Note: Descriptions are shown in the official language in which they were submitted.
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COM~ nJNS OONTAnnNG B~hnrrH, FOR '1~ TREAT~n~NT AND PRE~ ~.l OF
GASTROnrn~lNALI~l'O~
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~li7ed 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
administration of bismuth salts may be effective for the prevention and/or
treatment of gastroinleslinal 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 gasl, uinlesLi, ,al disorders
c:~llsecl or mediated by parasitic protc~oa. 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 descri~.lion which follows.
SUMMARY OF THE INVENTION
q The present invention relates to a method for treatment of a humanor lower animal subject having a gasl,ointeslinal disorder caused or
mediated by one or more parasitic p~l.,,oa comprising administering to the
subject from about 50 milligra",s 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 gastroi"leslinal disorder c~used or mediated by
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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 "gastroi"Leslil,al 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, gastroinLesLinal
disorders caused or mediated by parasitic protozoa may be more severe
and life threatening than the common disorders listed above. Therefore, the
term "gastroi"lesli"al disorder" also includes any condition commonly
associated with protozoa infecLion in immunocompromised subjects and
children, including but not limited to, acute diarrhea, dehydration, electrolyteimbalance, colitis, and fatal necrosis of the inle~li"e.
Parasitic P,uto~oa
Protozoa are unicelll ll~r, eucaryotic organisms which contain a
nucleus, or nuclei, and cytoplasm. Four groups of Protozoa cGnlain
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., "Plolo,oal Infections of the Intestinal
Tract in Children", Advances In Pediatric Infectious Dise~ses, 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
Sa, ~;o" ,asligophora such as Entamoeba, Giardia, Dientamoeba, and
Blastocystis; Ciliophora such as Balantidium; Apicomplexa such as Isospora
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and Cryptosporidium; 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 ad",i"istered
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
pule,,lial exposure to parasitic protc, oa. Such adminisl,dlion of bismuth
may vary depending on the likelihood of parasitic protozoa exposure and
con.lilion of the s~ ~hject and may be COI "" ,el ,ced at any time deemed
benericial 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-
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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 5~hs~ cylate (by The Procter & Gamble
Company).
As used herein, the term "acl,),i"istering" 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 l,~dl-"e"l of the gacil~oi~)lesli"al disorder. P,er~rdbly~ 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 i"lesli"al parasites, including organism
eggs, cysts, sporozoites, etc. Clinical parasitology specimens reveal the
presence of Crypfosporidium parvum. The subject is then treated by
administering a composition containing bismuth s~hs~licylate, sold by The
Procter & Gamble Company under the name "Pepto-Bismoltl9". The
composition, in liquid form, is ad",i"istered 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 inrecliG". The subject l~n)~dills asy,nptol),dlic~ and another
fecal analysis performed 5 IllGlllhs later is normal.
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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 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. 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,
Crypfosporidium parvum, and Entamoeba histolytica. Clinical results show
no evidence of the parasites. The subject is given approximately 1200
",il!;gr~",s of bismuth, (administered as bismuth subs~licylate 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
asy" Iplo, ~ IdLic. Fecal samples from the sl ~ject are analyzed and no
evidence of parasitic infection is found.
