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WO1997041875A1 - Sel de bismuth de sialyloligosaccharide et procede pour traiter et inhiber les ulceres gastriques et duodenaux avec cette substance - Google Patents

Sel de bismuth de sialyloligosaccharide et procede pour traiter et inhiber les ulceres gastriques et duodenaux avec cette substance Download PDF

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Publication number
WO1997041875A1
WO1997041875A1 PCT/US1997/006376 US9706376W WO9741875A1 WO 1997041875 A1 WO1997041875 A1 WO 1997041875A1 US 9706376 W US9706376 W US 9706376W WO 9741875 A1 WO9741875 A1 WO 9741875A1
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Prior art keywords
oligosaccharide
galactose
group
stomach
bismuth salt
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PCT/US1997/006376
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English (en)
Inventor
Herbert Swarz
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Neose Technologies Inc
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Neose Technologies Inc
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Priority to AU27326/97A priority Critical patent/AU710576B2/en
Priority to EP97921225A priority patent/EP0918526A1/fr
Priority to JP9539929A priority patent/JP2000509714A/ja
Publication of WO1997041875A1 publication Critical patent/WO1997041875A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K31/7135—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • 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
    • 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

Definitions

  • the present invention relates a method for treating and inhibiting gastric and duodenal ulcers in a patient, by administration of a bismuth salt of a sialyloligosaccharide, and a composition for practicing same.
  • H. pylori H. pylori
  • CampyloJbacter pylori (C. pylori ) , is a primary cause of non-
  • H. pylori has been isolated in gastric tissue biopsies in patients throughout the world. While the precise mechanism of inflammation is not well understood, H.
  • H. pylori Due to the site specificity of attachment, it has been suggested that there are specific attachment sites for H. pylori which exist on gastric and duodenal mucous-secreting cells. Numerous studies have been undertaken to attempt to identify the specific binding site of H. pylori .
  • Zopf et al U.S. 5,514,660 describe a method of treating and preventing ulcers in mammals by administering a sialyl oligosaccharide of the Formula I
  • X a chemical bond or a group capable of linking the p galactose to either the linking group Y or the multivalent support Z; wherein the Cj . glycosidic oxygen of galactose may be replaced by N, S or C;
  • Z a multivalent support
  • m 0 or 1
  • n 0 or 1
  • p an integer of 2-1,000. The specific use of a bismuth salt of a sialyloligosaccharide is not reported.
  • N-acetylneurammyl- ⁇ (2-3) -Gal ⁇ l-4 Glc (herein after NeuAc (2-3) -lactose) as compared with N-acetylneuraminyl- ⁇ (2-6) -Gal ⁇ l-4 Glc (herein after NeuAc (2-6) -lactose) .
  • Sialoproteins which contain the NeuAc (2-3) Gal isomer of NeuAc- lactose, i.e., human erythrocyte glycophorin A, fetuin, and human ⁇ 2 -macroglobulin also inhibited H. pylori binding, but
  • HAI inhibiting ability of several compounds containing a NeuAc-lactose structure. Based on the hemagglutination inhibition activity, the researches determined that in order to produce 100% HAI, 1.000 mg/ml of ⁇ 2 -Macroglobulin was needed, 0.500 mg/ml of fetuin was needed, 0.250 mg/ml of Glycophorin A was needed and 0.078 mg/ml of bovine NeuAc- lactose was needed.
  • mucin contains a variety of different saccharide groups and linkages.
  • Saitoh et al report a sulfate-containing glycerolipid as a ligand which is specifically recognized by H. pylori .
  • Hemagglutination assays have been used by many different researchers (see for example Evans et al (Infection and Immunity (1988) ££:2896-2906) , however Fi ⁇ ueroa et al report in Journal of Infection (1992) 2 ⁇ . 263-267, an adherence mechanism, which is not depending on the expression of specific hemagglutinin antigen. This report, openly questions the relationship between hemagglutination inhibition and H.
  • CBS Colloidal bismuth subcitrate
  • subsalicylate (BSS) has also been observed to inhibit H. pyl ori .
  • saccharide compositions are simple phosphates and sulfates of aldose and ketose monosaccharides .
  • one object of the present invention is a method for treating and/or preventing gastric and/or duodenal ulcers with a bismuth salt of a silalyoligosaccharide.
  • Another object of the present invention is a method for inhibiting Helicobacter pylori infection and/or reinfection to
