their combined active fractions or similar combinations or their fractions, can be used in case of e.g. diabetic patients, patients with a "leaky” intestine, allergy patients, patients with a neurodegenerative disease, cancer patients and patients with cardiovascular problems.
  • Functional foods containing whey or other fermented (milk) products and white wine or honey or their combined active fractions or similar combinations or their fractions, can be used in case of e.g. stress situations, sport and exercise and by elderly people. These foods are also part of the present invention.
  • Another application which can also be used in addition to in vitro screening for scavengers, is the use of antipyrine or similar compounds, as mentioned above in in- vivo diagnostics allowing the measurement of radical levels and changes therein by detecting the radicals formed from antipyrine upon reaction with radicals.
  • antipyrine or similar compounds, as mentioned above in in- vivo diagnostics allowing the measurement of radical levels and changes therein by detecting the radicals formed from antipyrine upon reaction with radicals.
  • patients or other people, like sportsmen for whom it might be useful to measure the radical levels in the body are given antipyrine.
  • the oxidative radicals in the body will react with antipyrine forming o-hydroxy and m-hydroxy phenolic products, which are different from enzymatic metabolites such as p-hydroxyphenol, all of those compounds can be detected after being expelled from the body.
  • the results of such studies can be used to measure the in vivo effect of food products which are supposed to diminish the radical levels, enabling quantitative intervention studies, or medicines having a potentially positive or negative effect

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Public Health (AREA)
  • Cell Biology (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Microbiology (AREA)
  • Polymers & Plastics (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

Cette invention se rapporte à l'utilisation de lactosérum et de produits issus de la fermentation microbienne, pour préparer un produit alimentaire ou un médicament destiné à réduire l'effet de radicaux sur des humains ou des animaux, dans le processus de vieillissement et dans des maladies, ainsi que les effets secondaires de la radiothérapie, de la chimiothérapie ou du traitement associé contre le SIDA; ce produit alimentaire ou ce médicament est conçu pour des soins intensifs ou pour le traitement de troubles postopératoires, pour le traitement ou la prophylaxie des fuites intestinales, des maladies auto-immunes, des infections à virus ou prions, du diabète, de la migraine, des maladies neurodégénératives, du cancer et des maladies cardio-vasculaires, ou pour le traitement des troubles liés aux stress ou à des efforts excessifs. L'invention se rapporte également aux produits alimentaires ou médicamenteux décrits ci-dessus.
PCT/NL1998/000034 1997-01-20 1998-01-20 Utilisation de produits alimentaires pour la protection contre les radicaux WO1998031377A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP97200152 1997-01-20
EP97200152.3 1997-01-20

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WO1998031377A1 true WO1998031377A1 (fr) 1998-07-23

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000060094A1 (fr) * 1999-04-07 2000-10-12 Institut National De La Recherche Agronomique (Inra) Lactocoques modifies exprimant une catalase et leurs utilisations
WO2002000231A1 (fr) * 2000-06-28 2002-01-03 Sericausa B.V. Utilisation d'une preparation constituee de ou contenant un minimum de lactoserum dissimule

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375852A1 (fr) * 1988-12-23 1990-07-04 Immunotec Research Corporation Ltd. Composition de protéines de petit lait biologiquement active, méthode de production et utilisation de la composition
SU1746986A1 (ru) * 1990-05-14 1992-07-15 Украинский Научно-Исследовательский Институт Мясной И Молочной Промышленности Молочный продукт дл детского питани
JPH0698717A (ja) * 1992-09-17 1994-04-12 Meiji Milk Prod Co Ltd 長期療養患者用液状調製栄養食品
EP0655245A2 (fr) * 1993-11-01 1995-05-31 FREE RADICAL SCIENCES Inc Compositions et leur utilisation pour retarder le processus de vieillissement

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0375852A1 (fr) * 1988-12-23 1990-07-04 Immunotec Research Corporation Ltd. Composition de protéines de petit lait biologiquement active, méthode de production et utilisation de la composition
SU1746986A1 (ru) * 1990-05-14 1992-07-15 Украинский Научно-Исследовательский Институт Мясной И Молочной Промышленности Молочный продукт дл детского питани
JPH0698717A (ja) * 1992-09-17 1994-04-12 Meiji Milk Prod Co Ltd 長期療養患者用液状調製栄養食品
EP0655245A2 (fr) * 1993-11-01 1995-05-31 FREE RADICAL SCIENCES Inc Compositions et leur utilisation pour retarder le processus de vieillissement

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 9326, Derwent World Patents Index; Class D13, AN 93-212745, XP002060938 *
DATABASE WPI Section Ch Week 9419, Derwent World Patents Index; Class B04, AN 94-155883, XP002060937 *
STELLA V ET AL: "[Evaluation of the antiradical protector effect of multifermented milk serum with reiterated dosage in rats]. Evaluation de l'effet protecteur antiradicalaire d'un lactoserum multifermente en doses reiterees chez le rat.", COMPTES RENDUS DES SEANCES DE LA SOCIETE DE BIOLOGIE ET DE SES FILIALES, (1995) 189 (6) 1191-7, XP002060936 *
ZOMMARA M ET AL: "Effect of milk whey and its fermentation products by lactic acid bacteria on mitochondrial lipid peroxide and hepatic injury in bile duct-ligated rats.", BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 58 (7). 1994. 1213-1217, XP002060935 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000060094A1 (fr) * 1999-04-07 2000-10-12 Institut National De La Recherche Agronomique (Inra) Lactocoques modifies exprimant une catalase et leurs utilisations
WO2002000231A1 (fr) * 2000-06-28 2002-01-03 Sericausa B.V. Utilisation d'une preparation constituee de ou contenant un minimum de lactoserum dissimule

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