COMPOSITIONS CONTAINING BISMUTH, FOR THE TREATMENT AND PREVENTION OF GASTROINTESTINAL DISORDERS

Abstract: The subject invention encompasses methods for the prevention and treatment of a human or lower animal subject having a gastrointesinal disorder caused or mediated by one or more parasitic protozoa comprising administering bismuth to the subject.

Description: COMPOSITIONS CONTAINING BISMUTH, FOR THE TREATMENT AND PREVENΗON OF GASTROINTESTINAL DISORDERS BACKGROUND OF THE INVENTION While bacteria and viruses have long been recognized as a leading cause of diarrhea throughout the world, it was not until about twenty years ago that parasites were considered in the etiology. The importance of diarrhea associated with parasitic protozoa was not realized in the United States, as it was generally believed that this was an illness of impoverished, developing countries. Since that time, parasites such as Cryptospo dium, Giardia, and Entamoeba among others, have been implicated with diarrhea and other gastrointestinal disorders at high incidence rates outside the United States and at an increasing frequency within the United States. For example, in a recent survey of drinking water supplies in fourteen states of the U. S., investigators found one in four to be tainted with Cryptospo dium parvum. Health. July/August 1993, p. 14. Therefore, diarrhea and other gastrointestinal disorders associated with parasitic protozoa represent a serious health concern and the need for effective anti-parasitic treatment therapies continues to grow. It has been discovered by the present invention that the administration of bismuth salts may be effective for the prevention and/or treatment of gastrointestinal disorders caused or mediated by parasitic protozoa. Thus, an object of the present invention is to provide a safe and effective method of preventing and/or treating gastrointestinal disorders caused or mediated by parasitic protozoa. A further object of the invention is to provide such a method comprising the administration of bismuth. These and other objects of the present invention will become readily apparent from the detailed description which follows. SUMMARY OF THE INVENTION The present invention relates to a method for treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 56 days. The present invention also relates to a method for prevention in a human or lower animal of a gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 28 days. DETAILED DESCRIPTION OF THE INVENTION The methods of the present invention comprise the prevention and/or treatment of gastrointestinal disorder caused or mediated by one or more parasitic protozoa. Such gastrointestinal disorders are prevented and/or treated by the administration of bismuth. The components of the present invention are more fully defined below. Gastrointestinal Disorder The term "gastrointestinal disorder", as used herein, encompasses any infection, disease or other disorder of body, typically of the upper and/or lower gastrointestinal tract, caused or mediated by one or more parasitic protozoa. Such disorders include one or more of the following conditions: diarrhea, abdominal pain and/or cramping, flatulence, nausea, abdominal distention, fever, constipation, blood, mucus and/or pus present in feces, vomiting, gastroenteritis, weight loss, anorexia, malaise, and any other condition commonly associated with infection by parasitic protozoa. In immunocompromised subjects and children, gastrointestinal disorders caused or mediated by parasitic protozoa may be more severe and life threatening than the common disorders listed above. Therefore, the term "gastrointestinal disorder" also includes any condition commonly associated with protozoa infection in immunocompromised subjects and children, including but not limited to, acute diarrhea, dehydration, electrolyte imbalance, colitis, and fatal necrosis of the intestine. Parasitic Protozoa Protozoa are unicellular, eucaryotic organisms which contain a nucleus, or nuclei, and cytoplasm. Four groups of Protozoa contain parasites which are contemplated in the present invention. These organisms are fully described in Zinsser Microbiology. 20th Edition, 1163- 1173, (1992) and T. L. Kuhls, M.D., "Protozoal Infections of the Intestinal Tract in Children", Advances In Pediatric Infectious Diseases, vol. 8, 177- 202, (1993), both of which are incorporated herein by reference. The term "parasitic protozoa", as used herein, refers to Protozoa of the phlya Sarcomastigophora such as Entamoeba, Giardia, Dientamoeba, and Blastocystis; Ciliophora such as Balantidium; Apicomplexa such as Isospora and Cryptospo dium; and Microspora such as Enterocytozoon. Preferred parasitic protozoa are Entamoeba, Cryptospoήdium, Giardia, Isospora, and combinations thereof. Most preferred parasitic protozoa are Entamoeba, Cryptospoήdium, Giardia, and combinations thereof. Diagnosis of gastrointestinal disorders caused or mediated by parasitic protozoa may be accomplished by any method commonly used in the medical community. Such methods are fully described in Zinsser Microbiology, and T.L. Kuhls, M.D. "Protozoal Infections of the Intestinal Tract in Children", as referenced above. Bismuth The methods of treatment and/or prevention in the present invention involve administration of bismuth. As used herein, the quantity of bismuth is by weight of elemental bismuth. The preferred duration of bismuth administration will vary according to the specific gastrointestinal disorder to be treated and the physical condition of the subject being treated. In general, as a method of treatment, bismuth may be administered in an amount of from about 50 milligrams to about 5000 milligrams, and preferably from about 50 milligrams to about 2500 milligrams, per day, for from about 1 to about 56 days, preferably for from about 2 to about 28 days, and most preferably for from about 7 to about 21 days. In general, as a method of prevention, bismuth may be administered in an amount of from about 50 milligrams to about 5000 milligrams, and preferably from about 50 milligrams to about 2500 milligrams, per day, for from about 1 to about 21 days, and preferably for from about 1 to about 14 days. In a method of prevention, bismuth may be administered prior to potential exposure to parasitic protozoa. Such administration of bismuth may vary depending on the likelihood of parasitic protozoa exposure and condition of the subject and may be commenced at any time deemed beneficial by the medical community including from about 1 to about 7 days, from about 2 to about 5 days, and from about 3 to about 4 days, prior to potential exposure. In the present methods, bismuth may be in the form of a pharmaceutically-acceptable salt or may be in the form of an organic complex which contains bismuth as an active ingredient. Such organic complexes include 2,2'-spirobi[1,3,2-benzodoxabismole]. Preferably, bismuth is administered in the present methods as a pharmaceutically- acceptable salt. Such bismuth salts include bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof are preferred bismuth salts for use in this invention. The bismuth useful herein may be administered alone, or in combination with other pharmaceutically-acceptable components in a bismuth-containing composition. A variety of such compositions containing bismuth salts are commercially available. Such compositions include DeNol, containing tripotassium dicitrato bismuthate (by Brocades); Bislumina, containing bismuth aluminate (by Mazuelos); Roter, containing bismuth subnitrate (by Roterpharma); Devrom®, containing bismuth subgallate (by The Parthenon Co., Inc.); and Pepto-Bismol®, containing bismuth subsalicylate (by The Procter & Gamble Company). As used herein, the term "administering" refers to any method which, in sound medical practice delivers the compounds or compositions used in this invention to the subject to be treated in such a manner so as to be effective in the treatment of the gastrointestinal disorder. Preferably, the bismuth is administered orally. The following non-limiting examples illustrate the methods and uses of the present invention. EXAMPLE I A human subject, suffering from severe diarrhea, is treated by a method of the present invention. Fecal samples are taken from the subject and analyzed for the presence of intestinal parasites, including organism eggs, cysts, sporozoites, etc. Clinical parasitology specimens reveal the presence of Cryptospoήdium parvum. 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 delivering approximately 2500 milligrams of bismuth per day, for 21 days. Thereafter, fecal samples from the subject are analyzed again, finding no trace of parasitic infection. The subject remains asymptomatic, and another fecal analysis performed 5 months later is normal. In the above example, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth citrate, and bismuth subnitrate are substituted, respectively, for bismuth subsalicylate, with substantially similar results. EXAMPLE II A three-year-old child with diabetes and in a day care center is suffering from chronic diarrhea, and abdominal distention. Analysis of fecal specimens shows the presence of Giardia lamblia. The infection is diagnosed and treated by orally administering approximately 400 milligrams of bismuth in the form of bismuth subcitrate ("DeNol", sold by Brocades), in four equal doses daily, for about 28 days. Thereafter, fecal samples from the subject are analyzed again, finding no trace of parasitic infection. EXAMPLE III A Peace Corps volunteer preparing to travel to a developing country with sub-standard sanitation and water purification systems has a fecal sample clinically analyzed for the presence of Giardia lamblia, Cryptospo ή dium parvum, and Entamoeba histolytica. Clinical results show no evidence of the parasites. The subject is given approximately 1200 milligrams of bismuth, (administered as bismuth subsalicylate in the composition Pepto-Bismol®, sold by The Procter & Gamble Company), in four equal doses daily, for about 21 days. Upon return to the U.S., approximately 30 days after the initial clinical analysis, the subject remains asymptomatic. Fecal samples from the subject are analyzed and no evidence of parasitic infection is found.