  • Another object of the present invention is to provide a pharmaceutical composition for inhibiting Helicojbacter pylori
  • X a chemical bond or a group capable of linking the p galactose to either the linking group Y or the multivalent support Z; wherein the C ⁇ glycosidic oxygen of galactose may be replaced by N, S or C;
  • the bismuth salt is formed with the carboxylic acid group of NeuAc .
  • the present invention is also provided for by a bismuth salt of an oligosaccharide composition of Formula III
  • A a group capable of bonding to the p galactose; wherein the C, glycosidic oxygen of galactose may be replaced by N, S or C.
  • oligosaccharide of Formula I i.e. the oligosaccharide of Formula I
  • oligosaccharide of Formula I a multivalent presentation of an oligosaccharide is unexpectedly superior, on a molar basis based on the oligosaccharide groups, than the monovalent presentation of the same oligosaccharide.
  • a method in which a pharmaceutical composition comprising the oligosaccharide of Formula I and/or Formula III alone, or in combination with an H 2 blocker, an antibiotic, oligosaccharide compounds and/or an antiulcerative compound is administered to a mammal has been found by the inventors to be effective at inhibiting the binding of Helicojbacter pylori to the gastric and duodenal mucosa and relieving the effects of gastric and duodenal ulcers.
  • X a chemical bond or a group capable of linking the p galactose to either the linking group Y or the multivalent support Z; wherein the C x glycosidic oxygen of galactose may be replaced by N, S or C;
  • X can be a substituted C 1-20 alkyl group, a substituted C ⁇ - 20 alkyl carboxylic ester group, a substituted C, -20 alkyl carboxy amide group, a hydroxy terminated polyether, an amine terminated polyether, inositol, an oligosaccharide, a disaccharide or a monosaccharide with the terminal reducing end of the oligosaccharide, disaccharide or monosaccharide in the pyranose or open chain form, an azaoligosaccharide, an azadisaccharide or an azamonosaccharide with the terminal reducing end of the azaoligosaccharide, azadisaccharide or azamonosaccharide in the pyranose or open chain form, wherein said substitution is capable of reacting with the linking group of the multivalent support, such as a hydroxyl group or an amine group.
  • the group X is a monosaccharide hexose group such as glucose, N-acetylglucosamine, galactose, N- acetylgalactosamine, mannose, fucose, allose, altrose, gulose, idose, talose and rhamnose.
  • a suitable group X is a reduced form of the above-identified hexose groups, such as glucitol.
  • n 0.
  • a suitable linker group has one terminal portion of the Y group capable of bonding with the group X, while the other terminal end is capable of bonding with the multivalent support.
  • a bond between X and Y can be formed by reacting an aldehyde or carboxylic acid at C x of the X group or any aldehyde or carboxylic acid group introduced onto the X group by oxidation, with the Y group, to form a suitable bond such as -NH-, -N(R)- where R is C 1-20 alkyl, a hydroxyalkylatnine, a amide, an ester, a thioester, a thioamide .
  • X is a saccharide such as an oligosaccharide, a disaccharide or a monosaccharide
  • a bond between X and Y can be formed by reacting the C, hydroxyl group, in the pyranose form with an acylating agent and a molecular halide, followed by reaction with a nucleophile to form a suitable bond such as -NH-, -N(R)- where R is C 1-20 alkyl, -S- and -0-
  • a bismuth salt of the compound of Formula I may be prepared by analogous methods as those described in L. Vanmo, cited in ⁇ Tellor's vol. IX 598 (1929) , C.J. McLoughlin et al
  • the bismuth salt may be prepared by mixing bismuth nitrate and an oligosaccharide of Formula I, in a solvent such as glycol as described by Schmitz, Pharmazi e 5,
  • the present invention may also allow for administration of a composition which is a mixture of a bismuth salt of a sialyloligosaccharide of Formula I, in admixture with the free carboxylic acid of the sialyloligosaccharide of Formula I or a non-bismuth pharmaceutically acceptable salt of the sialyloligosaccharide of Formula I.
  • a composition which is a mixture of a bismuth salt of a sialyloligosaccharide of Formula I, in admixture with the free carboxylic acid of the sialyloligosaccharide of Formula I or a non-bismuth pharmaceutically acceptable salt of the sialyloligosaccharide of Formula I.
  • Suitable pharmaceutically acceptable salts are described below.
  • the amount of Bi *3 which is present in the composition to be administered is not particularly limited, but is preferably from 0.001-40 wt.% of the total weight of the sialyloligosaccharide salt, more preferably from 0.01-20 wt.% of the total weight of the sialyloligosaccharide salt, most preferably from 0.1-15 wt.% of the total weight of the sialyloligosaccharide salt.
