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WO2020161522A1 - Composition à base de fibres - Google Patents

Composition à base de fibres Download PDF

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Publication number
WO2020161522A1
WO2020161522A1 PCT/IB2019/050940 IB2019050940W WO2020161522A1 WO 2020161522 A1 WO2020161522 A1 WO 2020161522A1 IB 2019050940 W IB2019050940 W IB 2019050940W WO 2020161522 A1 WO2020161522 A1 WO 2020161522A1
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Prior art keywords
composition
use according
diet
treatment
group
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Alfredo Di Leo
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THD SpA
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THD SpA
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/12—Ketones
    • 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
    • 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 
    • 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
    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/324—Boswellia, e.g. frankincense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger

Definitions

  • the present invention relates to a composition
  • a composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber for the treatment and/or for the prevention and/or for the follow-up of inflammatory pathologies of the gastro-intestinal tract and/or adenopolyposis and/or colorectal cancer.
  • Adenoma-carcinoma or carcinoma of the colon-rectum (CRC) is the third cause of death in the world.
  • the pathogenesis of CRC includes the formation of polyps on the intestinal mucosa, considered precancerous lesions. When they are diagnosed through colonoscopy, intestinal polyps are generally removed.
  • FAP Human familial adenomatous polyposis
  • APC cancer Adenomatous Polyposis Coli
  • FAP is characterized by the development of a large number of adenomas in the colon. While the genetic substrate facilitates the start of the tumorigenic process and cannot be modified with drugs or nutrition, the promotion of the tumorigenesis can be controlled, so as to hinder the progression towards cellular de-differentiation and neoplastic transformation.
  • the main objective of a colonoscopic screening is to monitor adenomas and their progression toward advanced forms and CRC.
  • HRT hormone replacement therapy
  • ERa alpha
  • beta beta
  • ERa is primarily located in the breast, in the cardiovascular system, in bones, in the urogenital system and in the central nervous system, while ERp is expressed in the prostate, salivary glands, testis, ovary, immune system and especially in the intestine.
  • ERp The involvement of ERp in adenomatous polyposis and CRC is demonstrated by its reduced expression, with respect to the normal intestinal mucosa in patients who have undergone polypectomy, already in the pre-cancerous stage.
  • the reduction of ERp refers to an increase in proliferation and to a progressive cellular de-differentiation, demonstrating that the silencing of ERp is involved in the cancer's progression.
  • Pre-cancerous lesions of the colon-rectum are therefore early warnings of the development of CRC in a significant part of the population.
  • the dramatic decline of ERp is also observed in the more advanced stages of the neoplastic transformation.
  • EP2254573 and WO2013045068 describe the use of a composition based on selective phytoestrogen agonists of the ERp receptor (i.e. milk thistle) and an insoluble fiber for the treatment of adenopolyposis/adenoma-carcinoma.
  • Said documents demonstrate the therapeutic efficacy of the composition of phytoestrogens and insoluble fiber in comparison with a composition comprising phytoestrogens and soluble fiber, which does not show significant therapeutic efficacy.
  • said documents teach that a composition based on phytoestrogens and selective agonists of the ERp receptor and an insoluble fiber is effective for the treatment of adenopolyposis/adenoma-carcinoma, while a composition comprising phytoestrogens and soluble fiber has not proved to be effective in the treatment of adenopolyposis/adenoma-carcinoma.
  • the present invention falls within this context, as it relates to a composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber for use in the treatment or in the prevention or in the follow up of inflammatory pathologies of the gastro-intestinal tract and/or adenopolyposis and/or colorectal cancer.
  • the Applicant has surprisingly found that the administration of the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is capable of:
  • said composition is able to reduce the formation of solid lesions in the colorectal region affected by low-grade or high-grade dysplasia and/or colorectal carcinoma,
  • Figure 1 shows the treatment schedule with a standard diet and with the THD diet of the control group
  • Figure 2 shows the treatment schedule with a standard diet and with the THD diet of the group of mice in which a colorectal carcinoma was induced (AOM/DSS group);
  • Figure 3 shows the results of the evaluation of the number of solid lesions detected in the AOM/DSS mice;
  • Figure 4 shows the histological score evaluated according to Yu et al. of inflammatory damage (mean ⁇ SD) of the group of AOM/DSS mice treated with a standard diet and the THD diet;
  • Figure 5 shows the mean number ⁇ SD/mouse of areas of microscopic pre-neoplastic and neoplastic lesions.
