Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-30
2001-08-07
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...
C514S393000, C514S394000, C514S925000, C424S653000
Reexamination Certificate
active
06271256
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 OF THE INVENTION
This invention provides methods of controlling gram negative bacteria and/or treating gram negative infections. In some embodiments, the methods involve the use of a polyether ionophore antibiotic to selectively control or kill such bacteria. In a preferred method, the gram negative bacteria is associated with gastric
Helicobacter pylori
infections.
The present invention provides various methods for controlling gram negative bacteria, such as
Helicobacter pylori,
by administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic such that gram negative bacteria in the mammal is controlled.
Polyether ionophore antibiotics useful for controlling gram negative bacteria in a mammal include monensin, nigericin and calcimycin and pharmaceutically acceptable salts or esters thereof. Preferred polyether antibiotics of the invention include those having the formula
wherein, R is either phenyl, pyridyl or aminoethyl-Fmoc (fluorenylmethoxycarbonyl). Coadministration of proton pump inhibitors, acid agonists or blockers, acid antagonists, bismuth salts or combinations thereof with polyether ionophore antibiotics of the invention is particularly preferred.
The present invention also provides methods for controlling gram negative bacteria in a mammal by administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that gram negative bacteria in the mammal is controlled.
The present invention provides methods for controlling gram negative bacteria in a mammal by administering to a mammal a therapeutically effective amount of a compound having the formula:
or such that gram negative bacteria in the mammal is controlled. R
1
is a hydrogen atom or a substituted or unsubstituted alkyl group and A is either a covalent bond connecting the cyclic ring to B or a substituted or unsubstituted alkylene diradical connecting the cyclic ring to B. B is a heterocyclic group, preferably a tetrahydrofuranyl group, and D is a substituted or unsubstituted alkyl group. The methylene carbon atoms of the cyclic rings are each independently substituted at one or more positions with one or two substitutents selected from hydrogen atoms, hydroxyl groups or substituted or unsubstituted alkyl groups. The methine carbon atoms are each independently substituted with hydrogen atoms or substituted or unsubstituted alkyl groups.
The present invention further provides methods for treating a state characterized by the presence of gram negative bacteria in a mammal. In one embodiment, the method includes administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that a state characterized by the presence of gram negative bacteria in the mammal is treated. In a preferred embodiment, the gram negative bacteria is
Helicobacter pylori.
In another embodiment, a method includes administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety attached to at least one of the ether rings, such that a state characterized by the presence of gram negative bacteria, such as
Helicobacter pylori
in the mammal is treated. The polyether ionophore antibiotics and bicyclo spiroether compounds of the invention are useful for both prophylactic and/or therapeutic treatments of gram negative bacteria found in the gastrointestinal tract of a mammal.
In still another embodiment, a method includes administering to a mammal a therapeutically effective amount of compound having the formula:
such that a state characterized by the presence of gram negative bacteria, such as
Helicobacter pylori,
in the mammal is treated. A, B, D and R
1
are as defined supra.
The present invention provides methods for controlling
Helicobacter pylori
in a mammal. In one embodiment, a method includes administering to a mammal a therapeutically effective amount of a polyether ionophore antibiotic, such that
Helicobacter pylori
in the mammal is controlled.
In another embodiment, a method includes administering to a mammal a therapeutically effective amount of a bicyclo spiroether compound having at least one heterocyclic moiety a
Berkowitz Barry
Blackburn Chris
Sachs George
DeConti, Jr. Giulio A.
Hanley Elizabeth A.
Lahive & Cockfield LLP
Millennium Pharmaceuticals Inc.
Weddington Kevin E.
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