Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1992-06-17
2002-06-11
Kunz, Gary L. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S802000, C514S834000, C424S094640, C435S013000, C435S215000, C435S216000, C435S217000
Reexamination Certificate
active
06403556
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a pharmaceutical preparation containing protein C.
Many surgical procedures increase the risk of venous and arterial thromboses and of thromboembolism. Arterial and venous thromboses also may be caused by diseases. However, antithrombotic and thrombolytic therapies involve undesired side effects, such as bleeding or reocclusion.
The thrombolytic activity of substances, such as t-PA, urokinase, streptokinase or plasminogen, is based on the release of plasmin, which enables the dissolution of thrombi. At the same time, it is observed that thrombin is generated when administering thrombolytically active substances. The thrombin generation and subsequent reocclusion are presumed to be a generally undesired side effect of successful thrombolysis (Circulation 83, 937-944, (1991)).
In addition to an elevated thrombin activity, a change of the protein C concentration in blood is observed in thrombolysis patients (Seminars in Thrombosis and Hemostasis 16, 242-244 (1990)). Therapy is effected either with t-PA or with heparin or with a combination of t-PA and heparin. A reduction of the protein C concentration is observed only when administering t-PA-containing preparations. The direct degradation of protein C by t-PA or plasmin has not been considered, however.
In connection with undesired side effects of thrombolysis, it is suggested in EP-A-0 318 201 to use activated protein C (aPC) alone or in combination with a thrombolytic agent to prevent acute arterial thrombotic occlusions, thromboembolism or stenosis. aPC is known to be an anticoagulatively effective enzyme, which, on the one hand, inhibits the formation of thrombin due to the proteolytic degradation of activated coagulation factor V and activated coagulation factor VIII and, on the other hand, supports fibrinolysis. For this reason, the dose of thrombolytic agent may be reduced.
Likewise, it is suggested in Blood 74, Suppl. 1, 50a, Abstract 176 (1989) to use a combined preparation containing aPC and urokinase to prevent the formation of thrombi in order to reduce the thrombolytic or antithrombotic doses of urokinase and simultaneously combat bleeding complications occurring in thrombolysis therapies. However, the administration of activated protein C suffers the disadvantage that the tendency to bleeding is favored by the immediate anticoagulant effect of aPC.
SUMMARY OF THE INVENTION
The invention has as its object to eliminate this disadvantage and to provide a pharmaceutical preparation that prevents reocclusion caused by an elevated thrombin activity after thrombolysis therapy has been carried out.
The preparation according to the invention contains protein C and a thrombolytically active substance that does not activate protein C.
It has been shown that the preparation according to the invention enables successful thrombolysis therapy without the risk of reocclusion.
Urokinase, tPA, Lys-plasminogen or streptokinase are particularly suitable as thrombolytically active substances.
Consequently, the invention also relates to the use of a thrombolytically active substance unable to activate protein C, in combination with protein C, to produce a drug for the treatment of thromboses and for the prevention of reocclusion.
The invention is based on the findings that plasmin generated by therapeutic thrombolytics not only degrades fibrin, but surprisingly also degrades protein C at the very high concentrations applied during thrombolysis therapy, thus provoking protein C deficiency and inducing hypercoagulability. This may be prevented by administering the thrombolytically active substance in combination with protein C or by administering protein C in the course of thrombolysis therapy, i.e., prior to, during and/or after thrombolysis therapy.
Preferably, protein C is contained in the preparation according to the invention at 10 to 50 U/mg protein. When ready for application, it should contain 90 to 450 U/ml. The content of thrombolytic agent in the preparation according to the invention appropriately is chosen so that usual amounts will be administered when applied.
The protein C-containing preparation according to the invention may be administered as an injection (30 to 80 U/kg) two or three times a day or as a continuous infusion (15 to 30 U/kg/h).
The invention will be described in more detail in the following.
REFERENCES:
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patent: 0 326 014 (1989-08-01), None
Eisenberg et al., Thrombosis Research, 50, 707-717, 1988.*
Okajima et al., Thrombosis and Haemostasis, 63, 48-53, 1990.*
Köhler et al., “Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity,”Nature, vol. 256, pp. 495-497 (Aug. 1975).
Stassen et al., “Thrombolysis with Human Extrinsic (Tissue-Type) Plasminogen Activator in Rabbits with Experimental Jugular Vein Thrombosis,”J. Clin. Invest., vol. 71, pp. 368-376 (Feb. 1983).
Gruber et al., “Inhibition of Thrombus Formation by Infusion of Activated Protein C with Urokinase in a Primate Thrombosis Model,”Blood, vol. 74, No. 7, Suppl. 1, Abstract No. 176 (Nov. 1989).
Yang et al., “Plasminogen, Alpha2-Antiplasmin, and Protein C Decline Following Infusions of Recombinanat Tissue Plasminogen Activator,”Seminars in Thrombosis and Hemostasis, vol. 16, No. 3, pp. 242-244 (1990).
Gulba et al., “Increased Thrombin Levels During Thrombolytic Therapy in Acute Myocardial Infarction,”Circulation, vol. 83, No. 3, pp. 937-944 (Mar. 1991).
Eibl Johann
Philapitsch Anton
Schwarz Hans Peter
Baxter Aktiengesellschaft
Heller Ehrman White & McAuliffe
Kunz Gary L.
Landsman Robert S.
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