  • CRC colorectal cancer
  • HGD high-grade dysplasia
  • LGD low-grade dysplasia
  • Figure 10 shows the results of the TUNEL staining method to evaluate epithelial apoptosis; in particular, Figure 10a shows the levels of epithelial apoptosis in the colon of the AOM/DSS mice fed a standard diet; Figure 10b shows the levels of epithelial apoptosis of the colon of the AOM/DSS mice fed the THD diet; while Figure 10c shows a summary analysis of apoptosis in the two groups of AOM/DSS mice; Figure 1 1 shows the treatment schedule with a standard diet and with the TFID diet of the group of mice with a genetically modified APC gene;
  • Figure 12 shows the results of the migration speed of the cells toward the free surface along the axis of the intestinal villi through immunofluorescence evaluated with confocal microscopy, in the APC mice fed a standard diet and those fed the TFID diet;
  • phytoestrogen refers to any non-steroid molecule able to bind estrogen receptors, by imitating or by modulating its activity.
  • “agonist” refers to a chemical that binds to a receptor and activates the receptor to produce a biological response.
  • a first aspect of the present invention relates to a composition
  • a composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber for use in the treatment or in the prevention or in the follow-up of inflammatory pathologies of the gastro-intestinal tract and/or adenopolyposis and/or colorectal cancer.
  • the administration of the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is able of inducing death by apoptosis in the epithelium of the colon- rectum, preferably in colorectal cancer cells. Therefore, the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is also useful for inducing cell death, preferably by apoptosis.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is able to reduce inflammation in the colon-rectum, in particular in colorectal areas affected by low- grade or high-grade dysplasia and/or in the colorectal region with colorectal carcinoma. Therefore, the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is capable of reducing inflammation, preferably by reducing the levels of IFN-gamma and/or IL-6 and/or TNF-alpha.
  • composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is moreover capable of reducing the formation of solid lesions in the colon-rectum, preferably, said composition is able to reduce the formation of solid lesions in the colorectal region affected by low-grade or by high-grade dysplasia and/or by colorectal cancer.
  • the at least one selective phytoestrogen agonist of the ER-beta receptor comprised in the composition of the present disclosure are phytoestrogens selective for ER-beta and with an anti-estrogenic activity, which do not induce significant proliferative activity on tissues that are classic objectives for estrogens.
  • the composition comprises at least one phytoestrogen selective for ER-beta in a concentration comprised between 0.5 and 15.0%, preferably between 1.0 and 13.0%, even more preferably between 2.0 and 8.0% by weight.
  • the at least one phytoestrogen agonist of the ER-beta receptor is selected from a group consisting of silymarin, silybin, isosilybin, silydianin, silychristin, the isoflavone genistein, the flavonoid resveratrol, the coumestrol and mixtures thereof.
  • the phytoestrogen or phytoestrogens can be present in the composition as a vegetable extract.
  • the at least one phytoestrogen agonist of the ER-beta receptor is silymarin, an extract of Silybum marianum comprising silybin, preferably with a content of silybin of 30-80% by weight, wherein the amount of silybin is referred to the total weight of the silymarin.
  • Dietary fibers are carbohydrates, preferably polysaccharides and/or oligosaccharides, resistant to digestion and absorption in the small intestine, with complete or partial fermentation in the large intestine (digestion-resistant carbohydrates).
  • the present invention may comprise any soluble fiber, however, especially preferred fibers are selected among digestion-resistant dextrins and/or digestion-resistant maltodextrins.
  • Preferred digestion-resistant dextrins and/or digestion-resistant maltodextrins are those which are produced by starch hydrolysis (e.g. corn starch or potato starch, hardened inulin (fructo-oligosaccharides) produced by plants such as dahlia or chicory and partially hydrolyzed, or diversely vegetable gums fractionated as partially hydrolyzed guar gum.
  • the at least one soluble fiber is a dextrin and/or a maltodextrin which is resistant to digestion, preferably produced by the hydrolysis of corn starch.
  • the composition comprises the at least one soluble fiber in a concentration comprised between 7 and 40%, preferably between 10 and 30%, even more preferably between 12 and 20% by weight.
  • the composition can further comprise at least one extract of vegetable origin, such as for example a polyphenolic extract and/or a triterpenes- containing extract.
  • at least one extract of vegetable origin such as for example a polyphenolic extract and/or a triterpenes- containing extract.
  • the polyphenolic extract is a curcuminoid extract, preferably selected from: curcumin, demethoxycurcumin, bisdemethoxycurcumin and mixtures thereof.
