MXPA01008806A - Methods and compositions using (-) norcisapride in combination with proton pump inhibitors or h2 - Google Patents

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-HT3 receptors, 5-HT4 receptors, and at least one of H2 receptors and proton pumps.

Description

METHODS AND COMPOSITIONS USING (-) NORCISAPRIDE IN COMBINATION WITH PROTON PUMP INHIBITORS OR RECEPTOR ANTAGONISTS FOR H2 1. FIELD OF THE INVENTION The invention relates to methods and compositions for the prevention, treatment or management of gastrointestinal disorders or symptoms thereof, by the administration of one or more agent (s) 10 compound (s) that at the same time or sequentially act on a receptor for 5-HT3, a receptor for 5-HT4 and a receptor for H2 or a proton pump. 2. BACKGROUND OF THE INVENTION 15 Gastrointestinal disorders are common conditions that affect the gastrointestinal tract, that is, the stomach and intestines. There are some gastrointestinal disorders that include: gastro-esophageal reflux disease, emesis, motility dysfunction gastrointestinal, gastrointestinal ulcers, pathological conditions of hypersecretion and gastric hyperacidity. These diseases can be treated by different non-invasive means such as the administration to a patient of a therapeutic agent such as ZANTAC® (ranitidine), TRITEC® (ranitidine), AXID® (nizatidine), TAGAMET® (cimetidine), PREVACID® (lansoprazole), PEPCID®, PEPCID AC® ACID CONTROLLER®, MYLANTA AR ACID REDUCER ™ (famotidine), PRISOLEC® (omeprazole), and others.

New compounds and pharmaceutical preparations are continuously developed. U.S. Patent Nos. 4,962,115, 5,075,525 and 5,137,896 (collectively "Van Daele") describe N- (3-hydroxy-4-piperidenyl) benzamides [sic]. It is said that these compounds stimulate the motility of the gastrointestinal system. Van Daele states that the diastereomeric cis and trans racemates of these compounds can be obtained separately by traditional methods, and the diastereomeric cis and trans racemates can also be resolved in their optical isomers. Such a racemate, cisapride, has the chemical name cis-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide. Schapira et al., Acta Gastroen terolog. Belg., Lili: 446-457 (1990). Cisapride is mainly used to treat gastroesophageal reflux disease ("GERD"), which is characterized as the backward flow of stomach contents into the esophagus. Cisapride is commercially available as the racemic mixture of the cis (-) and cis (+) diastereomeric enantiomers of cisapride known as PROPULSID®. The benzamide derivatives have some prominent pharmacological actions due to their effects on the neuronal systems modulated by the neurotransmitter serotonin. It has been reported that a major serotonin production and storage site is the enterochromaffin cell of the gastrointestinal mucosa. It was also reported that serotonin provides powerful intestinal transit and decreased absorption time, as with diarrhea. This stimulating action is also associated with nausea and vomiting. Because of its modulation of serotonin from the neuronal system in the gastrointestinal tract, some benzamide derivatives are effective antiemetic agents and are used to control vomiting during cancer chemotherapy or radiation therapy. Costall et al., Neuropharmacology, 26: 1321-1326 (1987). This action is the result of an ability to block serotonin at specific sites, in particular the receptors for 5-hydroxytryptamine type 3 (5-HT3). Clarke et al., Trends in Pharmacologi cal Sciences, 10: 385-386 (1989). Chemotherapy and radiation therapy can induce nausea and vomiting due to damage to enterochromaffin cells in the gastrointestinal tract. As a result, the neurotransmitter serotonin is released and stimulates the afferent fibers of the vagus nerve (thus initiating the vomiting reflex) and the serotonin receptors in the activation zone of the chemoreceptors in the region of the postrema area of the brain. The anatomical site for this action of the benzamide derivatives remains unresolved, and if its action is central (SNC), peripheral or a combination of these. Barnes et al., J. Pharm. Pharmacol. , 40: 586-588 (1988). A second prominent action of certain benzamide derivatives is in increasing the activity of the gastrointestinal smooth muscle from the esophagus to the proximal small intestine, thereby accelerating esophageal and small bowel transit, as well as facilitating gastric emptying and increasing the tone of the lower esophageal sphincter. Decktor et al., Eur. J. Pharmacol. , 147: 313-316 (1988). Although benzamide derivatives are not agonists of the cholinergic receptors per se, the aforementioned effects on smooth muscle can be blocked by muscarinic receptor blocking agents such as atropine or inhibitors of neuronal transmissions such as the tetrodotoxin type which blocks the sodium channels. Fernandez and assingham, Life Sci. , 36: 1-14 (1985). Similar blocking activity has been reported for the contractile effects of serotonin in the small intestine.

