WO1994003184A1 - Compositions for treating and inhibiting gastric and duodenal ulcers - Google Patents

Compositions for treating and inhibiting gastric and duodenal ulcers Download PDF

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Publication number
WO1994003184A1
WO1994003184A1 PCT/US1993/007010 US9307010W WO9403184A1 WO 1994003184 A1 WO1994003184 A1 WO 1994003184A1 US 9307010 W US9307010 W US 9307010W WO 9403184 A1 WO9403184 A1 WO 9403184A1
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formula
independently
composition
amino acids
moiety
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PCT/US1993/007010
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English (en)
French (fr)
Inventor
Stephen Roth
Edward J. Mcguire
Dennis H. Langer
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Neose Pharmaceuticals, Inc.
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Priority to AU49938/93A priority Critical patent/AU4993893A/en
Publication of WO1994003184A1 publication Critical patent/WO1994003184A1/en

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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
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • 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
    • A61K31/715—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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives 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

Definitions

  • compositions for Treating and Inhibiting Gastric and Duodenal Ulcers are Compositions for Treating and Inhibiting Gastric and Duodenal Ulcers
  • the present invention relates to compounds and compositions for treating and inhibiting gastric and duodenal ulcers, and to methods of treating and inhibiting gastric and duodenal ulcers.
  • H. pylori Helicobacter pylori
  • C. pylori Campylobactor pylori
  • 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. pylori is found in association with the apical surfaces of gastric mucous-secreting cells.
  • 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 . Evans et al (Infection and Immunity (1988) 56:2896-2906) reported that H. pylori binding to an erythrocyte receptor is preferentially inhibited by N-acetylneuraminyl- ⁇ (2 ⁇ 3)-Gal ⁇ l ⁇ A Glc [NeuAc(2 ⁇ 3)-lactose] as compared with NeuAc(2 ⁇ 6)-lactose.
  • Sialoproteins which contain the NeuAc(2 ⁇ 3)Gal iso er of NeuAc- lactose i.e. , human erythrocyte glycophorin A, fetuin, and human ⁇ 2 -macroglobulin, also inhibited H. pylori binding, but at much higher concentrations (mg/ml) than that observed for NeuAc(2 ⁇ 3)-lactose, while no inhibition was observed for the corresponding asialoproteins.
  • NeuAc-lactose also called sialyllactose
  • the receptor on the erythrocytes is a sialoprotein containing NeuAc(2 ⁇ 3)Gal.
  • the NeuAc(2 ⁇ 3)Gal moiety which Evans et al believed to be the specific site of binding for H. pylori , is a structure which occurs widely in nature, they rationalized the selective binding of H. pylori to be due to the unique gastrointestinal environment. This, in their view, accounts for the lack of further colonization by H. pylori .
  • H. pylori binds to monolayers of Y-l mouse adrenal cells. But, this adherence can be prevented by pretreating the Y-l cells with neuraminidase and is blocked by sialyllactose-containing fetuin.
  • Lingwood et al (Lancet (1989) 2.:238-241) have reported the isolation of a gastric glycerolipid material which they observed to behave as a receptor for H. pylori .
  • the material was isolated from red blood cells, and mucosal scrapings of pig stomach and human stomach. The investigators postulated that the material was a sulphated alkylacylglycero-lipid, but the actual structure of this material was not been reported. Subsequent investigations (Lingwood et al.. Infection and Immunitv (1992) 650:2470-2474) showed that this receptor is phospatidylethanolamine.
  • CBS Colloidal bismuth subcitrate
  • CBS has been used successfully in treating both gastric and duodenal ulcer diseases (for a review, see Lambert in Reviews of Infectious Diseases (1991) 13. (Suppl. 8):S691-5.
  • CBS has proven effective as a histamine H2 antagonist and has been associated with lower relapse rates after cessation of therapy attributed to CBS's ability to eradicate H. pylori .
  • BSS Bismuth subsalicylate
  • one object of the present invention is to provide novel compositions and methods for inhibiting and/or treating gastric and/or duodenal ulcers.
