METHODS FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS

Abstract: Method for the treatment of human and lower animals having an infectious gastrointestinal disorder, comprising the step of administering from about 50 to about 5000 milligrams of bismuth to said subject, per day, for from 3 to 56 days. Preferred processes also include a step for performing a diagnostic step on the subject for detection of campylobacter-­ like organism infection of the subject.

Description: This invention relates to manufacture of a medicament for the treatment of infectious gastrointestinal disorders in humans and other animals. Factors adversely affecting the function of the gastrointestinal system in humans are exceedingly varied in their nature. Such disorders may arise in the upper or lower gastrointestinal tracts or both. There is a broad range of causes of gastrointestinal disorders, including genetic, physiological, environmental, and psychogenic factors. Accordingly, the diagnosis and management of these disorders can be exceptionally difficult. A detailed discussion of gastrointestinal tract functions, disorders, causes, and treatments can be found in Spiro, Clinical Gastroenterology (3d. edition 1983). Among the chronic disorders of the upper gastrointestinal tract are those which fall under the general categories of gastritis and peptic ulcer disease. (The upper gastrointestinal tract is generally defined as including the esophagus, the stomach, the duodenum, the jejunum, and ilium.) Gastritis is, by definition, typified by an inflammation of the stomach mucosa. In practice, though, the disorder is manifested by a broad range of poorly-defined, and heretofore inadequately treated, symptoms such as indigestion, "heart burn", dyspepsia and excessive eructation. A general discussion of gastritis appears in B. J. Marshall and J. R. Warren, "Unidentified Curved Bacilli in the Stomach of Patients with Gastritis and Peptic Ulceration", The Lancet , 1311-1315 (1984), and in R. Greenlaw, et al., "Gastroduodenitis, A Broader Concept of Peptic Ulcer Disease", 25 Digestive Diseases and Sciences 660-672 (1980). Peptic ulcers are lesions of the gastrointestinal tract lining, characterized by loss of tissue due to the action of digestive acids and pepsin. It has been generally held that peptic ulcers are caused either by gastric hypersecretion, or (more often) by decreased resistance of the gastric lining to digestive acids and pepsin. The medical literature is replete with methods for treating ulcers, including modification of the diet, surgical removal of the lesions, and the use of drugs. Such drugs include: antacids, which serve to counteract excess gastric secretions; anticholinergics, which reduce acid secretion; H₂ antagonists, which also block the release of gastric acids; prostaglandins, which increase the resistance of the gastric lining to digestive fluids, and may also inhibit acid secretion; prokinetic agents, which enhance gastrointestinal tract motility; and compositions which form protective barriers over gastric lesions. Prescription and non-prescription drug therapies are generally described in Garnet, "Antacid Products", Handbook of Non-prescription Drugs , Chapter 3 (7th edition, 1982). One group of drugs which are thought to be effective due to coating of ulcer sites and forming protective barriers is the bismuth-containing drugs. See, for example, Koo, et al., "Selective Coating of Gastric Ulcers by Tripotassium Dicitrato Bismuthate in the Rat", 82 Gastroenterology 864-870 (1982). Regardless of the particular drug composition used in treating gastrointestinal disorders, such as peptic ulcer disease, the treatment is often imprecise and incomplete. Actual "cures", i.e., successful treatment resulting in total remission of disease, are very often not effected. See, A. J. McLean, et al., "Cyto-protective Agents and Ulcer Relapse", 142 The Medical Journal of Australia , Special Supplement S25-S28 (1985). Furthermore, many conventional treatments may render subjects hypochlorhydric (i.e., with low levels of hydrochloric acid in the stomach) which may predispose them to other disorders, e.g., gastrointestinal infection, halitosis, and gastric carcinomas. It has now been discovered that certain medicaments involving the use of bismuth, are effective for the treatment of infectious upper-gastrointestinal disorders. In particular, as compared to the prior art, these medicaments cure, or afford lower