WO2000054800A1 - Medicaments preventifs/curatifs pour troubles digestifs - Google Patents

Medicaments preventifs/curatifs pour troubles digestifs Download PDF

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Publication number
WO2000054800A1
WO2000054800A1 PCT/JP2000/001442 JP0001442W WO0054800A1 WO 2000054800 A1 WO2000054800 A1 WO 2000054800A1 JP 0001442 W JP0001442 W JP 0001442W WO 0054800 A1 WO0054800 A1 WO 0054800A1
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WO
WIPO (PCT)
Prior art keywords
pylori
enzyme
group
fucosidase
ammonia
Prior art date
Application number
PCT/JP2000/001442
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English (en)
Japanese (ja)
Inventor
Shigeki Kimura
Original Assignee
Amano Enzyme Inc.
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 Amano Enzyme Inc. filed Critical Amano Enzyme Inc.
Publication of WO2000054800A1 publication Critical patent/WO2000054800A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to a preparation for preventing or treating gastrointestinal diseases caused by Helicobacter pylori (hereinafter, referred to as "H. pylori").
  • the prophylactic / therapeutic agent for gastrointestinal diseases of the present invention targets inflammation or ulcer of the digestive tract in a human or non-human mammal.
  • omeprazole II which is a protein pump inhibitor (PPI)
  • PPI protein pump inhibitor
  • H. pylori is a gram-negative, slightly aerobic bacillus that produces ammonia from urea due to its strong protease activity.
  • the reason that H. pylori can live in the strongly acidic environment in the stomach is thought to be that the produced ammonia neutralizes the stomach acid.
  • This ammonia can cause many disorders of the gastric mucosa and may be associated with gastritis, gastric ulcer, gastric cancer, and malignant lymphoma of the stomach. From the above, it has been recognized that removing H. pylori is an effective treatment for gastrointestinal ulcers. In the past, antibiotics were administered, for example, to remove H. pylori from the digestive tract.
  • Japanese Patent Application Laid-Open No. 7-13816 / 66 discloses that fucoli as an active ingredient for removing H. pylori A method of utilizing idan is disclosed.
  • Japanese Patent Application Laid-Open No. 9-241173 discloses a method using lactic acid as an active ingredient for the same purpose.
  • Futuin II-secreted IgA As a substance that inhibits colonization of H. pylori in the stomach, Futuin II-secreted IgA is known. Futuin inhibits H. pylori from colonizing the gastric mucosa via sialic acid. Secreted IgA inhibits H. pylori from colonizing the gastric mucosa via fucosylated sugar chains. However, it is still difficult to put these fixation inhibitors to practical use due to the shortage of supply. Disclosure of the invention
  • the present invention provides a prophylactic / therapeutic agent for gastrointestinal diseases that is effective for preventing colonization of H. pylori on the digestive tract or removing already established H. pylori. It also provides a bacteriostatic method for H. pylori.
  • sugar chains containing fucose appearing on the gastric mucosa are strongly related to colonization of H. pylori in the stomach.
  • the H. pylori in the stomach requires ammonia produced by the H. pylori itself.
  • the present inventors have found that removal of fucose monmona using an enzyme significantly suppresses colonization and inhabitation of H. pylori in the stomach.
  • the colonization and inhabitation of H. pylori in the stomach is suppressed, the colonization and inhabitation of H. pylori in other digestive organs such as the duodenum are suppressed as a result.
  • Enzymes that are proteins have few harmful side effects such as antibiotics, and there is no possibility that resistant bacteria will appear.
  • the prophylactic / therapeutic agent for gastrointestinal diseases of the present invention comprises, as an active ingredient, an enzyme capable of removing H. pylori from the digestive organ or a composition thereof.
  • the agent for preventing or treating gastrointestinal diseases of the present invention comprises an enzyme capable of removing fucose or ammonia or a composition thereof as an active ingredient.
  • these enzymes bacteria, molds, yeasts, actinomycetes, basidiomycetes, plants or animals can be used.
  • One condition of enzymes that can be used is to maintain sufficient enzyme activity in the low pH range in the stomach.
  • Another condition of the enzymes that can be used is that they do not cause adverse side effects on the digestive tract of human or non-human mammals.
  • One group of enzymes used in the present invention are hydrolases, particularly enzymes that hydrolyze sugar chains, especially enzymes that hydrolyze sugars containing fucose.
  • Fucosidase can be exemplified as the most suitable enzyme.
  • Fucosidase is an enzyme that has the action of hydrolyzing and releasing fucose located at the non-reducing end of a sugar chain, regardless of its binding position.
  • fucosidase for example, those derived from the internal organs of animals such as the liver or the liver of a marine snail or the liver of a mouse can be used.
  • Fucosigsease derived from microorganisms such as Penicillium multicolor (IFO-6042) can be more preferably used because it is easily available.
  • Histidase is an enzyme that catalyzes the reaction to produce histidine from peroxidate and ammonia. Histidase is derived, for example, from the liver of animals or from microorganisms such as Pseudomonas fluorescence [The Enzyme (3rd ed.), Vol. 7, 75-166 (1972)]. Can be used.
  • Each of the above enzymes derived from microorganisms can be obtained by culturing the microorganism by a known method and purifying the enzyme from the culture.
  • the degree of purification may be such that it has an enzyme activity suitable for the purpose of use, ie, exerts its action in the digestive tract.
  • the preventive / therapeutic agent for gastrointestinal diseases of the present invention comprises one or more of the above-mentioned hydrolase groups, and / or one or more of the above-mentioned ammoniolytic enzymes, or As an active ingredient.
  • the above-mentioned hydrolase and Z or ammonia degrading enzyme can be used alone or in combination with other pharmaceutical preparations or by preparing a mixture with other medicines. Can also be taken. And the above other pharmaceutical, H 2 - blow Tsu car in a sheet main Ji di emissions, Ranichiji down or off ⁇ waxy di emissions, PFI der Ruome bra tetrazole, Ru can be exemplified a Ineba film-protecting agent .
  • the enzyme composition or a combination thereof with another drug can be made into various dosage forms according to a usual method. For example, they can be used in the form of powders, granules, liquids, solids, capsules, etc., and powders, tablets, capsules, and syrups are particularly preferred.
  • enzymes and other drugs mentioned above are used as main agents, and excipients, binders, disintegrants, coating agents, lubricants, stabilizers, flavoring agents, flavoring agents, solubilizing agents, Commonly used auxiliaries such as suspending agents and diluents may be added.