  • Another object of the present invention is to provide a method for inhibiting the adhesion of Helicobacter pylori to mammalian tissue, including eliminating Helicobacter pylori from the stomach and/or duodenum of a in need thereof patient.
  • Another object of the present invention is to provide a kit for detecting the presence of Helicobacter pylori in a sample.
  • composition comprising an oligosaccharide selected from the group consisting of Formula
  • X is independently OH or NHAc
  • Y is independently H, or an amino acid or a peptide of 2-100, preferably 2-20, amino acids;
  • W, W ', and W" are each independently H or
  • Z is independently H or a pharmaceutically acceptable cation
  • P is independently H or
  • W, W' or W" is an ⁇ -N- acetylneuraminic acid moiety
  • W' and W" are not simultaneously an ⁇ -N- acetylneuraminic acid moiety
  • the compound of Formula II is not NAN ⁇ (2 ⁇ 3)Gal 01-4 Glu or NAN ⁇ (2 ⁇ 6)Gal 01-4 Glu.
  • a composition containing at least one oligosaccharide of Formula I or Formula II alone, or in combination with an H2 blocker, an antibiotic and/or an antiulcerative compound, has been found by the inventors to be effective at inhibiting the binding of Helicobacter pylori to the gastric and duodenal mucosa and relieving the effects of gastric and duodenal ulcers.
  • GalNAc for N-Acetylgalactosamine
  • Gal for galactose
  • Glc for glucose
  • GlcNAc for N-Acetylglucosamine
  • NAN or “NeuAc” for N-Acetylneuraminic acid
  • serine for serine
  • the OH group at the 4-position of the sugar on the right side of the molecule represents both the axial and equatorial epimeres.
  • the sugar on the right side of the molecule is a Gal or GalNAc moiety.
  • the sugar on the right side of the molecule is a Glc or GlcNAc moiety.
  • the core structure of Formula I represents either a Gal 01-3 Gal, Gal 01-3 GalNAc, Gal 01-3 Glc or Gal 01-3 GlcNAc.
  • the oligosaccharides according to Formula I of the present invention comprise a core made up of an ⁇ -N- acetylneuraminic acid moiety bound via its 2-position to either the 3-position or 6-position of a 0-galactose moiety, which, in turn, is bound via its 1-position to the 3-position of a galactose, N-acetylgalactosamine, glucose or N- acetylglucosamine moiety, which is bound via its 6-position to the 2-position of an ⁇ -N-acetylneuraminic acid.
  • any of the ⁇ -N-acetylneuraminic acid groups, but not all simultaneously, may be replaced with H.
  • this core structure further comprises an amino acid bound to the oxygen at the 1-position of the galactose, N-acetylgalactosamine, glucose or N- acetylglucosamine moiety, to provide as shown below an oligosaccharide of Formula I:
  • oligosaccharide of Formula I may be Formula la
  • the oligosaccharide of Formula I is selected from the group NAN ⁇ 2-3Gal01-3(NAN ⁇ 2- 6)GalNAc, NAN ⁇ 2-3Gal01-3(NAN ⁇ 2-6)GalNAc ⁇ l-ser, NAN ⁇ 2-3Gal01- 3GalNAc,
  • NAN ⁇ 2-6Gal01-3(NAN ⁇ 2-6)GalNAc NAN ⁇ 2-6Gal01-3(NAN ⁇ 2- 6)GalNAc ⁇ l-ser
  • NAN ⁇ 2-6Gal01-3GalNAc Gal01-3(NAN ⁇ 2-6)GalNAc
  • NAN ⁇ 2-3Gal01-3 NAN ⁇ 2-6)Gal
  • NAN ⁇ 2-3Gal01-3(NAN ⁇ 2-6)Gal ⁇ l- ser NAN ⁇ 2-3Gal01-3Gal
  • NAN ⁇ 2-6Gal01-3 NAN ⁇ 2-6)GlcNAc
  • NAN ⁇ 2-6Gal01-3 NAN ⁇ 2- 6)GlcNAc ⁇ l-ser
  • NAN ⁇ 2-6Gal01-3GlcNAc Gal01-3(NAN ⁇ 2-6)GlcNAc
  • NAN ⁇ 2-3Gal01-3 NAN ⁇ 2-6)Glc
  • NAN ⁇ 2-3Gal01-3 NAN ⁇ 2-6)Glc ⁇ l- ser
  • NAN ⁇ 2-3Gal01-3Glc NAN ⁇ 2-3Gal01-3Glc
  • NAN ⁇ 2-6Gal01-3(NAN ⁇ 2-6)Glc NAN ⁇ 2-6Gal01-3(NAN ⁇ 2-6)Glc ⁇ l- ser
  • NAN ⁇ 2-6Gal01-3Glc Gal01-3(NAN ⁇ 2-6)Glc and a mixture thereof.