  • a stoichiometric salt of 2 moles of Bi +3 and 3 moles of sialyloligosaccharide of Formula I is formed.
  • the NeuAc group of Formula I or Formula III may be defined as a sialic acid of Formula II;
  • R 6 , R 7 , R ⁇ , and R 10 are each independently H, C 1-6 acyl, lactyl, C x . 6 alkyl, sulfate, phosphate, anhydro, a sialic acid of Formula II, ( ⁇ -l)Fuc, ( ⁇ -
  • R 9 is acyl, glycolylamido, amino or hydroxyl
  • A is H or a cation.
  • the group of Formula II is a sialic acid, which is a family of 9-carbon carboxylated sugars related to neuraminic acid.
  • the carboxylic acid may be in the form of a free acid, when A is H or a salt, including bismuth, when A is a cation.
  • Suitable cations, in addition to bismuth, include alkali metals, alkaline earth metals or ammonium. Any known suitable pharmaceutically acceptable cations may be used, including the cations of conventional non-toxic salts including a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) or an alkaline earth metal salt (e.g.
  • an ammonium salt e.g. calcium salt, magnesium salt, etc.
  • an organic base salt e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N 1 - dibenzylethylenediamine salt, etc.
  • an organic acid salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
  • the group of Formula II is selected from the group consisting of N-acetyl-neuraminic acid, N-glycolyl- neuraminic acid, keto-deoxy-nonulosonic acid, 9-0-acetyl N- acetyl-neurammic acid, 9-0-acetyl N-glycolyl-neuraminic acid, 9-0-acetyl-keto-deoxy-nonulosonic, 7-0-acetyl-N-acetyl- neuraminic acid, 7-0-acetyl-N-glycolyl-neuraminic acid, 4-0- acetyl-N-acetyl-neuraminic acid, 4-O-acetyl-N-glycolyl- neuraminic acid, 7, 9-di-0-acetyl-N-acetyl-neuraminic acid, 8, 9-di-O-acetyl-N-acetyl-neuraminic acid, 7,
  • the sialic acid of Formula II is N-acetyl- neuraminic acid or N-glycolyl-neuraminic acid.
  • These sialic acids are described in A.Varki Glycobiolo ⁇ y v2, (1992) p25-40. Accordingly the reference describes sources of the sialic acids as well as the appropriate sialyltransferase necessary for enzymatic synthesis of oiigosaccharides of Formula I.
  • substitution is preferably at the R 7 position.
  • a suitable multivalent support is a compound with multiple binding sites to a terminal end of the linking group, which is not bound to the group X of the linking group, with multiple binding sites to the group X, or with multiple binding sites to the C x glycosidic oxygen of galactose.
  • Examples include but are not limited to a polyol, a polysaccharide, polylysine, avidin, a polyacrylamide, dextran, lipids, lipid emulsions, liposomes, a dendritomer, human serum albumin, bovine serum albumin or a cyclodextrin.
  • the oligosaccharide is provided as a multivalent molecule according to Formula I .
  • the oligosaccharide portion is bound to a multivalent support using known techniques so as to produce a conjugate in which more than one individual molecule of the oligosaccharide is covalently attached through a linker to the multivalent support.
  • the oligosaccharide portion can be bound to the multivalent support via the free anomeric carbon of the group
  • the oligosaccharide portion can be bound via a phenethylamine-isothiocyanate derivative as described by Smith et al . Complex Carbohydrates part C, Methods in Enzymology, volume L, Ed by V. Ginsburg (1978) , p 169-171. It is preferable that the oligosaccharide of Formula I remains soluble in water, however it is also possible to administer the oligosaccharide of Formula I in the form of polymer particles .
  • the oligosaccharide portion of Formula I may be bound to a support to form a bead wherein the surface of the bead is bound with the oligosaccharide portion of Formula I.
  • A a group capable of bonding to the p galactose; wherein the C ! glycosidic oxygen of galactose may be replaced by N, S or C; is administered according to the present method.
  • A can be a C 1-20 alkyl group, a C 1 . ;o alkyl carboxylic ester group, a C 1-20 alkyl carboxy amide group, a polyether, inositol, an oligosaccharide, a disaccharide or a monosaccharide with the terminal reducing end of the oligosaccharide, disaccharide or monosaccharide in the pyranose or open chain form, an azaoligosaccharide, an azadisaccharide or an azamonosaccharide with the terminal reducing end of the azaoligosaccharide, azadisaccharide or azamonosaccharide in the pyranose or open chain form,
  • the group A is a monosaccharide hexose group such as glucose, N-acetylglucosamine, galactose, N- acetylgalactosamine, mannose, fucose, allose, altrose, gulose, idose, talose and rhamnose .
  • a suitable group A is a reduced form of the above-identified hexose groups, such as glucitol.
