Methods and compositions using (+) norcisapride in combination with proton pump inhibitors or H2 receptor antagonists

Abstract

The invention relates to methods and compositions for the prevention, treatment, or management of gastrointestinal disorders or symptoms thereof, employing two or more agents or compounds to provide a triple site action on 5-HT 3 receptors, 5-HT 4 receptors, and at least one of H 2 receptors and proton pumps.

What is claimed is:  
     
         1 . A method of treating gastrointestinal disorders in a patient which comprises administering a therapeutically effective amount of one or more agent(s) or compound(s) that simultaneously or sequentially act on 5-HT 3  receptors, 5-HT 4  receptors, and either proton pumps or H 2  receptors, or an optically pure stereoisomer or active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         2 . A method of treating gastrointestinal disorders in a patient which comprises administering a therapeutically effective amount of an agent or compound that antagonizes 5-HT 3  receptors and agonizes 5-HT 4  receptors, and a therapeutically effective amount of at least one of a proton pump inhibitor or an H 2  receptor antagonist, or an optically pure stereoisomer or active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         3 . A method of treating gastrointestinal disorders in a patient which comprises administering to said patient a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer, and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         4 . The method of  claim 3 , wherein the patient is a human.  
     
     
         5 . The method of  claim 3 , wherein the gastrointestinal disorder is gastrointestinal motility dysfunction.  
     
     
         6 . The method of  claim 5 , wherein the gastrointestinal motility dysfunction is selected from the group consisting of dyspepsia, gastroparesis, constipation, post-operative ileus, and intestinal pseudo obstruction.  
     
     
         7 . The method of  claim 3 , wherein the gastrointestinal disorder is gastro-esophageal reflux disease, emesis, gastrointestinal ulcers, pathological hypersecretory condition, and gastric hyperacidity.  
     
     
         8 . The method of  claim 7 , wherein the pathological hypersecretory condition is Zollinger-Ellison Syndrome.  
     
     
         9 . The method of  claim 7 , wherein the gastric hyperacidity is selected from the group consisting of heartburn, acid indigestion, sour stomach, erosive esophagitis, and upset stomach.  
     
     
         10 . The method of  claim 3 , wherein the amount of (+) norcisapride administered is from about 0.5 mg to about 500 mg.  
     
     
         11 . The method of  claim 10 , wherein the amount of (+) norcisapride administered is from about 1 mg to about 350 mg.  
     
     
         12 . The method of  claim 3 , wherein the proton pump inhibitor is administered and is selected from the group consisting of omeprazole, lansoprazole, rabeprazole, pantoprazole, hydroxy-omeprazole, desmethyl-pantoprazole, hydroxy-lansoprazole, and an optically pure stereoisomer thereof.  
     
     
         13 . The method of  claim 12 , wherein the amount of proton pump inhibitor is from about 1 mg to about 200 mg.  
     
     
         14 . The method of  claim 13 , wherein the amount of proton pump inhibitor is from about 5 mg to about 150 mg.  
     
     
         15 . The method of  claim 3 , wherein the H 2  receptor antagonist is administered and is selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine, and an optically pure stereoisomer or an active metabolite thereof.  
     
     
         16 . The method of  claim 15 , wherein the amount of H 2  receptor antagonist is from about 1 mg to about 2400 mg.  
     
     
         17 . The method of  claim 3 , wherein at least one of (+) norcisapride and the proton pump inhibitor is administered orally.  
     
     
         18 . The method of  claim 17 , wherein (+) norcisapride and the proton pump are orally administered as a tablet or a capsule.  
     
     
         19 . The method of  claim 3 , wherein at least one of (+) norcisapride and the H 2  receptor antagonist is administered orally.  
     
     
         20 . The method of  claim 3 , wherein the proton pump inhibitor or the H 2  receptor antagonist is administered together with (+) norcisapride parenterally, transdermally, rectally or sublingually.  
     
     
         21 . The method of  claim 3 , which comprises administering either the proton pump inhibitor or H 2  receptor antagonist, and the (+) norcisapride, concurrently or sequentially.  
     
     
         22 . A method of treating gastrointestinal motility dysfunction in a patient which comprises administering to said patient a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof substantially free of its (−) stereoisomer and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         23 . A method of treating emesis in a patient which comprises administering to said patient in need of such prevention, treatment, or management a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         24 . A method of treating gastro-esophageal reflux disease in a patient which comprises administering a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         25 . A method of treating gastro-esophageal reflux disease in a patient which comprises administering to said patient in need of such treatment a therapeutically effective amount of: (a) cisapride, or a pharmaceutically acceptable salt or an optically pure stereoisomer thereof; (b) ondansetron, or a pharmaceutically acceptable salt or an optically pure stereoisomer thereof; and (c) a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         26 . The method of  claim 25 , wherein optically pure (+) cisapride or optically pure (−) cisapride, or a pharmaceutically acceptable salt thereof, is administered.  
     
     
         27 . The method of  claim 25  or  26 , wherein optically pure R(+) ondansetron is administered.  
     
     
         28 . The method of  claim 25 , wherein the proton pump inhibitor administered is selected from the group consisting of omeprazole, lansoprazole, pantoprazole, rabeprazole, hydroxy-omeprazole, hydroxy-lansoprazole, the carboxylic derivative of omeprazole, and desmethyl-pantoprazole.  
     
     
         29 . The method of  claim 25 , wherein the amount of proton pump inhibitor administered is from about 1 mg to about 200 mg.  
     
     
         30 . The method of  claim 25 , wherein the H 2  receptor antagonist administered is selected from the group consisting of cimetidine, famotidine, ranitidine, nizatidine, and N2-desmethylnizatidine.  
     
