MXPA00012364A - Use of optically pure (+)-norcisapride for treating apnea, bulimia and other disorders - Google Patents

Abstract

Methods for the prevention, treatment, or management of apnea, apnea disorders, bulimia nervosa, irritable bowel syndrome, urinary incontinence, bradycardia, bradyarrhythmia, syncope, other disorders, or symptoms thereof using (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer.

Description

USE OF (+) NORCISAPRIDE PRACTICALLY PURE IN THE TREATMENT OF APNEA, BULIMIA AND OTHER ANOMALIES 1. FIELD OF THE INVENTION The invention relates to the methods of prevention, treatment or management of apnea, apnea disorders, bulimia, other conditions or symptoms thereof. 2. BACKGROUND OF THE INVENTION Apnea is defined in the Sted an 's Medical Dictionary, 26th edition, Williams and Wilkins (1995), as the absence of respiration. There are different disorders associated with apnea, which are characterized by interrupted breathing, in which a person stops breathing enough to decrease the amount of oxygen and increase the amount of carbon dioxide in the blood and brain. Each type of apnea includes the absence of airflow in the nose or mouth, usually for at least 10 seconds. There are different apnea disorders, including: central apnea, which results from medullar depression and inhibits respiratory movement; swallowing apnea which is the inhibition of breathing during swallowing; obstructive or peripheral apnea that is a result of obstruction of the airways or inadequate respiratory muscle activity; sleep apnea, which is central and / or obstructive apnea during sleep; and sleep-induced apnea, which results from the failure of the respiratory center to stimulate adequate breathing during sleep. Obstructive apneas usually occur in obese men and are much less common in women. Obesity, perhaps in combination with aging body tissues and other factors, gives rise to the narrowing of the upper airways. The habit of smoking, the excessive use of alcohol and lung diseases such as emphysema, increase the risk of the development of obstructive apneas. For those who suffer from sleep apnea, smoking cessation, avoidance of excessive alcohol use and weight loss are usually the first behavioral steps to treat the condition. To inhibit or avoid apnea, people who snore or who usually suffocate during sleep should not take tranquilizers, sleep medications or other sedative medications. Sleep apnea is one of the most common forms of apnea. Rarely, a person suffering from severe sleep apnea needs a tracheotomy, a surgical procedure that creates a permanent hole in the trachea through the neck. Occasionally, other surgical procedures are performed to expand the upper airways and alleviate the problem. However, these extreme measures are rarely necessary and never desired. Apnea can also be treated by non-invasive means administering a therapeutic agent to a patient. U.S. Patent No. 5,075,290 describes the medical treatment of obstructive sleep apnea and associated symptoms, such as snoring, by administering a nucleoside uptake blocker, dipyridamole, during sleep. U.S. Patent Nos. 5,502,067 and 5,407,953 describe a method of treating sleep apnea, hyponatre and snoring in a human patient by administering a pilocarpine compound. U.S. Patent No. 5,422,374 describes a method of treating sleep apnea by administering ubidecarenone to a patient. U.S. Patent No. 5,356,934 describes a method for employing (R) -fluoxetine to treat sleep apnea. Bulimia nervosa or bulimia is a condition described in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, American Psychiatric Association, 1996, ("DSM-IV"), which is characterized in part by recurrent episodes of overeating during which the patient experiences a loss of control resulting in overfeeding and self-induced vomiting. The condition mainly affects women of higher and middle socioeconomic status, especially young women. Currently, two methods are used to treat bulimia: cognitive-behavioral and pharmacological. Traditional pharmacological treatments include antidepressants. Latest research in the fundamental cases of bulimia, however, they have suggested other pharmacological treatments. In particular, some researchers have stated that the physiopathological characteristics that give rise to the characteristic behaviors of bulimia include an increase in the basal tone of the vagal nerve and have suggested that racemic ondansetron may be useful for the treatment of bulimia. Faris, P. L. et al., Biol. Psychia try, 32: 462-466 (1992); Du mis et al., N. S. Arch. Pharmacol. , 340: 403-410 (1989). Cisapride, chemically named cis-4-amino-5-chloro-N- [l- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide, is a benzamide derivative , being the compound of origin metoclopramide. Schapira et al., Acta Gastroenterolog. Belg. , Lili: 446-457 (1990). The benzamide derivatives have some prominent pharmacological actions due to their effects on the neuronal systems modulated by the neurotransmitter serotonin. Because of its modulation of the neuronal serotonin system in the gastrointestinal tract, many benzamide derivatives are effective antiemetic agents and are commonly used to control vomiting during cancer chemotherapy or radiation therapy. Costall et al., Neuropharmacology, 26: 1321-1326 (1987). This action is almost certainly the result of an ability to block serotonin at specific sites, particularly the type 3 receptors of 5-hydroxytryptamine (5-HT3). Clarke et al., Trends, in Pharmacological Sciences, 10: 385-386 (1989). In theory, the treatment of chemotherapy and radiation can reduce nausea and vomiting by damaging enterochromaffin cells in the gastrointestinal tract. As a result, the neurotransmitter serotonin is released and stimulates the afferent vagal nerve fibers (thus initiating the vomiting reflex) and the serotonin receptors in the chemoreceptor activating zone of the area of the postrema region of the brain. The anatomical site for this action of the benzamide derivatives, and whether such action is central (CNS), peripheral or a combination of these, remains unknown. Barnes et al., J. Pharm. Pharmacol. 40: 586-588 (1988). The racemic cisapride compound is used primarily to treat gastroesophageal reflux disease ("GERD"), which is characterized as the backward flow of stomach contents into the esophagus. The cisapride compound is commercially available as the racemic mixture of the cis-diastereomeric enantiomers of cisapride known as PROPULSID®.