  • the corresponding N and S glycosides of galactose can be prepared by conventional methods known to those of ordinary skill in the art from galactose followed by attachment of a sialyl acid group at the 3 position by conventional methods.
  • The- corresponding C glycoside of galactose can be made by conventional synthetic organic techniques, followed by attachment of a sialyl acid group at the 3 position by conventional methods.
  • Any known suitable pharmaceutically acceptable cations, in addition to bismuth may be used with the oiigosaccharides of Formula I and Formula III, to form a salt of the carboxylic acid group.
  • Suitable cations include conventional non-toxic salts including a metal salt such as an alkali metal salt (e.g.
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an ammonium salt e.g. calcium salt, magnesium salt, etc.
  • an organic base salt e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N' -dibenzylethylenediamine salt, etc.
  • an organic acid salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an inorganic acid salt e.g.
  • hydrochloride hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
  • the oiigosaccharides of the present invention may be obtained using any known method, including (1) enzymatically, using one of the inventor's method described in published international application WO 91/16449, (2) synthetically, using classical organic chemistry, (3) by degradation of a natural occurring oligosaccharide, glycolipid, or glycopeptide or (4) isolation from natural source such as bovine colostrum.
  • the isolation of 3 ' sialyl lactose from bovine colostrum is described in Veh et al. Journal of Chromatography, 212, (1981) 313-322.
  • 3' sialyl lactose may also be isloated from a cheese processing waste stream as described by Brian et al in U.S. Serial No. 08/337,181, filed in the U.S. Patent Office on November 7, 1994, the entire contents of which are hereby incorporated by reference.
  • the bismuth salt of a sialyl oiigosaccharides of Formula I and/or Formula III may be administered in conjunction with a known proton pump inhibitor or a known H 2 receptor antagonist .
  • a representative proton pump inhibitor is omeprazole, and representative H 2 antagonists include cimetidine, ranitidine, nizatidine and famotidine.
  • the amount of proton pump inhibitor and H 2 antagonist administered in conjunction with the present bismuth salt of a sialyl oligosaccharide is about the same amount administered for their known therapy. Accordingly, effective dosages of the proton pump inhibitor and H ; can be determined by routine experimentation.
  • Suitable antiulceratives include aceglutamide aluminum complex, e-acetamidocaproic acid zinc salt, acetoxolone, arbaprostil, benexate hydrochloride, bismuth subcitrate sol, bismuth subsalicylate, carbenoxolone, cetraxate, cimetidine, enprostil, esaprazole, famotidine, ftaxidide, gefarnate, guaiazulene, irsogladine, misoprostol, soloatidine, ornoprostil, ⁇ -oryzanol, pifarnine, pirenzepine, plaunotol, ranitidine, rioprostil, rosaprostol, rotraxate, roxatidine acetate, sofalcone, spizofurone, sucralfate
  • the bismuth salt of a sialyl oligosaccharide of Formula I and/or Formula III may be administered in conjunction with an antibiotic with activity against H. pylori .
  • Suitable antibiotics include
  • metronidazole metronidazole, tetracycline, bismuth, erythromycin, a macrolide, a quinolone, a cephalosporin and amoxicillin.
  • the amount of antibiotic administered in conjunction with the present bismuth salt of a sialyl oligosaccharide is about the same amount administered for its known therapy. Accordingly, effective dosage of the antibiotic can be determined by routine experimentation.
  • the bismuth salt of a sialyl oligosaccharide of Formula I and/or Formula III may be administered in conjunction with a H-type 1 or Lewis' 3 blood group antigen or an oligosaccharide such as NeuAc- ⁇ (2-6) -Gal ⁇ l-4 Glc.
  • a H-type 1 or Lewis' 3 blood group antigen or an oligosaccharide such as NeuAc- ⁇ (2-6) -Gal ⁇ l-4 Glc.
  • Suitable H-type 1 and Lewis 0 blood group antigens are reported in Boren et al (Science (1993) 2£2. :1892-1895) .
  • the anti-H. pylori compositions of the present invention contains the bismuth salt of a oligosaccharide of Formula I and/or Formula III in association with any suitable liquid or solid, pharmaceutically acceptable carrier or excipient, preferable in a form suitable for oral or enteral administration.
  • the pharmaceutical compositions are particularly useful as pharmaceuticals, especially, pharmaceuticals, pharmaceuticals, and/or pharmaceuticals.
  • compositions are usually administered as a mixture with a carrier suitably selected depending upon the route for administration using standard formulations.
