EP0749314A1 - Procede de traitement et d'inhibition des ulceres gastriques et duodenaux - Google Patents
Procede de traitement et d'inhibition des ulceres gastriques et duodenauxInfo
- Publication number
- EP0749314A1 EP0749314A1 EP95911945A EP95911945A EP0749314A1 EP 0749314 A1 EP0749314 A1 EP 0749314A1 EP 95911945 A EP95911945 A EP 95911945A EP 95911945 A EP95911945 A EP 95911945A EP 0749314 A1 EP0749314 A1 EP 0749314A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oligosaccharide
- galactose
- group
- stomach
- formula
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
Classifications
-
- 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
-
- 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
- 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
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates a method for treating and inhibiting gastric and duodenal ulcers in a patient.
- H. pylori Helicobacter pylori
- Campylobacter pylori C. 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.
- N-acetylneuraminyl- (2 ⁇ 3)-Gal /3l ⁇ 4 Glc herein after NeuAc(2 ⁇ 3)-lactose
- 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 at higher concentrations (mg/ml) than that observed for NeuAc(2 ⁇ 3)-lactose, while no inhibition was observed for the corresponding asialoglycoproteins.
- Evans et al ibid measured the hemagglutination inhibiting ability (HIA) of several compounds containing a NeuAc-lactose structure.
- 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.
- Lin wood 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 (Lincfwood et al.. Infection and Immunity (1992) 60:2470- 2474) showed that this receptor is phosphatidylethanolamine. Lin wood et al..
- H . pylori adherence can be assessed by microtiter assays and involves a bacterial surface material which co-purifies with urease and is different from the N- acetyl-neuraminyl-lactose binding hemagglutinin.
- Saitoh et al report a sulfate-containing glycerolipid as a ligand which is specifically recognized by H. pylori .
- 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 H 2 antagonist and has been associated with lower relapse rates after cessation of therapy attributed to CBS's ability to eradicate H. pylori .
- Bismuth subsalicylate (BSS) has also been observed to inhibit H. pylori .
- H. pylori plays in peptic ulcers has led to an announcement in February 1994 by an independent advisory panel of experts convened by the National Institutes of Health, to advise that patients diagnosed with peptic ulcers and H. pylori be treated for two weeks with a combination of antibiotics.
- fetuin has minimal activity in inhibiting binding of H. pylori cells, in vitro .
- the inventors have discovered that the binding inhibition activity associated with fetuin, appears to be attributable to a high molecular weight impurity which is a contaminate of commercially available fetuin.
- 3' sialyl lactose has an ability to inhibit binding of H. pylori to a degree far in excess of what would have been expected in light of that previously reported for fetuin.
- one object of the present invention is to a method for treating and/or preventing gastric and/or duodenal ulcers.
- Another object of the present invention is to provide a method for inhibiting Helicobacter pylori infection and/or reinfection to mammalian tissue, including eliminating Helicobacter pylori from the stomach and/or duodenum of a patient in need thereof.
- Another object of the present invention is to provide a pharmaceutical composition for inhibiting Helicobacter pylori infection or reinfection of mammalian tissue, including eliminating Helicobacter pylori from the stomach and/or duodenum of a patient in need thereof and for treating and/or preventing gastric and/or duodenal ulcers.
- All of the above objects of the present invention and other objects which are apparent from the description of the invention given herein below have been discovered by the inventors to be satisfied by administering a composition comprising an oligosaccharide of Formula I (NeuAc- ⁇ (2-3)-pGal-/3(1)-(-X-) m -(-Y-) n -) p -Z wherein
- 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;
- Y a linking group
- Z a multivalent support
- m 0 or 1
- n 0 or 1
- p an integer of 2-1,000.
- the present invention is also provided for by an oligosaccharide composition of Formula II
- 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 II 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 Helicobacter 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 . 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-. 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- . . 2 - alkyl, a hydroxyalkylamine, 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- . . 2 - alkyl, - S- and -0-.
- This type of linking chemistry is described by Stowe11 et al Advances in Carbohydrate Chemistry and Biochemistry, 31_ (1980) p 225+.
- 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 X.
- 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- L 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 ⁇ Q alkyl carboxylic ester group, a C x _ 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
- 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.
- Suitable pharmaceutically acceptable cations may be used with the oligosaccharides of Formula I and Formula II, 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. 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. trimethyla ine salt, triethyla ine 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. trimethyla ine salt,
- 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 oligosaccharides 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.
- the oligosaccharides of Formula I and Formula II 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
- 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, bismuth subsalicylate, carbenoxolone, cetraxate, cimetidine, enprostil, esaprazole, famotidine, ftaxidide, gefarnate, guaiazulene, irsogladine, misoprostol, monatidine, ornoprostil, ⁇ - oryzanol, pifamine, pirenzepine, plaunotol, ranitidine, rioprostil, rosaprostol, rotraxate, roxatidine acetate, sofalcone, spizofurone, sucralfate
- the amount of antiulcerative administered in conjunction with the present oligosaccharide is about the same amount administered for its known therapy. Accordingly, effective dosage of the antiulcerative can be determined by routine experimentation.
