Compositons for the prevention and treatment of urogenital disorders, containing bismuth

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

Description: BACKGROUND OF THE INVENTION While many industrialized countries have come to regard parasitic infection as a problem of impoverished developing countries, this is far from the truth. The incidence of parasitic infection, especially of the urogenital tract, continues to present a serious health concern. For example, in the United States in some areas, the incidence of urogenital infection due to Trichomonas vaginalis is reported to be as high as fifty percent with twenty to fifty percent of infected women and ninety percent of infected men being asymptomatic. Zinsser Microbiology , 20th Edition, 1173, (1992). Additionally, in the case of urogenital infection, incidence of infection is notoriously underestimated due to physicians prescribing broad spectrum antibiotics rather than isolating the offending, fastidious pathogen and the failure of physicians to report sexually transmitted vaginal diseases. Traditional treatment regimens for such infections consist of administration of a selective action antibiotic. However, antimicrobial resistance to such drugs raises concern about the ability to effectively treat parasitic infections in the future. Therefore, 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 urogenital disorders caused or mediated by parasitic protozoa. Thus, an object of the present invention is to provide for the use of bismuth, in the form of a pharmaceutically acceptable salt or complex, in the manufacture of safe and effective compositions for preventing and/or treating urogenital disorders caused or mediated by parasitic protozoa, through intravaginal administration. A further object of the invention is to provide such use comprising the administration of bismuth and one or more antimicrobials. 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 the use of bismuth, in the form of a pharmaceutically acceptable salt of complex, for the manufacture of a composition for treatment, by intravaginal administation of a human or lower animal subject having a urogenital disorder caused or mediated by one or more parasitic protozoa wherein the composition is administered to provide a level of from 50 milligrams to 10,000 milligrams of bismuth, per day, by weight of elemental bismuth. DETAILED DESCRIPTION OF THE INVENTION The use of the present invention provides compositions suitable for the prevention and/or treatment of urogenital disorders caused or mediated by one or more parasitic protozoa. Such urogenital disorders are prevented and/or treated by the administration of bismuth and, optionally, one or more antimicrobials. The components of the present invention are more fully defined below. Urogenital Disorder The term "urogenital disorder", as used herein, encompasses any infection, disease or other disorder of the urinary and/or reproductive systems, caused or mediated by one or more parasitic protozoa. Such disorders include one or more of the following conditions: vaginitis; vaginal burning, itching, discharge; ulcerative lesions; dysuria; painful urination; prostatitis; urethritis; epidiymitis; urethral stricture; and any other urogenital condition commonly associated with infection by parasitic protozoa. In immunocompromised subjects, urogenital disorders caused or mediated by parasitic protozoa may be more severe and life threatening than the common disorders listed above. Therefore, the term "urogenital disorder" also includes any condition commonly associated with protozoa infection in immunocompromised subjects including but not limited to foul smelling discharge, bleeding or purulent urogenital lesions, severe pruritus, painful dysuria, and microhematuria. Parasitic Protozoa Protozoa are unicellular, eucaryotic organisms which contain a nucleus, or nuclei, and cytoplasm. The term "parasitic protozoa", as used herein, refers to Protozoa such as Trichomonas vaginalis, and the microsporidia of the genera Pleistophora, Nosema, and Encephalitozoon . Preferred parasitic protozoa are Trichomonas vaginalis, Encephalitozoon hellem, and combinations thereof. Most preferred parasitic protozoa is Trichomonas vaginalis. The organisms are fully described in Manual of Clinical Microbiology , Sixth Edition, 1204-1205, 1213-1217, and 1225-1228 (1995), which is incorporated herein by reference. Diagnosis of urogenital 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 Manual of Clinical Microbiology , as referenced above. Bismuth The treatment and/or prevention provided by the present invention involve administration of bismuth in the form of a pharmaceutically acceptable salt or complex. As used herein, the quantity of bismuth is by weight of elemental bismuth. The preferred duration of bismuth administration vary according to the specific urogenital 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 50 milligrams to 10,000 milligrams, and preferably from 50 milligrams to 5000 milligrams, per day, for from 1 to 56 days, preferably for from 2 to 28 days, and most preferably for from 7 to 21 days. In general, as a method of prevention, bismuth may be administered in an amount of from 50 milligrams to 10,000 milligrams, and preferably from about 50 milligrams to about 5000 milligrams, per day, for from 1 to 21 days, and preferably for from 1 to 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 1 to 7 days, from 2 to 5 days, and from 3 to 4 days, prior to potential exposure. The term "bismuth", as used herein, includes bismuth in the form of a pharmaceutically-acceptable salt, bismuth or bismuth salt in the form of an organic or other complex which contains bismuth as an active ingredient, and mixtures thereof. Such organic complexes include 2,2'-spirobi[1,,32-benzodoxabismole]. Preferably, bismuth is administered 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 subgalate (by The Parthenon Co., Inc.); and Pepto-Bismol®, containing bismuth subsalicylate (by The Procter & Gamble Company). Bismuth may be administered in the form of a douche, douche powder, suppository, tablet, ointment, cream, gel, mousse, foam or any other form which would administer bismuth intravaginally to the subject. The delivery systems are described in detail in Remington's Pharmaceutical Sciences , 18th Edition, 1609-1614, 1632, 1525, 1519-1544, 1597-1614, 1633-1675, (1990); and Ansel, et al., Pharmaceutical Dosage Forms and Drug Delivery Systems , Fifth Edition, 373-389, (1990). A preferred composition manifactured according to the invention comprises: (a) from 50 milligrams to 5,000 