  • the compound of the present invention may be administered in the form of tablets which may be prepared using known techniques by adding to a powder of the active ingredient of the present invention an excipient such as starch, lactose, sucrose, glucose, crystalline cellulose, calcium carbonate or kaolin, a hydroxypropylcellulose, a glucose solution, a sucrose solution, water or ethanol, a disintegrator such as starch, agar, gelatin powder, carboxymethylcellulose calcium (CMC-Ca) , carboxymethylcellulose sodium (CMC-Na) , crystalline cellulose, calcium carbonate or sodium hydrogencarbonate, or a lubricant such as magnesium stearate, calcium stearate, talc, macrogoal 4,000, macrogoal 6,000 or stearic acid.
  • an excipient such as starch, lactose, sucrose, glucose, crystalline cellulose, calcium carbonate or
  • the mixture is then subjected to compression molding by a conventional tableting method, and if necessary, applying a sugar coating by means of a concentrated sugar solution containing e.g. gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium oxide, applying a film coating by means of a film-forming agent composed of e.g. polyvinyl acetal diethylaminoacetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose or polyvinylpyrrolidone or applying an enteric coating by means of a film-forming agent composed of e.g. ethylcellulose phthalate, cellulose acetate phthalate or hydroxypropylmethylcellulose phthalate.
  • a sugar coating by means of a concentrated sugar solution containing e.g. gum arabic, talc, polyvinylpyrrolidone, polyethyleneglycol and/or titanium oxide
  • a film coating by means of a film-
  • compositions may be in the form of granules or fine granules which may be prepared by adding to the active ingredient of the present invention a binder such as starch, gelatin, gum arabic, methylcellulose, sodium carboxymethylcellulose, heavy silicic anhydride or light silicic anhydride, followed by kneading and granulation by usual methods; or as a powder of the active ingredient of the present invention by itself; or as capsules which may be prepared by adding to the active ingredient of the present invention an excipient such as lactose, starch or crystalline cellulose and/or a lubricant such as magnesium stearate, calcium stearate or talc, and filling the mixture into capsules .
  • a binder such as starch, gelatin, gum arabic, methylcellulose, sodium carboxymethylcellulose, heavy silicic anhydride or light silicic anhydride, followed by kneading and granulation by usual methods
  • a solution or suspension may be prepared by adding any diluent customarily, used in the art.
  • suitable diluents include water, ethyl alcohol, propylene glycol, polyoxyethylene sorbitol, and sorbitan esters.
  • Sodium chloride, glucose or glycerol may be incorporated into such a liquid preparation in an amount sufficient to prepare an isotonic solution.
  • the therapeutic composition may also further contain ordinary dissolving aids, buffers, pain- alleviating agents, art preservatives, and optionally coloring agents, fragrances, flavors, sweeteners and other pharmacologically active agents such are well known in the art .
  • compositions may take the form of a solution, suspension, tablet, coated tablet or any pharmaceutically acceptable form suitable for delivery to the stomach or duodenum.
  • the bismuth salt of a sialyl oligosaccharide or pharmaceutical compositions are administered orally or enterally to a patient in need thereof to inhibit H. pylori
  • stomach and/or duodenum are stomach and/or duodenum.
  • suitable patients are humans.
  • the present method is also applicable to treatment of animals, including but not limited to mammals such as pigs, cows, horses, sheep, goats, dogs, cats, rodents and non-human primates.
  • the method of the present invention is suitable for preventing and treating patients with duodenal ulcers, gastric ulcers and the prevention of gastric cancers in patients.
  • Suitable amounts of the pharmaceutical composition containing the bismuth salt of a sialyl oligosaccharide of Formula I and/or Formula III to be administered include those which produce an effective stomach concentration of bismuth salt of a sialyl oligosaccharide of from 1 ⁇ g to 10,000 mg/ml per dose, preferably 10 ⁇ g to 1,000 mg/ml, more preferably 0.5mg to 50 mg/ml, most preferably 1 to 10 mg/ml. For example, based on an average human stomach volume of 500 ml, a dose of 3 gm would produce an effective stomach concentration of about 6 mg/ml .
  • Administration of the pharmaceutical composition comprising the bismuth salt of a sialyl oligosaccharide of Formula III is performed preferably to achieve a continuous effective stomach concentration of from 1 ⁇ g to 10,000 mg/ml per dose, preferably 10 ⁇ g to 1,000 mg/ml, more preferably 0.5mg to 50 mg/ml, most preferably 1 to 10 mg/ml. This can be achieved by administration, at least daily, preferably twice daily, more preferably three times a day and most preferably four times a day.