relapse rates of, gastritis and peptic ulcer disease. These medicaments also afford other benefits in the treatment and management of subjects having gastrointestinal diseases, such as in not rendering subjects hypochlorhydric. According to the present invention, there is provided the use of bismuth subsalicylate for the manufacture of a medicament for the treatment of a disorder of the upper gastrointestinal tract of a human or other animal subject in which the disorder is caused or mediated by Campylobacter pyloridis . In use, the medicaments are preferably administered to a subject who has been tested for the presence of infection by pyloric campylobacter organisms, with positive results. A preferred test for such infection is through the detection of urease enzyme in the stomach. Specific compounds and compositions to be used according to the present invention must be pharmaceutically-acceptable. As used herein, such a "pharmaceutically-acceptable" component is one which is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. Further, as used herein, the term "safe and effective amount" refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), and the specific formulations employed in the present invention. Specifically, the medicament is preferably administered to said subject in an amount from 50 mg to 5000 mg of bismuth, per day, for from 3 to 56 days. As used herein, "infectious gastrointestinal disorder" encompasses any disease or other disorder of the upper gastrointestinal tract of a human or lower animal which is caused or mediated by a Campylobacter pyloridis organism (herein "CLO"). Such infectious gastrointestinal disorders include, for example: CLO-mediated disorders not manifested by presence of ulcerations in the gastric mucosa (herein "non-ulcerative gastrointestinal disorder"), including chronic or atrophic gastritis, non-ulcer dyspepsia, esophogeal reflux disease and gastric motility disorders; and "peptic ulcer disease", i.e., CLO-mediated gastric duodenal, and jejunal ulcers. As used herein, "administering" refers to any method which, in sound medical practice, delivers the compounds or compositions to the subject to be treated in such a manner so as to be effective in the treatment of the infectious gastrointestinal disorder. Preferably, then, the bismuth is administered orally. In use, the medicament is administered in an amount of from 50 mg to 5000 mg of bismuth, per day, for from 3 to 56 days. (As used herein, the quantity of bismuth is by weight of elemental bismuth. Thus, the actual weight of a bismuth-containing compound will be greater.) Preferably, from 500 mg to 1500 mg of bismuth are administered, per day. The duration of bismuth administration will vary according to the specific gastrointestinal disorder to be treated. In general, though, in treatment of non-ulcerative gastrointestinal disorders, the bismuth is administered for from 3 to 21 days. The bismuth is preferably adminstered, in treatment of peptic ulcer disease, for from 14 to 56 days. The bismuth subsalicyate used herein may be administered alone, or in combination with other pharmaceutically-acceptable components, in a bismuth-containing composition. One such composition is Pepto-Bismol, containing bismuth subsalicylate (sold by The Procter & Gamble Company). Preferably, treatment using the medicaments herein includes a step for the detection of a CLO infection in the stomach of the human or other animal subject. Suitable methods of detection include gram stains of gastric tissues (obtained, for example, by biopsy), serologic tests to detect the presence of antibodies to the organisms, tests of body fluids to detect the presence of metabolites of the organisms, silver stain tissue sections of gastric tissues, and detection of urease enzyme in the stomach of the subject. The diagnostic step is preferably performed prior to administering bismuth. Also preferably the diagnostic step is repeated during administration of bismuth, and administration is terminated after the diagnostic step yields a negative result. One preferred method of detection is the detection of urease enzyme (urea amidohydrolase) in the stomach of the human or other animal having a gastrointestinal disorder. Such a detection step may include, for example, obtaining a sample of gastric fluid (e.g., from vomitus) or of gastric mucosa (e.g., by biopsy) and analyzing the material for the presence of urease enzyme. One such method for the