  • the enzyme composition can also be taken in advance by mixing it with various foods and the like.
  • the bacteriostatic method of the present invention comprises the steps of: administering a prophylactic / therapeutic agent for a gastrointestinal disease, which is a combination with the above-mentioned enzyme, enzyme composition or other medicine, to the digestive organ of a human or non-human mammal. It acts on bacteria.
  • the prophylactic / therapeutic agent for gastrointestinal disorders is taken before, between or after meals.
  • This bacteriostatic method can prevent the colonization of H. pylori in the digestive tract of a human or non-human mammal, or can remove the colonized H. pylori.
  • This bacteriostatic method is particularly effective in preventing or treating gastric or duodenal inflammation, ulcer or tumor caused by H. pylori.
  • the dosage of the above-mentioned hydrolase or ammonia-degrading enzyme varies depending on the type of human or non-human mammal and the type or degree of the target disease. For example, if humans take fucosidase and histidase, the dose can be 100 to 100,000 units per day, respectively.
  • the amount of enzyme that hydrolyzes 1 mol of PNPF (p-nitrophenol-L-fucopyrenoside) per minute at 37 ° C is 1 The unit was used.
  • the amount of the enzyme that decomposes 1 g of L-histidine per minute at 37 ° C. was defined as 1 unit.
  • fucosidase derived from Penicillium multicolor I F0-6042 or histidase derived from Shudomonas fluorescein were used.
  • the dosage of the enzyme, both fucosidase and histidase is 200 units / kg / mouse body weight / day.
  • 100 g of lococanet was administered per mouse per day.
  • the non-human mammal used was a male Danryu's mouse weighing 250-270 g. Five mice were prepared for the first group, and five mice for the fucosidase-administered group and the histidase-administered group were prepared for the second and third groups, respectively.
  • Group 1 A group that receives an enzyme-free diet from before H. pylori inoculation until just before slaughter.
  • Group 2 A group that receives an enzyme-free diet before inoculation with H. pylori and an enzyme-containing diet until immediately before slaughter.
  • Group 3 A group that receives the enzyme-containing diet from 2 weeks before inoculation of H. pylori to immediately before slaughter.
  • mice in each of the above groups were anesthetized with ether, 20% acetic acid was injected into the mucosal epithelium of the stomach to form ulcers. 5 days after lxl 0 8 CFU (colony forming unit ) pyro Li bacteria of the (ATCC-43504) was inoculated into the stomach Ri by the oral intubation. After a further 7 days, the mice were sacrificed and their stomachs removed.
  • CFU colony forming unit
  • the excised stomach was immersed in 20 mL of 0.1 M phosphate buffer (pH 7) and washed. After the stomach was spread on the plate to confirm the occurrence of ulcer, the stomach was returned to the same buffer and homogenized.
  • the homogenized solution of each example in each of the above groups was diluted 10-fold with the same buffer, and a part of the diluted solution (0.1 ml in each case) was inoculated on Brucella agar medium.
  • This Brucella agar medium contains 10% horse serum, 2.5 g ZmL of amphotericin B, 9 g ZmL of noncomicin, and 0.32 ⁇ g Polymixin B and 2,3,5—Including triphenyltetrachloride chloride. After inoculation into the medium, the cells were cultured at 37 ° C for 7 days, and the number of colonies of H. pylori was counted.
  • the number of colonies in the first group was 58,000-27,000. This number of colonies is defined as “fixing rate 100%”, and is used as a standard for evaluation.
  • the number of colonies in the histidase-administered group of the second group was 32,000, The fixing rate was 55 ⁇ 8%.
  • these sand rats were prepared by a predetermined number of solids in groups 1 to 3 to form ulcers, and 1 ⁇ 10 8 CFU of the H. pylori described above was removed. I was inoculated. In this example, all the sand rats were fasted for one day before the inoculation of H. pylori, fasted for 4 hours after the inoculation, and were not ingested with water. Two weeks later, the rats were killed, and the same process as in Example 1 was performed thereafter. However, culture on Brucella agar medium was performed at 37 ° C. for 4 weeks.
  • the number of colonies in the first group is 250, 0 00 Sat 80, 0 0 0 (Note: The numbers in Table 2 are crushed and cannot be read. Please check. This number of colonies is defined as “fixation rate 100%”.
  • the number of colonies in the fucosidase treatment group in the second group was 145,000 ⁇ 43,000, and the colonization rate was 58%, 11%.
  • the number of colonies in the second group, histidase administration group was 132,000 ⁇ 36,000, and the retention rate was 532-14%.
  • the number of colonies in the histidase-administered group of the third group was 133,000,29,000, and the retention rate was 55 ⁇ 4%.
  • KAT03 cells were used as cultured cells. Cultured cells were pre-incubated with the same fucosidase 1 unit / mL as in Example 1 and incubated for 30 minutes as Group 1, and incubated for 30 minutes without fucosidase. The result was designated as the second group. To 1 ⁇ 10 6 cultured cells, 1 ⁇ 10 8 H. pylori used in Example 2 was added, and the mixture was incubated at 37 ° C. for 30 minutes. Then 15% Sucrose solution was added to remove free H. pylori.
  • a primary antibody anti-H. Pylori-ephedra antibody
  • a secondary antibody FITC-anti-peacock-pig antibody
  • the sample was subjected to a flow cytometry to measure the fluorescence intensity.
  • These fluorescence intensities are considered to be proportional to the degree of implantation of H. pylori on cultured cells, that is, the colonization rate. Assuming that the fixing rate of the second group is 100%, the fixing rate of the first group is 60%. ⁇ ⁇ Business availability
  • the prophylactic / therapeutic agent for gastrointestinal diseases and the method of taking the same according to the present invention can effectively treat or prevent inflammation or ulcer of the digestive tract in a human or non-human mammal. It can be.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne des médicaments préventifs/curatifs pour troubles digestifs renfermant comme principe actif au moins un des enzymes qui hydrolisent les chaînes glucidiques renfermant du fucose et un autre enzyme décomposant l'ammoniac. L'invention concerne également un procédé bactériostatique consistant consiste à inhiber ou à empêcher la croissance de Helycobacter pylori dans un environnement fortement acide au moyens des médicaments préventifs/curatifs ci-dessus. En ce qui concerne les enzymes, l'emploi de fucosidase et histifidase est de loin préférable. Ainsi, on inhibe les conditions propices à la fixation ou à la croissance de H.pylori en milieu fortement acide et donc on freine ou l'on empêche le développement de H. pylori.
PCT/JP2000/001442 1999-03-12 2000-03-09 Medicaments preventifs/curatifs pour troubles digestifs WO2000054800A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/65806 1999-03-12
JP06580699A JP2003040799A (ja) 1999-03-12 1999-03-12 酵素を有効成分とする消化器疾患予防・治療剤