  • a pharmaceutical composition comprising the bismuth salt of a sialyl oligosaccharide of Formula I is administered so as to achieve a continuous effective stomach concentration of from 1 ⁇ g to 1,000 mg/ml per dose, preferably 10 ⁇ g to 100 mg/ml, more preferably 50 ⁇ g to 5 mg/ml, most preferably 10 ⁇ g to 2 mg/ml.
  • This can be achieved by administration, at least daily, preferably twice daily, more preferably three times a day and most preferably four times a day.
  • the composition is formulated to provide between 10-500 mg, preferably 100-300 mg of the proton pump inhibitor, H 2 antagonist, or antiulcerative daily.
  • suitable therapies include administration of tetracycline (500 mg four times daily) , bismuth subsalicylate (two tablets four times daily, with meals and at bedtime) , and metronidazole (250 mg three times daily, with meals) each taken for a 14 day period.
  • Dosage forms include such unit dosage forms such as tablets, capsules, solutions or suspensions.
  • maintenance dosages of are administered so as to achieve a continuous effective stomach concentration of from 1 ⁇ g to 1,000 mg/ml per dose, preferably 10 ⁇ g to 100 mg/ml, more preferably 50 ⁇ g to 5 mg/ml, most preferably 10 ⁇ g to 2 mg/ml.
  • This can be achieved by administration, at least daily, preferably twice daily, more preferably three times a day and most preferably four times a day.
  • binding inhibition were prepared from human carcinomas stomach cancer epithelial cells HuTu-80 obtained from the American Type Culture Collection Rockville, MD, according to a modified procedure from that reported in Fauchere et al Microbial Pathogenesis 1990;1 427-439.
  • the cultures were maintained in Basal medium Eagle containing 10% fetal calf serum in T-75 flasks, at 37°C and a 5% C0 2 atmosphere.
  • Cells were harvested by trypsin/EDTA release and plated on 96-well flat bottom microtiter plates. The microtiter plates were incubated for 2-3 days until the monolayers grew to confluence. Prior to binding inhibition tests, the monolayer was washed with Hanks Balanced Salt solution (HBSS) containing Ca *2 and Mg *2 , 0.1%BSA, 50mM HEPES, 0.01 phenol red or HBHPR.
  • HBSS Hanks Balanced Salt solution
  • H. pylori bacteria isolates were obtained from B.
  • the amount of bacterial adhesion to the monolayer was measured by incubating with 50 ⁇ l urea-phenol red (UPR) solution (0.2% urea, 0.03% phenol red in 0.85% NaCl) .
  • URR urea-phenol red
  • the presence of bound bacteria is indicated by the presence of bacterial urease which generates NH 3 , which raises the pH and changes the color to purple, near at OD 595 .
  • 3' sialyl lactose-HSA is a complex of 3 'sialyl lactose with HSA, with about 20 molecules of 3 ' sialyl lactose bound to the HSA;
  • the binding inhibiting activity of fetuin was determined as follows:
  • gnotobiotic piglets Twenty one day old gnotobiotic piglets were orally treated with seven doses of 100 mg each of 3' sialyl lactose, at about 8 hour intervals. As a control, the piglets were administered water. The third administration of 3' sialyl lactose and control was accompanied with 4 x 10 3 live H.
  • the piglets were evaluated by determining bacterial colonies in blood-agar as colony forming units/gram of gastric epithelium (CFU/g) .
  • CFU/g gastric epithelium
  • Gastric epithelium homogenates were plated on agar in serial 1:10 dilutions and bacterial colonies were counted on the plates, with 20-200 colonies/plate after 5 days .
  • An anti -Helicobacter composition is prepared by
  • An anti -Helicobacter composition is prepared by mixing 1
  • An anti-Helicojbacter composition is prepared by mixing 1
  • An anti -Helicobacter composition is prepared by mixing 1 g of a stoichiometric Bi" 3 salt of 3' sialyl lactose with 500 mg of a tetracycline. The mixture is then suspended in a mixture of water and propylene glycol.
  • Example 7 An anti -Helicobacter composition is prepared by mixing 1 g of a stoichiometric Bi" 3 salt of 3' sialyl lactose with 500 mg of a tetracycline. The mixture is then suspended in a mixture of water and propylene glycol. Example 7.
  • a patient infected with H. pylori is treated with the composition of Example 3.
  • the patient is treated orally four times daily with each dosage providing an effective stomach concentration of 2 mg/ml.
  • Therapy is continued for two weeks, after which examination showed eradication of the H. pylori bacteria.
  • maintenance therapy with the composition of the present invention is continued to prevent recurrence.

