CA2219758A1 - Compositions comprising bismuth and one or more antimicrobials, for the treatment and prevention of gastrointestinal disorders - Google Patents
Compositions comprising bismuth and one or more antimicrobials, for the treatment and prevention of gastrointestinal disorders Download PDFInfo
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- CA2219758A1 CA2219758A1 CA002219758A CA2219758A CA2219758A1 CA 2219758 A1 CA2219758 A1 CA 2219758A1 CA 002219758 A CA002219758 A CA 002219758A CA 2219758 A CA2219758 A CA 2219758A CA 2219758 A1 CA2219758 A1 CA 2219758A1
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- bismuth
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/245—Bismuth; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The subject invention encompasses methods for prevention and 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 bismuth and one or more antimicrobials. The subject invention also encompasses compositions comprising bismuth and one or more antimicrobials for the prevention and treatment of a human or lower animal subject having a gastrointestinal disorder caused or mediated by one or more parasitic protozoa.
Description
CA 022197~8 1997-10-29 W 096/35436 PCT~US~610C489 I
COMh~lU..~ CO~ff wsnNG B~hnrrH ~ND ONE OR MORB ~NmMncRoBLuLs~poR THE
TRE~l~n3NT ~NDPREVE~n~ON OF GASTRO~ ALl~-O~r~-c 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 re~li7~d in the United States, as it was generally believed that this was an illness of impoverished, developing countries. Since that time, parasites such as Cryptosporidium, 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 Cryptosporidium 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 adminisl, dliGI, of bismuth salts and one or more antimicrobials may be effective for the prevention and/or treatment of gastrointestinal disorders caused or mediated by parasitic p~uto~oan. Thus, an object of the present invention is to provide safe and effective compositions and methods for preventing and/or treating gastroi"leslinal disorders c~l~sed or n,edidled by pd,dsilic protozoa. A further object of the invention is to provide such a method comprising the administration of bismuth and one or more anlil "ic~ obials.
These and other objects of the present invention will become readily apparent from the det~iled 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 sl~bject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 56 days; and from about 100 milligrams to about CA 022197~8 1997-10-29 W09613S436 PCT/U~3~/~6~89 10,000 milligrams of each of one or more antimicrobiais, per day, for from about 1 to about 21 days.
The present invention also relates to a method of prevention in a human or lower animal for 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; and from about 100 milligrams to about 10,000 milligrams of each of one or more antimicrobials, per day, for from about 1 to about 14 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 and one or more a"lil~icrobials.
The components of the present invention are more fully defined below.
Gastrointestinal Disorder The term ''gasl,ui,,lesli,,al disorder", as used herein, encorrlp~sses any infection, disease or other disorder of body, typically the upper and/or iower gasfro~,~LesG"al tract, caused or mediafed by one or rnore parasitic proto,oa. 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 :~sso~ i~ted with infection by parasitic protozoa.
In immunocompromised subjects and children, gastroi"teslinal disorders c~ secl or medi~ted by parasitic protozoa may be more severe and life threatening than the common disorders listed above. Therefore, the term "ga~L,ui"leslinal disorder" also includes any condition commonly associated with protozoa infection in immunocompromised subjects and children, including but not limited to, acute diarrhea, dehydration, electrolyteimbalance, colitis, and fatal necrosis of the i, lleslil ,e.
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 Microbioloqv. 20th Edition, 1992, pp. 1 163-1 173, and T. L. Kuhls, M.D., "P, oto~oal Infections of the Intestinal CA 022197~8 1997-10-29 W 096/3~436 PCTAUS~IOC189 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 phyla Sarcomastigophora such as Entamoeba, Giardia, Dientamoeba, and Blastocystis; Ciliophora (ciliates) such as Balantidium; Apicomplexa such as Isospora and Clyptosporidium; and Microspora such as Enterocytozoon.
Preferred parasitic protozoa are Entamoeba, Cryptosporidium, Giardia, Isospora, and combinations thereof. Most preferred parasitic protozoa are Entamoeba, Cryptosporidium, 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 milligrari,s, 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 parasilic proLo,oa. 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 l"edical 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.
CA 022l97~8 l997-l0-29 W096/35436 PCTfUS9G/OC~189 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"32-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 subgallate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicyiate, 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); Devroma~, 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 gastroinleslinal disorder. P,~ferably, the bismuth is administered orally.
Ar~ ~,icrobial The processes of the present invention also include administration of a safe and effective amount of one or more antil,,i~;,ubials, per day. As used herein, the term "aoli",ic,ubial(s)" refers to one or more a"li",icrobials.
Typically, according to the present Ill~lhods for prevention and dl",ent, each of the one or more a"li")icrobials is adr"i,-istered at a level of from about 100 milligrams to about 10,000 milligrams, per day, for from about 1 to about 28 days. Preferably, each of the one or more anli",icrobials is adnlinistered at a level of from about 100 Illilligrdllls to about 8000 milligrams per day, and more preferdbly at from about 100 ",illi$~rd"~s to about 5000 milligran,s per day. It is also preferred that each of CA 022197~8 1997-10-29 W 096/35436 PCTrUS9G/OCq89 the antimicrobials is administered for from about 1 to about 7 to 10 days, more preferably for from about 1 to about 14 days, and most preferably for from about 1 to about 21 days. In the methods for prevention, it is further preferred that each of the one or more antimicrobials is administered for from about 1 to about 14 days, and preferably for from about 1 to about 7 to 10 days.