Craig and Clarke, Brit J. Pharmacol. , 96: 247P (1989). It is believed that the main effects on smooth muscle of benzamide derivatives are the result of an agonist action on a class of serotonin receptors known as receptors for 5-HT4, which are located in the interneurons in the myenteric plexus of the wall intestinal. Clarke et al., Trends in Pharmacological Sciences, 10: 385-386 (1989) and Dumuis et al., N. S. Arch. Pharmacol. , 340: 403-410 (1989). The activation of these receptors subsequently improves the release of acetylcholine from the nerve terminals for sympathetics located near the surrounding smooth muscle fibers. The combination of acetylcholine with its receptors on the smooth muscle membranes is the real activator of muscle contraction. It has been reported that cisapride enters the central nervous system and binds to the receptors for 5-HT4. This indicates that cisapride can have mid-effects from the center. Cisapride is a potential ligand in receptors for 5-HT4, which are located in some areas of the central nervous system. Dumuis et al., N. S. Arch Pharmacol. , 340: 403-410 (1989). The modulation of serotonergic systems can have a variety of behavioral effects. The co-administration of racemic cisapride with other therapeutic agents causes problems of inhibition with the metabolism of cisapride by the liver. For example, ketaconazole has a pronounced effect on the kinetics of cisapride resulting from the inhibition of the metabolic elimination of cisapride and gives rise to an 8-fold increase in plasma concentrations at steady state. Physicians Desk Reference®, Medical Economics Co., Inc., p. 1308-1309, 52nd edition (1988). The interaction of racemic cisapride and other therapeutic agents can also potentiate cardiovascular side effects such as cardiotoxicity. This potentiation occurs when other drugs present in the patient's system interfere with the metabolism of cisapride, thus causing an accumulation of racemic cisapride in the body. These interactions are a major disadvantage for the use of racemic cisapride; in particular, because racemic cisapride is usually used before, with or immediately after another therapeutic agent. In addition, it has been found that the administration of racemic cisapride to a human causes adverse effects such as cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, Qt prolongation and torsades de pointes, central nervous system ("CNS") effects, increase in systolic pressure, interactions with other medications, diarrhea, abdominal cramps and cardiac depression. Racemic Cisapride in humans is metabolized primarily by N-oxidative dealkylation of piperidine nitrogen or by aromatic hydroxylation occurring on either the 4-fluorophenoxy or benzamide rings. Meuldermans et al., Drug Metab. Dispos , 16 (3): 410-419 (1988); and Meuldermans et al., Drug Metab. Dispos , 16 (3): 403-409 (1988). Norcisapride, with the chemical 4-amino-5-chloro-N- (3-methoxy-4-piperidinyl) -2-methoxybenzamide is an active metabolite of cisapride. Recently, researchers have reported that the optically pure stereoisomer (-) of the metabolite of cisapride, norcisapride, has many useful characteristics, but without certain side effects of racemic cisapride. Specifically, U.S. Patent No. 5,712,293 describes a method of treating gastroesophageal reflux disease and other conditions including: emesis, dyspepsia, constipation, gastroparesis, pituitary intestinal obstruction, and postoperative ileus using optically pure (-) norcisapride. Other agents or compounds that have been studied for the treatment of gastrointestinal diseases include proton pump inhibitors and H2 receptor antagonists. Proton pump inhibitors treat gastrointestinal diseases by inhibiting H + -K + ATPase and by this means regulate acidity in gastric juices. H2-receptor antagonists inhibit the binding of histamine with H2 receptors to regulate the secretion of gastric acid. Goodman & Gilman, The Pharmacological Basis of Therapeutics, 9th edition, pp. 901-915 (1996). Concentration gradients of gastric acids across cell membranes vary widely. Perhaps the largest gradient in the body occurs through the plasma membrane of the parietal cells of the lining of the stomach, which secretes hydrochloric acid in the gastric juice. Since the concentration of hydrochloric acid in the gastric juice can be as high as 0.1 M and the concentration of H + in the cells is approximately 10 ~ 7 M, the parietal cells can secrete H + ions against a concentration gradient of approximately 1 million. a 1. A membrane-bound enzyme called H + -K + ATPase facilitates the active transport of H + through the membranes against concentration gradients in exchange for K + to form gastric hydrochloric acid. For each molecule of cytosolic ATP hydrolysed to ADP and phosphate, two H + ions are transported through the plasma membrane from the cytosol to the stomach. Goodman & Gilman, The Pharmacological Basis of Therapeutics, 9th edition, pp. 901-915 (1996). Proton pump inhibitors suppress the secretion of gastric acid, the final step of acid production, by the specific inhibition of the enzymatic system H + -K + ATPase in the secretory surface of gastric parietal cells. Proton pump inhibitors include benzimidazole compounds, for example, omeprazole (PRILOSEC®), lanzoprazole (PREVACID®), and pantoprazole. These proton pump inhibitors contain a sulfinyl group located between the substituted benzimidazole and pyridine rings. At neutral pH, omeprazole, lansoprazole and pantoprazole are chemically stable weak bases, soluble in lipids that are devoid of inhibitory activity. These weak, uncharged bases reach the parietal cells from the blood and diffuse into the secretory canaliculi, where the drugs are protonated and thereby become trapped. The protonated species are rearranged to form a sulfenic acid and a sulfenamide, the last species capable of interacting with the sulfhydryl groups of H + -K + ATPase. Complete inhibition occurs with two inhibitor molecules per enzyme molecule. The specificity of the effects of the proton pump inhibitors, it is believed, comes from: a) the selective distribution of the H + -K + ATPase b) the requirement of acidic conditions to catalyze the generation of the reactive inhibitor; and c) entrapment of the protonated medicament and the cationic sulfenamide within the acidic canaliculi adjacent to the chosen enzyme. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th edition, pp. 901-915 (1996). Antagonists of H2 receptors competitively inhibit the interaction of histamine with H2 receptors. These are highly selective and have little or no effect on the receivers for Hi. Although H2 receptors are present in numerous tissues, including vascular and bronchial smooth muscle, antagonists for H2 receptors interfere significantly with physiological functions other than gastric acid secretion. Antagonists of H2 receptors include nizatidine (AXID®), ranitidine (ZANTAC® and TRITEC®), famotidine (PEPCID AC®), and cimetidine (TAGAMET®). Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th edition, pp. 901-915 (1996). H2 receptor antagonists inhibit the secretion of gastric acid elucidated by histamine, other H2 agonists, gastrin, and, to a lesser extent, muscarinic agonists. Antagonists of the H2 receptors also inhibit base and nocturnal acid secretion, and this effect contributes in an important way to their clinical efficacy. Although therapeutic agents are available, a more effective, broad spectrum treatment or treatment for gastrointestinal disorders is still necessary. For example, it is desirable to have safe and effective methods and compositions for the prevention, treatment and management of gastrointestinal disorders without adverse effects or drug-drug interactions.

