Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-23
2003-05-13
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S236800, C514S376000, C514S008100
Reexamination Certificate
active
06562820
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the treatment and prevention of mastitis with known oxazolidinones, alone or in combination with exogenous lactoferrins.
2. Description of the Related Art
Mastitis, which has been known and treated for many years, is an inflammatory disease of the mammary gland of a mammal caused by infection of a multitude of bacteria. Bovine mastitis is one of the most difficult cattle diseases to deal with and is of considerable economic significance to the dairy industry. Bovine mastitis may be caused by Gram-negative bacteria such as
Escherichia coli
and Klebsiella spp, as well as Gram-positive bacteria such as
Staphylcoccus aureus
and
Streptococcus agalactiae
. The primary treatment for bovine mastitis so far has been the administration of antibiotics such as penicillin. However, the antibiotic therapies currently available for bovine mastitis do not always work, partly because these antibiotics are effective only against Gram-positive pathogens but have poor or strain-dependent activity against Gram-negative pathogens. Thus, there is clearly a need for more effective treatment for mastitis.
The oxazolidinones in the present invention are disclosed in, e.g., U.S. Pat. Nos. 5,688,792 and 6,040,306 and International Publication WO 98/54161, none of which discloses the use of oxazolidinones for treating or preventing mastitis.
Lactoferrin, a glycoprotein present in mammary gland secretions and many other exocrine secretions of mammals, is well known to those skilled in the art. The increased concentrations of endogenous lactoferrin in milk during dry period and the bacteriostatic or bactericidal effects of exogenous lactoferrins are disclosed. See, for example, Smith K L and Oliver S P, Exp. Med. Biol. 137:535-554 (1981); Lohuis, J. A. C. M., Hesen, S M, and Beers H, pages 110-111 in Proc. 3
rd
. Int. IDF Mastitis Sem., Tel Aviv, Israel, A. Saran and S. Soback, ed. M. Lachmann Printers LTD., Haifa, Israel (1995). None of these documents disclose the use of lactoferrin for treating or preventing mastitis.
Under in vitro conditions lactoferrin may enhance the antimicrobial effect of antibiotics against strains of Salmonellae and
Escherichia coli.
See, for example, A. S. Naidu and R. R. Arnold, Diagn. Microbiol. Infect. Dis 20:69-75 (1994); M. S. Sanchez and J. L. Watts, J Dairy Sci. 82: 494-499 (1999). Such enhancing effect of lactoferrins is, however, antibiotic specific. For example, lactoferrins can enhance the antimicrobial effect of erythromycin, ampicillin, ciprofloxacin, chloramphenicol, and rifampicin, but not cefalexin, gentamycin, or polymycin B, against Salmonellae. (A. S. Naidu and R. R. Arnold, Diagn. Microbiol. Infect. Dis 20:69-75 (1994). Thus, none of the prior art teaches or even suggests that lactoferrins may enhance the anti-mastitis effect of the oxazolidinones as disclosed in the present invention.
SUMMARY OF INVENTION
It has been surprisingly found that oxazolidinone is effective in treating and preventing mastitis caused by Gram-negative, as well as by Gram-positive, pathogens in mammals. It has also been surprisingly found that the anti-mastitis effect of oxazolidinone is enhanced by lactoferrins. The oxazolidinones in the present invention are disclosed in, e.g., U.S. Pat. Nos. 5,688,792 and 6,040,306 and International Publication WO 98/54161, none of which discloses the use of oxazolidinones for treating or preventing mastitis. The disclosure of each of U.S. Pat. Nos. 5,688,792 and 6,040,306 and International Publication WO 98/54161 is incorporated here by reference.
Disclosed is a method of treating or preventing mastitis in a mammal, comprising administration to said mammal during dry period of an therapeutically effective amount of an oxazolidinone selected from the group consisting of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and N[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide and pharmaceutically acceptable salts thereof.
Also disclosed is a method of treating or preventing mastitis in a mammal, comprising administration to said mammal of an therapeutically effective amount of an oxazolidinone selected from the group consisting of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide and pharmaceutically acceptable salts thereof, in combination with intramammary administration of a lactoferrin in an amount effective to enhance the therapeutic effect of the oxazolidinone.
Further disclosed is a composition for use in the treatment or prevention of mastitis in a mammal, comprising
(a) an oxazolidinone selected from (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide or pharmaceutically acceptable salts thereof, and
(b) a lactoferrin at an amount effective to enhance the therapeutic effect of said oxazolidinone.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment the invention is directed to a method of treating or preventing mastitis in a mammal comprising administering to said mammal a therapeutically effective amount of an oxazolidinone. In another embodiment the invention is directed to a method of treating or preventing mastitis in a mammal comprising administering to said mammal a therapeutically effective amount of an oxazolidinone in combination with administration of an exogenous lactoferrin at amount effective to enhance the therapeutic effect of the oxazolidinone. In a preferred embodiment the present invention is directed to a method of treating or preventing coliform mastitis in a cow by intramammary infusion of an oxazolidinone during the dry period. These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure therein.
The following description of the invention concerns mainly with dairy cows; however, it is to be understood that the invention is contemplated with the treatment and prevention of mastitis in all types of mammals.
The oxazolidinones in the present invention are disclosed in, e.g., U.S. Pat. Nos. 5,688,792 and 6,040,306 and International Publication WO 98/54161. Examples of suitable oxazolidinones include (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and N-[[(5S)-3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide, and pharmaceutically acceptable salts thereof.
The active agents of the subject invention can be given to a mammal either after the onset of mastitis, thus serving as a treatment, or prior to the onset of mastitis, thus serving as a preventive measure. The preventive use of the subject invention is particularly important, for instance, in case mastitis has been detected in some animals in the same herd. It is often desirable to treat all animals in same herd affected in order to eliminate the infection from the whole herd.
Regardless of whether the oxazolidinones are used to treat or prevent mastitis, the oxazolidinones can either be used individually, in combination with each other, or in combination with exogenous lactoferrins. When used during the dry period, the oxazolidinones are preferred to be administered without exogenous lactoferrins. When used during lactation period, the oxazolidinones are preferred to be administered in combination with the administration of exogenous lactoferrins.
Regardless of whether or not lactoferrins are administered, the oxazolidinones are administered either intramammarily or systemically. Intramammary administration, however, is the preferred route when the oxazolidinones are admini
Sanchez Margaret S.
Watts Jeffrey L.
Pharmacia & Upjohn Company
Weddington Kevin E.
Zhang Austin W.
LandOfFree
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