The specific dosage of antimicrobial(s) to be administered, as well as the duration of antimicrobial(s) treatment, are mutually dependent, and will also depend upon such factors as the specific anli"~icrobial used, the number of antimicrobials used in the treatment, the resistance pattern of the infecting organism to the antimicrobial used, the ability of the antimicrobial to reach minimum inhibitory concentrations at the site of the infection, the nature and extent of other infections (if any), the personal attributes of the subject, compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. Therefore, in the case of prevention or treatment with more than one a"li,~icrobial, the duration of administration should depend on the type of antimicrobial rather than the administration of the antimicrobials for the same number of days.
A wide variety of antimicrobials are useful in this invention. As used herein, the term "anlimicrobial" refers to any naturally-occurring, synthetic orsemi-synthetic compound or composition or mixture thereof, which is safe for human use as used in the methods of this invention, and is effective in killing or substantially inhibiting the parasitic protozoa when used in the methods of this invention. Antiprotozoal agents, antiparasitic agents and antibiotics are among the preferred antimicrobials useful herein.
Antiprotozoal and antiparasitic agents suitable for use in the present invention include any of the agents recognized in the medical community as acceptable for treating protozoal infection. Such antiprotozoal and antiparasitic agents include atovaquone, chloroquine phosphate, quinacrine hydrochloride, iodoquinol, pyrimethamine, and mefloquine hydrochloride.
Antibiotics can be generally classified by chemical composition, into the following principal groups: the aminoglycosides, such as gentamicin, neomycin, kanamycin, and streptomycin; the macrolides, such as erythromycin, clindamycin, and rifampin; the penicillins, such as penicillin G, penicillin V, ampicillin and amoxycillin; the polypeptides such as bacitracin and polymyxin; the tetracyclines such as tetracycline, chlortetracycline, oxytetracycline and doxycycline; the cephalosporins such as cephalexin and CA 022197~8 1997-10-29 W096135436 PCTrUS~/OG~89 cephalothin; quinolones such as ciprofloxacin, norf oxacin and ofloxacin;
and such miscellaneous antibiotics as chloramphenicol and clindamycin.
These antibiotics can generally be said to function in one of four ways:
inhibition of cell wall synthesis, alteration of cell wall permeability, inhibition of protein synthesis or inhibition of nucleic acid synthesis. -' Other antimicrobials useful herein include the sulfonamides;
nitrofurans, such nitrofurazon, nitrofurantoin, and furozolidone;
metronidazole, tinidazole, and nimorazole. Antimicrobials among those useful herein are described in Remington's Pharmaceutical Sciences. 18th Edition, pp. 1173-1232 (1990), which is incorporated herein by reference.
While any of these antimicrobials may be used, penicillin, erythromycin, metronidazole, doxycycline, tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone are among the preferred antimicrobials for use in the present invention.
As stated above, the specific preferred quantity of antimicrobial and duration of treatment used in the methods of this invention will, in addition toother factors, depend upon the particular a"lin,i-robial used and its pharmacology. In general, though, the tetracyclines are preferably administered at a level of from about 100 milligrams to about 2,000 milligrams per day. Macrolides (such as erythromycin) are preferably administered at a level of from about 1,000 milligrams to about 4,000 milligrams per day. Penicillins are preferably administered at a level of from about 500 milligralos to about 3,000 milligrams per day. The aminoglycosides (such as neomycin) are preferably administered at a level of from about 100 milligrams to about 8,000 milligrams per day. Nitrofurans (such as nitrofurantoin) are administered preferably at levels of from about 100 milligrams to about 800 Illilli5~ldms per day. Preferably, metronidazole is ad",i.,istered at a level of from about 500 to about 2,000 milligrams per day. P,eft:ral)ly, atovaquone is administered at a level of from about 750 to about 2250 milliyrar"s, per day.
The specific method of ad",i"istering the a"li",icrobial, according to the processes of this invention, may depend upon such factors as the particular antimicrobial(s) used, the site of infection, the amount of anli",icrobial(s) to be administered per day, the presence of any adverse side effects, and the interactions (if any) between the antimicrobial(s) and the bismuth. Thus, the a"li",ic~obial(s) may be administered under the process of this invention by single daily doses, or by administration in two, CA 022l97~8 l997-l0-29 three, four, or more doses per day. One factor, in particular, in potential interaction between the antimicrobial(s) and the bismuth administered under ~ these processes. For example, the presence of bismuth is known to adversely affect the efficacy of the tetracyclines. See, for example, C. D.
Ericsson, et al., "Influence of Subsalicylate Bismuth on Absorption of Doxycycline", 247 J. of American Medical Assoc. 2266 (1982). Hence, it is preferred to administer those a"li",icrobials that are subject to adverse bismuth interaction by methods that minimize such interactions, i.e., by minimizing the simultaneous presence of antimicrobial and bismuth in the stomach. Such methods include one or more of the following: staggered oral dosing of the bismuth and antimicrobial, through discreet administrations of each compound or composition separated by at least preferably two hours between dosages; oral administration of the antimicrobial in an enterically coated form, i.e., coating of the a"li",icrobialwhich prevents dissolution of the anli" ,icrobial in the stomach; use of optional processes of this invention, wherein the step of administering the bismuth is terminated prior to commencing the step of orally administering the antimicrobial; and administering the anli",icrobial by a non-oral route, e.g., by intravenous or intramuscular injection.