diagnosis of gastrointestinal disorder involves obtaining a sample of gastric mucosa and placing said sample into a composition which comprises: a) urea, at a concentration of from about 10 to about 40 g/l; b) a bactericide, at a concentration of from about 1 to about 5 g/l; c) an indicator having a pK a of from about 6.5 to about 8.5, at an effective concentration; and d) water; wherein said composition has a pH of from about 5.0 to about 6.5 and said pH is at least one pH unit lower than the pK a of said indicator. Preferably, the composition contains a gelling agent, such as a non-nutritive agar, at a concentration of from about 5 to about 50 g/l. Typically the indicator is present at a concentration of from about 20 to about 100 mg/l. (As used herein, all concentrations are by weight of component per volume of total composition.) A change in the color of the composition indicates the presence of urease enzyme, and the presence of a gastrointestinal disorder. The following non-limiting examples illustrate the uses of the present invention. EXAMPLE I A human subject, suffering from atrophic gastritis, is treated using a medicament prepared according to the present invention. Specifically, the subject is endoscoped and a biopsy taken of the gastric mucosa of the subject. Analysis of the biopsy sample shows inflammation of the mucosa, and depletion of the protective mucous layer. Histological examination of the sample also reveals the presence of Campylobacter pyloridis . The subject is then treated by administering a composition containing bismuth subsalicylate, sold by The Procter & Gamble Company under the name "Pepto-Bismol". The composition, in liquid form, is administered four times daily in equal doses of 30 ml (for a total of approximately 1200 mg of bismuth administered per day) for 21 days. Thereafter, the subject is endoscoped and biopsied again, finding essentially normal, healed gastric mucosa. Histological examination of the gastric material sample does not reveal any bacterial infection. The subject remains asymptomatic, and another biopsy performed five months later reveals normal gastric mucosa. EXAMPLE II A human subject, suffering from peptic ulcer disease, is treated using a medicament prepared according to the invention. Specifically, a biopsy of gastric mucosa is taken from the stomach of the subject. The sample is then placed in 0.5 milliliters of an aqueous gel having the following composition: Component Quantity (grams) Final Concentration urea 3.000 30 g/l phenol red 0.008 80 mg/l methyl hydroxy benzoate 0.200 2 g/l bacteriological agar 1.500 15 g/l citric acid 0.040 400 mg/l sodium phosphate 0.080 800 mg/l (The components, except for urea, are dissolved in 100 ml of water, heated to approximately 65°C, and stirred until the solution is clear. The composition is allowed to cool to below approximately 45°C, and the urea is added. Upon cooling to ambient temperature, a gel is formed, having a pH of 6.0 and a deep yellow color.) After the biopsy sample is inserted into the composition, the composition color changes from deep yellow to red over a period of fifteen minutes, indicating the presence of urease in the biopsy sample and presence of CLO in the stomach of the subject. The subject is then treated by administering 700 mg of bismuth, as bismuth subsalicylate, per day, for 35 days. Thereafter, the subject is endoscoped, revealing normal gastric mucosa and healing of the peptic ulcer crater, and a biopsy sample is obtained. The sample is then inserted into 0.5 ml of a test composition comprised as above, and the color of the composition remains unchanged after 24 hours, indicating lack of CLO infection.

Claims: The use of bismuth subsalicylate for the manufacture of a medicament for the treatment of a disorder of the upper gastrointestinal tract of a human or other animal subject in which the disorder is caused or mediated by Campylobacter pyloridis. The use of bismuth subsalicylate according to Claim 1 wherein said disorder caused or mediated by Campylobacter pyloridis is a non-ulcerative upper gastrointestinal disorder. The use of bismuth subsalicylate according to Claim 1 wherein said infectious disorder caused or mediated by Camoylobacter pyloridis is a peptic ulcer disease.

Inventors: MARSHALL, BARRY JAMES, M.D., MARSHALL, BARRY JAMES, DR.
Applicants: MARSHALL, BARRY JAMES, M.D.
Application year: 1986
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P31, A61P1, A61K33