COMPENDIUM OF THE INVENTION The invention comprises the prevention, treatment or management of gastrointestinal disorders by biological action at three different sites: the action on the receptors for 5-HT3, the receptors for 5-HT4 and the receptors for H2 or the pumps of protons It is considered that the use of the triple action provides an unexpectedly supertherapeutic profile. The use of this triple action treatment may be less toxic and / or more potent for the prevention, treatment and management of gastrointestinal disorders compared to the use of agents that act only on any of the three sites. In one embodiment, three therapeutic agents or compounds are used, one providing action at the 5-HT3 receptors, another providing action at the 5-HT4 receptors and the third being a proton pump inhibitor or a receptor antagonist for H2. For example, in a preferred embodiment, cisapride, ondansetron and any proton pump inhibitor or a H2 receptor antagonist is used to prevent, treat or manage gastrointestinal disorders. In a more preferred embodiment, optically pure (+) cisapride or optically pure (-) cisapride, or a pharmaceutically acceptable salt thereof, optically pure R (+) ondansentron or a pharmaceutically acceptable salt thereof, is used, and a proton pump inhibitor or a H2 receptor antagonist. In another embodiment, the invention comprises the synergistic use of two or more agents or compounds to provide triple site action on the 5-HT3 receptors, the 5-HT4 receptors and the H2 receptors or the proton pumps. In a preferred embodiment, two agents or compounds are used, one providing double action at the receptors for 5-HT3 and the receptors for 5-HT4, and the other providing action at the receptors for H2 or proton pumps. For example, in this preferred embodiment (-) optically pure norcisapride, or one of its pharmaceutically acceptable salts, which have 5-HT3 and 5-HT4 activity, and a proton pump inhibitor or H2 receptor antagonist. They are used to prevent, treat or manage gastrointestinal disorders. This invention also comprises the use of two separate pharmaceutical compositions adapted for the prevention, treatment or management of a patient suffering from gastrointestinal disorders or their symptoms, one of which comprises a therapeutically effective amount of optically pure (-) norcisapride or a salt acceptable for pharmaceutical use thereof, and another with an effective amount for therapeutic use of a proton pump inhibitor or H2 receptor antagonist. Otherwise, the invention also comprises pharmaceutical compositions comprising (-) optically pure norcisapride or a pharmaceutically acceptable salt thereof, in combination with a proton pump inhibitor or an H2 receptor antagonist. The individual unit dosage forms comprise from about 0.5 mg to about 500 mg of optically pure (-) norcisapride, or one of its pharmaceutically acceptable salts, and from about 1 mg to about 200 mg of a proton pump inhibitor or from about 1 mg to about 2400 mg of an H2 receptor antagonist, in a suitable vehicle. The pharmaceutical compositions and methods of the invention, particularly those comprising an effective amount for therapeutic use of optically pure (-) norcisapride or one of its pharmaceutically acceptable salts, can be used to prevent or alleviate symptoms of gastrointestinal disorders by reducing or avoiding at the same time adverse effects associated with the administration of traditional treatments such as 5-HT3 receptor antagonists, 5-HT receptor agonists or antagonists, H2 receptor antagonists and traditional proton pump inhibitors. In addition, the compositions and methods of the present invention comprise the treatment, prevention or management of gastrointestinal disorders by reducing or avoiding at the same time drug-drug adverse interactions that are known to occur with the use of existing commercial agents, such as cisapride. racemic 4. DETAILED DESCRIPTION OF THE INVENTION The invention comprises the prevention, treatment or management of gastrointestinal disorders by the biological action at three different sites, action on the receptors for 5-HT3, the receptors for 5-HT4 and the receptors for H2 or the pumps of protons (for example, the inhibition of the enzymatic system H + -K + ATPase). It is considered that the use of the triple action in the site provides a therapeutic profile unexpectedly superior to the traditional treatment of gastrointestinal disorders. The use of this triple action treatment may be safer and / or more effective for the prevention, treatment and management of gastrointestinal disorders than the use of agents that act only in one of the three sites. More specifically, the invention also comprises the use of at least three agents or compounds for preventing, treating or managing gastrointestinal disorders, or the symptoms thereof, one providing action at the 5-HT3 receptors, another providing action at the receptors for 5-HT3. -HT4 and a third providing action in the systems of proton pumps or H2 receivers. Preferably, the three compounds are cisapride, ondasetron and a proton pump inhibitor or a H2 receptor antagonist. More preferably, the three compounds are (+) optically pure cisapride or optically pure (-) cisapride, or one of its pharmaceutically acceptable salts, optically pure R (+) ondansetron or one of its pharmaceutically acceptable salts, and a proton pump inhibitor or a receptor antagonist for H2. The invention also comprises the use of synergist of at least two agents or compounds to provide triple action on the receptors for 5-HT3, the receptors for 5-HT and the receptors for H2 or the mechanism of the proton pump, in the prevention , treatment or management of gastrointestinal disorders. Preferably, two agents or compounds are used, one providing double action at the receptors for 5-HT3 and the receptors for 5-HT4, and the other providing action at the receptors for H2 or the proton pump systems. More preferably, the two agents or compounds are optically pure (-) norcisapride or one of its pharmaceutically acceptable salts, and a receptor antagonist for H2 or a proton pump inhibitor. Gastrointestinal disorders that can be treated by the compositions and methods of the invention include, but are not limited to, upper and lower gastrointestinal system disorders, gastroesophageal reflux disease ("GERD"), emesis, gastrointestinal motility dysfunction, ulcers. gastrointestinal, pathological states of hypersecretion and gastric hyperacidity. Gastrointestinal disorders also include, but are not limited to, dyspepsia, gastroparesis, constipation, postoperative ileus, pseudo intestinal obstruction, gastric ulcers, duodenal ulcers, heartburn, acid indigestion, erosive esophagitis, stomach acid, upset stomach, and Zollinger syndrome. -Ellisson. In a more preferred embodiment, the invention comprises the use of optically pure (-) norcisapride, or one of its pharmaceutically acceptable salts, and at least one proton pump inhibitor or an H2 receptor antagonist, in the prevention, treatment or management of gastrointestinal disorders, or symptoms of these. It should be noted that racemic norcisapride, or one of its pharmaceutically acceptable salts, can be used as an alternative to optically pure (-) norcisapride in the methods and compositions of the invention, although optically pure (-) norcisapride is preferred. Similarly, optically pure stereoisomers or active metabolites of proton pump inhibitors or H2 antagonists can also be used as alternatives where appropriate, as well as acceptable salts for pharmaceutical use thereof. Specific examples only as an illustration are set forth below. Without adhering to the theory, it is considered that the use of an agent or compound having double activity as a receptor antagonist for 5-HT3 and an antagonist for 5-HT4 receptors together with a proton pump inhibitor or a receptor antagonist for H2 provides triple action at the site, which surprisingly gives rise to definitions related to the clearest dose in terms of efficacy, decrease in adverse effects, superior treatment due to synergistic activity and, consequently, a better therapeutic index. For example, (-) optically pure norcisapride has dual activity as a receptor antagonist for 5-HT3 and 5-HT receptor agonist, and triple action is achieved on site when used with a proton pump inhibitor or a receptor antagonist for H2. Therefore, it is more desirable to use the compositions and methods of the invention than to use a 5-HT3 receptor antagonist, a 5-HT receptor agonist, an agent or compound having dual activity as a receptor antagonist. for 5-HT3 and a 5-HT4 receptor agonist, a proton pump inhibitor or a H2 receptor antagonist alone. The use of optically pure (-) norcisapride or one of its pharmaceutically acceptable salts with a proton pump inhibitor or a H2 receptor antagonist, in the prevention, treatment or management of gastrointestinal disorders, in accordance with the present invention is considered to reduce or avoid the adverse effects associated with existing treatment for gastrointestinal disorders such as racemic cisapride. In addition, it is considered that this modality reduces or avoids adverse drug-drug interactions associated with racemic cisapride. The invention also comprises the methods of prevention, treatment or management of a condition caused by a dysfunction of the receptors for 5-HT3, the receptors for 5-HT4 or the proton pumps or H2 receptors by administering an effective amount for Therapeutic use of optically pure (-) norcisapride or one of its pharmaceutically acceptable salts, with an effective amount for therapeutic use of a proton pump inhibitor or a H2 receptor antagonist. The invention comprises the methods of prevention, treatment or management of GERD, emesis, gastrointestinal motility dysfunction, gastrointestinal ulcers, pathological conditions of hypersecretion or gastric hyperacidity, which consists of administering to a patient an effective amount for therapeutic use of (-) optically pure norcisapride, or one of its acceptable pharmaceutically acceptable salts, with a proton pump inhibitor or a H2 receptor antagonist. In specific embodiments, the invention also comprises the use of these agents in combination for the prevention, treatment or management of erosive esophagitis, dyspepsia, gastroparesis, constipation, postoperative ileus, intestinal pseudo-obstruction, gastric ulcers, duodenal ulcers, heartburn, indigestion acid, erosive esophagitis [sic], heartburn, upset stomach and Zollinger-Ellison syndrome. The invention, which comprises the use of triple action treatment, may optionally further include the use of one or more additional therapeutic agents known to treat gastrointestinal disorders. Examples of additional therapeutic agents include, but are not limited to, hydroxyzine (ANTARAX®); diphenhydramine (BENADRYL PARENTAREL®); perchloroperazine (COMPAZINE®); dronabinol (MARINOL®); promethazine (PHENERGAN®); eclizine (ANTIVERT®); trimethobenzamide (TIGAN®); tietilperazine (TORECAN®); perphenazine (TRILAFON®); sucralfate (CARAFATE®); and the like, and as applicable, the optically pure stereoisomers or the active metabolites thereof. The administration of two or more therapeutic agents used according to the methods of the invention may be concurrent, sequential or both, ie, (-) optically pure norcisapride, or one of its pharmacologically acceptable salts, and an inhibitor of the Proton pump or a H2 receptor antagonist, and optionally an additional therapeutic agent, can be administered as a combination, concurrently but separately or by sequential administration. It is considered that the methods and compositions of this invention provide the benefit of reducing or avoiding the adverse effects associated with the above methods and compositions used in the treatment of gastrointestinal disorders. See, for example, Physícian's Desk Reference®, Medical Economics Co., Inc., 52nd edition (1998 and 1999). The terms "adverse effects" and "adverse side effects", when used herein, include, but are not limited to, cardiac arrhythmia, cardiac conduction disorders, appetite stimulation, weight gain, sedation, gastrointestinal distress, headache, dry mouth, constipation, diarrhea and medication-medication interactions. The term "cardiac arrhythmia" includes, but is not limited to, ventricular tachyarrhythmia, torsades de pointes, Qt prolongation, and ventricular fibrillation. The term "gastrointestinal disorder," when used herein, includes but is not limited to, gastrointestinal motility dysfunction, GERD, emesis, gastrointestinal ulcers, hypersecretory disease states, gastric hyperacidity, erosive esophagitis, dyspepsia, gastroparesis, constipation , postoperative ileus, intestinal pseudo-obstruction, gastric ulcers, duodenal ulcers, heartburn, acid indigestion, erosive esophagitis, stomach acid, upset stomach and Zollinger-Ellison syndrome. The term "patient" when used herein refers to a mammal, in particular a human. The term "racemic", when used herein, is defined as a mixture of the enantiomers (-) and (+) of a compound, wherein the (-) and (+) enantiomers are present in a ratio of about 1: 1. The phrase "optically pure" when used herein means that the composition contains more than about 90% by weight of the desired stereoisomer, preferably more than about 95% by weight of the desired stereoisomer, and, more preferably, more than about 99. % by weight of the desired stereoisomer, based on the total weight of the active ingredient, for example, norcisapride when used to qualify (-) norcisapride. The term "practically free", when used herein, means less than about 10% by weight, preferably less than about 5% by weight and more preferably less than about 1% by weight of the unwanted stereoisomer, for example , (+) norcisapride, is present according to the invention. The phrase "5-HT3 receptor antagonist," when used herein means a compound capable of reversibly binding to a receptor for 5-hydroxytryptamine type 3. Receptor antagonists for 5-HT3 include, but are not limited to, granisetron (KYTRIL®), metoclopramide (REGLAN®), ondansetron (ZOFRAN®), renzapride, zacopride, tropisetron and, where appropriate, optically pure stereoisomers or their active metabolites.

