carboprostacyclin and ataprost

Antiplatelet and antithrombotic effects of OP-41483, a PGl2 analog, were studied in experimental animals, and the following results were obtained: 1) With 10 min-intravenous infusion to guinea pigs, OP-41483 inhibited platelet adhesiveness and platelet aggregation at 300-1000 ng/kg/min and 1000 ng/kg/min, respectively. In these effects, OP-41483 was 1-3 times more potent than carbacyclin and 3 times less potent than PGl2. 2) With oral administration to guinea pigs, OP-41483 given as its alpha-cyclodextrin clathrate (OP-41483 alpha-CD) inhibited platelet adhesiveness at doses higher than 1.0 mg/kg (expressed in terms of OP-41483), whereas PGl2 and carbacyclin did not at 10 mg/kg. OP-41483 alpha-CD also inhibited platelet aggregation after a single dose of 3 mg/kg and repeated doses of 3 mg/kg/day for 7 days. 3) In the electrically induced thrombosis model of guinea pig mesenteric artery, OP-41483 (300-1000 ng/kg/min, i.v.-infusion) and OP-41483 alpha-CD (1.0-3.0 mg/kg, p.o.) inhibited thrombus formation, but heparin (1.0-10 U/kg/min, i.v.-infusion) did not. 4) In the rabbit extracorporeal circulation thrombosis model, OP-41483 (100 and 300 ng/kg/min, i.v.-infusion) inhibited thrombus formation in the extracorporeal shunt and prevented the decrease in platelet count, hematocrit and fibrinogen level in circulating blood. Heparin (1.0-3.0 U/kg/min, i.v.-infusion) also inhibited the thrombus formation and the decrease in fibrinogen level, but did not inhibit the decrease in hematocrit and platelet count.

Topics: Animals; Electric Stimulation; Electrocoagulation; Epoprostenol; Extracorporeal Circulation; Guinea Pigs; Hematocrit; Heparin; In Vitro Techniques; Male; Platelet Aggregation Inhibitors; Platelet Function Tests; Rabbits; Thrombosis

15-cyclopentyl-omega-pentanor-5(E)-carbacyclin (ONO 41483), a chemically stable carboprostacyclin analogue, was 3.3 times less active than prostacyclin but was 2.6 times more active than carboprostacyclin in inhibiting aggregation of ADP-induced baboon platelet in vitro. On human platelets in vitro, ONO 41483 was 9.4 times less active than prostacyclin and 12.7 times more active than carboprostacyclin. ONO 41483 was 3.7 times less active than prostacyclin but was 2.2 times more active than carboprostacyclin in producing a fall in arterial blood pressure in anaesthetised baboons. Intravenous and oral administration of ONO 41483 in baboons produced ex vivo inhibition of ADP-induced platelet aggregation at doses that did not affect blood pressure or heart rate. In addition, bolus intravenous doses (3 to 10 micrograms/kg) of ONO 41483 reversed vasopressin-induced ECG changes in the monkey, suggesting an ability of the compound to relieve coronary spasm.

Topics: Adenosine Diphosphate; Animals; Blood Pressure; Cardiovascular System; Electrocardiography; Epoprostenol; Female; Hemodynamics; Humans; Papio; Platelet Aggregation; Prostaglandins; Prostaglandins, Synthetic; Vasopressins