Bismuth/Antimicrobial ComPositions:
The present invention also provides compositions for the treatment of gasl,oi"testinal disorders comprising a safe and effective amount of bismuth and a safe and effective amount of one or more al,li",icrobials. Typically, these compositions comprise a safe and effective amount one or more a"li" ,icr(,l,ials; a safe and effective amount of bismuth; and pl,al",aceutically-accepl~ble carrier materials; wherein the safe and effective amount of the one or more antimicrobials and the bismuth is effective for preventing and/or treating a gastrGinLes~li"al disorder caused or me-Ji~led by one or more parasitic protozoa.
A preferred composition comprises:
(a) from about 50 milligrams to about 5,000 milliyrdms of bismuth;
and (b) from about 100 milligrams to about 10,000 milligrams of each of one or more a"li",icrobials.
Preferably, the bismuth salt is present at a level of from about 50 milligrams to about 2500 milligrams. Also, preferably each of the one or more CA 022197~8 1997-10-29 antimicrobials is present at a level of from about 100 milligrams to about 8000 milligrams.
The compositions of 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 dosage form to be used. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders.
Tablets can be compressed, tablet triturates, enteric-coated, sugar coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions, and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents.
Specific examples of pharmaceutically-acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Patent 3,903,297, Robert, issued Septel"ber 2, 1975, incorporated by reference herein. Techniques and compositions for making dosage forms useful herein are described in the following references, all incorporated by reference herein: 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker and Rhodes, editors, 1979); an Lieberman, et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms (2d edition,1976).
As ~iscusseri above, care must be taken in avoiding any interactions between the bismuth compound or composition and the particular anli",ic,~bial(s) used in these cornrositions. Accordingly, in prefe"ed compositions of this invention, one or more of the al,li",icrobials is physically separated from the bismuth in such a manner so that the antimicrobial(s) and the bismuth are not simultaneously dissolved in the sLolllach. Hence, a preferred composition of this invention comprises a capsule containing bismuth particles and enterically-coated antimicrobial particles.
The compositions of this invention may be used according to the methods of this invention by administering the composition from 1 to 7 times per day, and p~ferably from 1 to 4 times per day; for from 1 to 21 days, CA 022l97~8 l997-l0-29 W 096/35436 PCTrUS9GI*6189 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 and antimicrobial(s) used, 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.
The present invention comprises methods wherein the administration of bismuth and the administration of one or more arlLi",ic,obials are 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 administeri"g 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 gastrointestinal disorder. Frer~rdbly, the bismuth is administered orally. Also preferably, the a"li",icrobial(s) is administered either orally, intravenously, or any other method which effects systemic distribution, or local distribution to the site of the gastroi"le~li"aldisorder, of the anlil "ic, ~,bial(s) in the subject. Oral ingestion of the anli",i obial(s) is a preferred method of administering the antimicrobial(s) in the methods of this invention.
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 lod of the present invention. Fecal samples are taken from the subject and analyzed for the presence of i"lesli"al parasites, including organism eggs, cysts, sporozoites, etc. Clinical parasitology specimens reveal the presence of Cryptosporidium parvum. The subject is then treated by admir,isteri"g a composition containing bismuth 5l~hs~licylate~ 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.
Atovaquone tablets (750 milligrams per tablet) is concurrently administered three times a day for 21 days, delivering a total of 2250 Illilligldllls of atovaquone per day. Thereafter, fecal samples from the s~bject are CA 022197~8 1997-10-29 W 096/35436 PCTrUS~6/OC~89 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, J
respectively, for bismuth subsalicylate, with substantially similar results.
EXAMPLE ll 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 and 100 milligrams of furolzolidone, four times daily, for about 10 days. Thereafter, fecal samples from the subject are analyzed again, finding no trace of parasitic infection.
EXAMPLE lll 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, Cryptosporidium parvum, and Entamoeba hisfolyfica. 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, and 750 milligrams of metronir~a~ , three times daily, for about 21 days. Upon return to the U.S., approxi"lately 30 days after the initial clinical analysis, the subject remains asymptomatic. Fecal samples from the subject are analyzed and no evidence of parasitic inr~ctiol, is found.
EXAMPLE IV
Four young Boy Scouts, having enjoyed a week of primitive camping and fishing in the bayous of Louisiana, reported flulike symptoms, including nausea, vomiting, anorexia, weight loss, and explosive diarrhea one week following their trip return. Fecal bacterial isolates and immunodiagnostics fail to identify the offending pathogen. Direct wet mount exan,i"dlion of the boys' diarrheic fecal specimens reveal the presence of the trophozoite stage of Dientamoeba fragilis. Following the diagnosis, the pdlienls are treated by administering 500 milligra,.,s of bismuth subgallate per day (two doses per CA 022197~8 1997-10-29 W 096/35436 PCTtUS9GtOC489 day) for 21 days. After the second day (commencing on the third day) of bismuth treatment, the patients are aiso treated by administering 750 milligrams of nitrofurantoin, per day, for 10 days. (Hence, bismuth treatment continues for 9 days after the last antimicrobial treatment). Fecal specimens ~ are then collected from the patients and wet mount examinations are performed. There is no indication of parasitic infection.
