A multi-center post-marketing surveillance study was conducted in previously untreated patients with hemophilia A in order to evaluate the safety and efficacy of recombinant factor VIII (Recombinate) in the long term (≥2 years) management and prevention of bleeding episodes. Twenty-five patients were enrolled into this study and 22 patients were evaluable. A total of 378 bleeding episodes were assessed during the study period; hemostatic efficacy was judged to be excellent in 226 and good in 138 for an overall efficacy rate of 96.3%. Two patients received three prophylactic treatments per week with recombinant factor VIII during this study (primary and secondary prophylaxis). These patients had few spontaneous bleeding episodes and no joint bleeding episodes for over 2.5 years. Five adverse reactions in 5 patients (22.7%) were reported. Four patients (18.2%) developed evidence of an inhibitor to factor VIII(2 high responders, and 2 low responders, one of which was transient) and, one patient (4.5%) developed evidence of an anti-bovine serum albumin antibody. The incidence of anti-factor VIII inhibitor formation in this study is comparable to that reported in recent prospective studies of this and other factor VIII products. The patient who developed an anti-bovine serum albumin antibody showed no clinical symptoms. These results indicate that recombinant factor VIII (Recombinate) is safe and efficacious for the long-term managemant and prevention of bleeding episodes in previously untreated patients with hemophilia A.

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We have previously reported that an increase in plasma level of NOX, a metabolite of nitric oxide(NO), was marked but that of endothelin remained rather slight in the tissue factor(TF)-induced DIC models in rats, and that these findings appeared to be characteristic in the TF-induced animal DIC models. In this study, we have investigated whether nafamostat mesilate (FUT) was able to affect and modify the pathophysiology of DIC in these animal models. DIC was induced in the Wistar strain male rats by administering TF at 3.75units/kg of body weight via their tail vein over a period of 4 hours. The effect of FUT on the TF-induced DIC was observed by continuous administration of FUT, either at 0.1 mg/kg or 1.0 mg/kg, which had been started 30 minutes prior to the TF administration. The decreased platelet counts and plasma fibrinogen and the increased thrombin-antithrombin complex and the D-dimer, which had been generally noted in these animal models, were all considerably reduced. Appearance of hematuria frequently observed in these animal models was also markedly reduced. Furthermore, the increase of NOX was nearly completely suppressed. From these results, we conclude that FUT was able to reduce the bleeding tendency and to inhibit the enhancement of fibrinolysis in the TF-induced DIC models in rats. Further studies are required to clarify the mechanism of effective inhibition by FUT of these reations including the increase of NO production widely noted in the DIC models in rats.

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