Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-27
2002-04-30
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S290000, C514S365000
Reexamination Certificate
active
06380217
ABSTRACT:
BACKGROUND
Helicobacter pylori
bacterial infections are a serious problem in humans. They have been shown to be a strong causative factor in gastric ulcer disease, such as stomach ulcers and small intestine ulcers which can result in death.
Helicobacter pylori
is a gram-negative, S-shaped, microaerophilic bacterium that was discovered and cultured from a human gastric biopsy specimen. (Warren, J. R. and B. Marshall, (1983)
Lancet
1: 1273-1275; and Marshall et al., (1984)
Microbios Lett.
25: 83-88).
H. pylori
bacterial cells can survive in a low pH environment because of an enzyme on their outer cell wall called urease. Urease converts urea in the stomach into bicarbonate and ammonia. The bicarbonate and ammonia neutralize the acid gastric juices, thereby providing a protective layer around the
H. pylori.
Since
H. pylori
are gram-negative rod type bacteria, it is difficult to treat
H. pylori
infections without using agents that will also affect other gram-negative bacteria elsewhere in the body.
H. pylori
has been strongly linked to chronic gastritis and duodenal ulcer disease. (Rathbone et. al., (1986)
Gut
27: 635-641). Moreover, evidence is accumulating for an etiologic role of
H. pylori
in nonulcer dyspepsia, gastric ulcer disease, and gastric adenocarcinoma. (Blaser M. J., (1993)
Trends Microbiol.
1: 255-260). Transmission of the bacteria occurs via the oral route, and the risk of infection increases with age. (Taylor, D. N. and M. J. Blaser, (1991)
Epidemiol. Rev
13: 42-50).
H. pylori
colonizes the human gastric mucosa, establishing an infection that usually persists for decades. Infection by
H. pylori
is prevalent worldwide. Developed countries have infection rates over 50% of the adult population, while developing countries have infection rates reaching 90% of the adults over the age of 20. (Hopkins R. J. and J. G. Morris (1994)
Am. J. Med.
97: 265-277).
The bacterial factors necessary for colonization of the gastric environment, and for virulence of this pathogen, are poorly understood. Examples of the putative virulence factors include the following: urease, an enzyme that may play a role in neutralizing gastric acid pH (Eaton et al., (1991)
Infect. Immunol.
59: 2470-2475; Ferrero, R. L. and A. Lee (1991)
Microb. Ecol. Hlth. Dis.
4: 121-134; Labigne et al., (1991)
J. Bacteriol.
173: 1920-1931); the bacterial flagellar proteins responsible for motility across the mucous layer (Hazell et al., (1986)
J. Inf. Dis.
153: 658-663; Leying et al., (1992)
Mol. Microbiol.
6: 2863-2874; and Haas et al., (1993)
Mol. Microbiol.
8: 753-760; Vac A), a bacterial toxin that induces the formation of intracellular vacuoles in epithelial cells (Schmitt, W. and R. Haas, (1994)
Molecular Microbiol.
12(2): 307-319) and several gastric tissue-specific adhesions (Boren et al., (1993)
Science
262: 1892-1895; Evans et al., (1993)
J. Bacteriol.
175: 674-683; and Falk et al., (1993)
Proc. Natl. Acad. Sci.
USA 90: 2035-2039).
Certain therapeutic agents are known to eradicate
H. pylori
infections in vitro. (Huesca et. al., (1993)
Zbl. Bakt.
280: 244-252; Hopkins, R. J. and J. G. Morris, supra). However, many agents are suboptimally effective in vivo because of bacterial resistance, altered drug distribution, patient non-compliance, poor drug availability and lack of selectivity for
H. pylori.
(Hopkins, R. J. and J. G. Morris, supra). Treatment with antibiotics combined with bismuth are part of a standard regime used to treat
H. pylori
infection. (Malfertheiner, P. and J. E. Dominguez-Munoz (1993)
Clinical Therapeutics
15 Supp. B: 37-48). Recently, combinations of a proton pump inhibitor and a single antibiotic have been shown to ameliorate duodenal ulcer disease. (Malfertheiner, P. and J. E. Dominguez-Munoz supra).
SUMMARY
The invention pertains to a method for controlling GGT-positive bacteria, advantageously
H. pylori
, in a mammal, preferably a human, by administering to the mammal a therapeutically effective amount of a GGT modulating compound.
It also pertains to a method treating a state characterized by the presence of GGT-positive bacteria in a mammal, by administering to a mammal a therapeutically effective amount of a GGT modulating compound.
The invention also includes a method of controlling GGT-positive bacteria by contacting the bacteria with a GGT modulating compound.
In another embodiment, the invention pertains to a pharmaceutical preparation for the treatment of a state characterized by the presence of GGT-positive bacteria in a mammal. The pharmaceutical preparation consists of a therapeutically effective amount of a GGT modulating compound and a pharmaceutically acceptable carrier.
The invention also pertains to a method for controlling
Helicobacter pylori
in a mammal. The method includes administering to the mammal a therapeutically effective amount of a GGT-modulating compound, such that
Helicobacter pylori
in the mammal is controlled.
The invention further pertains to a method for treating an ulcer e.g., an ulcer associated with
H. pylori,
in the gastrointestinal tract of a mammal, by administering to a mammal a therapeutically effective amount of a GGT-modulating compound.
The invention also features a packaged pharmaceutical composition for controlling GGT-positive bacteria in a mammal. The packaged pharmaceutical composition consists of a container holding a therapeutically effective amount of a pharmaceutical composition for treating GGT-positive bacteria in a mammal, the pharmaceutical composition comprising at least one GGT modulating compound, and instructions for using the pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.
The present invention pertains to a method for controlling GGT-positive bacteria in a mammal, e.g. a human. The method includes administering to a mammal a therapeutically effective amount of a GGT modulating compound.
The term “GGT-positive bacteria” includes bacteria which express gamma glutamyl transpeptidase (GGT). GGT is an enzyme involved in the transfer of glutamic acid from glutathione to other acceptors. It is also involved in the hydrolysis of glutathione and other gamma-glutamyl amino acids and dipeptides, possibly as a means for amino acid uptake. Examples of GGT-positive bacteria include agents associated with disorders of the gastrointestinal tract, e.g.,
H. pylori.
For
H. pylori,
GGT has been shown to be an essential colonization factor in mouse models. Therefore, although not wishing to be bound by theory, it has been suggested that GGT inhibiting compounds may control GGT positive bacteria by disrupting the formation of bacterial colonies.
The language “controlling GGT-positive bacteria” includes changes in growth or replication of the GGT positive bacteria or eradication of GGT positive bacteria. The language includes preventing survival or inhibiting continued growth and replication of GGT positive bacteria. In a preferred embodiment, the control of the GGT positive bacteria is such that a GGT positive bacterial infection is treated.
The language “GGT modulating compound” includes compounds which interact with GGT and modulate its activity. In one embodiment, the GGT modulating compound may inhibit GGT activity. Compounds which inhibit GGT activity can be identified through the Cell Based GGT Inhibitor (CBGI) Assay. The CBGI Assay is described in detail in the Example section. The compounds of this invention, e.g., the particular species described herein, can be purchased and/or synthesized using art-recognized techniques. Examples of preferred GGT modulating compounds include:
Another preferred GGT-modulating compound is:
Another preferred GGT modulating
Hanley Elizabeth A.
Lahive & Cockfield LLP
Millennium Pharmaceuticals Inc.
Weddington Kevin E.
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