In the above example, nitrofurazone, metronidazole, and tinidazole are substituted, respectively, for nitrofurantoin, with substantially-similar results.
EXAMPLE V
A pig farmer reports chronic abdominal pain, severe cramps, n~l-se~, vomiting, tenesmus, and frequent watery, mucoid diarrhea. Examination of saline mounts of sigmoidoscopic aspirates reveal the presence of numerous ciliated trophozoites of Balanfidium co/i, readily recognized by their characteristic large size (50-200 micrometers), shape, and rapid rotating motion. The subject is treated, according to the present invention, by concurrent ad."i.,istration of 500 milligrams of tetracycline four times a day (for a daily total of 2 grams) and 650 milligrams of iodoquinol three times a day (for a daily total of 1850 milligrams) for 20 days. After five days (commencing on the sixth day), a composition containing tripotassium dicitrato bismuthate manufactured by Gist Brocades,. and sold under the name "De-Nol") is administered four times a day (for a daily total of 480 milligrams) for 15 days. Sigmoidoscopic aspirates were taken following the conclusion of treatment and ev~ t~ci for parasitic presence. The specimens were normal and the patient was asy""~to",dLic.
In the above example, bismuth citrate, bismuth tartrate, bismuth suL,cil, dle~ bismuth alu" ,i, ldte and bismuth subsalicylate are substituted, respsctively, for tripotassium dicitrato bismuthate, with substantially similar results. Similarly, penicillin, erythromycin, metronid~ - ~ l o, doxycycline, tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone are substituted respectively for tetracycline or iodoquinol, with substantially similar results. In addition, either a"liLiJIic can be eliminated from the regimen (e.g. due to hypersensitivity) and maintain therapeutic efficacy.
COMh~lU..~ CO~ff wsnNG B~hnrrH ~ND ONE OR MORB ~NmMncRoBLuLs~poR THE
TRE~l~n3NT ~NDPREVE~n~ON OF GASTRO~ ALl~-O~r~-c 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 re~li7~d in the United States, as it was generally believed that this was an illness of impoverished, developing countries. Since that time, parasites such as Cryptosporidium, 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 Cryptosporidium 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 adminisl, dliGI, of bismuth salts and one or more antimicrobials may be effective for the prevention and/or treatment of gastrointestinal disorders caused or mediated by parasitic p~uto~oan. Thus, an object of the present invention is to provide safe and effective compositions and methods for preventing and/or treating gastroi"leslinal disorders c~l~sed or n,edidled by pd,dsilic protozoa. A further object of the invention is to provide such a method comprising the administration of bismuth and one or more anlil "ic~ obials.
These and other objects of the present invention will become readily apparent from the det~iled 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 sl~bject from about 50 milligrams to about 5000 milligrams of bismuth, per day, for from about 1 to 56 days; and from about 100 milligrams to about CA 022197~8 1997-10-29 W09613S436 PCT/U~3~/~6~89 10,000 milligrams of each of one or more antimicrobiais, per day, for from about 1 to about 21 days.
The present invention also relates to a method of prevention in a human or lower animal for 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; and from about 100 milligrams to about 10,000 milligrams of each of one or more antimicrobials, per day, for from about 1 to about 14 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 and one or more a"lil~icrobials.
The components of the present invention are more fully defined below.
Gastrointestinal Disorder The term ''gasl,ui,,lesli,,al disorder", as used herein, encorrlp~sses any infection, disease or other disorder of body, typically the upper and/or iower gasfro~,~LesG"al tract, caused or mediafed by one or rnore parasitic proto,oa. 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 :~sso~ i~ted with infection by parasitic protozoa.
In immunocompromised subjects and children, gastroi"teslinal disorders c~ secl or medi~ted by parasitic protozoa may be more severe and life threatening than the common disorders listed above. Therefore, the term "ga~L,ui"leslinal disorder" also includes any condition commonly associated with protozoa infection in immunocompromised subjects and children, including but not limited to, acute diarrhea, dehydration, electrolyteimbalance, colitis, and fatal necrosis of the i, lleslil ,e.
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 Microbioloqv. 20th Edition, 1992, pp. 1 163-1 173, and T. L. Kuhls, M.D., "P, oto~oal Infections of the Intestinal CA 022197~8 1997-10-29 W 096/3~436 PCTAUS~IOC189 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 phyla Sarcomastigophora such as Entamoeba, Giardia, Dientamoeba, and Blastocystis; Ciliophora (ciliates) such as Balantidium; Apicomplexa such as Isospora and Clyptosporidium; and Microspora such as Enterocytozoon.
Preferred parasitic protozoa are Entamoeba, Cryptosporidium, Giardia, Isospora, and combinations thereof. Most preferred parasitic protozoa are Entamoeba, Cryptosporidium, 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 milligrari,s, 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 parasilic proLo,oa. 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 l"edical 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.
CA 022l97~8 l997-l0-29 W096/35436 PCTfUS9G/OC~189 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"32-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 subgallate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicyiate, 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); Devroma~, 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 gastroinleslinal disorder. P,~ferably, the bismuth is administered orally.