  • the oligosaccharides according to Formula II of the present invention comprise a core made up of an ⁇ -N- acetylneuraminic acid moiety bound via its 2-position to either the 3-position or 6-position of a 0-galactose moiety, which, in turn, is bound via its l-position to the 4-position of a glucose or N-acetylglucosamine moiety, which is bound via its 6-position to the 2-position of an ⁇ -N-acetylneuraminic acid.
  • any of the ⁇ -N-acetylneuraminic acid groups, but not all simultaneously, may be replaced with H.
  • the compound of Formula II does not include NAN ⁇ (2 ⁇ 3)Gal 01-4 Glu or NAN ⁇ (2 ⁇ 6)Gal 01-4 Glu.
  • this core structure further comprises an amino acid bound to the oxygen at the l-position of the glucose or N-acetylglucosamine moiety, to provide as shown below an oligosaccharide of Formula II:
  • X is OH or NHAc
  • Y is serine or threonine
  • W and W' are each an ⁇ -N-acetylneuraminic acid moiety and Z is independently H or a known pharmaceutically acceptable cation.
  • the oligosaccharide of Formula I is selected from the group NAN ⁇ 2-3Gal01-4(NAN ⁇ 2- 6)GlcNAc, NAN ⁇ 2-3Gal01-4(NAN ⁇ 2-6)GlcNAc ⁇ l-ser, NAN ⁇ 2-3Gal01- 4G1CNAC,
  • NAN ⁇ 2-6Gal01-4 (NAN ⁇ 2-6)GlcNAc, NAN ⁇ 2-6Gal01-4 (NAN ⁇ 2- 6)GlcNAc ⁇ l-ser, NAN ⁇ 2-6Gal01-4GlcNAc, Gal01-4(NAN ⁇ 2-6)GlcNAc,
  • NAN ⁇ 2-3Gal01-4 NAN ⁇ 2-6)Glc
  • NAN ⁇ 2-3Gal01-4 NAN ⁇ 2-6)Glc ⁇ l- ser
  • NAN ⁇ 2-6Gal01-4 (NAN ⁇ 2-6)Glc, NAN ⁇ 2-6Gal01-4 (NAN ⁇ 2-6)Glc ⁇ l- ser, Gal01-4(NAN ⁇ 2-6)Glc and a mixture thereof.
  • the group Y may represent an amino acid or peptide of from 2-100 amino acids, preferably 2-20 amino acids. It is noted that the glycoprotein fetuin, contains a peptide of at least 500 amino acids.
  • any one of or all of the free hydroxy1 groups on the oligosaccharide of Formula I or Formula II may be acylated with a C 1-6 acyl group by treatment with a suitable acylating agent such as acetyl chloride, propionyl chloride, butyryl chloride or acetic anhydride.
  • a suitable acylating agent such as acetyl chloride, propionyl chloride, butyryl chloride or acetic anhydride.
  • ⁇ -N-acetylneuraminic acid moieties as they appear in Formula I or II may further be substituted at the 8-position with an ⁇ -N-acetylneuraminic acid moiety. Accordingly for all of the above-identified compounds of Formula I and Formula II any of the ⁇ -N-acetylneuraminic acid moieties may be replaced by NAN ⁇ 2-8NAN ⁇ 2-. This may be done by treating a mono ⁇ -N- acetylneuraminic acid compound of Formula I or II with CMP-NAN and an ⁇ -N-acetylneuraminic acid transferase specific for transfer to an ⁇ -N-acetylneuraminic acid.