The phrase "receptor agonist for 5-HT4," when used herein means a compound capable of reversibly binding to a receptor for 5-hydroxytryptamine type 4. Receptor agonists for 5-HT4 include, but are not limited to, norcisapride and cisapride, and where appropriate, optically pure stereoisomers or active metabolites thereof. The phrase "proton pump" when used herein refers to H + -K + ATPase, an enzyme bound to the membrane that facilitates the active transport of H + through the membranes against a concentration gradient. The phrase "proton pump inhibitor", when used herein, refers to any agent or compound that inhibits or suppresses the secretion of gastric acid by inhibiting the enzymatic system H + -K + ATPase on the secretory surface of the cells gastric apriétales. Proton pump inhibitors include, but are not limited to, prazol derivatives such as omeprazole, lanzoprazole, pantoprazole, rabeprazole, and, as applicable, optically pure stereoisomers such as (+) optically pure lanzoprazole, (-) optically pure lanzoprazole , (+) optically pure omeprazole, (-) optically pure omeprazole, (+) optically pure rabeprazole, (-) optically pure rabeprazole, (+) optically pure pantoprazole and (-) optically pure pantropazole, or the active metabolites thereof. The active metabolites of proton pump inhibitors suitable for use in accordance with the invention include, but are not limited to, hydroxy-omeprazole, hydroxy-lazoprazole, the carboxylic acid derivative of omeprazole and desmethyl-pantropazole, and as applicable , the optically pure stereoisomers of these. Omeprazole, lanzoprazole, pantoprazole and rabeprazole, for example, can be prepared by the syntheses known to those skilled in the art, particularly from U.S. Patent Nos. 4,544,750, 4,620,008, 4,620,008 [sic], 4,758,579, 5,045,552, 5,374,730, 5,386,032, 5,470,983 and 5,502,195, the descriptions of which are incorporated herein by express reference thereto. The phrase "H2 receptor antagonist" when used herein refers to any agent or compound that competitively inhibits the interaction of histamine with H2 receptors. H2-receptor antagonists include, but are not limited to, cimetidine, famotidine, ranitidine, nizatidine and, where appropriate, optically pure stereoisomers or their active metabolites. The active metabolites of the H2 receptor antagonists include, but are not limited to, N2-monodesmethylnizatidine and, where appropriate, the optically pure stereoisomers thereof. Nizatidine can be prepared by synthesis known to those skilled in the art, particularly from U.S. Patent Nos. 5,541,335 and 5,700,945, the descriptions of which are each incorporated herein by express reference thereto. Ranitidine can be prepared by the synthesis known to those skilled in the art, particularly from U.S. Patent No. 5,118,813, the disclosure of which is hereby incorporated by express reference thereto. Cimetidine can be prepared by the synthesis known to those skilled in the art, particularly from U.S. Patent Nos. 4,413,129, 4,855,439, 4,886,910, 4,886,912 and 5,118,813, the descriptions of which are each incorporated herein by reference. In addition, famotidine can be prepared by the synthesis known to those skilled in the art, described in, for example, Guimaraens et al., Contact Derma ti tis, 31 (4): 259 (1994). The diseases that can be prevented, treated or handled in the invention are used in the present in a consistent manner according to Stedman's Medical Dictionary, 26th edition Williams and Wilkins (1995). The terms "gastroesophageal reflux disease" or "GERD" when used herein is defined as a state characterized by backward flow of stomach contents into the esophagus. The term, "gastrointestinal ulcer" when used herein is defined as a condition characterized by a lesion or lesions on the surface of the lining of the gastrointestinal tract, caused by superficial loss of tissue, usually accompanied by inflammation. Gastrointestinal ulcers include, but are not limited to, duodenal ulcers and gastric ulcers. The phrase "erosive esophagitis" when used herein is defined as a condition characterized by inflammation of the lower esophagus by refurgitation of acid gastric contents, usually due to malfunction of the lower esophageal sphincter. The term "dyspepsia" when used herein, is defined as a condition characterized by a deterioration in the strength or function of digestion that may arise as a symptom of primary gastrointestinal dysfunction or as a complication due to other disorders, such as appendicitis, gallbladder disorders or malnutrition.

The term "gastroparesis" when used herein is defined as a stomach paralysis caused by motor abnormality in the stomach or as a complication of diseases such as diabetes, progressive systemic sclerosis, anorexia nervosa, or myotonic dystrophy. The term "constipation" when used in the present is defined as a state characterized by infrequent or difficult stool evacuation resulting from conditions such as lack of intestinal muscle tone or intestinal spasticity. The phrase "postoperative ileus", when used herein is defined as an obstruction in the intestine due to disruption in muscle tone after surgery. The terms "prevent" and "prevention" when used herein are respectively defined as interrupting or preventing and the act of interrupting or preventing states or disorders in a patient who is at risk of suffering from such conditions or conditions including, but They are not limited to, patients suffering from stress. The phrase "pseudo intestinal obstruction" when used herein is defined as a condition characterized by constipation, colic pain and vomiting, but without evidence of physical obstruction.