The co-administration of racemic cisapride with other therapeutic compounds causes problems of inhibition with the metabolism of cisapride by the liver. For example, ketoconazole has a pronounced effect on the kinetics of cisapride resulting from the inhibition of the metabolic elimination of cisapride and gives rise to an eightfold increase in plasma concentrations at steady state. Physician's Desk Reference® 52nd Edition, Medical Economics Co., Inc., 1998. The interaction of racemic cisapride and other therapeutic compounds 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 giving rise to the accumulation of racemic cisapride in the body. These interactions are important disadvantages for the use of racemic cisapride; in particular, because racemic cisapride is usually used before, with or immediately after another therapeutic compound. In addition, the administration of racemic cisapride to a human, as found, causes adverse effects such as cardiac arrhythmia, including ventricular tachycardia, ventricular fibrillation, prolongation of Qt and torsades de pointes, effects on the central nervous system ("CNS") , increase in systolic pressure, interactions with other medications, diarrhea, abdominal cramps and cardiac depression. Racemic cisapride is almost completely absorbed after oral administration in humans, but the bioavailability of cisapride is only 40-50% due to the rapid metabolism of the first step in the liver. Van Peer et al., In Progress in the Area of Gastrointestinal Motili and Disorders: The Role of Cisapride, Proceedings of a Symposium in Frankfurt, Germany, November 1986, Excerpta Medica, AG Johnson and G Lux Eds., Amsterdam, pp. . 23-29 (1988). More than 90% of a dose of racemic cisapride in humans is metabolized primarily by N-oxidative dealkylation of piperidine nitrogen or by aromatic hydroxylation occurring in any of the 4-fluorophenoxy or benzamide rings. Meuldermans et al., Drug Metab. Dispos , 16 (3): 410-419 (1989); and Mauldermans et al., Drug Metab. Dispos , 16 (3): 403-409 (1988). Norcisapride, with the chemical name 4-amino-5-chloro-N- (3-methoxy-4-piperidinyl) -2-methoxybenzamide, is a metabolite of cisapride. > Currently, researchers have reported that the optimally pure stereoisomer (+) of the norcisapride metabolite of cisapride presents many of the useful features, but without certain side effects of racemic cisapride. U.S. Patent No. 5,739,151 describes the methods for producing an antiemetic effect by the administration of (+) - norcisapride. It is desirable to provide safe and effective methods for preventing, treating or managing apnea, apnea disorders, bulimia nervosa and related disorders, or symptoms thereof, particularly a treatment that allows the patient to be subjected to other related treatments without adverse effects or interactions. medicine-medication. 3. COMPENDIUM OF THE INVENTION The present invention comprises the use of optically pure norcisapride (+), or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-) in the prevention, treatment or management of apnea, apnea disorders, bulimia, irritable bowel syndrome, asthma, urinary incontinence, syncope, bradycardia, bradyarrhythmia or symptoms of these. It should be understood that the invention comprises any combination for the prevention, treatment or management of each of the multiple conditions or ailments. This invention also relates to pharmaceutical compositions adapted for the prevention, treatment or management of a patient suffering from a condition mediated by the vagus nerve or symptoms thereof, comprising an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-). This invention also relates to pharmaceutical compositions adapted for the prevention, treatment or management of a patient suffering from apnea, apnea disorders, or symptoms thereof, which contain an effective amount for therapeutic use of (+) norcisapride, or a pharmaceutically acceptable thereof, practically without its stereoisomer (-). This invention also relates to pharmaceutical compositions adapted for the prevention, treatment or management of bulimia, irritated bowel syndrome, asthma, urinary incontinence, bradycardia, bradyarrhythmia, syncope, related disorders, and symptoms of these in a mammal, which contain a an effective amount for therapeutic use of (+) norcisapride, or a pharmaceutically acceptable thereof, practically without its (-) stereoisomer, the amount being sufficient to alleviate the symptoms of these conditions by reducing at the same time or avoiding adverse effects associated with the administration of racemic cisapride. The invention also comprises individual unit dosage forms of optically pure (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its (-) stereoisomer, which contain from about 0.05 mg to about 500 mg of the active ingredient in a compressed tablet . This dosage form is particularly suitable for the prevention, treatment or management of apnea, apnea disorders, bulimia, irritated bowel syndrome, asthma, urinary incontinence, bradycardia, bradyarrhythmia, syncope, related disorders or symptoms thereof. 4. DETAILED DESCRIPTION OF THE INVENTION The present invention comprises the use of optically pure (+) norcisapride or a pharmaceutically acceptable salt thereof, practically free from its (-) stereoisomer in the prevention, treatment or management of disorders including, but not limited to, limited to, apnea, apnea disorders, bulimia, irritated bowel syndrome, asthma, urinary incontinence, bradycardia, bradyarrhythmia, syncope, and related conditions or symptoms of these, apnea or apnea disorders include, but are not limited to , central apnea, apnea due to swallowing, obstructive or peripheral apnea, sleep apnea and sleep-induced apnea, or a combination of these. The present invention also comprises the use of optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its (-) stereoisomer in the prevention, treatment or management of apnea, apnea disorders, bulimia, bowel syndrome irritated, asthma, urinary incontinence, bradycardia, bradyarrhythmia, syncope and related disorders or symptoms thereof, preferably reducing or avoiding at the same time the adverse effects associated with the administration of racemic cisapride. In one embodiment, the present invention relates to a method of prevention, treatment or management of bulimia that consists in the administration to a patient of a therapeutically effective amount of (+) - norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-). In another embodiment, the present invention relates to a method of prevention, treatment or management of apnea or apnea disorders, which consists of administering to a patient a therapeutically effective amount of (+) - norcisapride, or a pharmaceutically acceptable salt thereof. , practically without its stereoisomer (-). In another embodiment, the present invention relates to a method for preventing, treating or managing conditions mediated by vagal activity in a patient, which consists in the administration of a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof. this, practically without its stereoisomer (-).