  • bis sialylated oligosaccharides of the present invention are for example the bis sialylated compounds of Formula II, NAN ⁇ 2-8NAN ⁇ 2-3Gal01-4Glc and NAN ⁇ 2-8NAN ⁇ 2-6Gal01- 4Glc.
  • any known suitable pharmaceutically acceptable cations may be used with the oligosaccharides of Formula I or Formula II, 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. calcium salt, magnesium salt, etc.), an ammonium salt, 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.
  • a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) or an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, di
  • formate acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobro ide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.
  • NAN ⁇ 2-3Gal01-3(NAN ⁇ 2-6)GalNAc has been identified as an O-linked carbohydrate found in bovine Factor X (Mizvochi et al. J. Biol. Chem. (1977) 255:3526), bovine high-molecular weight ininogen (Endo et al. J. Biochem. Tokyo
  • bovine fetuin R. Spiro et al. J. Biol. Chem. (1974) 249:5704
  • human apolipoprotein C-III P. Yaith, Biochem. Biophvs. Acta (1978) 541:234 .
  • the oligosaccharide 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, or (3) by degradation of a natural occurring oligosaccharide, glycolipid, or glycopeptide.
  • the compound NAN ⁇ 2-3Gal01-3 (NAN ⁇ 2-6)GalNAc-itol, wherein the acetal of the terminal GalNAc has been reduced to the primary alcohol, may be obtained by alkaline hydrolysis and NaBH 4 reduction of fetuin.
  • Illustrative hydrolysis conditions consist of reacting fetuin in 0.05 M NaOH and IM NaBH 4 at 50°C for 16h in water.
  • the compound NAN ⁇ 2-3Gal01-3(NAN ⁇ 2-6)GalNAc-peptide may be obtained by protease mediated degradation of fetuin in aqueous solution at about 50°C.
  • the hydrolysis product of fetuin may be disfavored due to the possible presence of mad cow's disease. While purification and treatment techniques can rule out transfer of this virus to the composition, enzymatic synthesis is still preferred.
  • the present oligosaccharide may be administered in conjunction with a known proton pump inhibitor or a known H2 receptor antagonist.
  • a representative proton pump inhibitor is omeprazole
  • 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 oligosaccharide is about the same amount administered for their known therapy. Accordingly, effective dosages of the proton pump inhibitor and H 2 can be determined by routine experimentation.
  • Suitable antiulceratives include aceglutamide aluminum complex, e-acetamidocaproic acid zinc salt, acetoxolone, arbaprostil, benexate hydrochloride, bismuth subcitrate sol, carbenoxolone, cetraxate, cimetidine, enprostil, esaprazole, famotidine, ftaxidide, gefarnate, guaiazulene, irsogladine, misoprostol, seratidine, ornoprostil, ⁇ -oryzanol, pifamine, pirenzepine, plaunotol, ranitidine, rioprostil, rosaprostol, rotraxate, roxatidine acetate, sofalcone, spizofurone, sucralfate, teprenone, trim
  • the present oligosaccharide may be administered in conjunction with an antibiotic with activity against H. pylori .
  • suitable antibiotics include metronidazole, tetracycline, bismuth, erythromycin, macrolide, quinoline and amoxicillin.
  • the amount of antibiotic administered in conjunction with the present oligosaccharide is about the same amount administered for its known therapy. Accordingly, effective dosage of the antibiotic can be determined by routine experimentation.
  • the anti-ff. pylori compositions of the present invention contains one or a plurality of oligosaccharides of Formula I or Formula II in association with any suitable liquid or solid, pharmaceutically acceptable carrier or excipient, preferable in a form suitable for oral or enteral administration.
  • the anti-ff. pylori compositions of the present invention are preferably pyrogen free.
