Effects of DX-9065a, an Orally Active, Newly Synthesized and Specific Inhibitor of Factor Xa, against Experimental Disseminated Intravascular Coagulation in Rats

Summary

We investigated the protective effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against two kinds of experimental disseminated intravascular coagulation (DIC) in rats. Endotoxin-induced experimental DIC was induced by a 4-h sustained infusion of endotoxin at a dose of 100 mg/kg. Thromboplastin-induced experimental DIC was induced by a bolus injection of thromboplastin at a dose of 150 mg/kg. The rats were orally administered DX-9065a at 10, 30 or 100 mg/kg 30 min before endotoxin or thromboplastin injection.

In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi.

When DX-9065a was orally administrated at 100 mg/kg without endotoxin or thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens.

These findings suggest that the new oral anti-Xa drug, DX-9065a, has an effect in reducing the severity of DIC. However, further dose-finding and safety studies of this drug have still to be assessed.

• References

• 1 Asakura H, Jokaji H, Saito M, Uotai C, Kumabashiri I, Morishita E, Yama-zaki M, Matsuda T. Changes in plasma levels of tissue-plasminogen activator/inhibitor complex and active plasminogen activator inhibitor in patients with disseminated intravascular coagulation. Am J Haematol 1991; 36: 176-83
• 2 Müller-Berghaus GM, Hasegawa H. Pathogenesis of disseminated intravascular coagulation. In: Disseminated intravascular coagulation Abe T, Yamanaka M. (Eds) University of Tokyo press; Tokyo: 1981. pp 3-13
• 3 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
• 4 Ferreira HC, Murat LG. Immunological method for demonstrating fibrin degradation products in serum and its use in the diagnosis of fibrinolytic states. Br J Haemat 1963; 9: 299-310
• 5 Goodwin JF. Estimation of plasma fibrin using sodium sulfate fractionation. Am J Clin Pathol 1961; 35: 227-32
• 6 Yoshikawa T, Murakami M, Yoshida N, Seto O, Kondo M. Effects of superoxide dismutase and catalase on disseminated intravascular coagulation in rats. Thromb Haemost 1983; 50: 869-72
• 7 Quick AJ, Stanly-Brown M, Bancroft FW. A study of the coagulation defect in hemophilia and in jaundice. Am J Med Sci 1935; 190: 501-11
• 8 Langdell RD, Wagner RH, Brinkhouse KM. Effect of antihemophilic factor on one-stage clotting time. J Lab Clin Med 1953; 47: 637-47
• 9 Weigert C. Uber eine neue Methode zur Farbung von Fibrin und von Micro-organismen. Fortschr Med 1987; 5: 228-37 (in German)
• 10 Hara T, Kunitada S, Iwamoto M. DX-9065a, a synthetic and selective factor Xa inhibitor; species difference in its anticoagulant activity. Thromb Haemost 1993; 69: 890 (Suppl)
• 11 Tanabe K, Hara T, Morishima Y, Ishihara H, Yokoyama A, Honda Y, Iwamoto M. An orally active, specific inhibitor of factor Xa prevents thrombosis without bleeding time in rats. Thromb Haemost 1993; 69: 890 (Suppl)