Ar~ ~,icrobial The processes of the present invention also include administration of a safe and effective amount of one or more antil,,i~;,ubials, per day. As used herein, the term "aoli",ic,ubial(s)" refers to one or more a"li",icrobials.
Typically, according to the present Ill~lhods for prevention and dl",ent, each of the one or more a"li")icrobials is adr"i,-istered at a level of from about 100 milligrams to about 10,000 milligrams, per day, for from about 1 to about 28 days. Preferably, each of the one or more anli",icrobials is adnlinistered at a level of from about 100 Illilligrdllls to about 8000 milligrams per day, and more preferdbly at from about 100 ",illi$~rd"~s to about 5000 milligran,s per day. It is also preferred that each of CA 022197~8 1997-10-29 W 096/35436 PCTrUS9G/OCq89 the antimicrobials is administered for from about 1 to about 7 to 10 days, more preferably for from about 1 to about 14 days, and most preferably for from about 1 to about 21 days. In the methods for prevention, it is further preferred that each of the one or more antimicrobials is administered for from about 1 to about 14 days, and preferably for from about 1 to about 7 to 10 days.
The specific dosage of antimicrobial(s) to be administered, as well as the duration of antimicrobial(s) treatment, are mutually dependent, and will also depend upon such factors as the specific anli"~icrobial used, the number of antimicrobials used in the treatment, the resistance pattern of the infecting organism to the antimicrobial used, the ability of the antimicrobial to reach minimum inhibitory concentrations at the site of the infection, the nature and extent of other infections (if any), the personal attributes of the subject, compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. Therefore, in the case of prevention or treatment with more than one a"li,~icrobial, the duration of administration should depend on the type of antimicrobial rather than the administration of the antimicrobials for the same number of days.
A wide variety of antimicrobials are useful in this invention. As used herein, the term "anlimicrobial" refers to any naturally-occurring, synthetic orsemi-synthetic compound or composition or mixture thereof, which is safe for human use as used in the methods of this invention, and is effective in killing or substantially inhibiting the parasitic protozoa when used in the methods of this invention. Antiprotozoal agents, antiparasitic agents and antibiotics are among the preferred antimicrobials useful herein.
Antiprotozoal and antiparasitic agents suitable for use in the present invention include any of the agents recognized in the medical community as acceptable for treating protozoal infection. Such antiprotozoal and antiparasitic agents include atovaquone, chloroquine phosphate, quinacrine hydrochloride, iodoquinol, pyrimethamine, and mefloquine hydrochloride.
Antibiotics can be generally classified by chemical composition, into the following principal groups: the aminoglycosides, such as gentamicin, neomycin, kanamycin, and streptomycin; the macrolides, such as erythromycin, clindamycin, and rifampin; the penicillins, such as penicillin G, penicillin V, ampicillin and amoxycillin; the polypeptides such as bacitracin and polymyxin; the tetracyclines such as tetracycline, chlortetracycline, oxytetracycline and doxycycline; the cephalosporins such as cephalexin and CA 022197~8 1997-10-29 W096135436 PCTrUS~/OG~89 cephalothin; quinolones such as ciprofloxacin, norf oxacin and ofloxacin;
and such miscellaneous antibiotics as chloramphenicol and clindamycin.
These antibiotics can generally be said to function in one of four ways:
inhibition of cell wall synthesis, alteration of cell wall permeability, inhibition of protein synthesis or inhibition of nucleic acid synthesis. -' Other antimicrobials useful herein include the sulfonamides;
nitrofurans, such nitrofurazon, nitrofurantoin, and furozolidone;
metronidazole, tinidazole, and nimorazole. Antimicrobials among those useful herein are described in Remington's Pharmaceutical Sciences. 18th Edition, pp. 1173-1232 (1990), which is incorporated herein by reference.
While any of these antimicrobials may be used, penicillin, erythromycin, metronidazole, doxycycline, tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone are among the preferred antimicrobials for use in the present invention.
As stated above, the specific preferred quantity of antimicrobial and duration of treatment used in the methods of this invention will, in addition toother factors, depend upon the particular a"lin,i-robial used and its pharmacology. In general, though, the tetracyclines are preferably administered at a level of from about 100 milligrams to about 2,000 milligrams per day. Macrolides (such as erythromycin) are preferably administered at a level of from about 1,000 milligrams to about 4,000 milligrams per day. Penicillins are preferably administered at a level of from about 500 milligralos to about 3,000 milligrams per day. The aminoglycosides (such as neomycin) are preferably administered at a level of from about 100 milligrams to about 8,000 milligrams per day. Nitrofurans (such as nitrofurantoin) are administered preferably at levels of from about 100 milligrams to about 800 Illilli5~ldms per day. Preferably, metronidazole is ad",i.,istered at a level of from about 500 to about 2,000 milligrams per day. P,eft:ral)ly, atovaquone is administered at a level of from about 750 to about 2250 milliyrar"s, per day.
The specific method of ad",i"istering the a"li",icrobial, according to the processes of this invention, may depend upon such factors as the particular antimicrobial(s) used, the site of infection, the amount of anli",icrobial(s) to be administered per day, the presence of any adverse side effects, and the interactions (if any) between the antimicrobial(s) and the bismuth. Thus, the a"li",ic~obial(s) may be administered under the process of this invention by single daily doses, or by administration in two, CA 022l97~8 l997-l0-29 three, four, or more doses per day. One factor, in particular, in potential interaction between the antimicrobial(s) and the bismuth administered under ~ these processes. For example, the presence of bismuth is known to adversely affect the efficacy of the tetracyclines. See, for example, C. D.