  • the anti-ff. pylori 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,
  • 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 oligosaccharide or anti-ff. pylori compositions are administered enterally to a patient in need thereof to inhibit ff. pylori binding or eliminate ff. pylori colonies from the patient's 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 cows, horses, sheep, goats, dogs, cats, rodents and non-human primates, fowl such a chickens, turkeys and ducks, and fish.
  • Suitable amounts of the composition to be administered include those which produce an effective stomach concentration of oligosaccharide of from 1 ⁇ g to 10,000 mg/ml per dose. preferably 100 to 1000 ⁇ g/ml.
  • the composition is formulated to provide between 10-500 mg, preferably 100-300 mg of the proton pump inhibitor, H2 antagonist, or antiulcerative daily.
  • Dosage forms include such unit dosage forms such as tablets, capsules, solutions or suspensions.
  • the oligosaccharide of Formula I or Formula II is provided as a multivalent molecule.
  • at least one type of the oligosaccharide of Formula I or Formula II is bound to a polymer using known techniques so as to produce a polymer to which more than one individual molecules of the oligosaccharide of Formula I or Formula II are covalently attached.
  • the polymer backbone is sufficiently long to provide a multivalent molecule leaving from between 2-1,000, preferably 10-100, more preferably 20-30 molecules- of the compound of Formula I or Formula II bound to the polymer.
  • Suitable polymers are any polymer material which may be reacted with the anomeric carbon of a saccharide, such as a polylysine, a polyacryla ide or a cyclodextrin.
  • the oligosaccharide of Formula I or Formula II may be bound to a support to form a bead wherein the surface of the bead is bound with the compound of Formula I or Formula II.
  • Another embodiment of this invention which relates to one of the inventor's application serial no. 07/241,012, filed September 2, 1988, provides a kit for detecting ff. pylori .
  • the kit is analogous to a kit for performing ELISAs, but uses a compound of Formula I or Formula II which is bound to a solid support, instead of the antigens or antibodies bound to solid supports normally found with ELISA kits.
  • the kit comprises a container, and contained therein, the compound of Formula I or Formula II bound to a solid support.
  • a sample to be tested for ff. pylori is contacted with the bound compound of Formula I or Formula II. Bound ff. pylori may be detected by standard means such as labeled antibodies.
  • aqueous solution of equimolar equivalents of galNAc and UDP-gal is stirred at 40°C in the presence of a 0 1-3 galactosyltransferase for a sufficient time to effect coupling of the two moieties.
  • the 0 1-3 galactosyltransferase is isolated from porcine submaxillary glands.
  • three molar equivalents of CMP-NAN are introduced along with an ⁇ 2-6 sialyltransferase, to form the monosialo compound.
  • an ⁇ 2-3 sialyltransferase is introduced in the presence of three more equivalents of CMP-NAN to form the tetrasaccharide.
  • An anti-ffeli ⁇ oJacter composition is prepared by mixing 100 mg of the tetrasaccharide of Example 1 with 250 mg of the H 2 receptor antagonist ranitidine. The mixture is then suspended in a mixture of water and propylene glycol.
  • An anti-ffelicoJacter composition is prepared by mixing 100 mg of the tetrasaccharide of Example 1 with 250 mg of the proton pump inhibitor omeprazole. The mixture is then suspended in a mixture of water and propylene glycol.
  • An anti-ffelicoJbacter composition is prepared by mixing 100 mg of the tetrasaccharide of Example 1 with 250 mg of a combination of metronidazole, tetracycline, and amoxicillin. The mixture is then suspended in a mixture of water and propylene glycol.
  • a patient infected with ff. 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 100 ⁇ g/ml.
  • Therapy is continued for two weeks, after which examination showed eradication of the ff. pylori bacteria.
  • maintenance therapy with the composition of the present invention is continued to prevent recurrence.
  • aqueous solution of equimolar equivalents of glcNAc and UDP-gal is stirred at 40°C in the presence of a 0 1-4 galactosyltransferase for a sufficient time to effect coupling of the two moieties.
  • the 0 1-4 galactosyltransferase is isolated from porcine submaxillary glands.