The present invention also comprises a method of preventing, treating or managing irritated bowel syndrome which consists of administering to a patient a therapeutically effective amount of (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its (-) stereoisomer: In another embodiment, the present invention relates to methods of prevention, treatment or management of syncope, and in particular vasovagal syncope and cardiac syncope or carotid sinus, which consists of administering to a patient a therapeutically effective amount of (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-). The present invention also comprises the methods of prevention, treatment or management of bradycardia or bradyarrhythmia, which consist of administering to a patient a therapeutically effective amount of (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-) . In another embodiment, the present invention relates to a method of prevention, treatment or management of asthma or asthma symptoms, which consists in administering to a patient a therapeutically effective amount of (+) norcisapride or a pharmaceutically acceptable salt thereof. , practically without its stereoisomer (-).

The present invention also comprises a method of preventing, treating or managing urinary incontinence which consists of administering to a patient a therapeutically effective amount of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-). In another embodiment, this invention comprises individual unit dosage forms of (+) norcisapride, or a pharmaceutically acceptable salt thereof., practically without its stereoisomer (-), which contain from about 0.05 mg to about 500 mg of the active ingredient in a compressed tablet. This dosage form is particularly suitable for the prevention, treatment or management of apnea, apnea disorders, bulimia, irritated bowel syndrome, asthma, urinary incontinence, bradycardia, bradyarrhythmia, syncope, related disorders or symptoms thereof. The vagus nerve is the largest nerve in the cranial nerves. There are two main branches of the vagus nerve, each of which acts to provide motor and sensory functions. The vagus nerves contain efferent fibers that carry impulses from the origin of the nerve in the strict medulla of the brain to a visceral tissue or organ, the afferent fibers, which carry impulses from the organ back to the brain. It is present in a large portion of the body, extending from the trunk of the brain to the organs of the neck, chest and abdomen. Vagal stimulation occurs in different organs including the heart, lungs, bronchi, trachea, esophagus, stomach, pancreas, small intestine, large intestine, colon, liver, urinary bladder, and portions of the urinary tract. Without being limited by theory, it is also considered that by depolarization induced by 5-HT blocker in the vagus or vagal nerve, the (+) norcisapride reduces or inhibits the symptoms of these conditions. Therefore, in one embodiment, the present invention relates to the use of optically pure (+) - norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-), in the prevention, treatment or management of bulimia, of irritated bowel, asthma, urinary incontinence, bradycardia, bradyarrhythmia, syncope and related disorders or symptoms of these. In addition, the invention includes the use of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-), in combination with other therapeutic compounds. Examples of other therapeutic compounds include, but are not limited to, fluoxetine or the stereoisomers R or S of this; descarboethoxyloratidine; ondansetron or the stereoisomer R or S thereof, preferably ondansetron R; ubidecarenone; dipyridamole; pilocarpine and its stereoisomers; primidone or the stereoisomers R or S of this; Orphenadrine citrate; and the like, as well as any of the active metabolites thereof. The administration of (+) - norcisapride or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-), in combination with these other therapeutic compounds for the prevention, treatment or management of apnea, apnea disorders, bulimia, bowel syndrome irritated, urinary incontinence, bradycardia, bradyarrhythmia, asthma, syncope or symptoms of these in the methods of the present invention, can be done concurrently or in sequence, ie, (+) norcisapride and at least one other therapeutic compound can be administered as a combination, concurrently but separately, or by sequential administration. The compositions administered in each of these methods may be concurrent, sequential or in any combination of concurrent or sequential. The methods and compositions of this invention also include the benefit of reducing or avoiding adverse effects associated with the administration of racemic cisapride. The invention also allows the concurrent or sequential use of antidepressant drugs, such as tricyclic antidepressants, fluoxetine or its R or S stereoisomers, Zoloft®, and the like, and other drugs, such as anxiolytic drugs. The term "patient" when used herein refers to mammals, particularly humans. The methods of the present invention for the prevention, treatment or management of bulimia are particularly useful in adolescents and young adults. In a preferred embodiment, the bulimia prevention, treatment or management method is directed to women ages 13 to 25. It should be recognized that the methods of the present invention can be used to prevent, treat or manage bulimia in men and women , including children and adults, notwithstanding the aforementioned preferences. The methods of the present invention for the prevention, treatment or management of apnea or apnea disorders are particularly useful in obese men. In a preferred embodiment, the methods are directed to the prevention, treatment or management of obstructive apnea in obese men. It should be recognized that the methods can be used to prevent, treat or manage apnea or apnea disorders in men and women, including children and adults, notwithstanding the aforementioned preferences. When used herein, the terms "adverse effects" and "adverse side effects" include, but are not limited to, cardiac arrhythmia, disturbances of cardiac conduction, appetite stimulation, weight gain, sedation, gastrointestinal discomfort, pain headache, dry mouth, constipation, diarrhea and drug-medication interactions. See, for example, Physician's Desk Reference® 52nd Edition, Medical Economics Co., Inc., 1998. The term "cardiac arrhythmia" includes, but is not limited to, ventricular tachyarrhythmia, torsades de pointes, Qt prolongation, and fibrillation. ventricular The term "racemic" when used herein means a mixture of the (-) and (+) enantiomers of a compound wherein the (-) and (+) enantiomers are present in a ratio of about 1: 1. The terms "substantially optically pure", "optically pure" and "optically pure enantiomers", when used herein, mean that the composition contains more than about 90% of the stereoisomer (+) norcisapride by weight, preferably more than about 95% of the desired enantiomer by weight, and more preferably more than about 99% of the desired enantiomer by weight, based on the total weight of norcisapride. In other words, the term "practically without" means less than about 10% by weight, preferably less than about 5% by weight, and more preferably less than about 1% by weight of (+) norcisapride is present in accordance with the invention. The terms "5-hydroxytryptamine receptor antagonist""serotonin receptor antagonist" and "5-HT3 receptor antagonist" when used herein means a compound capable of reversibly binding to a 5-hydroxytryptamine receptor, either in the vagus nerve or anywhere in a mammal. The phrases "bulimia", and "bulimia nervosa", are used in the present in a constant way with the definition according to the DSM-IV. The terms "apnea" and "apnea disorders", when used herein, include, but are not limited to, a disorder characterized by interrupted breathing, in which a person stops breathing enough to decrease the amount of oxygen and increase the amount of carbon dioxide in the blood and brain. The term "asthma" when used herein, is defined as a disorder characterized by increased response of the trachea and bronchi to different stimuli1, which gives rise to symptoms that include, but are not limited to, asthmatic wheezing or wheezing, cough, short breath, dyspnea, and the like. Asthma includes, for example, allergic asthma. The term "syncope", when used herein, is defined as a disorder characterized by loss of consciousness and postural tone caused by decreased cerebral blood flow. The syncope includes, for example, Adams-Stokes syncope, cardiac syncope, sincope of the carotid sinus, hysterical sincope, laryngeal sincope, local syncope, syncope of urination, orthostatic syncope, postural syncope, syncope of swallowing, syncope due to seizures, syncope due to pulmonary embolism, syncope of gradual onset, sinus syncope, vasodepressor syncope or vasovagal syncope. The phrase "therapeutically effective amount of (+) norcisapride", when used herein, means that the amount of substantially optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, which alone, or in combination with others medications, provides a therapeutic benefit in prevention, treatment or management, or apnea, apnea disorders, bulimia, irritable bowel syndrome, urinary incontinence, bradycardia, bradyarrhythmia, asthma, syncope, or one or more of these symptoms. It is possible to apply different therapeutically effective amounts for each disorder, as will be recognized by those skilled in the art. "(+) Substantially pure norcisapride can be obtained from a racemic mixture of cisapride, the chemical synthesis of which can be made from according to the method that is described in the application of the European Patent No. 0,076,530, A2 published on April 13, 1983, the US Patents Nos. 4,962,115, 5,057,525, ,137,896, the descriptions of which are incorporated herein by 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 (1989); and Mauldermans, W., 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 reference. Optically pure (+) norcisapride can also be obtained from racemic norcisapride by HPLC separation or resolution of the enantiomers using conventional means, for example, from an acid for optically active resolution. The resolution of racemic norcisapride is also known to those skilled in the art, particularly from Jacques, J., et al, Enantiomers, Racemates 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, p. 268 (EL Eliel, Ed. Univ. Of Notre Dame Press, Notre Dame, IN, (1972).) In addition to separation techniques, such as those described above, (+) norcisapride can be synthesized by stereospecific synthesis using good methodology. known to those skilled in the art, chiral synthesis may give rise to products of high enantiomeric purity, however, in some cases, the enantiomeric purity of the product is not