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Thromb Haemost 1999; 81(05): 828-34
DOI: 10.1055/s-0037-1614577
Rapid Communication
Schattauer GmbH

DX-9065a, an Orally Active Factor Xa Inhibitor, Does not Facilitate Haemorrhage Induced by Tail Transection or Gastric Ulcer at the Effective Doses in Rat Thrombosis Model

Kiyoshi Tanabe
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
2   Department of Radiological Sciences, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Japan
,
Yoshiyuki Morishima
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Tomoko Shibutani
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Yasuko Terada
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Tsuyoshi Hara
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Yasutaka Shinohara
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Kazuharu Aoyagi
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Satoshi Kunitada
1   From the Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Tokyo, Japan
,
Takashi Kondo
2   Department of Radiological Sciences, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Japan
› Author Affiliations
Further Information

Publication History

Received 22 September 1998

Accepted after revision 18 January 1999

Publication Date:
09 December 2017 (online)

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Summary

DX-9065a is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). We evaluated the effects of DX-9065a and warfarin on bleeding time and blood loss in rat tail transection model and on blood loss in hydrochloride (HCl)-induced rat gastrointestinal haemorrhage model. The blood loss was determined by measuring the haemoglobin content in saline immersed with transected tail or hematin chloride content in the gaster after HCl administration. DX-9065a or warfarin was administered orally at 1 h or 15-21 h before the haemorrhagic stimuli, respectively. The dose required for 50% inhibition of thrombus formation (ID50) was 21 mg/kg for DX-9065a and 0.75 mg/kg for warfarin in a copper wire-inserted arteriovenous (AV) shunt model. In contrast to DX-9065a (10 or 30 mg/kg), warfarin (0.75 mg/kg) significantly prolonged the bleeding time. In rat tail transection model, the blood loss for the control group was 102 ± 41 μl at 20 min after the transection. While warfarin (0.75 mg/kg) facilitated the blood loss about 5 times as much as the control, DX-9065a (10 or 30 mg/kg) did not. In rat gastrointestinal model, the blood loss for the control group was 15.9 ± 5.6 μl at 15 min after HCl administration. In contrast to DX-9065a (10 or 30 mg/kg), warfarin (0.75 mg/kg) increased the blood loss about twice as much as the control. Thus, compared with warfarin, DX-9065a only increased bleeding time or blood loss to a minor extent in the doses tested. These observations suggest that direct inhibition of FXa could be preferable to warfarin in the suppression of thrombosis without haemorrhagic complications.

 