  • three molar equivalents of CMP-NAN are introduced along with an ⁇ 2-6 sialyltransferase, to form the monosialo compound.
  • an ⁇ 2-3 sialyltransferase is introduced in the presence of three more equivalents of CMP-NAN to form the tetrasaccharide.
  • aqueous solution of equimolar equivalents of glcNAc and UDP-gal is stirred at 40°C in the presence of a 0 1-3 galactosyltransferase for a sufficient time to effect coupling of the two moieties.
  • the 0 1-3 galactosyltransferase is isolated from porcine submaxillary glands.
  • three molar equivalents of CMP-NAN are introduced along with an ⁇ 2-6 sialyltransferase, to form the monosialo compound.
  • an ⁇ 2-3 sialyltransferase is introduced in the presence of three more equivalents of CMP-NAN to form the tetrasaccharide.

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PCT/US1993/007010 1992-07-31 1993-07-29 Compositions for treating and inhibiting gastric and duodenal ulcers WO1994003184A1 (en)

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994018986A1 (en) * 1993-02-26 1994-09-01 Jan Staffan Normark Use of oligosaccharide glycosides as inhibitors of bacterial adherence
WO1995032717A1 (en) * 1994-05-27 1995-12-07 Pharmacia Ab The use of an anti-helicobacter substance
FR2721612A1 (fr) * 1994-06-23 1995-12-29 Idm Nouveaux dérivés d'oligosides, leur procédé de préparation et leurs applications.
WO1995033467A3 (en) * 1994-06-06 1996-01-04 Univ Rockefeller Modulators of pneumococcal adherence to pulmonary and vascular cells and diagnostic and therapeutic applications
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WO2002006821A3 (en) * 2000-07-17 2002-06-27 Hansa Medical Ab Antimicrobial agent
EP0749314A4 (en) * 1994-03-02 2002-09-18 Neose Technologies Inc PROCESS FOR THE TREATMENT AND INHIBITION OF GASTRIC AND DUODENAL ULCERS
ITFI20090071A1 (it) * 2009-04-06 2010-10-07 Inalco Spa Sali di 6'-sialillattosio e processo per la loro sintesi e per la sintesi di altri alfa-sialiloligosaccaridi.
EP2098238A4 (en) * 2007-01-12 2010-11-10 Inst Noguchi GROWTH HAMPER FOR HELICOBACTER PYLORI WITH AN N-ACETYLGLUCOSAMINYL-BINDING MONOSACCHARIDE DERIVATIVE
WO2010114425A3 (ru) * 2009-03-30 2011-01-06 Dikovskiy Aleksander Vladimirovich Фармацевтическая композиция ингибитора протонной помпы и пребиотика для лечения язвенных поражений желудка и 12- перстной кишки
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US8859511B2 (en) 2008-10-10 2014-10-14 The Noguchi Institute Proliferation inhibitor of Helicobacter pylori bacteria

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WO1994018986A1 (en) * 1993-02-26 1994-09-01 Jan Staffan Normark Use of oligosaccharide glycosides as inhibitors of bacterial adherence
EP0749314A4 (en) * 1994-03-02 2002-09-18 Neose Technologies Inc PROCESS FOR THE TREATMENT AND INHIBITION OF GASTRIC AND DUODENAL ULCERS
WO1995032717A1 (en) * 1994-05-27 1995-12-07 Pharmacia Ab The use of an anti-helicobacter substance
US5665561A (en) * 1994-06-06 1997-09-09 The Rockefeller University Modulators of pneumococcal adherence to pulmonary and vascular cells and diagnostic and therapeutic applications
WO1995033467A3 (en) * 1994-06-06 1996-01-04 Univ Rockefeller Modulators of pneumococcal adherence to pulmonary and vascular cells and diagnostic and therapeutic applications
US6251858B1 (en) 1994-06-23 2001-06-26 I.D.M. Immuno-Designed Molecules Derivatives of oligosides, their process of preparation and their applications
WO1996000229A1 (fr) * 1994-06-23 1996-01-04 I.D.M. Immuno-Designed Molecules Nouveaux derives d'oligosides, leur procede de preparation et leurs applications
FR2721612A1 (fr) * 1994-06-23 1995-12-29 Idm Nouveaux dérivés d'oligosides, leur procédé de préparation et leurs applications.