sufficiently high.The skilled artisan will appreciate that the separation methods described above may be used to further improve the enantiomeric purity of (+) norcisapride obtained by chiral synthesis.Optically pure (+) norcisapride can also be prepared from the racemic mixture by enzymatic biocatalytic resolution.See, for example, U.S. Patent Nos. 5,057,427 and 5,077,217, the descriptions of which are incorporated herein by reference.The magnitude of a prophylactic dose or Therapeutics of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-), in the acute or chronic management of diseases and disorders described herein will vary with the severity of the condition that is 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 administration. Dosage forms include tablets, lozenges, lozenges, dispersions, suspensions, suppositories, solutions, capsules, soft 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. Suitable dosage schemes can be easily selected by one skilled in the art with due consideration of these factors. In general, the total daily dosage for the conditions described herein is from about 0.05 mg to about 500 mg of (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-). Preferably, a daily dose range is from about 1 mg to about 250 mg and most preferably, a daily dose range is between about 1 mg to about 100 mg. Preferably, the active ingredient is administered in single or divided doses orally one to four times a day, or by slow intravenous injection. The preferred route of administration for the present invention is oral. Oral dosage forms can be conveniently presented in unit dosage forms and prepared by methods well known in the art of pharmacy. In the management of the patient, the treatment can be ^ - ^^ started at a lower dose, for example, from about 0.5 mg to about 10 mg, and 5 increased at the recommended daily dose or higher depending on the patient's overall response. In addition, it is recommended that in children, patients older than 65 years and those who have impaired renal or hepatic function, initially receive low doses, and that they be certified with basis in the individual response (s) and blood concentrations. It may be necessary to use doses outside these ranges in some cases, as will be apparent to those skilled in the art. In addition, it will be noted that the treating physician or clinician will know how and when to interrupt, adjust or finish the treatment according to the patient's individual response. Any convenient route of administration may be employed to provide the patient with an effective dose of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-). The most convenient way in any case will depend on the nature and severity of the condition that is being prevented, treated or managed. The pharmaceutical compositions for use in the present invention contain optically pure (+) norcisapride, or a The pharmaceutically acceptable salt thereof, practically without its (-) stereoisomer, as the active ingredient, and may also contain a pharmaceutically acceptable carrier and, optionally, other therapeutic ingredients. When used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates or clarates [sic] thereof. Examples of the inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric and phosphoric. Suitable organic acids can be selected, for example, from the aliphatic, aromatic, carboxylic, and sulphonic classes of the organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic acids. , isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furobic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamico), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate) , stearic, sulphanilic, alginic, glutaric and the like. Particularly preferred acids are hydrobromic, hydrochloric, phosphoric and sulfuric. In a preferred embodiment, the (+) norcisapride is administered as the free base or hydrate. In practical use, the (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its (-) stereoisomer, can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to the traditional pharmaceutical composition techniques . The carrier can take a wide variety of forms and can comprise different 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 carriers, including, but not limited to, starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Due to their ease of administration, tablets and capsules are preferred and represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are employed. If desired, the tablets can be coated by normal aqueous or non-aqueous techniques, the pharmaceutical compositions of the present invention suitable for oral administration can be presented as small pharmaceutical unit dosage forms, such as capsules, dragees, soft gelatin capsules, tablets or aerosol sprays, each containing a predetermined amount of the active ingredient, such as a powder or granules, or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or water-in-oil liquid emulsion. These compositions may be prepared by any of the methods of the pharmacy, but all methods include the step of associating the active ingredient with the pharmaceutically acceptable carrier which constitutes one or more of the necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or 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 is capsules but the most preferred oral solid preparation are tablets. For example, a tablet may be prepared 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 as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, granulating agent, surface active agent, dispersing agent or the like. 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 contains from about 0.5 mg to about 500 mg of the active ingredient, more preferably from about 1 mg to about 250 mg. Preferably, each dragee or capsule contains from about 0.05 mg to about 500 mg of the active ingredient, more preferably from about 1 mg to about 250 mg. However, the amount of the active ingredient that is in the composition may vary depending on the amount of the active ingredient that is to be administered to the patient. The optically pure (+) norcisapride or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-), can be formulated as a composition in a unit dosage form of soft gelatin capsule using the traditional methods well known in the art, such as It can be in Ebert, Pharm. Tech, 1 (5): 44-50 (1977). The soft elastic gelatin capsules have a soft, globular gelatin shell somewhat thicker than hard gelatin capsules, wherein a gelatin is plasticized by the addition of plasticizing agent, for example, glycerin, sorbitol or a similar polyol. The hardness of the capsule shell can change 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 may be dissolved or suspended in a liquid carrier 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, of the common dosage forms set forth above, the compounds of the present invention may also be administered by controlled release means, devices for delivery or both, as is well known to those skilled in the art, such as those described in US Patent Nos. 3,845,770 3,916,899; 3,536,809; 3,598,123; 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 hereby incorporated by reference herein. These pharmaceutical compositions can be used to provide slow or controlled release of the active ingredient contained therein using, for example, hydropropylmethylcellulose [sic] in different proportions to provide the desired release profile, other polymer matrices, gels, permeable membranes, osmotic systems , multilayer coatings, microparticles, liposomes, microspheres or the like, or a combination thereof. Appropriate controlled release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the (+) - norcisapride compositions of the invention. Thus, individual unit dosage forms suitable for oral administration such as tablets, capsules, gelatin capsules, dragees and the like which are adapted for controlled release are encompassed by the present invention. All pharmaceutical products for controlled release have a common goal of improving the treatment of the drug over that obtained by the uncontrolled counterparts. In theory, the use of a controlled release preparation optimally designed in medical treatment is characterized by a minimum of active substances being 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) reduction in the frequency of the dosage; and 3) greater comfort for the patient. Most controlled release formulations are designed to initially release an amount of the drug that immediately produces the desired therapeutic effect, and the gradual and continuous release of other amounts of medication to maintain this level of therapeutic effect for a prolonged period of time. To maintain this constant concentration of the drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of the drug that is being metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by different inducers, for example, pH, temperature, enzymes, water or other physiological or compound states. The term "controlled release component" in the context of the present invention is defined herein as a compound or compounds, including polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres or the like, or a combination thereof, which it facilitates the controlled release of the active ingredient (e.g., (+) norcisapride) in the pharmaceutical composition. Optically pure (+) norcisapride, or a pharmaceutically acceptable salt thereof, substantially free of its (-) stereoisomer, can be formulated for parenteral administration by injection (subcutaneous, bolus, intramuscular or intravenous injection), and can be dosed a unit dosage form, such as in a multi-dose container or in an ampoule. The compositions of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-), for parenteral administration may be in the form of suspensions, solutions, emulsions or the like in aqueous or oily vehicles, and in addition of the active ingredient may contain one or more formulating agents, such as dispersing agents, suspending agents, stabilizing agents, preservatives and the like. In the case where an intravenous injection composition is employed, a convenient daily dosage range is, for example, from about 0.5 mg to about 500 mg of the total daily dose, preferably from about 1 mg to about 250 mg, more preferably from about 1 mg to about 100 mg. Another preferred route of administration is transdermal delivery, for example, through an abdominal skin patch. The invention is further defined by reference to the following examples, describing in detail the preparation of the compound and compositions of the present invention, as well as its utility. It will be apparent to those skilled in the art that many modifications of the materials and methods may be practiced without departing from the purpose and interest of this invention.