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Abstract

Procédé pour traiter et/ou inhiber les ulcères gastriques et duodénaux, comprenant l'administration d'une composition pharmaceutique contenant un sel de bismuth d'un oligosaccharide défini par la formule (I): (NeuAc-$(a)(2-3)-pGal-β(1)-(-X-)m-(-Y-)n-)p-Z dans laquelle X = une laison chimique ou un groupe capable de lier la p galactose soit au groupe de liaison Y soit au support multivalent Z; dans laquelle l'oxygène glycosidique C1 de galactose peut être remplacé par N, S ou C; Y = un groupe de liaison; Z = un support multivalent; m = 0 ou 1; n = 0 ou 1; et p = un nombre entier de 2-1000. L'invention propose également un procédé pour traiter et/ou inhiber les ulcères gastriques et duodénaux par l'administration d'une composition pharmaceutique comprenant un sel de bismuth d'un oligosaccharide défini par la formule (III) (NeuAc-α(2-3)-pGal-β(1)-A dans laquelle A = un groupe capable de se lier avec la p galactose et dans laquelle l'oxygène glycosidique C1 de galactose peut être remplacé par N, S ou C.
PCT/US1997/006376 1996-05-03 1997-04-28 Sel de bismuth de sialyloligosaccharide et procede pour traiter et inhiber les ulceres gastriques et duodenaux avec cette substance Ceased WO1997041875A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU27326/97A AU710576B2 (en) 1996-05-03 1997-04-28 Bismuth salt of sialyloligosaccharide and a method for treating and inhibiting gastric and duodenal ulcers with same
EP97921225A EP0918526A1 (fr) 1996-05-03 1997-04-28 Sel de bismuth de sialyloligosaccharide et procede pour traiter et inhiber les ulceres gastriques et duodenaux avec cette substance
JP9539929A JP2000509714A (ja) 1996-05-03 1997-04-28 シアリルオリゴ糖のビスマス塩並びに該化合物を用いて胃および十二指腸潰瘍を処置および阻害するための方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1676596P 1996-05-03 1996-05-03
US60/016,765 1996-05-03