  • References

  • 1 Lind SE. The bleeding time does not predict surgical bleeding.. Blood 1991; 77: 2547-52.
    PubMedGoogle Scholar
  • 2 Ferraris VA, Swanson E. Aspirin usage and perioperative blood loss in patients undergoing unexpected operations.. Surg Gynecol Obstet 1983; 156: 439-42.
    PubMedGoogle Scholar
  • 3 Installe ER, Gonzalez M, Schoevaerdts JC, Tremouroux J. Prevention by ticlopidine of platelet consumption during extracorporeal circulation for heart surgery and lack of effect on operative and postoperative bleeding.. J Cardiovasc Pharmacol 1981; 3: 1174-83.
    CrossrefPubMedGoogle Scholar
  • 4 Brommer EJ. The effect of ticlopidine upon platelet function, haemorrhage and post-operative thrombosis in patients undergoing suprapubic prostatectomy.. J Int Med Res 1981; 9: 203-10.
    CrossrefPubMedGoogle Scholar
  • 5 Topol EJ, Plow EF. Clinical trials of platelet receptor inhibitors.. Thromb Haemost 1993; 70: 94-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Stella L, Donati MB, de Gaetano G. Bleeding time in laboratory animals. I. Aspirin does not prolong bleeding time in rats.. Thromb Res 1975; 7: 709-16.
    CrossrefPubMedGoogle Scholar
  • 7 De Clerck F, Goossens J, Reneman R. Effects of anti-inflammatory, anticoagulant and vasoactive compounds on tail bleeding time, whole blood coagulation time and platelet retention by glass beads in rats.. Thromb Res 1976; 8: 179-93.
    PubMedGoogle Scholar
  • 8 Minsker DH, Kling PJ. Bleeding time in rats is prolonged by aspirin.. Thromb Res 1977; 10: 619-22.
    CrossrefPubMedGoogle Scholar
  • 9 Dejana E, Villa S, de Gaetano G. Bleeding time in rats: a comparison of different experimental conditions.. Thromb Haemost 1982; 48: 108-11.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Hara T, Yokoyama A, Ishihara H, Yokoyama Y, Nagahara T, Iwamoto M. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa.. Thromb Haemost 1994; 71: 314-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Morishima Y, Tanabe K, Terada Y, Hara T, Kunitada S. Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: Comparison with a direct thrombin inhibitor and antithrombin-dependent anticoagulants.. Thromb Haemost 1997; 78: 1366-71.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Hara T, Yokoyama A, Tanabe K, Ishihara H, Iwamoto M. DX-9065a, an orally active, specific inhibitor of factor Xa, prevents thrombosis without affecting bleeding time in rats.. Thromb Haemost 1995; 74: 635-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent.. J Biol Chem 1951; 193: 265-75.
    PubMedGoogle Scholar
  • 14 Pelzer H, Schwarz A, Heimburger N. Determination of human thrombin anti-thrombin complex in plasma with an enzyme-linked immunosorbent assay.. Thromb Haemost 1968; 59: 101-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Finney D.. Probit analysis.. London: Cambridge University Press; 1952
    Google Scholar
  • 16 Owen Jr CA , Bollman JL, Grindlay JH. Radiochromium-labeled erythrocytes for the detection of gastrointestinal hemorrhage.. J Lab & Clin Med 1954; 44: 238-45.
    PubMedGoogle Scholar
  • 17 Crosby WH, Furth FW.. Blood. 1956; 11:: 380.
    PubMedGoogle Scholar
  • 18 Altman R, Rouvier J, Gurfinkel E, D"Ortencio O, Manzanel R, de La Fuente L, Favaloro RG. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves.. J Thorac Cardiovasc Surg 1991; 101: 427-31.
    PubMedGoogle Scholar
  • 19 Petersen P, Boysan G, Godtfredsen J, Anderson ED, Anderson B. Placebo-controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study.. Lancet 1989; 1: 175
    PubMedGoogle Scholar
  • 20 Preliminary report of the Stroke Prevention in Atrial Fibrillation study. N Engl J Med. 1990; 322: 863-8.
    PubMedGoogle Scholar
  • 21 De Feo G, Del Vecchio A, Orticelli G, Valeri P, Mazzanti G. Misleading results in studying pharmacodynamic interaction with oral anticoagulant.. Boll Chim Farmaceutico 1991; 130: 94-6.
    PubMedGoogle Scholar
  • 22 Hirsh J, Dalen JE, Deykin D, Poller L, Bussey H. Oral anticoagulants. Mechanism of action, clinical effectiveness, and optimal therapeutic range.. Chest 1995; 108: 231S-46S.
    CrossrefPubMedGoogle Scholar
  • 23 Edmunds LH, Salzman EW. Hemostatic problems transfusion therapy, and cardiopulmonary bypass in surgical patients. In Hemostasis and Thrombosis.. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: JB Lippincott; 1994: 956-68.
    Google Scholar
  • 24 Vigano S, Mannucci PM, Solinas S. Decrease in protein C antigen and formation of an abnormal protein soon after starting oral anticoagulant therapy.. Br J Haematol 1984; 57: 213-20.
    CrossrefPubMedGoogle Scholar
  • 25 Okajima K, Koga S, Kaji M, Inoue M, Nakagaki T, Funatsu A. Effect of protein C and activated protein C on coagulation and fibrinolysis in normal human subjects.. Thromb Haemost 1990; 63: 48-53.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Vainieri H, Wingard Jr LB. Effect of warfarin on the kinetics of the vitamin K-dependent clotting factors in rats.. J Pharmacol Exp Ther 1977; 201: 507-17.
    PubMedGoogle Scholar
  • 27 Tollersrud OK, Kvalvaag AH, Helgeland L. Biosynthesis and clearance of prothrombin in warfarin-treated rats.. Biochim Biophys Acta 1989; 1010: 35-40.
    CrossrefPubMedGoogle Scholar
  • 28 Cai S-R, Kennedy SC, Bowling WM, Flye MW, Ponder KP. Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy.. J Clin Invest 1998; 101: 2831-41.
    CrossrefPubMedGoogle Scholar
  • 29 Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients treated with warfarin: Relation to the prothrombin time and important remediable lesions.. Am J Med 1989; 87: 153-9.
    CrossrefPubMedGoogle Scholar
  • 30 Gruber A, Griffin JH, Hawker LA, Hanson SR. Inhibition of platelet-dependent thrombus formation by human activated protein C in a primate model.. Blood 1989; 73: 639-42.
    PubMedGoogle Scholar
  • 31 Gruber A, Hanson SR, Kelly AB, Yan BS, Bang N, Griffin JH, Harker LA. Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis.. Circulation 1982; 82: 578-85.
    PubMedGoogle Scholar
  • 32 Majerus PW, Tollefson DM, Shuman MA. The interaction of platelets with thrombin. In Platelets in Biology and Pathology.. Gordon JL. ed. Amsterdam: North-Holland Publishing; 1976: 241-60.
    Google Scholar
  • 33 Millis DCB, Macfarlene DE. Platelet receptors. In Platelets in Biology and Pathology.. Gordon JL. ed. Amsterdam: North-Holland Publishing; 1976: 160-202.
    Google Scholar