Ericsson, et al., "Influence of Subsalicylate Bismuth on Absorption of Doxycycline", 247 J. of American Medical Assoc. 2266 (1982). Hence, it is preferred to administer those a"li",icrobials that are subject to adverse bismuth interaction by methods that minimize such interactions, i.e., by minimizing the simultaneous presence of antimicrobial and bismuth in the stomach. Such methods include one or more of the following: staggered oral dosing of the bismuth and antimicrobial, through discreet administrations of each compound or composition separated by at least preferably two hours between dosages; oral administration of the antimicrobial in an enterically coated form, i.e., coating of the a"li",icrobialwhich prevents dissolution of the anli" ,icrobial in the stomach; use of optional processes of this invention, wherein the step of administering the bismuth is terminated prior to commencing the step of orally administering the antimicrobial; and administering the anli",icrobial by a non-oral route, e.g., by intravenous or intramuscular injection.
Bismuth/Antimicrobial ComPositions:
The present invention also provides compositions for the treatment of gasl,oi"testinal disorders comprising a safe and effective amount of bismuth and a safe and effective amount of one or more al,li",icrobials. Typically, these compositions comprise a safe and effective amount one or more a"li" ,icr(,l,ials; a safe and effective amount of bismuth; and pl,al",aceutically-accepl~ble carrier materials; wherein the safe and effective amount of the one or more antimicrobials and the bismuth is effective for preventing and/or treating a gastrGinLes~li"al disorder caused or me-Ji~led by one or more parasitic protozoa.
A preferred composition comprises:
(a) from about 50 milligrams to about 5,000 milliyrdms of bismuth;
and (b) from about 100 milligrams to about 10,000 milligrams of each of one or more a"li",icrobials.
Preferably, the bismuth salt is present at a level of from about 50 milligrams to about 2500 milligrams. Also, preferably each of the one or more CA 022197~8 1997-10-29 antimicrobials is present at a level of from about 100 milligrams to about 8000 milligrams.
The compositions of 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 dosage form to be used. Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders.
Tablets can be compressed, tablet triturates, enteric-coated, sugar coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions, and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring, and flavoring agents.
Specific examples of pharmaceutically-acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Patent 3,903,297, Robert, issued Septel"ber 2, 1975, incorporated by reference herein. Techniques and compositions for making dosage forms useful herein are described in the following references, all incorporated by reference herein: 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker and Rhodes, editors, 1979); an Lieberman, et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms (2d edition,1976).
As ~iscusseri above, care must be taken in avoiding any interactions between the bismuth compound or composition and the particular anli",ic,~bial(s) used in these cornrositions. Accordingly, in prefe"ed compositions of this invention, one or more of the al,li",icrobials is physically separated from the bismuth in such a manner so that the antimicrobial(s) and the bismuth are not simultaneously dissolved in the sLolllach. Hence, a preferred composition of this invention comprises a capsule containing bismuth particles and enterically-coated antimicrobial particles.
The compositions of this invention may be used according to the methods of this invention by administering the composition from 1 to 7 times per day, and p~ferably from 1 to 4 times per day; for from 1 to 21 days, CA 022l97~8 l997-l0-29 W 096/35436 PCTrUS9GI*6189 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 and antimicrobial(s) used, 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.
The present invention comprises methods wherein the administration of bismuth and the administration of one or more arlLi",ic,obials are 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 administeri"g 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 gastrointestinal disorder. Frer~rdbly, the bismuth is administered orally. Also preferably, the a"li",icrobial(s) is administered either orally, intravenously, or any other method which effects systemic distribution, or local distribution to the site of the gastroi"le~li"aldisorder, of the anlil "ic, ~,bial(s) in the subject. Oral ingestion of the anli",i obial(s) is a preferred method of administering the antimicrobial(s) in the methods of this invention.
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 lod of the present invention. Fecal samples are taken from the subject and analyzed for the presence of i"lesli"al parasites, including organism eggs, cysts, sporozoites, etc. Clinical parasitology specimens reveal the presence of Cryptosporidium parvum. The subject is then treated by admir,isteri"g a composition containing bismuth 5l~hs~licylate~ 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.
Atovaquone tablets (750 milligrams per tablet) is concurrently administered three times a day for 21 days, delivering a total of 2250 Illilligldllls of atovaquone per day. Thereafter, fecal samples from the s~bject are CA 022197~8 1997-10-29 W 096/35436 PCTrUS~6/OC~89 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, J
respectively, for bismuth subsalicylate, with substantially similar results.
EXAMPLE ll 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 and 100 milligrams of furolzolidone, four times daily, for about 10 days. Thereafter, fecal samples from the subject are analyzed again, finding no trace of parasitic infection.
EXAMPLE lll 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, Cryptosporidium parvum, and Entamoeba hisfolyfica. 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, and 750 milligrams of metronir~a~ , three times daily, for about 21 days. Upon return to the U.S., approxi"lately 30 days after the initial clinical analysis, the subject remains asymptomatic. Fecal samples from the subject are analyzed and no evidence of parasitic inr~ctiol, is found.
