The effects of TFC-612, a 7-THIA prostaglandin E1 derivative, on platelet function.

The anti-platelet activities of TFC-612, methyl 6-(( 1R,2S,3R)-3-hydroxy-2-((1E,3S,5R)-3-hydroxy-5-methyl-1-nonenyl)-5- oxocyclopentyl) thio)hexanoate, were compared to prostaglandin E1 (PGE1). TFC-612 inhibited human, guinea-pig and rabbit platelet aggregation induced by ADP, collagen or epinephrine with potency 1-8 times that of PGE1. TFC-612 also inhibited thrombin induced (14C) serotonin release in rabbit platelets. Platelet aggregation was dose dependently inhibited 1 hr after oral administration of TFC-612 (0.32-1.0 mg/kg) and the inhibition lasted up to 6 and 24 hours at 0.32 and 1.0 mg/kg, respectively, in guinea-pigs. In contrast, PGE1 had no effect with oral administration at a dose of 3.2 mg/kg. TFC-612 (0.32-3.2 micrograms/kg, iv) induced platelet disaggregation of thrombi on Achilles tendon in the extracorporeal shunt model in cats. In addition, TFC-612 (1 mg/kg, po) inhibited the adhesiveness of guinea-pig platelets to a glass bead column ex vivo. TFC-612 increased cyclic AMP (cAMP) levels in rabbit platelets. Thus, the anti-platelet action of TFC-612 may be due to an increase in cAMP levels. These results indicate that TFC-612 might be an orally active anti-thrombotic drug.