In vivo profile of the anticoagulant effect of 17ß-amino-1,3,5(10)estratrien-3-ol

Abstract

The anticoagulant activity of 17ß-amino-1,3,5(10)estratrien-3-ol (AE2) was established for the first time. Experiment 1: mice groups were treated with a single subcutaneous (s.c.) AE2 injection (0.5, 1, 2, 4, and 8mg/100g BW) or vehicle (propylenglycol; 0.5ml/100g). After 24h, AE2 produced dose-dependent blood clotting time increases related to control, Emax=+121% (P<0.01) finishing the sixth day. Experiment 2: four groups received a single s.c. administration of AE2 (4 or 8mg/100g BW) or 17ß-estradiol (E2; 3mg/100g BW) or vehicle. After 24 and 48h post-administration, the times of blood clotting, prothrombin, thrombin, and activated partial thromboplastin and fibrinogen concentrations were assessed. Both AE2 doses increased blood clotting and fibrinogen similarly, blood clotting time: 64, 94%; fibrinogen: 71, 107% (P<0.01). Prothrombin, activated partial thromboplastin and thrombin times, increased 13–15%, 27–55%, and 15–29%, respectively (P<0.01). Meanwhile E2 decreased blood clotting 20% (P<0.01) and thrombin 23% (P<0.01) after 48h. Experiment 3: for five consecutive days, mice received AE2 or E2 (0.1, 1, 10, 100, and 1000μg/kg/day), or vehicle. Blood clotting time was assessed at 1, 2, 3, 4, 5, 8, and 11 days after treatment. AE2 at all doses were anticoagulant for 2–3 days after administration whereas E2 was procoagulant for 8–11 days. These opposite effects were: AE2 Emax=+29%; E2 Emax=−30%; (P<0.01). AE2 is the parent compound of the 17ß-aminoestrogens, with the largest and longest anticoagulant effect until now reported.