EXAMPLE IV
Four young Boy Scouts, having enjoyed a week of primitive camping and fishing in the bayous of Louisiana, reported flulike symptoms, including nausea, vomiting, anorexia, weight loss, and explosive diarrhea one week following their trip return. Fecal bacterial isolates and immunodiagnostics fail to identify the offending pathogen. Direct wet mount exan,i"dlion of the boys' diarrheic fecal specimens reveal the presence of the trophozoite stage of Dientamoeba fragilis. Following the diagnosis, the pdlienls are treated by administering 500 milligra,.,s of bismuth subgallate per day (two doses per CA 022197~8 1997-10-29 W 096/35436 PCTtUS9GtOC489 day) for 21 days. After the second day (commencing on the third day) of bismuth treatment, the patients are aiso treated by administering 750 milligrams of nitrofurantoin, per day, for 10 days. (Hence, bismuth treatment continues for 9 days after the last antimicrobial treatment). Fecal specimens ~ are then collected from the patients and wet mount examinations are performed. There is no indication of parasitic infection.
In the above example, nitrofurazone, metronidazole, and tinidazole are substituted, respectively, for nitrofurantoin, with substantially-similar results.
EXAMPLE V
A pig farmer reports chronic abdominal pain, severe cramps, n~l-se~, vomiting, tenesmus, and frequent watery, mucoid diarrhea. Examination of saline mounts of sigmoidoscopic aspirates reveal the presence of numerous ciliated trophozoites of Balanfidium co/i, readily recognized by their characteristic large size (50-200 micrometers), shape, and rapid rotating motion. The subject is treated, according to the present invention, by concurrent ad."i.,istration of 500 milligrams of tetracycline four times a day (for a daily total of 2 grams) and 650 milligrams of iodoquinol three times a day (for a daily total of 1850 milligrams) for 20 days. After five days (commencing on the sixth day), a composition containing tripotassium dicitrato bismuthate manufactured by Gist Brocades,. and sold under the name "De-Nol") is administered four times a day (for a daily total of 480 milligrams) for 15 days. Sigmoidoscopic aspirates were taken following the conclusion of treatment and ev~ t~ci for parasitic presence. The specimens were normal and the patient was asy""~to",dLic.
In the above example, bismuth citrate, bismuth tartrate, bismuth suL,cil, dle~ bismuth alu" ,i, ldte and bismuth subsalicylate are substituted, respsctively, for tripotassium dicitrato bismuthate, with substantially similar results. Similarly, penicillin, erythromycin, metronid~ - ~ l o, doxycycline, tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone are substituted respectively for tetracycline or iodoquinol, with substantially similar results. In addition, either a"liLiJIic can be eliminated from the regimen (e.g. due to hypersensitivity) and maintain therapeutic efficacy.
Claims (26)
1. The use of from 50 milligrams to 5000 milligrams of bismuth per day for from 1 to 56 days and from 100 milligrams to 10000 milligrams of each of one or more antimicrobials per day for from 1 to 28 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 administered at a level of from 50 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 subgallate, bismuth subsalicylate, bismuth tartrate, and mixtures thereof.
4. The use according to Claims 1-3 wherein each of the one or more antimicrobials is administered at a level of from 100 milligrams to 8000 milligrams, per day.
5. The use according to Claims 14 wherein the one or more antimicrobials are selected from the group consisting of penicillin, erythromycin, metronidazole, doxycycline, tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone.
6. The use according to Claims 1-5 wherein the bismuth is administered for from 2 to 28 days and the one or more antimicrobials are administered for from 1 to 21 days.
7. The use according to Claims 1-6 wherein the parasitic protozoa are selected from the group consisting of Cryptosporidium, Giardia, Entamoeba, Isospora, and combinations thereof.
8. The use according to Claims 1-7 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; and from 100 milligrams to 10,000 milligrams of each of one or more antimicrobials, per day, for from 1 to 14 days.
9. The use according to Claim 8 wherein the bismuth is administered for from 1 to 14 days and the one or more antimicrobials are administered for from 1 to 7 to 10 days.
10. The use according to Claims 1-8 wherein the parasitic protozoa are selected from the group consisting of Cryptosporidium, Giardia, Entamoeba, Isospora, and combinations thereof.
11. 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; and from about 100 milligrams to about 10,000 milligrams of each of one or more antimicrobials, per day, for from about 1 to about 28 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 12 wherein the bismuth is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subsalicylate, bismuth tartrate, and mixtures thereof.
14. The method of Claim 11 wherein each of the one or more antimicrobials is administered at a level of from about 100 milligrams to about 8000 milligrams, per day.
15. The method of Claim 14 wherein the one or more antimicrobials are selected from the group consisting of penicillin, erythromycin, metronidazole, doxycycline, tinidazole, amoxycillin, ampicillin, nitrofurantoin, and atovaquone.
16. The method of Claim 11 wherein the bismuth is administered for from about 2 to 28 days and the one or more antimicrobials are administered for from about 1 to about 21 days.
17. The method of Claim 11 wherein the parasitic protozoa are selected from the group consisting of Cryptosporidium, Giardia, Entamoeba, Isospora, and combinations thereof.
