Anti-thrombotic activity of KBT-3022 in experimental models of thrombosis.
In this study, we investigated the effects of KBT-3022 (ethyl 2-[4,5-bis(4-methoxyphenyl)-thiazol-2-yl]pyrrol-1-ylacetate) , a potent and long-lasting anti-platelet agent, in several experimental thrombosis models and compared them with those of other anti-platelet drugs. Oral administration of KBT-3022 prevented arachidonic acid-induced death due to pulmonary embolism in mice and rabbits with respective ED50 values of 0.29 and 0.12 mg/kg. The protective effect of acetylsalicylic acid (ASA) against mortality was weaker than that of KBT-3022, and ticlopidine hydrochloride (TP) showed no such effect in these models. In a guinea pig arterio-venous shunt model, the inhibition by KBT-3022 of thrombus formation on a silk thread inserted into the shunt was dose-dependent and 300 and 30 times more potent than the inhibition obtained with ASA and indomethacin, respectively. In a model of aortic thrombosis induced by perivascular application of 20% silver nitrate solution, KBT-3022 (1 mg/kg, p.o.) inhibited thrombus formation significantly, ASA (100 mg/kg, p.o.) tended to inhibit it, and TP had no effect. However, in a stasis-induced venous thrombosis model in guinea pigs, TP inhibited thrombus formation significantly, but KBT-3022 and ASA were ineffective. These results suggest that KBT-3022 may be a useful drug for the treatment and/or prophylaxis of thrombus formation in shunts and aortic thrombosis.
Yokota
K
K
New Drug Research Laboratories, Kanebo, Ltd., Osaka, Japan.
Yamashita
A
A
Oda
M
M
D000818:Animals; D016718:Arachidonic Acid; D001241:Aspirin / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005112:Extracorporeal Circulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D011817:Rabbits; D012835:Silver Nitrate; D013844:Thiazoles / Q000627:therapeutic use*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy*; D013988:Ticlopidine / Q000627:therapeutic use
D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D013844:Thiazoles; C064847:KB 3022; D016718:Arachidonic Acid; D012835:Silver Nitrate; D013988:Ticlopidine; D001241:Aspirin; D007213:Indomethacin