- the oligosaccharides of Formula I and Formula II may be administered in conjunction with an antibiotic with activity against H. pylori . Suitable antibiotics include metronidazole, tetracycline, bismuth, erythromycin, a macrolide, a quinolone, a cephalosporin 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.
- Formula II may be administered in conjunction with a H-type 1 or Lewis b blood group antigen or an oligosaccharide such as NeuAc- ⁇ (2 ⁇ 6)-Gal / 3l ⁇ 4 Glc.
- a H-type 1 or Lewis b blood group antigen or an oligosaccharide such as NeuAc- ⁇ (2 ⁇ 6)-Gal / 3l ⁇ 4 Glc.
- Suitable H-type 1 and Lewis b blood group antigens are reported in Boren et al (Science (1993) 262:1892-1895) .
- the anti-H. pylori compositions of the present invention contains the oligosaccharides of Formula I and 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 pharmaceutical compositions of the present invention are preferably pyrogen free.
- 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.
- Suitable 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 pharmaceutical compositions are administered orally or enterally to a patient in need thereof to inhibit H. pylori binding or eliminate H. 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 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 oligosaccharides of Formula I and/or Formula II 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 10 ⁇ g to 1,000 mg/ml, more preferably 0.5mg to 50 mg/ml, most preferably 1 to 10 mg/ml.
- an effective stomach concentration of 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.
- a dose of 3 gm would produce an effective stomach concentration of about 6 mg/ml.
- Administration of the pharmaceutical composition comprising the oligosaccharide of Formula II 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 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.
- H. pylori bacteria isolates were obtained from B. Marshall (from the University of Virginia) and grown on sheep blood agar, collected at 48 h, washed and suspended in a binding buffer of HBSS + 0.1% bovine serum albumin + 50mM HEPES buffer + 0.01% phenol red or HBHPR.
- H. pylori concentration of H. pylori which bound to the monolayer was assigned an intermediate OD 595 (optical density at 595 nm) (about 0.4 OD units).
- concentration of bacteria and test compound were combined for 10 minutes, then transferred onto the monolayer. Binding was allowed to occur for 20 min at room temperature under mild agitation. The unbound bacteria was washed away with 1 wash of HBHPR, then 2 washes of the same buffer without HEPES buffer (HBPR) .
- 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 .
- HSA — > 1 x 10 "4 1 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 derived piglets (delivered by cesarean section and housed in a germ-free environment) were orally treated with 100 mg of 3'sialyl lactose in 5.0 ml of water.
- 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 9 live H. pylori . Four piglets were administered 3'sialyl lactose and 2 piglets were administered the control. The results are shown below in Table 3.
- 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
- An anti-Helico-bacter composition is prepared by suspending 1 g of the 3'sialyl lactose in a mixture of water and propylene glycol.
- Example 4 An anti-Helico-bacter composition is prepared by suspending 1 g of the 3'sialyl lactose in a mixture of water and propylene glycol.
- An ant i-Helicobacter composition is prepared by mixing 1 g of 3' sialyl lactose with 250 mg of the H 2 receptor antagonist ranitidine. The mixture is then suspended in a mixture of water and propylene glycol. Example 5.
- An anti-He2icoJbacter composition is prepared by mixing 1 g of 3' sialyl lactose with 250 mg of the proton pump inhibitor omeprazole. The mixture is then suspended in a mixture of water and propylene glycol. Example 6.
- An anti-Helico-bacter composition is prepared by mixing 1 g of 3' sialyl lactose with 500 mg of a tetracycline. The mixture is then suspended in a mixture of water and propylene glycol.
- a patient infected with H. pyl ⁇ ri 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.
