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Description  |
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TECHNICAL FIELD
The present invention relates to methods for the treatment and prophylaxis
of infectious gastrointestinal disorders in humans and other animals.
BACKGROUND OF THE INVENTION
Factors adversely affecting the function of the gastrointestinal system in
humans are exceedingly varied in their nature. Such disorders may arise in
the upper or lower gastrointestinal tracts or both. There is a broad range
of causes of gastrointestinal disorders, including genetic, physiological,
environmental, and psychogenic factors. Accordingly, the diagnosis and
management of these disorders can be exceptionally difficult. A detailed
discussion of gastrointestinal tract functions, disorders, causes, and
treatments can be found in Spiro, Clinical Gastroenterology (3d. edition
1983).
Among the chronic disorders of the upper gastrointestinal tract are those
which fall under the general categories of gastritis and peptic ulcer
disease. (The upper gastrointestinal tract as used herein is defined as
including the esophagus, the stomach, the duodenum and the jejunum.)
Gastritis is, by definition, typified by an inflammation of the stomach
mucosa. In practice, though, the disorder is manifested by a broad range
of poorly-defined, and heretofore inadequately treated, symptoms such as
indigestion, "heart burn", dyspepsia and excessive eructation. A general
discussion of gastritis appears in B. J. Marshall and J. R. Warren,
"Unidentified Curved Bacilli in the Stomach of Patients with Gastritis and
Peptic Ulceration", The Lancet, (1984), pp. 1311-1315, and in R. Greenlaw,
et al., "Gastroduodenitis, A Broader Concept of Peptic Ulcer Disease",
Digestive Diseases and Sciences, Vol. 25 (1980), pp. 660-672.
Peptic ulcers are lesions of the gastrointestinal tract lining,
characterized by loss of tissue due to the action of digestive acids and
pepsin. It has been generally held that peptic ulcers are caused either by
gastric hypersecretion, or (more often) by decreased resistance of the
gastric lining to digestive acids and pepsin. The medical literature is
replete with methods for treating ulcers, including modification of the
diet, surgical removal of the lesions, and the use of drugs. Such drugs
include; antacids, which serve to counteract excess gastric secretions;
anticholinergics, which reduce acid secretion; H.sub.2 antagonists, which
also block the release of gastric acids; prostaglandins, which increase
the resistance of the gastric lining to digestive fluids, and may also
inhibit acid secretion; prokinetic agents, which enhance gastrointestinal
tract motility; and compositions which form protective barriers over
gastric lesions. Prescription and non-prescription drug therapies are
generally described in Garnet, "Antacid Products", Handbook of
Non-prescription Drugs, 7th edition (1982), Chapter 3.
Regardless of the particular drug composition used in treating
gastrointestinal disorders, such as gastritis or peptic ulcer disease, the
treatment is often imprecise and incomplete. Actual "cures", i.e.,
successful treatment resulting in total remission of disease, are very
often not effected. See A. J. McLean, et al., "Cyto-protective Agents and
Ulcer Relapse", 142 The Medical Journal of Australia, Special Supplement
S25-S28 (1985). Furthermore, many conventional treatments may render
subject hypochlorhydric (i.e., with low levels of hydrochloric acid in the
stomach) which may predispose them to other disorders, e.g.,
gastrointestinal infection, halitosis, and gastric carcinomas.
Nitrofurantoin is a well-known antibacterial compound and has been used
extensively as an active ingredient in antibacterial pharmaceutical
compositions. See, for example, Mintzer, S., E. R. Kadison, W. H. Shlaes &
O. Felsenfeld, "Treatment of Urinary Tract Infections with a New
Antibacterial Nitrofuran", Antibiotics & Chemotherapy, Vol. 3, No. 2
(Feb., 1953), pp. 151-157; Richards, W. A., E. Riss, E. H. Kass & M.
