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, i.v.) 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.
Motoyama
Y
Y
Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan.
Sakata
Y
Y
Seki
J
J
Asada
T
T
Namikawa
Y
Y
Horiai
H
H
Ono
T
T
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002415:Cats; D000242:Cyclic AMP / Q000097:blood; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D012701:Serotonin; C054546:TFC 612; D000242:Cyclic AMP; D000527:Alprostadil