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Abstract
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US20451594A | 1994-03-02 | 1994-03-02 | |
US204515 | 1994-03-02 | ||
PCT/US1995/002388 WO1995023605A1 (fr) | 1994-03-02 | 1995-03-02 | Procede de traitement et d'inhibition des ulceres gastriques et duodenaux |
Publications (2)
Publication Number | Publication Date |
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EP0749314A1 true EP0749314A1 (fr) | 1996-12-27 |
EP0749314A4 EP0749314A4 (fr) | 2002-09-18 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP95911945A Withdrawn EP0749314A4 (fr) | 1994-03-02 | 1995-03-02 | Procede de traitement et d'inhibition des ulceres gastriques et duodenaux |
Country Status (5)
Country | Link |
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EP (1) | EP0749314A4 (fr) |
JP (1) | JP3179108B2 (fr) |
AU (1) | AU709149B2 (fr) |
CA (1) | CA2183329A1 (fr) |
WO (1) | WO1995023605A1 (fr) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5736533A (en) * | 1995-06-07 | 1998-04-07 | Neose Technologies, Inc. | Bacterial inhibition with an oligosaccharide compound |
EP0918526A1 (fr) * | 1996-05-03 | 1999-06-02 | Neose Technologies, Inc. | Sel de bismuth de sialyloligosaccharide et procede pour traiter et inhiber les ulceres gastriques et duodenaux avec cette substance |
WO2000044367A2 (fr) * | 1999-02-01 | 2000-08-03 | Dermal Research Laboratories, Inc. | Composition pharmaceutique d'hydrates de carbone complexes et d'huiles essentielles et methode d'utilisation de celle-ci |
SE9901007D0 (sv) * | 1999-03-19 | 1999-03-19 | Thomas Boren | Use of fucosylated sialylated N-acetyl lactosamin carbohydrate structures for inhibition of bacterial adherence |
US7879824B2 (en) | 2001-07-31 | 2011-02-01 | Dermal Research Laboratories, Inc. | Methods of preventing or treating diseases and conditions using complex carbohydrates |
FI20021989A0 (fi) * | 2002-11-06 | 2002-11-06 | Halina Miller-Podraza | Korkean affiniteetin Helicobacter pylori-reseptorit ja niiden käyttö |
NL2007931C2 (en) * | 2011-12-07 | 2013-06-10 | Friesland Brands Bv | Methods for providing sialylated oligosaccharides and products obtainable thereby. |
WO2020060260A1 (fr) * | 2018-09-20 | 2020-03-26 | 가톨릭대학교 산학협력단 | Composite polymère pour la reconnaissance de l'helicobacter pylori et composition pour la thérapie photodynamique la comprenant |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2662697A1 (fr) * | 1990-06-01 | 1991-12-06 | Snow Brand Milk Products Co Ltd | Nouveau ganglioside provenant du lait et son procede d'obtention. |
WO1993018775A1 (fr) * | 1992-03-19 | 1993-09-30 | The University Of British Columbia | Procede et composition permettant de supprimer les effets secondaires de medicaments anti-inflammatoires |
WO1993023055A1 (fr) * | 1992-05-15 | 1993-11-25 | The University Of British Columbia | Glucosamine d'acetyle-n en tant qu'agent gastroprotecteur |
WO1994003184A1 (fr) * | 1992-07-31 | 1994-02-17 | Neose Pharmaceuticals, Inc. | Compositions destinees a traiter et inhiber les ulceres gastriques et duodenaux |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE464687B (sv) * | 1987-11-10 | 1991-06-03 | Biocarb Ab | Foerfarande foer framstaellning av en gelprodukt |
US5089479A (en) * | 1988-11-28 | 1992-02-18 | Krivan Howard C | Adhesion of mycoplasma pneumoniae and mycoplasma hominus to sulfatide |
US5260280A (en) * | 1989-02-07 | 1993-11-09 | Snow Brand Milk Products Co., Ltd. | Bacterial toxin neutralizer |
US5211937A (en) * | 1990-07-30 | 1993-05-18 | Glycomed Incorporated | Method of determining a site of inflammation utilizing elam-1 ligands |
US5164374A (en) * | 1990-12-17 | 1992-11-17 | Monsanto Company | Use of oligosaccharides for treatment of arthritis |
US5254676A (en) * | 1991-11-22 | 1993-10-19 | E. I. Du Pont De Nemours And Company | Oligosaccharide inhibitors for influenza virus |
-
1995
- 1995-03-02 JP JP52295595A patent/JP3179108B2/ja not_active Expired - Fee Related
- 1995-03-02 WO PCT/US1995/002388 patent/WO1995023605A1/fr not_active Application Discontinuation
- 1995-03-02 CA CA002183329A patent/CA2183329A1/fr not_active Abandoned
- 1995-03-02 AU AU19323/95A patent/AU709149B2/en not_active Ceased
- 1995-03-02 EP EP95911945A patent/EP0749314A4/fr not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2662697A1 (fr) * | 1990-06-01 | 1991-12-06 | Snow Brand Milk Products Co Ltd | Nouveau ganglioside provenant du lait et son procede d'obtention. |
WO1993018775A1 (fr) * | 1992-03-19 | 1993-09-30 | The University Of British Columbia | Procede et composition permettant de supprimer les effets secondaires de medicaments anti-inflammatoires |
WO1993023055A1 (fr) * | 1992-05-15 | 1993-11-25 | The University Of British Columbia | Glucosamine d'acetyle-n en tant qu'agent gastroprotecteur |
WO1994003184A1 (fr) * | 1992-07-31 | 1994-02-17 | Neose Pharmaceuticals, Inc. | Compositions destinees a traiter et inhiber les ulceres gastriques et duodenaux |
Non-Patent Citations (2)
Title |
---|
FALK P ET AL: "AN IN VITRO ADHERENCE ASSAY REVEALS THAT HELICOBACTER PYLORI EXHIBITS CELL LINEAGE-SPECIFIC TROPISM IN THE HUMAN GASTRIC EPITHELIUM" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 90, no. 5, 1 March 1993 (1993-03-01), pages 2035-2039, XP000560389 ISSN: 0027-8424 * |
See also references of WO9523605A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH09509931A (ja) | 1997-10-07 |
CA2183329A1 (fr) | 1995-09-08 |
AU1932395A (en) | 1995-09-18 |
EP0749314A4 (fr) | 2002-09-18 |
JP3179108B2 (ja) | 2001-06-25 |
WO1995023605A1 (fr) | 1995-09-08 |
AU709149B2 (en) | 1999-08-19 |
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