milligrams of bismuth, in the form of a pharmaceutically acceptable salt or complex, by weight of elemental bismuth. Preferably, the bismuth salt or comphex is present at a level of from 50 milligrams to 2500 milligrams. The compositions manufactured according to the present invention may contain optional components which affect the physical and therapeutic characteristics of the present compositions. In particular, a variety of pharmaceutically-acceptable carriers and excipients may be included, depending upon the particular intravaginal dosage form to be used. Suppositories, and tablets can be compressed, coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flow-inducing agents and melting agents. Liquid intravaginal dosage forms include aqueous solutions, emulsions, suspensions, solutions, and/or suspensions reconstituted from granules or powders containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, melting agents, and coloring agents. Techniques and compositions for making intravaginal dosage forms useful herein are more fully described in the following references: Remington's Pharmaceutical Sciences , 18th Edition, 1609-1614, 1632, 1525, 1519-1544, 1597-1614, 1633-1675, (1990); and Ansel, et al., Pharmaceutical Dosage Forms and Drug Delivery Systems , Fifth Edition, 373-389 (1990). The compositions may be used by administering the composition from 1 to 7 times per day, and preferably from 1 to 4 times per day; for from 1 to 21 days, preferably for from about 1 to about 14 days. The specific frequency of administration will depend upon such factors as the specific bismuth compound or composition, the levels at which the components are incorporated in the composition, the nature and severity of the condition to be treated, and the nature of any concurrent therapy, if any. Administration The administration of bismuth and one or more antimicrobials can be performed simultaneously (beginning and ending on the same day), concurrently (overlapping), or consecutively (sequential, but wherein the course of the treatment is substantially continuous). Preferably, the step of administering the antimicrobial(s) is not commenced prior to commencing the step of administering bismuth. 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 urogenital disorder. Preferably, the bismuth is administered intravaginally in the form of a douche. The following non-limiting examples illustrate the uses of the present invention. EXAMPLE I A young, college coed visits a campus health center for her routine annual gynecological exam, complaining of vaginal irritation. Upon examination of the vagina, the physician observes the presence of a foamy, yellowish-green discharge and chafing of the vagina, vulva, and perineum. Using a vaginal speculum, exudate is collected from the vaginal canal and a wet mount preparation is made promptly and analyzed microscopically. The presence of organisms, 5-20 m in length with a jerky-type motion confirms the presence of Trichomonas vaginalis . The patient is treated by a method of the present invention. A composition containing bismuth subsalicylate is administered in a liquid douche delivering approximately 2500 mg of bismuth per liter of douching solution, twice daily (a total of 5000 milligrams of bismuth daily) for twenty-one days. Atovaquone tablets (750 milligrams per tablet) are concurrently administered three times a day for 21 days, delivering a total of 2250 milligrams of atovaquone per day. Thereafter, vaginal samples from the patient are analyzed again, finding no trace of parasitic infection. The subject remains asymptomatic, and another vaginal analysis performed 5 months later is normal. In the above example, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth citrate, and bismuth subgallate, bismuth subnitrate may be substituted, respectively, for bismuth subsalicylate, with substantially similar results. Similarly, penicillin erythromycin, metronidazole, doxycycline, tinidazole, amoxicillin, ampicillin, nitrofurantoin, chloroquine phosphate, quinacrine hydrochloride, iodoquinol, pyrimethamine, and mefloquine hydrochloride may be substituted for atovaquone with substantially similar results. EXAMPLE II A young man, in the presence of his physician, confides to his future bride two days before their marriage that he is being treated for a urethral infection caused by Trichomonas vaginalis , reportedly from using a contaminated towel at his gym. The physician advises the groom to continue his current therapy until eradication of the parasite is complete. Clinical analyses indicate that the bride currently is not infected. Since the use of condoms is not considered due to religious beliefs, the bride is given 3500 milligrams of bismuth, administered as bismuth subnitrite in a vaginal suppository, for use thirty minutes before sexual intercourse. Following intercourse, a douche is administered delivering 500 milligrams of furolzolidone in one liter of douching solution. The suppository and douching regimen are used for about 30 days or until her husband is determined to be free of infection. At this time, vaginal samples are taken from the wife and analyzed and no evidence of parasitic infection is found.

Claims: The use of bismuth, in the form of a pharmaceutically acceptable salt or complex, for the manufacture of a composition for the treatment or prevention, by intravaginal administration of a composition, of a urogenital disorder caused or mediated by one or more parasitic protozoa, wherein the composition is administered to provide a level of from 50 milligrams to 10,000 milligrams of bismuth per day, by weight of elemental bismuth. The use according to Claim 1 wherein the bismuth is administered in the form of a douche at a level of from 50 milligrams to 5,000 milligrams, by weight of elemental bismuth, per day. 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. The use according to any of Claims 1-3 wherein the parasitic protozoa are selected from the group consisting of Trichomonas vaginalis, Encephalitozoon hellem , and combinations thereof. The use according to any of Claims 1-4 wherein said bismuth prevents a urogenital disorder caused or mediated by one or more parasitic protozoa comprising administering to the subject from 50 milligrams to 10,000 milligrams of bismuth per day, by weight of elemental bismuth, for from 1 to 21 days. The use according to any of Claims 1-5 wherein the bismuth is administered in the form of a vaginal suppository at a level of from 50 milligrams to 5,000 milligrams, by weight of elemental bismuth, per day.

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