  • the composition may comprise curcumin (diferuloylmethane), the polyphenolic curcuminoid principle of turmeric.
  • the composition comprises curcumin in a concentration comprised between 0.2 and 10%, preferably between 0.5 and 8%, even more preferably between 1 and 6% by weight.
  • the triterpenes-containing extract is an extract of Boswellia serrata comprising triterpenic acids, the triterpenic acids preferably comprising acetyl- 1 1 -keto-p-boswellic acid (AKBA), a polycyclic triterpene extracted from the gum resin of Boswellia serrata.
  • AKBA acetyl- 1 1 -keto-p-boswellic acid
  • the triterpenes-containing extract comprises 15-40% in weight of triterpenic acids, the amount of terpenic acids being referred to the total weight of the triterpenes-containing extract.
  • the composition comprises acetyl-1 1 -keto-p-boswellic acid in a concentration comprised between 0.05 and 5%, preferably between 0.1 and 3% by weight.
  • the composition comprises silymarin, acetyl-1 1 - keto-p-boswellic acid (AKBA), curcumin and digestion-resistant maltodextrins, more preferably in the amounts indicated above.
  • AKBA acetyl-1 1 - keto-p-boswellic acid
  • composition can further comprise other phytoestrogens such as lignans derived from certain types of seeds selected from sunflower seeds, pumpkin seeds and flax seeds.
  • lignans are derived (extracted) from flax seeds.
  • the composition comprises lignans in a concentration comprised between 0.01 and 5%, preferably between 0.05 and 3%, even more preferably between 0.1 and 2% by weight.
  • the composition can further comprise at least one excipient acceptable for pharmaceutical use or for cosmetic use, which is useful for the preparation of the composition and is generally biologically safe and non-toxic.
  • the composition further comprises a flavoring agent preferably selected from: essential oils, synthetic flavors or mixtures, including but not limited to oils derived from plants and fruits such as citrus oil, fruit essences, peppermint oil, mint oil, other mint oils, clove oil, sugar oil, anise and the like, aromatic oils such as menthol, eucalyptus, thymol, spices such as cocoa powder and ground cinnamon, and combinations thereof.
  • the composition further comprises a sweetening agent preferably selected from: sucrose, dextrose, maltose, dextrin, fructose, levulose, galactose, sucralose, sorbitol, natural sweeteners such as, for example, stevia, corn syrup and the like, alone or in any combination.
  • a sweetening agent preferably selected from: sucrose, dextrose, maltose, dextrin, fructose, levulose, galactose, sucralose, sorbitol, natural sweeteners such as, for example, stevia, corn syrup and the like, alone or in any combination.
  • the present disclosure refers to a food intended for special medical purposes, preferably formulated as beverage, comprising the composition for use as described in detail above.
  • the composition is formulated for enteral and/or parenteral administration.
  • the composition can be formulated in liquid form, more preferably in the form of a sterile solution, emulsion or suspension.
  • a further aspect of the present invention relates to a method for the treatment of inflammatory pathologies of the gastrointestinal tract and/or adenopolyposis and/or colorectal cancer.
  • Said method comprises a step of administering an effective amount of a composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber as described above in detail, to a subject in need thereof.
  • the subject in need thereof is a patient suffering from an inflammatory pathology of the gastrointestinal tract and/or by adenopolyposis and/or by a colorectal cancer.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber as described above in detail, can be taken once a day.
  • composition for use as described in detail above is taken at a total daily dose of equal to or less than 10000 mg/die.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber is taken as a single dose or as multiple daily doses in a continuous way or according to need.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber as described above in detail can be also administered in combination with drugs used in the therapy for the treatment of inflammatory pathologies of the gastrointestinal tract.
  • Said drugs are, for example: mesalazine, steroids, eg. cortisone, biologies anti TNF-alpha and their combinations.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber as described above in detail, can also be administered in combination with drugs used in the therapy for the treatment of adenopolyposis and/or colorectal cancer.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber as described above in detail, can also be administered in combination with drugs used in the therapy for the treatment of adenopolyposis and/or colorectal cancer and with drugs used in the therapy for the treatment of inflammatory pathologies of the gastrointestinal tract, said drugs being described above in detail.
  • the composition comprising at least one selective phytoestrogen agonist of the ER-beta receptor and at least one soluble fiber as described above in detail, can be administered in association or in combination with a surgical treatment, preferably for the treatment of adenopolyposis and/or colorectal cancer, more preferably before and/or after a polypectomy.
