Effect of a Synthetic Factor Xa Inhibitor, YM-60828, on Blood Vessel Patency in Combination with a Thrombolytic Agent and on Blood Loss from the Operation Site in a Rat Model of Arterial Thrombosis

Summary We examined the adjunctive effect of a novel factor Xa inhibitor, YM-60828, on vessel patency and blood loss from the operation site after successful thrombolysis with a modified tissue-type plasminogen activator (moPA) in an electrically-induced carotid artery thrombosis model in rats. Five minutes after the induction of occlusive thrombus, a test drug (YM-60828, argatroban, heparin or saline) was administered by i.v. bolus injection followed by continuous infusion. Thrombolysis was induced with moPA by i.v. bolus injection at a dose of 650,000 IU/ kg. YM-60828 at 1 mg/kg i.v. followed by 3 mg/kg/h significantly prevented reocclusion, increased the duration of patency, and improved vessel patency after successful thrombolysis without any significant increase in blood loss from the operation site. Argatroban at 1 mg/kg i.v. followed by 3 mg/kg/h and heparin at 300 U/kg i.v. followed by 150 U/kg/h also significantly improved these parameters, but were accompanied by a significant increase in blood loss. These results suggest that the factor Xa inhibitor YM-60828 may be a potent and useful adjunctive agent with a lower risk of bleeding complications than argatroban and heparin in thrombolytic therapy.

[1]  M. Kayama,et al.  Biochemical and Pharmacological Characterization of YM-60828, a Newly Synthesized and Orally Active Inhibitor of Human Factor Xa , 1998, Thrombosis and Haemostasis.

[2]  Y. Matsumoto,et al.  Comparative Studies of an Orally-active Factor Xa Inhibitor, YM-60828, with other Antithrombotic Agents in a Rat Model of Arterial Thrombosis , 1998, Thrombosis and Haemostasis.

[3]  J. Giddings,et al.  The antithrombotic effect of synthetic low molecular weight human factor Xa inhibitor, DX-9065a, on He-Ne laser-induced thrombosis in rat mesenteric microvessels. , 1997, Thrombosis research.

[4]  T. Takenaka,et al.  Comparative Study of a Mutant Tissue‐type Plasminogen Activator, YM866, with a Tissue‐type Plasminogen Activator in a Canine Model of Femoral Arterial Thrombosis , 1996, The Journal of pharmacy and pharmacology.

[5]  P. Wong,et al.  Antithrombotic actions of selective inhibitors of blood coagulation factor Xa in rat models of thrombosis. , 1996, Thrombosis research.

[6]  H. Büller,et al.  Comparison of sustained antithrombotic effects of inhibitors of thrombin and factor Xa in experimental thrombosis. , 1996, Circulation.

[7]  M. Fishbein,et al.  VCL, an antagonist of the platelet GP1b receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat. , 1995, Circulation.

[8]  H. Ishihara,et al.  DX-9065a, an Orally Active, Specific Inhibitor of Factor Xa, Inhibits Thrombosis without Affecting Bleeding Time in Rats , 1995, Thrombosis and Haemostasis.

[9]  J. Zablocki,et al.  SC-54684A: an orally active inhibitor of platelet aggregation. , 1995, Circulation.

[10]  L. Wilkins.  Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. , 1994, Circulation.

[11]  B. Sobel.  Intracranial bleeding, fibrinolysis, and anticoagulation. Causal connections and clinical implications. , 1994, Circulation.

[12]  Christine Girardot,et al.  Effects of the Synthetic Thrombin Inhibitor Argatroban on Fibrin- or Clot-Incorporated Thrombin: Comparison with Heparin and Recombinant Hirudin , 1994, Thrombosis and Haemostasis.

[13]  H. Asakura,et al.  Effects of DX-9065a, an Orally Active, Newly Synthesized and Specific Inhibitor of Factor Xa, against Experimental Disseminated Intravascular Coagulation in Rats , 1994, Thrombosis and Haemostasis.