EXAMPLES 5.1 EXAMPLE 1: Bioavailability A unit dose of the test substance or vehicle is administered to male beagle dogs intravenously as a bolus for one minute using a 23-gauge butterfly needle in the saphenous vein, or as a single dose to through an oral bait. 2.1 ml of whole blood is collected from each dog before and at intervals of 0.083, 0.25, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 hours after intravenous or oral administration of the optical isomers or the racemic mixture of cisapride or norcisapride. Dogs are placed limited in motion prior to administration of the test substance and are transferred to metabolic cages after collection of the blood sample at 0.083 hours. Blood samples are collected from an angiocatheter placed in a cephalic vein on the morning of the experiment. The blood is removed in a 3-cc syringe. The first 1.0-2.0 ml of blood is discarded. The next 2.0 ml of whole blood is rapidly transferred to a heparinized tube. The heparinized tubes are kept on ice until the blood is added. After adding the blood to the tube, the contents of the tube are mixed and centrifuged to obtain plasma. The plasma is carefully decanted and transferred to a test tube marked with: the animal number, the dose of test substance administered, the route of administration, the date of administration and the time of blood collection. The tubes are stored at -20 ° C until analysis. The analysis of the concentration of the optical isomers or racemates of norcisapride in each plasma sample is determined using high performance liquid chromatography. For each test substance the concentration of plasma with respect to the sampling time is plotted for both administration routes. The oral bioavailability of each test substance is determined by comparing the Cmax and AUC for the oral administration route against the intravenous administration route. The t? / 2 of each test substance for both routes is calculated as an indicator of the duration of the action. . 2 EXAMPLE 2: Activity of the receptor Activity of the receiver 5-HT? A The technology of the selection and amplification of the receiver (R-SAT) (Receptor Technologies, Inc., Winooski, VT) is used to determine the agonist activity and / or potential antagonist of racemic norcisapride, cisapride and its enantiomers in human serotonin 5-HT? A receptor subtypes cloned expressed in NIH 3T3 cells, as in Burstein et al. J. Biol. Chem. , 270: 3141-3146 (1995); and Messier et al., Pharmacol. Toxicol , 76 (5): 308-311 (1995). The assay includes the co-expression of a marker enzyme, β-galactosidase, with the serotonin receptor of interest. The ligands stimulate the proliferation of the cells that express the receptor and, therefore, the marker. The effects induced by the ligand can be determined by the marker assay. NIH 3T3 cells are incubated, plated and then transfected using human serotonin 5-HT? A receptors pSV-β-galactosidase, and salmon sperm DNA. The medium is changed one day later, and after 2 days, aliquots of trypsinized cells are placed in wells of a 96-well plate, after 5 days in culture in the presence of the ligands, the concentrations of β-galactosidase are measured. The cells are then rinsed and incubated with the substrate, o-nitrophenyl-β-D-galactopyranoside. After 16 hours, the plates are read at 405 nm in a plate reader. Each compound is tested for activity in triplicate in 7 different concentrations (10, 2.5, 0.625, 0.156, 0.039.0.0098 and 0.0024 nM). None of the tested compounds shows agonist activity with the serotonin 5-HT? A human receptors. The data of the inhibition of the agonists of the compounds fits the equation: Answer = answer max + (answer min) 1 + (conc ligand / ECso) The IC50 values (concentration necessary to inhibit 50% of the specific binding) are calculated for the antagonist activity against a concentration of 5-HT 2 μM? 10 using the nonlinear least squares analysis of KaleidaGraph, the results of which are set out in Tables 1 and 2.