Publications (1)

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WO1997041875A1 true WO1997041875A1 (fr) 1997-11-13

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PCT/US1997/006376 Ceased WO1997041875A1 (fr) 1996-05-03 1997-04-28 Sel de bismuth de sialyloligosaccharide et procede pour traiter et inhiber les ulceres gastriques et duodenaux avec cette substance

Country Status (6)

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EP (1) EP0918526A1 (fr)
JP (1) JP2000509714A (fr)
KR (1) KR20000010732A (fr)
AU (1) AU710576B2 (fr)
CA (1) CA2253913A1 (fr)
WO (1) WO1997041875A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002128A1 (fr) * 2001-06-29 2003-01-09 Biotie Therapies Corp. Methodes et compositions pour traiter des maladies gastriques
WO2003002127A1 (fr) * 2001-06-29 2003-01-09 Glykos Finland Oy Utilisation d'au moins une substance glyco-inhibitrice

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5014018B2 (ja) * 2006-10-18 2012-08-29 旭化成ケミカルズ株式会社 ピロリ菌の抑制剤または静菌剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4935406A (en) * 1988-09-20 1990-06-19 Marion Laboratories, Inc. Use of bismuth (phosph/sulf)ated saccharides against Camplyobacter-associated gastrointestinal disorders
WO1994003184A1 (fr) * 1992-07-31 1994-02-17 Neose Pharmaceuticals, Inc. Compositions destinees a traiter et inhiber les ulceres gastriques et duodenaux
WO1995023605A1 (fr) * 1994-03-02 1995-09-08 Neose Pharmaceuticals, Inc. Procede de traitement et d'inhibition des ulceres gastriques et duodenaux
US5514660A (en) * 1992-07-31 1996-05-07 Neose Pharmaceuticals, Inc. Method for treating and inhibiting gastric and duodenal ulcers

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4935406A (en) * 1988-09-20 1990-06-19 Marion Laboratories, Inc. Use of bismuth (phosph/sulf)ated saccharides against Camplyobacter-associated gastrointestinal disorders
WO1994003184A1 (fr) * 1992-07-31 1994-02-17 Neose Pharmaceuticals, Inc. Compositions destinees a traiter et inhiber les ulceres gastriques et duodenaux
US5514660A (en) * 1992-07-31 1996-05-07 Neose Pharmaceuticals, Inc. Method for treating and inhibiting gastric and duodenal ulcers
WO1995023605A1 (fr) * 1994-03-02 1995-09-08 Neose Pharmaceuticals, Inc. Procede de traitement et d'inhibition des ulceres gastriques et duodenaux

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003002128A1 (fr) * 2001-06-29 2003-01-09 Biotie Therapies Corp. Methodes et compositions pour traiter des maladies gastriques
WO2003002127A1 (fr) * 2001-06-29 2003-01-09 Glykos Finland Oy Utilisation d'au moins une substance glyco-inhibitrice

Also Published As

Publication number Publication date
AU2732697A (en) 1997-11-26
EP0918526A1 (fr) 1999-06-02
AU710576B2 (en) 1999-09-23
JP2000509714A (ja) 2000-08-02
KR20000010732A (ko) 2000-02-25
CA2253913A1 (fr) 1997-11-13

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