Finland, "Nitrofurantoin-Clinical and Laboratory Studies in Urinary Tract
Infections", Archives of Internal Medicine, Vol. 96 (1955), pp. 437-450;
Eudy, W. W., "Correlations Between In Vitro Sensitivity Testing and
Therapeutic Response in Urinary Tract Infections", Urology, Vol. II, No. 5
(Nov., 1973), pp. 519-587; Bush, I. M., W. I. Metzger, I. Garlovsky, R. B.
Bush, R. J. Ablin & N. Sadoughi, "Urinary Tract Infection-Antibacterial
Susceptibility Patterns", Urology, Vol. III, No. 6 (Jun., 1974), pp.
697-700; Dickey, L., "A Comparison of the In Vitro Effectiveness of
Nitrofurantoin and Five Antibiotics Against Bacteria from Urinary Tract
Infections", American Journal of Medical Technology, (Sept.-Oct., 1961),
pp. 273-279; Karmali, M. A., S. DeGrandis & P. C. Fleming, "Antimicrobial
Susceptibility of Campylobacter jejuni with Special Reference to
Resistance Patterns of Canadian Isolates", Antimicrobial Agents and
Chemotherapy, Vol. 19, No. 4 (1981), pp. 593-597. allergic response)
commensurate with a reasonable benefit/risk ratio when used in the manner
of this invention. The specific "safe and effective amount" will,
obviously, vary with such factors as the particular condition that is
being treated, the physical condition of the patient, the nature of
concurrent therapy (if any), and the specific formulations employed in the
present invention. Specifically, the processes of the present invention,
for the treatment and prophylaxis of a human or lower animal subject
having an infectious gastrointestinal disorder, comprise the step of
administering to said subject a safe and effective amount of
nitrofurantoin.
As used herein, "infectious gastrointestinal disorder" encompasses any
disease or other disorder of the upper gastrointestinal tract of a human
or lower animal which is caused or mediated by Campylobacter-like (renamed
Helicobacter) organisms (herein "CLO"), e.g., Campylobacter pyloridis
(renamed Helicobacter pylori). Such CLO include those described in J. R.
Warren and B. J. Marshall, "Unidentified Curved Bacilli on Gastric
Epithelium in Active Chronic Gastritis", The Lancet, (1983), pp.
1273-1275, incorporated by reference herein, and G. Kasper and N.
Dickgiesser, "Isolation from Gastric Epithelium of Campylobacter-like
Bacteria that are Distinct from `Campylobacter Pyloridis`", The Lancet,
(1985), pp. 111-112. Such infectious gastrointestinal disorders include,
for example: CLO-mediated disorders not manifested by presence of
ulcerations in the gastric mucosa (herein "non-ulcerative gastrointestinal
disorder"), including chronic or atrophic gastritis, non-ulcer dyspepsia,
esophogeal reflux disease and gastric motility disorders; and "peptic
ulcer disease", i.e., CLO-mediated gastric, duodenal, and jejunal ulcers.
As used herein, "administering" refers to any method which, in sound
medical practice, delivers the compounds or compositions used
SUMMARY OF THE INVENTION
It is an object of the present invention to provide novel methods of
treating infectious gastrointestinal disorders of the upper
gastrointestinal tract of a human or lower animal which are caused or
mediated by Campylobacter-like organisms.
It is also an object of the present invention to provide novel methods for
preventing recurrence of infectious gastrointestinal disorders of the
upper gastrointestinal tract of a human or lower animal which are caused
or mediated by Campylobacter-like organisms.
The present invention involves methods for the treatment of a human or
lower animal subject having an infectious gastrointestinal disorder or for
prevention of recurrence of such disorder comprising the step of
administering to such subject a safe and effective amount of
nitrofurantoin.