  • TFD mixture a mixture of phytoestrogens
  • AOM/DSS and APC/min anti-inflammatory substances
  • AOM/DSS an inflammatory basis
  • APC/min a genetic one
  • mice were used overall: 1 10 wild type mice of the strain C57BL/6J and 40 genetically modified mice (APC/min) at 8 weeks of age and of the male sex. Of the wild type mice, 40 were used for the control group (Safety Test) and 70 were used as a model wherein intestinal carcinoma was induced on an inflammatory basis (AOM/DSS).
  • the APC/min mice presenting a heterozygote mutation of the APC gene (oncosuppressor), represented the model wherein a condition spontaneously develops which simulates human familial adenomatous polyposis (FAP).
  • FAP familial adenomatous polyposis
  • Standard diet Hard Teklad Rodent diet: 18.5% proteins, 3% oils and fats, 6% fibers, 7% crude ash and 65.5% of non-nitrogenous compounds— wheat, maize, toasted soybean meal, corn gluten feed, wheat straw, fish meal, lucerne meal, mineral dicalcium phosphate, calcium carbonate, sodium chloride, whey powder, soybean oil, yeast and hazelnut skins, poly-vitamin complex (Mucedola srl, Settimo Milanese, Milan, Italy).
  • THD diet (or THD mixture): the standard diet was enriched by a formulation containing silymarin (4 g %), AKBA (3 g %), curcumin (2 g %), maltodextrins (69.553 g %) and excipients (soluble fibers 16.667 g %, citric acid 1 g %, silicon dioxide 1 g %, lignans 0.5 g %, sucralose 0.280 g % and orange flavour 2 g %) and was administered at the cumulative dose of 22.4 mg/100 g of body weight.
  • mice For the control group, 40 male mice at 8 weeks of age were used, strain C57BL/6J (Charles River), wild type. Immediately after their arrival, the mice were kept in compliance with the established rules and left to settle for about two weeks. During this period, there was a mortality rate of 3 mice out of 40.
  • the schedule of the test is summarized in figure 1.
  • mice were killed, 3 belonging to the standard diet group and 3 belonging to the special diet group. This made it possible to verify that both the standard diet and the THD diet did not provoke intestinal disorders (fecalith); the remaining mice were killed around the 100th day to exactly reproduce the control of the experimental model of the second group (azoxymethane - AOM + Dextran sulfate sodium - DSS).
  • mice at 8 weeks of age were used, of the strain C57BL/6J (Charles River), wild type, with the same characteristics as those of the Safety Test. These animals were subjected to treatment with Azoxymethane (AOM) + Dextran sulfate sodium (DSS) to induce the intestinal carcinoma on an inflammatory basis. Immediately after their arrival, the mice were kept in compliance with the established rules and left to settle for about 2 weeks. Once the mice were situated, the study passed to the real and proper experimental phase. The animals were divided into two groups, one group was administered the standard diet and the other group was administered the THD diet at a concentration of 224 mg/Kg.
  • AOM Azoxymethane
  • DSS Dextran sulfate sodium
  • mice of both groups were administered an intraperitoneal injection of AOM at a concentration of 10mg/Kg. After 7 days DSS was administered in water at 2% for 7 days.
  • mice were suitably prepared. 24 hours before the execution of the exam, the mice were administered an electrolytic solution for gastrointestinal washing with a base of macrogol 3g, simeticon 0.29g, anhydrous sodium sulphate 0.09g, sodium bicarbonate 0.07g and sodium chloride 0.04g (SELG® 1000, Promefarm). The dose was calculated on the basis of the standard parameters used for man. Shortly before the examination, the animals were sedated by injection of Megaxilor (Xylazine) 0.5ml/kg + Zoletil (Zolazepam+Tiletamine) 0.8 ml/kg. The endoscopic examination was carried out using a STORZ paediatric endoscope.
  • mice of the AOM/DSS group showed a state of health which was compatible with the treatment given; toward the end of the treatment certain animals presented a prolapse of the rectum. As regards mortality, only one death was observed in the THD diet group (2.8%) and two deaths in the standard group (5.7%).
  • mice that ate the standard diet appeared shorter and also more inflamed with respect to the colon of the mice that ate the THD diet (table 2).
  • mice that had eaten the standard diet developed on average 6.0 ⁇ 1.9 lesions at the level of the colon, while the group of mice that had eaten the THD diet developed on average 2.08 ⁇ 1.8 lesions (figure 3).