Claims: 1. The use of from 50 milligrams to 5000 milligrams of bismuth per day for from 1 to 56 days for the manufacture of a composition for the treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by one or more parasitic protozoa. 2. The use according to Claim 1 wherein the bismuth is to be administered at a level of from 0 milligrams to 2500 milligrams, per day. 3. The use according to Claim 1 or 2 wherein the bismuth is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgalate, bismuth subsalicylate, bismuth tartrate, and mixtures thereof. 4. The use according to Claims 1-3 wherein the parasitic protozoa are selected from the group consisting of Cryptospoήdium, Giardia, Entamoeba, Isospora, and combinations thereof. 5. The use according to Claims 1-4 wherein said bismuth prevents gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from 50 milligrams to 5000 milligrams of bismuth, per day, for from 1 to 21 days. 6. The use according to Claims 1-5 wherein the bismuth is administered at a level of from 50 milligrams to 2500 milligrams, per day. 7. A method for treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 56 days. 8. The method of Claim 7 wherein the bismuth is administered at a level of from about 50 milligrams to about 2500 milligrams, per day. 9. The method of Claim 7 wherein the bismuth is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgalate, bismuth subsalicylate, bismuth tartrate, and mixtures thereof. 10. The method of Claim 7 wherein the parasitic protozoa are selected from the group consisting of Cryptospoήdium, Giardia, Entamoeba, Isospora, and combinations thereof. 11. A method for prevention in a human or lower animal subject of a gastrointestinal disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 21 days. 12. The method of Claim 11 wherein the bismuth is administered at a level of from about 50 milligrams to about 2500 milligrams, per day. 13. The method of Claim 11 wherein the bismuth is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgalate, bismuth subsalicylate, bismuth tartrate, and mixtures thereof. 14. The method of Claim 11 wherein the parasitic protozoa are selected from the group consisting of Cryptospoήdium, Giardia, Entamoeba, Isospora, and combinations thereof.

Inventors: FITZGERALD JAMESINA ANNE, LEDERBERG JOSHUA, FITZGERALD, JAMESINA, ANNE, LEDERBERG, JOSHUA
Applicants: PROCTER & GAMBLE, THE PROCTER & GAMBLE COMPANY
Application year: 1996
Main classification: A61K33
IPC codes: A61K31, A61K33, A61P33