WO1997023207A1 (fr) * 1995-12-22 1997-07-03 Teikoku Chemical Industries Co., Ltd. Agent contre l'helicobacter pylori
AU710576B2 (en) * 1996-05-03 1999-09-23 Neose Technologies, Inc. Bismuth salt of sialyloligosaccharide and a method for treating and inhibiting gastric and duodenal ulcers with same
WO1997041875A1 (en) * 1996-05-03 1997-11-13 Neose Technologies, Inc. Bismuth salt of sialyloligosaccharide and a method for treating and inhibiting gastric and duodenal ulcers with same
US6096725A (en) * 1997-07-02 2000-08-01 Neose Technologies, Inc. Methods of using αGal oligosaccharides as immune system targeting agents
WO2002006821A3 (en) * 2000-07-17 2002-06-27 Hansa Medical Ab Antimicrobial agent
US7335355B2 (en) 2000-07-17 2008-02-26 Hansa Medical Ab Antimicrobial agent
US8575117B2 (en) 2007-01-12 2013-11-05 The Noguchi Institute Proliferation inhibitor of helicobacter pylori including alpha-n-acetyl-glucosaminyl bond-containing monosaccharide derivatives
EP2098238A4 (en) * 2007-01-12 2010-11-10 Inst Noguchi GROWTH HAMPER FOR HELICOBACTER PYLORI WITH AN N-ACETYLGLUCOSAMINYL-BINDING MONOSACCHARIDE DERIVATIVE
US8859511B2 (en) 2008-10-10 2014-10-14 The Noguchi Institute Proliferation inhibitor of Helicobacter pylori bacteria
EA022204B1 (ru) * 2009-03-30 2015-11-30 Александр Владимирович ДИКОВСКИЙ Фармацевтическая композиция ингибитора протонной помпы и пребиотика для лечения язвенной болезни желудка и 12-перстной кишки
WO2010114425A3 (ru) * 2009-03-30 2011-01-06 Dikovskiy Aleksander Vladimirovich Фармацевтическая композиция ингибитора протонной помпы и пребиотика для лечения язвенных поражений желудка и 12- перстной кишки
RU2410100C2 (ru) * 2009-03-30 2011-01-27 Александр Владимирович Диковский Фармацевтическая композиция ингибитора протонной помпы и пребиотика для лечения язвенных поражений желудка и 12-перстной кишки
ITFI20090071A1 (it) * 2009-04-06 2010-10-07 Inalco Spa Sali di 6'-sialillattosio e processo per la loro sintesi e per la sintesi di altri alfa-sialiloligosaccaridi.
JP2012522761A (ja) * 2009-04-06 2012-09-27 イナルコ ソシエタ ペル アチオニ ６’−シアリルラクトース塩並びに６’−シアリルラクトース塩及び他のａ−シアリルオリゴ糖の合成方法
US20120071441A1 (en) * 2009-04-06 2012-03-22 Inalco S.P.A. 6'-sialyllactose salts and process for their synthesis and for the synthesis of other alpha-sialyloligosaccharides
US9034844B2 (en) 2009-04-06 2015-05-19 Inalco S.P.A. 6′-sialyllactose salts and process for their synthesis and for the synthesis of other alpha-sialyloligosaccharides
WO2010116317A1 (en) * 2009-04-06 2010-10-14 Inalco S.P.A. 6"-sialyllactose salts and process for their synthesis and for the synthesis of other a-sialyloligosaccharides
WO2012006718A1 (en) * 2010-07-14 2012-01-19 Vancouver Biotech Ltd. Carbohydrate hapten-based anti-cancer vaccines and antibody drugs
WO2014035295A1 (ru) 2012-08-30 2014-03-06 Dikovskiy Alexander Vladimirovich Фармацевтическая композиция для лечения гастроэзофагеальной рефлюксной болезни

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