Heparin compositions that inhibit clot associated coagulation factors

A technology of heparin and factor, applied in the field of treatment of cardiovascular diseases, can solve the problems of short can not bridge thrombin and antithrombin, bad inhibitor, can not bridge thrombin and fibrin, etc.

Inactive Publication Date: 2002-09-25
HAMILTON CIVIC HOSPITALS RESARCH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Furthermore, with an average molecular weight of 4,500 to 5,000 Daltons, most LMWH chains are too short to bridge thrombin and fibrin
However, since most LMWH chains are also too short to bridge thrombin and antithrombin, LMWHs are poor inhibitors of both fluid-phase and fibrin-bound thrombin

Method used

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  • Heparin compositions that inhibit clot associated coagulation factors
  • Heparin compositions that inhibit clot associated coagulation factors
  • Heparin compositions that inhibit clot associated coagulation factors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] Experimental observation

[0110] 1.1 Clinical limitations of currently available anticoagulants:

[0111] Heparin, LMWH and directed thrombin inhibitors have limitations in acute coronary syndrome. For patients with unstable angina, recurrent ischemic effects are central when treatment with these drugs is discontinued (Theroux, P., et al. (1992) N. Engl. J. Med. 327: 141-145; Granger, C. B., et al. (1996), Circulation 93: 870-888; Oldgren, J., et al. (1996), Circulation 94 (Suppl 1): 1-431). This is due to reactivation of coagulation, as there are elevated plasma levels of the associated prothrombin fragments F1.2 (F1.2) and fibrinopeptide A (FPA), reflecting increased thrombin generation and thrombin activity, respectively (Granger, C.B., et al. (1995), Circulation 91:1929-1935). In patients with acute myocardial infarction, induction of thrombosis with tissue plasminogen activator (tPA), streptokinase is characterized by increased levels of The prothrombin state o...

Embodiment 2

[0131] 2.0 Production of medium molecular weight heparins:

[0132] To catalyze thrombin inhibition, heparin bridges antithrombin and thrombin (Danielsson, A., et al. (1986), J. Biol. Chem. 261: 15467-15473). The premise is that the bridging function requires heparin chains with a minimum molecular weight of 5,400 (Jordan, R.E., et al. (1980), J. Biol. Chem. 225:10081-10090). Since most LMWH molecules are smaller than 5,400 Daltons, LMWHs have minimal antithrombin inhibitory activity (Jordan, R.E., et al. (1980), J. Biol. Chem. 225:10081-10090 ). Since heparin bridges thrombin and fibrin to form a ternary fibrin-thrombin-heparin complex, it was hypothesized that this function would also require heparin chains of minimum molecular mass. Furthermore, it is hypothesized that if this minimum molecular mass is not the same as that required to bridge antithrombin and thrombin, there may be cases where the heparin chain is too short to bridge thrombin and fibrin but long enough to ...

Embodiment 3

[0138] MMWH composition of the present invention compares with other known anticoagulant efficacy and safety

[0139] This example illustrates a study comparing the efficacy and safety of the MMWH component of the invention (indicated as V21 in the figure), LMWH, heparin and hirudin in a rabbit arterial thrombosis prevention model. The results show that the MMWH of the present invention is more effective than LMWH and heparin and safer than hirudin. Modification of the arterial thrombosis prevention model allows evaluation of both efficacy and safety in the same animals. Efficacy was evaluated by measuring the flow rate at 95% distal stenosis in the injured rabbit aorta over 90 minutes, and safety was evaluated by measuring blood loss over 30 minutes using a rabbit ear phantom. Four mixtures were compared at three dosage levels. Each mixture was administered as a bolus and infusion for 90 minutes. Doses listed in the graph below represent boluses and infusions / 60 minutes, a...

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Abstract

The present invention provides compositions and methods for treating cardiovascular disease. More specifically, the invention relates to thrombin by administering, inter alia, capable of (1) inactivating thrombin in the fluid phase by catalytic antithrombin and either binding to fibrin in a clot or binding to some other surface; and (2) Substances that inhibit thrombin production by antithrombin III (ATIII) catalyzing factor Xa inactivation to alter thrombus formation. The compositions and methods of the present invention are particularly useful for the prevention of thrombosis in cardiac bypass circulation and in patients undergoing renal dialysis, and for the treatment of patients with, or at risk of, cardiovascular disease associated with thrombosis In patients with thrombosis-related cardiovascular diseases such as unstable angina, acute myocardial infarction (heart attack), cerebrovascular accident (stroke), pulmonary embolism, deep vein thrombosis, arterial thrombosis, etc.

Description

field of invention [0001] The present invention generally relates to compositions and methods for treating cardiovascular disease. More specifically, the present invention relates to thrombin by administering, inter alia, capable of (1) inactivating thrombin in the fluid phase by catalytic antithrombin and either binding to fibrin in a clot or binding to some other surface; and (2) Inhibition of the medium molecular weight heparin (MMWH) component of thrombin generation by antithrombin III (ATIII) catalyzed factor Xa inactivation to alter thrombus formation and growth. Additionally, the present invention provides methods and compositions for treating cardiovascular disease. Background of the invention [0002] Heparin acts as an anticoagulant by binding antithrombin and greatly increasing the ratio of its inhibition of activated factor X (factor Xa) to thrombin. The interaction of heparin with antithrombin is mediated through unique pentasaccharide sequences randomly distr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/727A61K45/06A61P7/02A61P9/10C08B37/00C08B37/10
CPCA61K31/727A61K45/06C08B37/0078A61P7/02A61P9/10A61K31/715
Inventor J·I·维茨J·希尔斯
Owner HAMILTON CIVIC HOSPITALS RESARCH DEV
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