  • the average number of lesions indicated above also includes a group of animals wherein the absence of solid lesions of the colon was registered. In fact, 28% of the animals of the THD group did not present any solid lesions of the colon, compared to 0% of the standard group animals. The dimensions of the solid lesions are summarized and compared in the two groups in table 3.
  • the histological preparations were viewed with an optical microscope; the reading occurred in double-blind by two expert observers.
  • the average number per animal of areas of low-grade dysplasia (LGD) was equal to 3.5 ⁇ 0.8 in the standard group and 2.6 ⁇ 0.5 in the THD group (p ⁇ 0.05).
  • the average number per animal of areas of high-grade dysplasia (HGD) was equal to 1.8 ⁇ 0.2 in the standard group and 0.30 ⁇ 0.17 in the THD group (p ⁇ 0.001 ).
  • the number of sites of colorectal cancer (CRC) detected was equal to 1.84 ⁇ 0.43 in the standard group and 0.38 ⁇ 0.21 in the THD group (p ⁇ 0.005). ( Figure 5).
  • cytokines such as IFN-gamma, interleukin-6 and TNF- alpha is also higher in the colon of the animals in the standard group than in the animals of the TFID group, confirming that the inflammatory process, chemically induced for both groups, is attenuated by the presence of substances present in the TFID diet (table 4).
  • Table 4 expression of tissue cytokines evaluated through real-time PCR on tissues (fold change: mean ⁇ SD).
  • the data obtained as a result of the reading of the histological preparations with the optical microscope were expressed as a labelling index (% of positive cells for the staining of the receptor - LI).
  • N normal tissue
  • N LGD ⁇ FIGD ⁇ CRC in the standard group (p O.001 ; fig. 6a)
  • the diet containing the THD mixture induces greater expression of ER-beta in the LGD areas and a lower expression of ER-beta in the CRC areas.
  • the ER-alpha/ER-beta ratio shows statistically significant differences only in the CRC areas.
  • Figure 9 illustrates the percentage of crypt axis covered by the highest labelled cell at the 48th hour after injection. This parameter was significantly higher in the THD than in the standard diet group (80.6% ⁇ 5.1% versus 61.7% ⁇ 5.2%, respectively; P O.001 ).
  • Apoptosis was evaluated through TUNEL staining in immunofluorescence with observation through confocal microscopy (figure 10 a, b, c).
  • N ⁇ LGD> HGD CRC in the standard group (p ⁇ 0.0001 ; fig. 10a) and N ⁇ LGD> HGD> CRC in the THD group (p O.0001 , fig. 10b).
  • mice 40 male mice of 8 weeks of age (Charles River) were used for this study, genetically modified for the APC gene, as previously mentioned. Immediately after their arrival, the mice were kept in compliance with the established rules and left to settle for about 2 weeks. Once the mice were situated, the study passed to the real and proper experimental phase. The mice were divided into two groups, one group was administered a standard diet rich in fat (5K20, Mucedola) and the other group was administered the diet rich in fat, in addition to the THD mixture at a concentration of 224 mg/Kg.
  • a standard diet rich in fat 5K20, Mucedola
  • Small intestine length this parameter indicates fibrosis of the organ as a result of an extended inflammation over time. In this case no significant difference was observed in the length of the intestine (table 6), and the phenomenon is explained by the absence of significant inflammation in this animal model, as also detected from the data relating to the dosage of cytokines and the histological scores of inflammatory damages (reported in table 13 in the context of the microscopic findings).
  • cytokines a significant difference was not observed in the expression of cytokines, confirming that the dysplastic and neoplastic lesions do not have an inflammatory basis but a genetic one (table 7).
  • Table 7 expression of tissue cytokines evaluated through real-time polymerase- chain-reaction (RT-PCT) on tissues
  • Table 11 histological scores of inflammatory damage
  • the average number per animal of areas of low-grade dysplasia (LGD) was significantly higher in the THD group with respect to the control group (p ⁇ 0.05).
  • the average number per animal of high-grade dysplasia (HGD) areas was equal to 4. 5 ⁇ 1.04 in the standard group and 3.50 ⁇ 1.7 in the THD group (difference not statistically significant).
  • the number of colorectal cancer sites (CRC) detected was equal to 4.4 ⁇ 0.54 in the standard group and 2.5 ⁇ 0.57 in the THD group (p ⁇ 0.05). (tables 12a, 12b, 12c respectively).