     
         31 . The method of  claim 25 , wherein the amount of H 2  receptor antagonist administered is from about 1 mg to about 2400 mg.  
     
     
         32 . The method of  claim 25 , wherein at least one of optically pure (+) cisapride, optically pure (−) cisapride, optically pure R(+) ondansetron, and the proton pump inhibitor is administered orally.  
     
     
         33 . The method of  claim 25 , wherein at least one of cisapride, optically pure R(+) ondansetron, and the H 2  receptor antagonist is administered orally.  
     
     
         34 . A method of preventing or managing gastrointestinal disorders in a patient which comprises administering to said patient in need of prevention or management a therapeutically effective amount of a 5-HT 3  antagonist, a 5-HT 4  agonist, and at least one of an H 2  receptor antagonist or a proton pump inhibitor, or an optically pure stereoisomer or active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         35 . A method of preventing or managing gastrointestinal disorders in a patient which comprises administering a therapeutically effective amount of an agent or compound that acts on 5-HT 3  receptors and 5-HT 4  receptors, and a therapeutically effective amount of at least one of a proton pump or an H 2  receptor, or an optically pure stereoisomer or active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         36 . A method of preventing or managing gastrointestinal disorders in a patient which comprises administering to said patient a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer, and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         37 . A method of preventing or managing gastrointestinal motility dysfunction in a patient which comprises administering to said patient a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         38 . A method of preventing or managing emesis in a patient which comprises administering to said patient in need of such prevention, treatment, or management a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         39 . A method of preventing or managing gastro-esophageal reflux disease in a patient which comprises administering a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer and a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         40 . A method of preventing or managing gastro-esophageal reflux disease in a patient which comprises administering to said patient in need or such prevention or management a therapeutically effective amount of: (a) cisapride, or an optically pure stereoisomer or a pharmaceutically acceptable salt thereof; (b) ondansetron, or a pharmaceutically acceptable salt or an optically pure stereoisomer thereof; and (c) a therapeutically effective amount of at least one of a proton pump inhibitor, an H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         41 . The method of  claim 40 , wherein optically pure (+) cisapride or optically pure (−) cisapride, or a pharmaceutically acceptable salt thereof, is administered.  
     
     
         42 . The method of  claim 40 , wherein optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof, is administered.  
     
     
         43 . The method of  claim 40 , wherein the proton pump inhibitor administered is selected from the group consisting of omeprazole, lansoprazole, pantoprazole, rabeprazole, hydroxy-omeprazole, hydroxy-lansoprazole, the carboxylic acid derivative of omeprazole, and desmethyl-pantoprazole.  
     
     
         44 . The method of  claim 40 , wherein the amount of proton pump inhibitor administered is from about 1 mg to about 200 mg.  
     
     
         45 . The method of  claim 40 , wherein the H 2  receptor antagonist administered is selected from the group consisting of cimetidine, famotidine, ranitidine, nizatidine, and N2-desmethylnizatidine.  
     
     
         46 . The method of  claim 40 , wherein the amount of H 2  receptor antagonist administered is from about 1 mg to about 2400 mg.  
     
     
         47 . The method of  claim 40 , wherein at least one of cisapride, R(+) ondansetron, and the proton pump inhibitor is administered orally.  
     
     
         48 . The method of  claim 40 , wherein at least one of cisapride, R(+) ondansetron, and the H 2  receptor antagonist is administered orally.  
     
     
         49 . A pharmaceutical composition adapted for the treatment of a patient suffering from a gastrointestinal disorder which comprises a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (−) stereoisomer; and a therapeutically effective amount of at least one of a proton pump inhibitor, H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         50 . The pharmaceutical composition of  claim 49 , wherein the proton pump inhibitor is present and is selected from the group consisting of omeprazole, pantoprazole, rabeprazole, lansoprazole, hydroxy-omeprazole, hydroxy-lansoprazole, the carboxylic acid derivative of omeprazole, and desmethyl-pantoprazole.  
     
     
         51 . The pharmaceutical composition of  claim 49 , wherein the H 2  receptor antagonist is present and is selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine, and N2-desmethylnizatidine.  
     
     
         52 . A pharmaceutical composition adapted for the treatment of a patient suffering from a gastrointestinal disorder which comprises: (a) a therapeutically effective amount of an optically pure stereoisomer of cisapride, or a pharmaceutically acceptable salt thereof; (b) a therapeutically effective amount of optically pure R(+) ondansetron, or a pharmaceutically acceptable salt thereof; and (c) a therapeutically effective amount of at least one of a proton pump inhibitor, H 2  receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or a pharmaceutically acceptable salt thereof.  
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein the proton pump inhibitor is present and is selected from the group consisting of omeprazole, pantoprazole, rabeprazole, lansoprazole, hydroxy-omeprazole, hydroxy-lansoprazole, the carboxylic acid derivative of omeprazole, and desmethyl-pantoprazole.  
     
     
         54 . The pharmaceutical composition of  claim 52 , wherein the H 2  receptor antagonist is present and is selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine, and N2-desmethylnizatidine.  
     
     
         55 . The method of  claim 12  wherein the proton pump inhibitor is optically pure (+) pantoprazole, optically pure (−) pantoprazole, optically pure (+) rabeprazole, optically pure (−) rabeprazole, optically pure (+) lansoprazole, optically pure (−) lansoprazole, optically pure (+) omeprazole, or optically pure (−) omeprazole.  
     
     
         56 . The pharmaceutical composition of  claim 50  or  53  wherein the proton pump inhibitor is (+) pantoprazole, optically pure (−) pantoprazole, optically pure (+) rabeprazole, optically pure (−) rabeprazole, optically pure (+) lansoprazole, optically pure (−) lansoprazole, optically pure (+) omeprazole, or optically pure (−) omeprazole.