DETAILED DESCRIPTION OF INVENTION
The methods of the present invention comprise treatment of humans or lower
animals, having infectious gastrointestinal disorders, by administering
nitrofurantoin. Specific compositions to be used in the processes of the
present invention must, accordingly, be pharmaceutically acceptable. As
used herein, a "pharmaceutically-acceptable" component is one which is
suitable for use with humans and/or animals without undue adverse side
effects (such as toxicity, irritation, and allergic response) commensurate
with a reasonable benefit/risk ratio. Further, as used herein, the term
"safe and effective amount" refers to the quantity of a component which is
sufficient to yield a desired therapeutic response without undue adverse
effects (such as toxicity, irritation, or in this invention to the subject
to be treated in such a manner so as to be effective in the treatment or
prophylaxis of the infectious gastrointestinal disorder. Preferably, the
nitrofurantoin is administered orally.
As used herein, "prophylaxis" refers to the prevention of the occurrence of
infectious gastrointestinal disorders in human or lower animals. While the
methods of the present invention could be used for the prevention of such
disorders in any human or lower animals, it is preferred to use the
prophylactic treatment of nitrofurantoin in subjects which have a history
of recurring infectious gastrointestinal disorders.
As used herein, "nitrofurantoin" is the compound which has the chemical
structure:
##STR1##
or its pharmaceutically acceptable salts, hydrates, or complexes. As used
herein, nitrofurantoin "complexes" refer to chemical complexes of
nitrofurantoin with other chemical constituents which result in entities
which retain at least a substantial portion of the antimicrobial activity
of nitrofurantoin. Examples of such complexes include
nitrofurantoin-phthaloyl glycine and nitrofurantoin-phthaloyl aminocaproic
acid.
Nitrofurantoin has been found to have a high degree of antimicrobial
activity against Campylobacter-like bacteria, especially Campylobacter
pyloridis. This activity of nitrofurantoin is surprising in light of the
finding that related antibacterial substances have substantially less
activity than nitrofurantoin against Campylobacter-like organisms
including Campylobacter pyloridis. Also, other antibacterial substances
known to be useful in combatting the same types of bacterial infections
for which nitrofurantoin is commonly used and other antibacterial
substances commonly used for treatment of gastrointestinal disorders have
substantially less activity than nitrofurantoin against Campylobacter-like
organisms including Campylobacter pyloridis.
The methods of the present invention involve the administration of a safe
and effective amount of nitrofurantoin to a human or lower animal for the
treatment or prophylaxis of infectious gastrointestinal disorders. The
preferred daily dosage of nitrofurantoin is from about 1 mg to about 600
mg of nitrofurantoin per day, especially preferred is from about 10 mg to
about 400 mg of nitrofurantoin per day, more preferred still is from about
20 mg to about 200 mg of nitrofurantoin per day.
The methods of the present invention for treatment of infectious
gastrointestinal disorders preferably involve the administration of the
above daily doses of nitrofurantoin until the disorder has been eradicated
from the human or lower animal. It is preferred that the daily dosages be
administered to the human or lower animal for a period of from about 1 day
to about 200 days, more preferably from about 3 days to about 60 days,
more preferably still from about 7 days to about 30 days.
The methods of the present invention for prophylaxis of infectious
gastrointestinal disorders preferably involve the administration of the
above doses of nitrofurantoin on a daily or less frequent basis in order
to prevent recurrence of the disorder in the human or lower animal. It is
preferred that the dosages be administered to the human or lower animal
daily from about 1 day to about 200 days, more preferably from about 7
days to about 150 days, more preferably still from about 30 days to about
100 days. It is also preferred that the dosages be administered to the
human or lower animal every 2 or 3 days for from about 7 days to about 400
days, more preferably from about 30 days to about 300 days, more
preferably still from about 60 days to about 200 days. It is also
preferred that the dosages be administered to the human or lower animal
about weekly for a period of from about 14 days to about 800 days, more
preferably from about 30 days to about 600 days, more preferably still
from about 60 days to about 400 days.
Optional Components and Methods:
The methods of this invention may incorporate optional steps modifying the
methods of treatment of this invention. Such optional steps may also
utilize optional components or compositions. Such optional components or
compositions must not, however, adversely affect the therapeutic activity
of the nitrofurantoin used in the present methods.