The phrase "gastric hyperacidity", when used herein is defined as a state characterized by an abnormally high degree of acidity in gastric juices. The phrase "effective amount for therapeutic use", when used herein is defined as the amount of a therapeutic agent that alone or in combination with other drugs provides a therapeutic benefit in the prevention, treatment or management of gastrointestinal disorders, but does not it is limited to, gastrointestinal motility dysfunction, GERD, emesis, gastrointestinal ulcers, pathological hypersecretion states, gastric hyperacidity or symptoms of these. It is possible to apply each disorder to different effective therapeutic amounts, as is well known to those skilled in the art. The optically pure (-) norcisapride can be obtained from a racemic mixture of cisapride, the chemical synthesis of which can be carried out according to the method described in the application of European Patent No. 0,076,530 A2 published on April 13, 1983, or U.S. Patents 4,962,115, 5,057,525 or 5,137,896, the descriptions of which are each incorporated herein by express reference thereto. See also, Van Daele, et al., Drug Development Res., 8: 225-232 (1986). The metabolism of cisapride to norcisapride is described in Meuldermans, W., et al., Drug Metab. Dispos., 16 (3): 410-419 (1988); and Meuldermans et al., Drug Metab. Dispos., 16 (3): 403-409 (1988). The preparation of racemic norcisapride is also known to those skilled in the art, particularly in view of EP 0,076,530 A2 and U.S. Patent No. 5,137,896 to Van Daele, the disclosures of which are incorporated herein by express reference thereto. The optically pure stereoisomers of the chiral compounds described herein can also be obtained from the racemic mixture by resolution of the enantiomers using traditional means, for example, from an optically active acid that can be resolved. The resolution of racemic compounds is also known to those skilled in the art, in particular from Jacques, J., et al., Enantiomers, Racema tes and Resolutions, Wiley-Interscience, New York (1981); Wilen, S. H. et al., Tetrahedron, 33: 2725 (1977); Eliel, E. L. Stereochemistry of Coal Compounds, McGraw-Hill, NY, (1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions, E. L. Elile, Ed., Univ. Of Notre Dame Press, Notre Dame, IN, p. 268 (1972). In addition to separation techniques, such as those described above, optically pure compounds can be synthesized by stereospecific synthesis using methods well known to those skilled in the art. The chiral synthesis can give rise to products of high enantiomeric purity. However, in some cases, the enantiomeric purity of the product is not high enough. The skilled person will appreciate that the separation methods described in the above can be used to further improve the enantiomeric purity of the active stereoisomers that are obtained by chiral synthesis. For example, optically pure (-) norcisapride can also be prepared from the mixture of racemic norcisapride by enzymatic biocatalytic resolution. This synthesis is known to those skilled in the art, particularly from U.S. Patent Nos. 5,057,427 and 5,077,217, the descriptions of which are incorporated herein by express reference thereto. The magnitude of a prophylactic or therapeutic dose of the active ingredients described herein, for example, (-) norcisapride, a 5-HT3 antagonist, a 5-HT4 agonist or antagonist, a proton pump inhibitor or a H2 receptor antagonist, in the acute or chronic management of the disorders and diseases described herein, will vary with the nature and severity of the condition to be prevented, treated or managed and the route of administration. For example, it is possible to employ oral, mucosal (including rectal), parenteral (including subcutaneous, intramuscular, bolus and intravenous), sublingual, transdermal, nasal, buccal and the like. Dosage forms include tablets, dragees, troches, lozenges, dispersions, suspensions, suppositories, solutions, capsules, soft elastic gelatin capsules, patches and the like. The dose, and perhaps the frequency of the dose, will also vary according to the age, body weight and response of the individual patient. Convenient dosage schemes can be easily selected by those skilled in the art taking these factors into account. In general, the total daily dose of 5-HT3 receptor antagonists, a 5-HT4 receptor agonist or a therapeutic agent that provides double action at 5-HT3 receptors and 5-HT4 receptors for The conditions described herein are from about 0.5 mg to about 500 mg, preferably from about 1 mg to about 350 mg, and most preferably from about 2 mg to about 250. The ranges of convenient daily doses can be easily determined by those skilled in the art. In general, the total daily dose of a proton pump inhibitor for the presently described conditions, such as lansoprazole, pantoprazole, rabeprezole, omeprazole, or the optically pure stereoisomers or active metabolites thereof, is from about 1 mg to about 200 mg, preferably from about 5 mg to about 150 mg, and more preferably from about 10 mg to about 100 mg. In addition, those skilled in the art can easily determine the ranges of convenient daily doses of the H2 receptor antagonists. For example, see Physi cians Desk Reference® Medical Economics Co., Inc., 52nd edition (1999) for the convenient doses currently used for known H2 receptor antagonists. For example, ranitidine can be administered using an oral daily dose range of from about 1 mg to about 800 mg, preferably from about 100 mg to about 600 mg, and most preferably from about 250 mg to about 500 mg. For cimetidine, the range of the oral daily dose may be from about 1 mg to about 2400 mg, preferably from about 400 mg to about 1600 mg, more preferably from about 600 mg to about 1000 mg. For famotidine, the range of the oral daily dose may be from about 1 mg to about 200 mg, preferably from about 10 mg to about 80 mg, more preferably from about 15 mg to about 500 mg. For nizatidine, the range of the oral daily dose may be from about 1 mg to about 600 mg, preferably from about 50 mg to about 500 mg, more preferably from about 250 mg to about 350 mg. In the management of the patient, the treatment can be initiated at a lower dose, for example, from about 0.5 mg to about 10 mg of (-) norcisapride and from about 1 mg to about 5 mg of a proton pump inhibitor, or from about 1 mg to about 5 mg of a H2 receptor antagonist, and increasing to the recommended daily dose or higher depending on the overall response of the patient. Furthermore, it is recommended that children, patients over 65 years of age and those with impaired renal or hepatic function, receive low doses initially, and that these be titrated based on the individual response (s) and blood concentrations. It may be necessary to use dosages of each active ingredient outside the ranges herein described in some cases, as will be apparent to those skilled in the art. In addition, it should be indicated that the treating physician or clinician will know how and when to interrupt, adjust or terminate the treatment in relation to the patient's individual response. The pharmaceutical compositions for use in the present invention may comprise a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, or a therapeutic agent that provides double action at 5-HT3 receptors and 5-HT3 receptors. -HT4 with a proton pump inhibitor or a H2 receptor antagonist as the active ingredients, and in addition may contain an acceptable carrier for pharmaceutical use and, optionally, other therapeutic ingredients. In one embodiment, the pharmaceutical compositions comprise three therapeutic agents, a 5-HT3 receptor antagonist and a 5-HT4 receptor agonist with a proton pump inhibitor or an H2 receptor antagonist, and it may also contain an acceptable carrier for pharmaceutical use and, optically pure, other therapeutic ingredients. In a preferred embodiment, the pharmaceutical compositions comprise two therapeutic agents, one providing double action in the para receptors. 5-HT3 and the receptors for 5-HT4, and the other is a proton pump inhibitor or a H2 receptor antagonist. When used herein the term "pharmaceutically acceptable salt" refers to a salt prepared from non-toxic acids acceptable for pharmaceutical use including, but not limited to, inorganic acids, organic acids, solvates, hydrates. or clathrates of these. Examples of these inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric acids. Suitable organic acids can be selected, for example, from the classes of organic acids aliphatic, aromatic, carboxylic and sulphonic, examples of which are formic, acetic, propionic, succinic, benzoic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furobic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamico), mentansulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulphanilic , alginic, galacturonic and the like. Particularly preferred acids are hydrochloric, phosphoric and sulfuric hydrochloric acids. In one embodiment, a 5-HT3 receptor antagonist, a 5-HT4 receptor agonist or a therapeutic agent providing double action as a 5-HT3 receptor antagonist and a 5-HT receptor agonist they are administered as free base or hydrate. For example, (-) optically pure norcisapride is administered as a free base or hydrate. The invention also contemplates the use of active agents or compounds which are acidic, in which it is possible to prepare the salts from non-toxic bases acceptable for pharmaceutical use including organic, inorganic bases, solvates, hydrates or clathrates thereof. Such inorganic bases include, but are not limited to, metal salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Suitable organic bases include, but are not limited to, N, N-dibenzylethylenedia ina, chloroprocaine, choline, diethanolamine, ethylenediamine meglumain (N-methylglucamine), lysine and procaine.

