Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-03-06
2004-09-21
Kim, Vickie (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S309000, C514S355000
Reexamination Certificate
active
06794412
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of thrombosis in mammals and more particularly to such treatment by the administration of a combination of (i) a Factor Xa inhibitor, and (II) a compound selected from the group consisting of aspirin, TPA, GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose.
BACKGROUND OF THE INVENTION
The selected class of Factor Xa inhibitors and the selected class of aspirin, GPIIb/IIIa antagonist, tissue plasminogen activator (TPA), low-molecular-weight-heparin and heparin are essential as component parts of the novel compositions of this invention. Aspirin and GPIIb/IIIa antagonists are known in the art as antiplatelet agents. Tissue plasminogen activator (TPA) is known as a thrombolytic agent. Low-molecular-weight heparin and heparin are known as anticoagulants.
Factor Xa is a blood coagulation protein. It plays a major role in blood coagulation because of its central position at the convergent point of the intrinsic and extrinsic pathways of coagulation. It is believed that inhibition of Factor Xa may eliminate the production of thrombin by either the extrinsic or intrinsic pathways without interfering with a basal level of thrombin activity necessary for normal hemostasis (Harke L A, Hanson S R and Kelly A B. Antithrombotic strategies targeting thrombin activities, thrombin receptors and thrombin generation. Thrombosis and Haemostasis 78: 736-741, 1997).
Both peptide and nonpeptide Factor Xa inhibitors are currently available (Kaiser B. Thrombin and factor Xa inhibitors. Drugs of the Future 23: 423-436, 1998). Examples of peptide Factor Xa inhibitors are antistasin and tick anticoagulant peptide, and nonpeptide Factor Xa inhibitors are described in WO98/2326, Thromb Haemost 1994; 71: 314-9, Thromb Haemost 1994; 72:393-6, and Thromb Haemost 1998; 79: 859-64. The antithrombotic effects of these peptide and nonpeptide Factor Xa inhibitors have been well demonstrated in various experimental models of arterial and venous thrombosis (Kaiser B. Thrombin and factor Xa inhibitors. Drugs of the Future 23: 423-436, 1998).
SUMMARY OF THE INVENTION
One object of the present invention is to provide a method of treating thrombosis in a mammal comprising: administering to said mammal a therapeutically effective amount of a combination of (i) a Factor Xa inhibitor, and (ii) a compound selected from the group consisting of aspirin, TPA a GPIIb/IIIa antagonist, low molecular weight heparin and heparin, wherein the dose administered for at least one of (i) and (ii) is a subtherapeutic dose.
Another object of the present invention is to provide a method of treating thrombosis in a mammal wherein the combination of (i) and (ii) above are administered in amounts to provide a synergistic effect.
These and other objects, which will become apparent during the following detailed description, have been achieved by the discovery that the administration of a Factor Xa inhibitor (i) in combination with one of (ii) aspirin, tissue plasminogen activator (TPA), a GPIIb/IIIa antagonist, low molecular weight heparin or heparin, with at least one of (i) and (ii), preferably both, being administered at a dose which would be a subtherapeutic dose when administered alone.
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Harke et al., Antithrombotic Strategies Targeting Thrombin Activities, Thrombin Receptor and Thrombin Generation,Thrombosis and Haemostasis,1997, pp. 736-741.
Kaiser, B., Thrombin and Factor Xa Inhibitors,Drugs of the Future,1998, pp.423-436.
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Lefkovits, Jeffrey et al.: “Selective inhibition of factor Xa is more efficient than factor VIIa-tissue factor complex blockade at facilitating coronary thrombolysis in the canine model” J. Am. Coll. Cardiol. (1996), 28(7), 1858-1865.
Bristol-Myers Squibb Pharma Company
Kim Vickie
LandOfFree
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