  • Table 12a Areas of low-grade dysplasia (LGD - mean ⁇ SD/animal)
  • Table 12b Areas of high-grade dysplasia (HGD - mean ⁇ SD/animal)
  • Table 12c Areas of neoplasia (CRC - mean ⁇ SD/animal)
  • the migration speed of cells toward the free surface along the axis of the intestinal villi was performed by immunofluorescence and the evaluation was carried out with confocal microscopy after 48 hours, at which time the marked cells are detectable not only in the crypts and in the lower part of the villi, but also all along its entire axis.
  • the evaluation was carried out on the normal tissue areas, where the cell proliferation and migration are not subverted by the structural alterations that characterize the other stages of carcinogenesis. The evaluation was performed in accordance with the method described by Javid et al. (2005).
  • Epithelial apoptosis was evaluated through TUNEL staining in immunofluorescence with observation through confocal microscopy (figure 13).

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Abstract

La présente invention concerne une composition comprenant au moins un agoniste de phytoestrogènes sélectif du récepteur ER-beta et au moins une fibre soluble pour le traitement et/ou pour la prévention et/ou pour le suivi de pathologies inflammatoires du tractus gastro-intestinal et/ou de l'adéno-polypose et/ou du cancer colorectal.
PCT/IB2019/050940 2019-02-06 2019-02-06 Composition à base de fibres Ceased WO2020161522A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2884422A1 (fr) * 2005-04-18 2006-10-20 Roquette Freres Composition anti-inflammatoire de l'intestin comprenant des maltodextrines branchees
WO2009103788A1 (fr) * 2008-02-22 2009-08-27 Cm & D Pharma Limited Compositions comprenant des phytoœstrogènes sélectifs pour le récepteur bêta de l'œstrogène et des fibres alimentaires
WO2011060123A1 (fr) * 2009-11-12 2011-05-19 Nestec S.A. Composition nutritionnelle permettant de favoriser l'équilibre de microbiotes digestifs et la santé
WO2013045068A1 (fr) 2011-09-30 2013-04-04 Cm&D Pharma Limited Compositions comprenant des agonistes de récepteur bêta des phytoœstrogènes et des fibres alimentaires pour le traitement chimiopréventif de la polypose adénomateuse sporadique

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2884422A1 (fr) * 2005-04-18 2006-10-20 Roquette Freres Composition anti-inflammatoire de l'intestin comprenant des maltodextrines branchees
WO2009103788A1 (fr) * 2008-02-22 2009-08-27 Cm & D Pharma Limited Compositions comprenant des phytoœstrogènes sélectifs pour le récepteur bêta de l'œstrogène et des fibres alimentaires
EP2254573A1 (fr) 2008-02-22 2010-12-01 CM&D Pharma Limited Compositions comprenant des phyto strogènes sélectifs pour le récepteur bêta de l' strogène et des fibres alimentaires
WO2011060123A1 (fr) * 2009-11-12 2011-05-19 Nestec S.A. Composition nutritionnelle permettant de favoriser l'équilibre de microbiotes digestifs et la santé
WO2013045068A1 (fr) 2011-09-30 2013-04-04 Cm&D Pharma Limited Compositions comprenant des agonistes de récepteur bêta des phytoœstrogènes et des fibres alimentaires pour le traitement chimiopréventif de la polypose adénomateuse sporadique

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AIRONG XU ET AL: "Efficient and sustainable solvents for lignin dissolution: aqueous choline carboxylate solutions", GREEN CHEMISTRY, vol. 19, no. 17, 1 January 2017 (2017-01-01), GB, pages 4067 - 4073, XP055630632, ISSN: 1463-9262, DOI: 10.1039/C7GC01886J *
M. BARONE ET AL: "Dietary-induced ERbeta upregulation counteracts intestinal neoplasia development in intact male ApcMin/+ mice", CARCINOGENESIS, vol. 31, no. 2, 1 February 2010 (2010-02-01), pages 269 - 274, XP055043812, ISSN: 0143-3334, DOI: 10.1093/carcin/bgp275 *
MICHELLE COTTERCHIO: "Dietary Phytoestrogen Intake Is Associated with Reduced Colorectal Cancer Risk", NUTRITIONAL EPIDEMIOLOGY, 21 September 2006 (2006-09-21), pages 3046 - 3053, XP055044067, Retrieved from the Internet <URL:http://jn.nutrition.org/content/136/12/3046.full.pdf#page=1&view=FitH> [retrieved on 20121113] *

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