In practical use, the active agents in the pharmaceutical compositions of the invention can be combined as the active ingredients in intimate admixture with an acceptable carrier for pharmaceutical use according to the traditional pharmaceutical composition techniques. The carrier can take a wide variety of forms and comprises a number of components depending on the form of preparation desired for administration. The compositions of the present invention include, but are not limited to, suspensions, solutions and elixirs; aerosol sprays; or excipients including, but not limited to starches, sugars, microcrystalline cellulose, diluents, granulating agents, binding lubricants, disintegrating agents and the like. Preferably, the pharmaceutical composition is in the form of an oral preparation. Because of their ease of administration, tablets and capsules are preferred and represent the most advantageous oral dosage unit form, in which case solid pharmaceutical excipients are employed. If desired, the tablets may be coated by normal aqueous or non-aqueous techniques. Preferably, the oral pharmaceutical compositions of the present invention can be administered in single or divided doses, from 1 to 4 times a day. Oral dosage forms may conveniently be presented in unit dosage forms and prepared by methods well known in the art of pharmacy. The pharmaceutical compositions of the present invention, suitable for oral administration, may be present as small pharmaceutical unit dosage forms, such as capsules, dragees, soft elastic gelatin capsules, tablets, or aerosol sprays, each containing a predetermined amount of the active ingredients, such as powder or granules, or as a solution or suspension in aqueous liquid, non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions can be prepared by any of the methods well known in the art of pharmacy, but all methods include the step of associating one or more active ingredients (s) with the carrier. In general, the compositions are prepared by uniformly and intimately mixing the active ingredients with the liquid carriers or the finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired presentation. Oral solid preparations are preferred over oral liquid preparations. A preferred oral solid preparation are capsules, but the most preferred oral solid preparation is tablets. For example, it is possible to prepare a tablet by compression or molding, optionally, with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, granulating agent, surface activating or dispersing agent, or Similary. The molded tablets can be prepared by molding, in a convenient machine, a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet, dragee, capsule contains from about 0.5 mg to 500 mg of optically pure (-) norcisapride, more preferably from about 1 mg to about 350 mg, in combination with from about 1 mg to about 200 mg of a proton pump inhibitor or from about 1 mg to about 2400 mg of a H2 receptor antagonist. The pharmaceutical compositions of the present invention, suitable for oral administration, can be formulated as a pharmaceutical composition in a soft elastic gelatin capsule unit dosage form using traditional methods well known in the art., see, for example, Ebert, Pharm. Tech. 1 (5): 44-50 (1997). Soft elastic gelatin capsules have a soft, globular gelatin shell somewhat thicker than that of hard gelatin capsules, where a gelatin is plasticized by the addition of a plasticizing agent, for example, glycerin, sorbitol or a similar polyol . The hardness of the capsule shell can be changed by varying the type of gelatin used and the amounts of plasticizer and water. The soft gelatin covers may contain a preservative, such as methyl- and propylparabens and sorbic acid, to prevent the growth of fungi. The active ingredient can be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates or a combination thereof. In addition to the common dosage forms set forth above, the compounds of the present invention may also be administered by controlled release delivery means or devices that are well known to those skilled in the art, such as those described in US Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556 and 5,733,566, the descriptions of which are each incorporated herein by express reference thereto. These pharmaceutical compositions can be used to provide slow or controlled release of one or more of the active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres or the like. , or a combination of these to provide the desired release profile in different proportions. Suitable controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention. Thus, individual unit dosage forms suitable for oral administration, such as tablets, capsules, soft gelatin capsules, dragees and the like, which are adapted for controlled release are encompassed by the present invention.

All controlled release pharmaceutical products have a common goal of improving pharmacotherapy over that obtained by their non-controlled counterparts. In theory, the use of a controlled release preparation with optimized design in medical treatment is characterized by a minimum of the medicinal substance used to cure or control the condition in a minimum amount of time. The advantages of controlled release formulations may include: 1) prolonged activity of the medicament; 2) reduced frequency of the dosage; and 3) greater patient compliance. Most controlled release formulations are designed to initially release an amount of the drug that immediately produces the desired therapeutic effect, and gradually and continuously release other amounts of medication to maintain this level of the therapeutic effect for a prolonged time. To maintain this constant concentration of the medication in the body, the medication must be released from the dosage form at a rate that will replace the amount of medication that is metabolized and excreted from the body. The controlled release of an active ingredient can be stimulated by different inducers, for example, pH, temperature, enzymes, water or other conditions or physiological compounds. The term "controlled release component" in the context of the present invention is defined herein as a compound or compounds that includes, but is not limited to, polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres or the like, or a combination thereof, which facilitates the controlled release of the active ingredient. The pharmaceutical compositions of the present invention can also be formulated for parenteral administration by injection (subcutaneous, bolus, intramuscular or intravenous injection) and can be dispensed in a unit dosage form, such as a multi-dose container or ampoule. . Such compositions for parenteral administration may be in the form of suspensions, solutions, emulsions or the like in aqueous or oily vehicles and, in addition to the active ingredients may contain one or more form agents such as dispersing agents, suspending agents, stabilizing agents, preservatives and the like. Another route of administration is transdermal delivery, for example, by means of an abdominal skin patch.

The invention is further defined by reference to the following examples which describe in detail the preparation of the compound and the compositions of the present invention, as well as its utility. It will be apparent to those skilled in the art that modifications can be made to both materials and methods without departing from the purpose and interest of this invention.

. EXAMPLES . 1 EXAMPLE 1: Receptor binding to 5-HT3 Racemic norcisapride, racemic cisapride and its stereoisomers (-) and (+) (Cerep, Celle l'Evescault, France) were tested for binding to the subtypes of the receptors for 5-HT3. -HT3 from the N1E-115 cells. After incubation with the appropriate ligands, the preparations were rapidly filtered in vacuo through GF / B glass fiber filters and washed with ice-cold buffer using a Brandel or Packard cell harvester. The bound radioactivity was determined with a liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation cocktail (Formula 989). The binding of the radio ligand specific to the receptor was defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. The results were expressed as a percentage of the inhibition of the specific binding obtained in the presence of the compounds. The IC 50 was determined using concentrations in the range from 3 x 10"10 M to 10" 5 M to obtain complete competition curves and were calculated by non-linear regression analysis. The results are shown in Tables 3 and 4 below. Using the methods described above it is possible to test other active ingredients such as granisetron, metoclopramide, ondansetron, renzapride, zacopride, tropisetron and others.

Receptors for 5-HT4 Racemic norcisapride, racemic cisapride and its stereoisomers (-) and (+) (Cerep, Celle l'Evescault, France) were tested for binding to the subtypes of 5-HT4 receptors from striatum bodies. of guinea pig. After incubation with the appropriate ligands, the preparations were rapidly filtered in vacuo through GF / B glass fiber filters and washed with ice-cold buffer using a Brandel or Packard cell harvester. The unit radioactivity was determined with a liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation cocktail (Formula 989). The binding of the radio ligand specific to the receptor was defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of unlabeled ligand. The results were expressed as a percentage of the inhibition of the specific binding obtained in the presence of the compounds. The IC 50 was determined using concentrations in the range from 3 x 10 ~ 10 M to 10"5 M to obtain full competition curves and were calculated by non-linear regression analysis, the results are shown in Tables 3 and 4 below. Using the methods described above it is possible to test other active ingredients such as cisapride and the like.