-HT2 receptor activity 15 The technology of receptor selection and amplification (R-SAT) is used (Receptor Technologies Inc., Winooski, VT) to determine the agonist and / or antagonist activity ^ p potential of racemic norcisapride, cisapride, and its enantiomers on the 5-HT2 receptor subtypes of human serotonin expressed in NIH 3T3 cells as it can be in Burstein et al., J. Biol. Chem. 270: 3141-3146 (1995); and Messier et al., Pharmacol. Toxicol 76 (5): 308-311 (1995). The trial includes the coexpression of an enzyme marker, β-galactosidase, with the serotonin receptor of interest. The ligands stimulate the proliferation of cells that express the receptor and, therefore, the marker. The effects induced by the ligand can be determined by the marker assay. NIH 3T3 cells are incubated, plated and then transfected using human 5-HT2 serotonin receptors, pSV-β-galactosidase, and salmon sperm DNA. The medium is changed one day later, and after 2 days, the aliquots of the trypsinized cells are placed in wells of a 96-well plate. After 5 days in culture in the presence of the ligands, the concentrations of β-galactosidase are measured. The cells are then rinsed and incubated with the substrate, o-nitrophenyl-β-D-galactopyranoside. After 16 hours, the plates are read at 405 nm in a plate reader. Each compound is tested for activity in triplicate in seven different concentrations (10, 2.5, 0.625, 0.156, 0.039, 0.0098 and 0.0024 nM). None of the tested compounds shows agonist activity with human 5-HT2 serotonin receptors. The data of the antagonist inhibition of the compounds is adjusted to the equation: Response = response max + (response min) 1 + (conc ligand / EC50) The IC5o values are calculated for the antagonist activity against a 2 μM 5-HT concentration using the non-linear least squares analysis of KaleidaGraph, the results of which are set forth in Tables 1 and 2.