A preferred method of this invention includes a diagnostic step for the
detection of a CLO infection in the upper gastrointestinal tract of the
human or lower animal subject by taking a biopsy of the affected tissue
and identifying the presence of the CLO organism by conventional
histological examination, e.g. fixing the tissue in paraffin for
Hematoxylin and Eosin stain and in plastic for Warthin Starry Silver
stain. (See Steer, H. W. and D. G. Colin-Jones, "Mucosal changes in
gastric ulceration and their response to carbenoxolone sodium", Gut, Vol.
16 (1975), pp. 590-597; McNulty, C. A. M. and D. M. Watson, "Spiral
Bacteria of the Gastric Antrum", The Lancet, Vol. 1, No. 8385 (May, 1984),
pp. 1068-1069; Jones, D. M., A. M. Lessells and J. Eldridge,
"Campylobacter like organisms on the gastric mucosa: culture,
histological, and serolopical studies", Journal of Clinical Pathology,
"Vol. 37 (1984), pp. 1002-1006; Rollason, T. P., J. Stone and J. M.
Rhodes, "Spiral organisms in endoscopic biopsies of the human stomach",
Journal of Clinical Pathology, Vol. 37 (1984), pp. 23-26.) This diagnostic
step is preferably performed prior to the step of administering
nitrofurantoin. Also preferably, the diagnostic step is repeated during
the step of administering the nitrofurantoin, and the step of
administering the nitrofurantoin is terminated after the diagnostic step
yields a negative result, unless prophylactic treatment of the human or
lower animal is desired.
The following non-limiting examples illustrate the methods of the present
invention.
EXAMPLE I
A human subject, suffering from atrophic gastritis, is treated by a method
of the present invention. Specifically, the subject is endoscoped and a
biopsy taken of the gastric mucosa of the subject. Analysis of the biopsy
sample shows inflammation of the mucosa, and depletion of the protective
mucous layer. Histological examination of the sample also reveals the
presence of Campylobacter pyloridis. The subject is then treated,
according to the present invention, by administering a composition
containing nitrofurantoin, sold by Norwich Eaton Pharmaceuticals, Inc.
under the name "Furadantin". The composition, in oral suspension form, is
administered 4 times daily in equal doses of 100 milligrams (for a total
of approximately 400 milligrams of nitrofurantoin administered per day)
for 14 days. Thereafter, the subject is endoscoped and biopsied again,
finding essentially normal, healed gastric mucosa. Histological
examination of the gastric material sample does not reveal any bacterial
infection. The subject remains asymptomatic, and another biopsy performed
five months later reveals normal gastric mucosa.
EXAMPLE II
A human subject, suffering from peptic ulcer disease, is treated by a
method of the present invention. Specifically, a biopsy of gastric mucosa
is taken from the stomach of the subject. Histological examination of the
mucosa reveals the presence of a Campylobacter-like organism.
The subject is then treated by orally administering 100 milligrams of
nitrofurantoin in capsule form per day for 30 days. Thereafter, the
subject is endoscoped, revealing normal gastric mucosa and healing of the
peptic ulcer crater.
EXAMPLE III
A human subject, with a history of periodic recurring peptic ulcer disease
but not currently suffering from such disease, is treated by a method of
the present invention. A biopsy of gastric mucosa taken from the stomach
of the subject reveals no presence of any Campylobacter-like organisms.
The subject is then treated by orally administering 25 mg of
nitrofurantoin in tablet form every 3 days for 365 days. The subject
remains free of symptoms of peptic ulcer disease over the entire period;
biopsies taken periodically which are histologically examined show no
presence of Campylobacter-like organisms.
While particular embodiments of the present invention have been described,
it will be obvious to those skilled in the art that various changes and
modifications of the methods of the present invention for treating
infectious gastrointestinal disorders can be made without departing from
the spirit and scope of the invention. It is intended to cover, in the
appended claims, all such modifications that are within the scope of this
invention.
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