TABLE 3 IC50 Values (nM) for binding to the 5-HT3 and 5-HT4 sites TABLE 4 IC50 Values (nM) for binding to the 5-HT3 and 5-HT4 sites The 'agonist activity in the receptor sites. for 5-HT4 can also be evaluated using an assay based on the ability of the active compounds to increase the production of cyclic AMP in neurons of mouse embryos grown in tissue culture (see Dumuis et al., NS Arch. Pharmacol., 340 : 403-410 (1989)). . 2 EXAMPLE 2: Oral formulation Tablets Formula Quantity per tablet in mg Active ingredients: A B C (-) norcisapride 5.0 10.0 25.0 Lansoprazole 5.0 15.0 30.0 Lactose BP 57.0 92.0 107.0 Starch BP 20.0 20.0 25.0 Microcrystalline cellulose 10.0 10.0 10.0 Hydrogenated vegetable oil 1.5 1.5 1.5 Polyvinylpyrrolidone 1.5 1.5 1.5 Compression weight 100.0 150.0 200.0 The active ingredients, (-) norcisapride and lansoprazole, are sieved through a convenient mesh and mixed with the lactose until a uniform mixture is formed. The suitable volumes of water are added and the powders are granulated. After drying, the granules are then sieved and mixed with the remaining excipients. The resulting granules are then compressed into tablets of desired shape. It is possible to prepare tablets in other concentrations by modifying the ratio of the active ingredient to the excipient (s) or the compression weight. . 3 EXAMPLE 3: Oral formulation Tablets Formula Quantity per tablet in mg Active ingredients: A B C (-) norcisapride 5.0 10.0 25.0 Famotidine 10.0 20.0 40.0 Lactose BP 38.5 73.5 43.5 Starch BP 30.0 30.0 60.0 Corn Starch 15.0 15.0 30.0 Pregelatinized BP Magnesium Stearate BP 1.5 1.5 1.5 Compression weight 100.0 150.0 540.0 The active ingredients (-) norcisapride and famotidine are screened through a suitable mesh and mixed with lactose, starch and pregelatinized corn starch until a uniform mixture is formed. The suitable volumes of water are added and the powders are granulated. After drying, then the granules are sieved and mixed with the remaining excipients. The resulting granules are then compressed into tablets of the desired shape. It is possible to prepare tablets of other concentrations by modifying the ratio of the active ingredient to the excipient (s) or the weight of the compression. . 4 EXAMPLE 4: Oral formulation Tablets Formula Quantity per tablet in mg Active ingredient: A B C (-) norcisapride 5.0 10.0 25.0 Lactose BP 48.5 43.5 78.5 Starch BP 30.0 30.0 30.0 Corn Starch 15.0 15.0 15.0 Pregelatinized BP Magnesium Stearate BP 1.5 1.5 1.5 Compression weight 100.0 100.0 150.0 The active ingredient, (-) norcisapride, is sieved through a convenient mesh and mixed with lactose, starch and pregelatinized corn starch until a uniform mixture is formed. The suitable volumes of water are added and the powders are granulated. After drying, then the granules are sieved and mixed with the remaining excipients. Then the resulting granules are compressed into tablets of desired shape. It is possible to prepare tablets of other concentrations by modifying the ratio of the active ingredient to the excipient (s) or the compression weight. Although the present invention has been described with respect to the specific embodiments, it will be apparent to those skilled in the art that it is possible to make various changes and modifications without departing from the spirit and scope of the invention as defined in the clauses. Such modifications are also proposed to be within the scope of the attached clauses.

Claims (56)

1. A method of treating gastrointestinal disorders in a patient, which consists of administering an effective therapeutic amount of one or more agent (s) or compound (s) acting simultaneously or sequentially on the receptors for 5-HT3, the receptors for 5-HT4 and proton pumps or H2 receptors, or an optically pure stereoisomer or metabolite thereof, or one of its acceptable pharmaceutical salts.

2. A method for treating gastrointestinal disorders in a patient which consists of administering an effective therapeutic amount of an agent or compound that antagonizes the 5-HT3 receptors and agonizes with the 5-HT4 receptors, and an effective therapeutic amount of at least one of the following: a proton pump inhibitor or a receptor antagonist for H2, or an optically pure stereoisomer or active metabolite thereof, or one of its acceptable pharmaceutical salts.

3. A method for treating gastrointestinal disorders in a patient, which consists in administering to the patient an effective therapeutic amount of (-) norcisapride, or one of its acceptable pharmaceutical salts, practically without its (+) stereoisomer, and a therapeutically effective amount of when less a proton pump inhibitor, a receptor antagonist for H2 or an optically pure stereoisomer or a metabolite thereof, or one of its acceptable pharmaceutical salts.

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 dysfunction of gastrointestinal motility is selected from the group consisting of dyspepsia, gastroparesis, constipation, postoperative ileus and pseudo intestinal obstruction.

7. The method of claim 3, wherein the gastrointestinal disorder is gastroesophageal reflux disease, emesis, gastrointestinal ulcers, pathological state of hypersecretion and gastric hyperacidity.

8. The method of claim 7, wherein the pathological state of hypersecretion is the syndrome of Zollinger-Ellison.

9. The method of claim 7, wherein the gastric hyperacidity is selected from the group consisting of heartburn, acid indigestion, stomach acidity, erosive esophagitis and upset stomach.

10. The method of claim 3, wherein the amount of (-) norcisapride being administered is from about 0.5 mg to about 500 mg.

11. The method of claim 10, wherein the amount of (-) norcisapride being 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, hydroxylansoprazole, and an optically pure stereoisomer of these.

13. The method of claim 12, wherein the amount of the proton pump inhibitor is from about 1 mg to about 200 mg.

14. The method of claim 13, wherein the amount of the proton pump inhibitor is from about 5 mg to about 150 mg.

15. The method of claim 3, wherein the H2 receptor antagonist is administered and is selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine, or an optically pure stereoisomer or an active metabolite thereof.

16. The method of claim 15, wherein the amount of the H2 receptor antagonist is from about 1 mg to about 2400 mg.

17. The method of claim 3, wherein at least one of the following is administered orally (-) norcisapride and the proton pump inhibitor.

18. The method of claim 17, wherein it is administered orally (-) norcisapride and the proton pump [sic] as a tablet or capsule.

19. The method of claim 3, wherein at least one of the following is administered orally: (-) norcisapride and the H2 receptor antagonist.

20. The method of claim 3, wherein a proton pump inhibitor or the H2 receptor antagonist is administered together with (-) norcisapride parenterally, transdermally, straightly or sublingually.

21. The method of claim 3, which consists of administering the proton pump inhibitor or the H2 receptor antagonist, and (-) norcisapride, concurrently or in sequence.

