Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig
| Autor: | Yoshimi Hirasawa-Taniyama, Mie Nishio, Toshio Yamanaka, Kayoko Mihara, Yasuhiro Kita, Kiyotaka Ito, Jiro Seki, Susumu Miyata, Yasuko Kato, Seitaro Mutoh |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Bleeding Time Platelet Aggregation Injections Subcutaneous Guinea Pigs Thrombin time Pharmacology Arginine Ferric Compounds Guinea pig Chlorides Bleeding time In vivo Antithrombotic medicine Animals Receptor PAR-1 Platelet Carotid Artery Thrombosis Blood Coagulation Sulfonamides Dose-Response Relationship Drug medicine.diagnostic_test Heparin business.industry Thiazoles Pipecolic Acids Anesthesia Benzamides Thiazolidines Platelet aggregation inhibitor Receptors Thrombin business Platelet Aggregation Inhibitors Ex vivo |
| Zdroj: | European Journal of Pharmacology. 473:163-169 |
| ISSN: | 0014-2999 |
| Popis: | The antiplatelet and antithrombotic effects of FR171113, 3-(4-chlorophenyl)-2-(2,4-dichlorobenzoylimino)-5-(methoxycarbonyl methylene)-1,3-thiazolidin-4-one, a non-peptide protease-activated receptor 1 (PAR1) antagonist, were evaluated in guinea pigs. FR171113 inhibited Ser-Phe-Leu-Leu-Arg-Asn-NH2 (a synthetic PAR1 agonist peptide)-induced and thrombin-induced aggregation of guinea pig platelets in a concentration-dependent manner in vitro (IC50=1.5 and 0.35 microM, respectively). Subcutaneous administration of FR171113 (0.1-3.2 mg/kg) produced a dose-dependent inhibition of platelet aggregation ex vivo. The ED50 value of FR171113 for platelet aggregation was 0.49 mg/kg s.c. However, FR171113 did not have an inhibitory effect on ADP- or collagen-induced platelet aggregation in vitro and ex vivo. One hour after FR171113 treatment at 1.0 mg/kg s.c., significant inhibition of arterial thrombosis without a prolongation of thrombin time or coagulation time was seen in the FeCl3-induced carotid artery thrombosis model in guinea pigs. Furthermore, FR171113 did not prolong bleeding time even at 32 mg/kg s.c., which is a much higher dose than that required in the thrombosis model. These observations indicate that FR171113 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antithrombotic activity is efficacious without causing a prolongation of bleeding time. |
| Databáze: | OpenAIRE |
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