Characteristics of the hemostatic action of KFA-1411, an inhibitor of coagulation factor Xa (FXa), in humans and various animals
| Autor: | Masami Kojima, Takashi Koizumi, Kiyoto Hara, Atsushi Matsuzawa, Akane Matsuzawa, Masahiko Uchida, Satoshi Akahane, Toshiki Honma |
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| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.drug_mechanism_of_action medicine.drug_class Factor Xa Inhibitor Pharmacology Arginine Toxicology Argatroban Mice Dogs Thrombin Piperidines Antithrombotic medicine Animals Humans Platelet Rats Wistar Blood Coagulation Sulfonamides Chemistry Serine Endopeptidases Anticoagulant Anticoagulants Haplorhini Heparin Rats Coagulation Pipecolic Acids Models Animal Rabbits Factor Xa Inhibitors medicine.drug |
| Zdroj: | The Journal of Toxicological Sciences. 28:25-34 |
| ISSN: | 1880-3989 0388-1350 |
| Popis: | This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4- yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate-dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans. |
| Databáze: | OpenAIRE |
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