22. A method for treating gastrointestinal motility dysfunction in a patient, which consists of administering to the patient an effective therapeutic amount of (-) norcisapride, or one of its acceptable pharmaceutical salts, substantially free of its stereoisomer (+) and a therapeutic amount effective of at least one of the following: a proton pump inhibitor, an H2 receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

23. A method for treating emesis in a patient, which consists of administering to the patient in need of such prevention, treatment or management, an effective therapeutic amount of (-) norcisapride, or one of its acceptable pharmaceutical salts, substantially free of its stereoisomer ( +) and an effective therapeutic amount of at least one of the following: a proton pump inhibitor, an H2 receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof .

24. A method for treating gastroesophageal reflux disease in a patient, which is to administer an effective therapeutic amount of (-) norcisapride, or one of its acceptable pharmaceutical salts, substantially free of its stereoisomer (+) and an effective therapeutic amount of at least one of the following: a proton pump inhibitor, a receptor antagonist for H2 or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

25. A method for treating gastroesophageal reflux disease in a patient, which consists of administering to the patient in need of such treatment, an effective therapeutic amount of: (a) cisapride, or one of its acceptable pharmaceutical salts or an optically pure stereoisomer of this; (b) ondansetron, or one of its acceptable pharmaceutical salts or an optically pure stereoisomer thereof; and (c) an effective therapeutic amount of at least one of the following: a proton pump inhibitor, a receptor antagonist for H2, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt of these.

26. The method of claim 25, wherein (+) optically pure cisapride or optically pure (-) cisapride, or one of its pharmaceutically acceptable salts 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 being administered is selected from the group consisting of omeprazole, lanzoprazole, pantoprazole, rabeprazole, hydroxy-omeprazole, hydroxy-lazoprazole, the carboxyl derivative of omeprazole, and desmethyl. -pantoprazole

29. The method of claim 25, wherein the amount of the proton pump inhibitor that is administered is from about 1 mg to about 200 mg.

30. The method of claim 25, wherein the H2-receptor antagonist that is administered is selected from the group consisting of cimetidine, famotidine, ranitidine, nizatidine and N2-demethylnizatidine.

31. The method of claim 25, wherein the amount of H2 receptor antagonist that is administered is from about 1 mg to about 240 mg.

32. The method of claim 25, wherein at least one of the following is administered orally: (+) optically pure cisapride, (-) optically pure cisapride, optically pure R (+) ondansetron, and the inhibitor of the protons

33. The method of claim 25, wherein at least one of the following is administered orally: cisapride, optically pure R (+) ondansetron and the H2 receptor antagonist.

34. A method for the prevention or management of gastrointestinal disorders in a patient, which consists of administering to the patient in need of prevention or management an effective therapeutic amount of an antagonist for 5-HT3, an agonist for 5-HT4 and at least one of the following: a receptor antagonist for H2 or a proton pump inhibitor, or an optically pure stereoisomer or active metabolite thereof, or an acceptable pharmaceutical salt thereof.

35. A method for the prevention or management of gastrointestinal disorders in a patient, which consists of administering an effective therapeutic amount of an agent or compound acting on the receptors for 5-HT3 and the receptors for 5-HT4, and a therapeutic amount effective of at least one of the following: a proton pump [sic] or a receptor for H2 [sic], or an optically pure stereoisomer or active metabolite thereof, or an acceptable pharmaceutical salt thereof.

36. A method for the prevention or management of gastrointestinal disorders in a patient, which consists of administering to the patient an effective therapeutic amount of (-) norcisapride, or one of its acceptable pharmaceutical salts, substantially free of its stereoisomer (+), and a The effective therapeutic amount of at least one of the following: a proton pump inhibitor, an H2 receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

37. A method for the prevention or management of gastrointestinal motility dysfunction in a patient, which consists of administering to the patient an effective therapeutic amount of (-) norcisapride, or an acceptable pharmaceutical salt thereof, substantially free of its stereoisomer (+ ) and an effective therapeutic amount of at least one of the following: a proton pump inhibitor, an H2 receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

38. A method for the prevention or management of emesis in a patient, which consists of administering to the patient in need of such prevention, treatment or management, an effective therapeutic amount of (-) norcisapride, or an acceptable pharmaceutical salt thereof, substantially without its stereoisomer (+) and an effective therapeutic amount of at least one of the following: a proton pump inhibitor, a receptor antagonist for H2, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

39. A method for the prevention or management of gastroesophageal reflux disease in a patient, which consists of administering an effective therapeutic amount of (-) norcisapride, or an acceptable pharmaceutical salt thereof, substantially without its (+) stereoisomer and a therapeutic amount effective of at least one of the following: a proton pump inhibitor, an H2 receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

40. A method for the prevention or management of gastroesophageal reflux disease in a patient, which consists in administering to the patient in need of such prevention or management an effective therapeutic amount of: (a) cisapride, or an optically pure stereoisomer or a pharmaceutical salt acceptable from this one; (b) ondansetron, or an acceptable pharmaceutical salt or an optically pure stereoisomer thereof; and (c) an effective therapeutic amount of at least one of the following: a proton pump inhibitor, a receptor antagonist for H2, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt of these.

41. The method of claim 40, wherein (+) pure cisapride or optically pure (-) cisapride, or an acceptable pharmaceutical salt thereof is administered.

42. The method of claim 40, wherein optically pure R (+) ondansetron, or an acceptable pharmaceutical salt thereof, is administered.

43. The method of claim 40, wherein the administered proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, pantoprazole, rabeprazole, hydroxy-omeprazole, hydroxylansoprazole, the carboxylic acid derivative of omeprazole, and desmethyl pantoprazole .

44. The method of claim 40, wherein the amount of the proton pump inhibitor that is administered is from about 1 mg to about 200 mg.

45. The method of claim 40, wherein the H2 receptor antagonist that is administered is selected from the group consisting of cimetidine, famotidine, ranitidine, nizatidine and N2-demethylnizatidine.

46. The method of claim 40, wherein the amount of the H2 receptor antagonist that is 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 H2 receptor antagonist is administered orally.

49. A pharmaceutical composition adapted for the treatment of a patient suffering from gastrointestinal disorder, which comprises an effective therapeutic amount of (-) norcisapride, or one of its acceptable pharmaceutical salts, substantially free of its stereoisomer (+); and an effective therapeutic amount of at least one of the following: a proton pump inhibitor, an H2 receptor antagonist, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt thereof.

50. The 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, hydroxylansoprazole, the carboxylic acid derivative of omeprazole and desmethyl pantoprazole

51. The pharmaceutical composition of claim 49, wherein the H2 receptor antagonist is present and is selected from the group consisting of cimetidine, famotidine, ranitidine, nizatidine and N2-demethylnizatidine.

52. A pharmaceutical composition adapted for the treatment of a patient suffering from a gastrointestinal disorder, which comprises: (a) an effective therapeutic amount of an optically pure stereoisomer of cisapride, or an acceptable pharmaceutical salt thereof; (b) an effective therapeutic amount of optically pure T (+) ondansetron, or an acceptable pharmaceutical salt thereof; and (c) an effective therapeutic amount of at least one of the following: a proton pump inhibitor, a receptor antagonist for H2, or an optically pure stereoisomer or an active metabolite thereof, or an acceptable pharmaceutical salt of these.

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, hydroxylansoprazole, the carboxylic acid derivative of omeprazole and Desmethyl pantoprazole

54. The pharmaceutical composition of claim 52, wherein the H2 receptor antagonist is present and is selected from the group consisting of cimetidine, ranitidine, famotidine, nizatidine and N2-demethylnizatidine.

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 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.