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WO2000054800A1 true WO2000054800A1 (fr) 2000-09-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019524744A (ja) * 2016-07-19 2019-09-05 エーオーバイオーム， エルエルシー．ＡＯＢｉｏｍｅ， ＬＬＣ． 使用および消化器系への送達のためのアンモニア酸化微生物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927767A (en) * 1987-11-19 1990-05-22 Takara Shuzo Co., Ltd. Method for the detection of diseases associated with the metabolic abnormality of L-fucose

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4927767A (en) * 1987-11-19 1990-05-22 Takara Shuzo Co., Ltd. Method for the detection of diseases associated with the metabolic abnormality of L-fucose

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS ON STN ITO Y.: "Glycoprotein metabolism and gastric ulcer" *
MEGRAUD, F. ET. AL.: "Further evidence on the toxic effect of ammonia produced by Helicobacter pylori urease on human epithelial cells.", INFECTION AND IMMUNITY, vol. 60, no. 5, 1992, pages 1858 - 1863, XP002928897 *
NIPPON SHOKAKIBYO GAKKAI ZASSHI, vol. 76, no. 9, 1979, pages 1757 - 1767, XP002928898 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019524744A (ja) * 2016-07-19 2019-09-05 エーオーバイオーム， エルエルシー．ＡＯＢｉｏｍｅ， ＬＬＣ． 使用および消化器系への送達のためのアンモニア酸化微生物

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