18. 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 about 21 days; and from about 100 milligrams to about 10,000 milligrams of each of one or more antimicrobials, per day, for from about 1 to about 14 days.
19. The method of Claim 18 wherein the bismuth is administered at a level of from about 50 milligrams to about 2500 milligrams, per day.
20. The method of Claim 19 wherein the bismuth is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgallate, bismuth subsalicylate, bismuth tartrate, and mixtures thereof.
21. The method of Claim 18 wherein each of the one or more antimicrobials is administered at a level of from about 100 milligrams to about 8000 milligrams, per day.
22. The method of Claim 21 wherein the one or more antimicrobials are selected from the group consisting of penicillin, erythromycin, metronidazole doxycycline tinidazole amoxycillin ampicillin nitrofurantoin and atovaquone.
23. The method of Claim 18 wherein the bismuth is administered for from about 1 to about 14 days and the one or more antimicrobials are administered for from about 1 to about 7 to 10 days.
24. The method of Claim 18 wherein the parasitic protozoa are selected from the group consisting of Cryptosporidium, Giardia, Entamoeba, Isospora, and combinations thereof.
25. The method of Claim 11 wherein the subject is administered a composition comprising:
(a) a safe and effective amount of bismuth;
(b) a safe and effective amount of one or more antimicrobials;
(c) pharmaceutically-acceptable carriers materials; and wherein the safe and effective amount of the bismuth and one or more antimicrobials is effective for treating the gastrointestinal disorder caused or mediated by one or more parasitic protozoa.
(a) a safe and effective amount of bismuth;
(b) a safe and effective amount of one or more antimicrobials;
(c) pharmaceutically-acceptable carriers materials; and wherein the safe and effective amount of the bismuth and one or more antimicrobials is effective for treating the gastrointestinal disorder caused or mediated by one or more parasitic protozoa.
26. The method of Claim 18 wherein the subject is administered a composition comprising:
a) a safe and effective amount of bismuth;
(b) a safe and effective amount of one or more antimicrobials;
(c) pharmaceutically-acceptable carriers materials; and wherein the safe and effective amount of the bismuth and one or more antimicrobials is effective for preventing the gastrointestinal disorder caused or mediated by one or more parasitic protozoa.
a) a safe and effective amount of bismuth;
(b) a safe and effective amount of one or more antimicrobials;
(c) pharmaceutically-acceptable carriers materials; and wherein the safe and effective amount of the bismuth and one or more antimicrobials is effective for preventing the gastrointestinal disorder caused or mediated by one or more parasitic protozoa.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US43747595A | 1995-05-09 | 1995-05-09 | |
| US437,475 | 1995-05-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2219758A1 true CA2219758A1 (en) | 1996-11-14 |
Family
ID=23736610
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002219758A Abandoned CA2219758A1 (en) | 1995-05-09 | 1996-05-08 | Compositions comprising bismuth and one or more antimicrobials, for the treatment and prevention of gastrointestinal disorders |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0830135A1 (en) |
| JP (1) | JPH11504940A (en) |
| AU (1) | AU5733696A (en) |
| CA (1) | CA2219758A1 (en) |
| PE (1) | PE48297A1 (en) |
| WO (1) | WO1996035436A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2791888B1 (en) * | 1999-04-06 | 2004-10-08 | Ethypharm Lab Prod Ethiques | ORAL PHARMACEUTICAL SUSPENSION |
| AU771516B2 (en) | 1999-04-06 | 2004-03-25 | Laboratoires Des Produits Ethiques Ethypharm | Drinkable ibuprofen pharmaceutical suspension |
| KR20190026962A (en) | 2014-09-05 | 2019-03-13 | 심바이오믹스 세러퓨틱스 엘엘씨 | Secnidazole for use in the treatment of bacterial vaginosis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG72632A1 (en) * | 1985-04-18 | 2000-05-23 | Procter & Gamble | Treatment of non-ulcer dyspepsia with bismuth salts |
| DE3650504T2 (en) * | 1985-06-13 | 1996-10-31 | Barry James Marshall | Methods and compositions for the treatment of gastrointestinal disorders |
| EP0439453B1 (en) * | 1987-10-12 | 1994-01-19 | Exomed Australia Pty. Ltd. (ACN 051 976 446) | Improved method for treatment of gastrointestinal disorders |
| DE59309771D1 (en) * | 1993-05-11 | 1999-10-14 | Spirig Ag | Solid bismuth and amoxycillin medicinal product and its use |
-
1996
- 1996-05-08 JP JP8534218A patent/JPH11504940A/en active Pending
- 1996-05-08 CA CA002219758A patent/CA2219758A1/en not_active Abandoned
- 1996-05-08 WO PCT/US1996/006489 patent/WO1996035436A1/en not_active Application Discontinuation
- 1996-05-08 AU AU57336/96A patent/AU5733696A/en not_active Abandoned
- 1996-05-08 PE PE1996000327A patent/PE48297A1/en not_active Application Discontinuation
- 1996-05-08 EP EP96915594A patent/EP0830135A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO1996035436A1 (en) | 1996-11-14 |
| AU5733696A (en) | 1996-11-29 |
| EP0830135A1 (en) | 1998-03-25 |
| PE48297A1 (en) | 1998-02-04 |
| JPH11504940A (en) | 1999-05-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |