Use of kinin antagonists for preparing a pharmaceutical...

Details Use of kinin antagonists for preparing a pharmaceutical... Use of kinin antagonists for preparing a pharmaceutical...

1999-06-25

2001-04-24

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S012200

Reexamination Certificate

active

06221845

ABSTRACT:

INTRODUCTION
The present invention relates to kinin antagonists and pharmaceutical acceptable derivatives or salts thereof for use as a pharmaceutical. Especially the invention relates to the use of these substances for the manufacture of a pharmaceutical composition useful against symptoms caused by micro-organisms releasing kinins.
Some micro-organisms such as Streptococci and Salmonella may cause severe invasive infections due to inherent resistance to antibiotics or a defect immune system of the individual affected. Hence there is need for another effective agent to stop the infection.
Bradykinin, and its physiologically important related peptides kallidin (Lys-bradykinin) and Met-Lys-bradykinin, contract smooth muscle, (for example to produce diarrhea and inflammatory bowel disease and asthma) lower blood pressure, mediate inflammation as in allergies, arthritis and asthma, participate in blood-clotting and complement-mediated reactions in the body, mediate rhinitis (viral, allergic and non-allergic) and are overproduced, in pathological conditions such as acute pancreatitis, hereditary angioneurotic edema, post-gastrectomy dumping syndrome, carcinoid syndrome, anaphylactic shock, reduced sperm motility, and certain other conditions.
As a result of the fact that bradykinin is involved in all the above mentioned clinical indications, a large amount of bradykinin antagonists have been developed. Such antagonists are disclosed in e.g. U.S. Pat. No. 4,693,993. Wirth et al., Can J. Physiol. Pharmacol. vol. 73: pp. 797-804 presents clinical studies regarding administrating bradykinin antagonists for treating postoperative pain, asthma, anaphylyactoid reactions, systemic inflammatory response syndrome, and suspected sepsis, head injury and hantavirusinfections. A review on clinical applications of bradykinin antagonists can be found in Cheronis et al., eds: Proteases, Protease Inhibitors and Protease-Derived Peptides; pp. 167-176. Although some of these citations discloses administration of bradykinin antagonists for treating sepsis, it is evident that the suspected sepsis treated by said antagonists is not primarily caused by bacterial infections. Accordingly, the citations are completely silent about using bradykinin antagonists for treating bacterial infections. Moreover, it is evident that bradykinin antagonists have been administrated in order to relieve the symptoms of inflammation.
SUMMARY OF THE INVENTION
Now it has turned out that many pathogenic bacteria used kinin release as a major virulence mechanism. It appears that infections and pathogenic bacteria are able to benefit from the increased vascular permeability conferred by bradykinin. Accordingly it has been shown to be advantageous to treat bacterial infections by administrating an appropriate amount of a bradykinin antagonist.
DETAILED DESCRIPTION OF THE INVENTION
As disclosed herein, the term “HK” relates to H-kininogen.
As disclosed herein, the term “BK” relates to bradykinin.
As disclosed herein, the term “SCP” relates to streptococcal cysteine protease which is described in WO 96/08569.
As disclosed above, it has been shown that bradykinin and similar kinins are released upon infection by many pathogenic bacteria, such as
Escherichia coli,
Streptococcus ssp, Staphylococcus ssp, and Salmonella ssp. The bradykinin release mechanisms are not identical in all these species, but it is considered not to be important to know the mechanisms as such in order to carry out the present invention.


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