TABLE 1 Calculated IC50 values (μM) at the 5-HTIA and 5-HT2 receptors TABLE 2 Calculated IC5o values (μM) at the 5-HT? A and 5-HT2 receptors . EXAMPLE 3: Receptor binding 5-HT3 receptor Racemic norcisapride, racemic cisapride and its stereoisomers (+) and (-) are tested (Cerep, Cellle I'Evescault, France) for binding to the subtypes of the receptors 5- HT3 from N1E-115 cells. After incubation with the appropriate ligands, the preparations are rapidly filtered under vacuum through GF / B glass fiber filters and washed with ice-cooled buffer using a Brandel or Packard cell harvester. - The bound radioactivity is determined with a liquid scintillation counter (LS 6000 Beckman) using a cocktail for liquid scintillation (formula 989). The specific binding of the radioligand to the receptor is defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of the unlabeled ligand. The results are expressed as a percent inhibition of the specific binding obtained in the presence of the compounds. The IC5o is determined using concentrations in the range from 3 x 10"10 M to 10" 5 M to obtain complete proficiency curves and calculated by non-linear regression analysis. The results are shown in Tables 3 and 4 below.

-HT4 receptor The racemic norcisapride, racemic cisapride and its stereoisomers (+) and (-) are tested (Cerep, Cellle I'Evescault, France) for binding to the 5-HT4 receptor subtypes from the guinea pig striatum. After incubation with the appropriate ligands, the preparations are rapidly filtered under vacuum through GF / B glass fiber filters and washed with ice-cooled buffer using a Brandel or Packard cell harvester. The bound radioactivity is determined with a liquid scintillation counter (LS 6000 Beckman) using a liquid scintillation cocktail (formula 989). The specific binding of the radioligand to the receptor is defined as the difference between the total binding and the non-specific binding determined in the presence of an excess of the unlabeled ligand. The results are expressed as a percent inhibition of the specific binding obtained in the presence of the compounds. The IC50 is determined using concentrations in the range from 3 x 10 ~ 10 M to 10"5 M to obtain full competition curves and calculated by non-linear regression analysis, the results are shown in Tables 3 and 4 below.

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 at the 5-HT4 receptor sites can also be assessed using an assay. based on the ability of the active compounds to increase the production of cyclic AMP in neurons of the mouse embryo colliculus grown in tissue culture, such as Du uis et al., N. S. Arch. Pharmacol. 340: 403-410 (1989). . 4 EXAMPLE 4: Oral formulation Tablets Formula Quantity per tablet in mg ABC Active ingredient 5.0 10.0 25.0 (+) norcisapride Lactose BP 62.0 57.0 42.0 Starch BP 20.0 20.0 20.0 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 100.0 100.0 100.0 The active ingredient, (+) norcisapride, is sieved through a suitable screen and mixed with the lactose until a uniform mixture is formed. Suitable volumes of water are added and the powders are granulated. After drying, the granules are then screened 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 resistances by concentrations by modifying the ratio of the active ingredient of the excipient (s) or the weight in the compression. . 5 EXAMPLE 5: Oral formulation Tablets Formula Quantity per tablet in mg A B C Active ingredient 5.0 10.0 25.0 (+) norcisapride Lactose BP 48.5 43.5 28.5 Starch BP 30.0 30.0 30.0 Pregelatinized corn starch BP 15.0 15.0 15.0 Magnesium Stearate BP 1.5 1.5 1.5 Weight for compression 100.0 100.0 100.0 The active ingredient, (+) norcisapride, is screened through a suitable screen and mixed with the lactose, starch and pregelatinized corn starch until a uniform mixture is formed. Suitable volumes of water are added and the powders are granulated. After drying, the granules are then screened 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 resistances by concentrations by modifying the ratio of the active ingredient of the excipient (s) or the weight in the compression. . 6 EXAMPLE 6: Oral formulation Capsules Formula Quantity per tablet in mg A B C Active ingredient 5.0 10.0 25.0 (+) norcisapride Starch 1500 94.0 89.0 74.0 Magnesium Stearate BP 1.0 1.0 1.0 Total weight 100.0 100.0 100.0 The active ingredient is sifted and mixed with the excipients. The mixture is filled into No. 2 size hard gelatin capsules using the appropriate machinery. It is possible to prepare other doses by modifying the filling weight, and if necessary, changing the size of the capsule to the appropriate one. . 7 EXAMPLE 7 INTRAVENOUS FORMULATION Formula Active ingredient 1000 μg / ml (+) norcisapride Diluted hydrochloric acid BP at pH 3.5 Sodium chloride for injection BP 1 ml The active ingredient is dissolved in diluted hydrochloric acid BP to form a solution with a concentration of 1000 μg / ml of (+) norcisapride. Then the solution is mixed with sodium chloride for BP injection before use. Although the present invention has been described with respect to the specific embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the clauses.

These modifications are also proposed to be within the scope of the attached clauses.

Claims (71)

1. A method for treating bulimia in a patient, which consists of administering to said patient in need of a treatment an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-) .

2. The method of claim 1, wherein the mammal is a human.

3. The method of claim 1, wherein (+) norcisapride is administered orally.

4. The method of claim 3, wherein (+) norcisapride is administered as a tablet or capsule. The method of claim 1, wherein the amount administered is from about 0.

5 mg to about 500 mg.

6. The method of claim 5, wherein the amount administered is from about 1 mg to about 250 mg.

The method of claim 1, wherein the (+) norcisapride is administered together with a carrier acceptable for pharmaceutical use.

The method of claim 3, wherein the (+) norcisapride is administered one to four times a day.

The method of claim 1, wherein the (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

10. A method of treatment of conditions mediated by vagal activity in a patient, which consists of administering to the patient in need of this treatment an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-).

The method of claim 10, wherein the mammal is a human.

The method of claim 10, wherein (+) norcisapride is administered orally.

The method of claim 12, wherein (+) norcisapride is administered as a tablet or capsule.

The method of claim 10, wherein the amount administered is from about 0.5 mg to about 500 mg.