[14]  H. Ishihara,et al.  DX-9065a, a New Synthetic, Potent Anticoagulant and Selective Inhibitor for Factor Xa , 1994, Thrombosis and Haemostasis.

[15]  J. Lynch,et al.  Antithrombotic effects of MK-0852, a platelet fibrinogen receptor antagonist, in canine models of thrombosis. , 1993, The Journal of pharmacology and experimental therapeutics.

[16]  B. Francis,et al.  Antithrombotic activity of recombinant tick anticoagulant peptide and heparin in a rabbit model of venous thrombosis. , 1993, Thrombosis research.

[17]  S. Durham,et al.  Effects of Antithrombotic Drugs in a Rat Model of Aspirin-Insensitive Arterial Thrombosis , 1993, Thrombosis and Haemostasis.

[18]  J. Lynch,et al.  Enhancement of recombinant tissue plasminogen activator-induced reperfusion by recombinant tick anticoagulant peptide, a selective factor Xa inhibitor, in a canine model of femoral arterial thrombosis , 1993 .

[19]  T. Takenaka,et al.  Experimental model of carotid artery thrombosis in rats and the thrombolytic activity of YM866, a novel modified tissue-type plasminogen activator. , 1993, Japanese journal of pharmacology.

[20]  C. Kawai,et al.  Thrombolytic activity of a novel modified tissue-type plasminogen activator, YM866, in a canine model of coronary artery thrombosis. , 1993, Japanese journal of pharmacology.

[21]  C. Dunwiddie,et al.  Selective factor Xa inhibition by recombinant antistasin prevents vascular graft thrombosis in baboons. , 1992, Arteriosclerosis and thrombosis : a journal of vascular biology.

[22]  C. Dunwiddie,et al.  Acceleration of recombinant tissue-type plasminogen activator-induced reperfusion and prevention of reocclusion by recombinant antistasin, a selective factor Xa inhibitor, in a canine model of femoral arterial thrombosis. , 1992, Circulation research.

[23]  J. Lynch,et al.  Conjunctive Enhancement of Enzymatic Thrombolysis and Prevention of Thrombotic Reocclusion With the Selective Factor Xa Inhibitor, Tick Anticoagulant Peptide: Comparison to Hirudin and Heparin in a Canine Model of Acute Coronary Artery Thrombosis , 1992, Circulation.

[24]  D. Collen,et al.  Requirement of heparin for arterial and venous thrombolysis with recombinant tissue-type plasminogen activator. , 1991, Blood.

[25]  Burton E. Sobel,et al.  Relative Efficacy of Antithrombin Compared With Antiplatelet Agents in Accelerating Coronary Thrombolysis and Preventing Early Reocclusion , 1991, Circulation.

[26]  H. Weisman,et al.  Monoclonal Antibodies to Platelet Glycoprotein IIb/IIIa as Antithrombotic Agents a , 1991, Annals of the New York Academy of Sciences.

[27]  H. Gold,et al.  Comparative effects of aspirin, a synthetic thrombin inhibitor and a monoclonal antiplatelet glycoprotein IIb/IIIa antibody on coronary artery reperfusion, reocclusion and bleeding with recombinant tissue-type plasminogen activator in a canine preparation. , 1990, Journal of the American College of Cardiology.

[28]  D. Massel,et al.  Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. , 1990, The Journal of clinical investigation.

[29]  P. Hogg,et al.  Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: implications for heparin efficacy. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Aoyama,et al.  Heparin requirement in tissue-type plasminogen activator-induced experimental coronary thrombolysis: comparison with urokinase-induced coronary thrombolysis. , 1987, Japanese circulation journal.

[31]  B. Warren,et al.  Comparison of antithrombotic activity of heparin, ASA, sulfinpyrazone and VK 744 in a rat model of arterial thrombosis. , 1978, Haemostasis.

[32]  S. Wessler,et al.  Investigation of the Apparent Thrombogenicity of Thrombin , 1968, Thrombosis and Haemostasis.