15. The method of claim 14, wherein the amount administered is from about 1 mg to about 250 mg.

The method of claim 10, wherein the (+) norcisapride is administered together with a carrier acceptable for pharmaceutical use.

The method of claim 12, wherein the (+) norcisapride is administered one to four times a day.

18. The method of claim 10, wherein the (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

19. A method for treating irritated bowel syndrome in a patient, which consists of administering to the patient in need of this treatment an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-).

The method of claim 19, wherein the mammal is a human.

The method of claim 19, wherein (+) norcisapride is administered orally.

22. The method of claim 21, wherein (+) norcisapride is administered as a tablet or capsule.

23. The method of claim 19, wherein the amount administered is from about 0.5 mg to about 500 mg.

The method of claim 23, wherein the amount administered is from about 1 mg to about 250 mg.

25. The method of claim 19, wherein the (+) norcisapride is administered together with a carrier acceptable for pharmaceutical use.

26. The method of claim 21, wherein the (+) norcisapride is administered one to four times a day.

The method of claim 19, wherein the (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

28. A method of treating bradycardia or bradyarrhythmia in a patient consisting of administering to the patient in need of this treatment, an effective amount for therapeutic use of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer (-).

29. The method of claim 28, where the patient is a human.

30. The method of claim 28, wherein (+) norcisapride is administered orally.

31. The method of claim 30, wherein (+) norcisapride is administered as a tablet or capsule.

32. The method of claim 28, wherein the amount administered is from about 0.5 mg to about 500 mg.

The method of claim 32, wherein the amount administered is from about 1 mg to about 250 mg.

34. The method of claim 28, wherein the (+) norcisapride is administered together with an acceptable carrier for pharmaceutical use.

35. The method of claim 30, wherein the (+) norcisapride is administered one to four times a day.

36. The method of claim 28, wherein the (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

37. A method of treating asthma in a patient consisting of administering to the patient in need of this treatment, an effective amount for therapeutic use of (+) norcisapride, or a pharmaceutically acceptable salt thereof, practically without its stereoisomer ( -).

38. The method of claim 37, wherein the patient is a human.

39. The method of claim 37, wherein (+) norcisapride is administered orally.

40. The method of claim 39, wherein (+) norcisapride is administered as a tablet or capsule.

41. The method of claim 37, wherein the amount administered is from about 0.5 mg to about 500 mg.

42. The method of claim 41, wherein the amount administered is from about 1 mg to about 250 mg.

43. The method of claim 37, wherein the (+) norcisapride is administered together with a carrier acceptable for pharmaceutical use.

44. The method of claim 39, wherein the (+) norcisapride is administered one to four times a day.

45. The method of claim 37, wherein the (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

46. A method of treatment of urinary incontinence in a patient, which consists of administering to the patient in need of this treatment, an effective amount for therapeutic use of (+) norcisapride or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-).

47. The method of claim 46, wherein the patient is a mammal.

48. The method of claim 46, wherein (+) norcisapride is administered orally.

49. The method of claim 48, wherein (+) norcisapride is administered as a tablet or capsule.

50. The method of claim 46, wherein the amount administered is from about 0.5 mg to about 500 mg.

51. The method of claim 50, wherein the amount administered is from about 1 mg to about 250 mg.

52. The method of claim 46, wherein the (+) norcisapride is administered together with a carrier acceptable for pharmaceutical use.

53. The method of claim 48, wherein the (+) norcisapride is administered one to four times a day.

54. The method of claim 46, wherein the (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

55. A method of treating apnea or apnea disorders in a patient, which consists of administering to the patient in need of this treatment, an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-).

56. The method of claim 55, wherein the apnea to be treated consists of central apnea, apnea, deglutition, obstructive apnea, sleep apnea, or sleep-induced apnea.

57. The method of claim 55, wherein the patient is a human.

58. The method of claim 55, wherein (+) norcisapride is administered orally.

59. The method of claim 58, wherein (+) norcisapride is administered as a tablet or capsule.

60. The method of claim 55, wherein the amount administered is from about 0.5 mg to about 500 mg.

61. The method of claim 60, wherein the amount administered is from about 1 mg to about 250 mg.

62. The method of claim 55, wherein the (+) norcisapride is administered together with a carrier acceptable for pharmaceutical use.

63. The method of claim 58, wherein the (+) norcisapride is administered one to four times a day.

64. The method of claim 55, where (+) norcisapride is administered parenterally, transdermally, rectally or sublingually.

65. A method for the prevention or management of bulimia in a patient, which consists of administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use of this, practically without its stereoisomer (-).

66. A method for the prevention or management of conditions mediated by vagal activity in a patient, which consists of administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) norcisapride, or a salt acceptable for pharmaceutical use thereof, practically without its stereoisomer (-).

67. A method for the prevention or management of irritated bowel syndrome in a patient, which consists of administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use thereof, practically without its stereoisomer (-).

68. A method for the prevention or management of bradycardia or bradyarrhythmia in a patient, which consists of administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for use pharmaceutical of this, practically without its stereoisomer (-).

69. A method for the prevention or management of asthma in a patient, which consists in administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use of this, practically without its stereoisomer (-).

70. A method for the prevention or management of urinary incontinence in a patient, which consists of administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) norcisapride, or an acceptable salt for pharmaceutical use of it, practically without its stereoisomer (-).

71. A method for the prevention or management of apnea or apnea disorders in a patient, which consists of administering to the patient in need of this prevention or management, an effective amount for therapeutic use of (+) f norcisapride, or a salt acceptable for pharmaceutical use thereof, practically without its stereoisomer (-). 5 •