title: Evaluation of anti-platelet and anti-thrombotic effects of cilostazol with PFA-100® and Multiplate® whole blood aggregometer in vitro, ex vivo and FeCl3-induced thrombosis models in vivo.
abstract: We evaluate the anti-platelet and anti-thrombotic effects of cilostazol using Multiplate® and PFA-100® in vitro and ex vivo with freshly isolated rat whole blood and in vivo venous and arterial thrombosis models in the same species, in an effort to assess the sensitivity of the whole blood aggregometer assays without potential issues of species differences. In vitro assay of anti-platelet effects of cilostazol against collagen-induced aggregation using Multiplate® produced a graded dose-dependent inhibition curve with IC50 value of 75.4 ± 2.4 μM while it showed a highly sensitive and all-or-none type inhibition response from 25 μM in PFA-100®. Interestingly, cilostazol manifested anti-thrombotic effects in vivo at much lower plasma concentrations than the effective concentrations measured in ex vivo or in vitro aggregation tests using PFA-100® or Multiplate®. In addition, the tail bleeding time measurement demonstrated that rats have lower sensitivity to the anti-platelet effects of cilostazol than mice. These results suggest that the detailed comparative evaluation of whole blood aggregometer assays with anti-thrombotic effects in vivo should be preceded before the application of these methods for the pharmacodynamic studies of anti-thrombotic agents.
authors.affiliation: Amorepacific CO R&D Center, Yongin 446-729, Republic of Korea.
authors.forename: Chae-Wook
authors.initials: CW
authors.lastname: Kim
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.forename: Il-Hong
authors.initials: IH
authors.lastname: Bae
authors.forename: Yang-Hui
authors.initials: YH
authors.lastname: Park
authors.forename: Yeon Su
authors.initials: YS
authors.lastname: Jeong
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Chung
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Park
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002712:Chlorides; D000077407:Cilostazol; D005290:Ferric Compounds; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010979:Platelet Function Tests / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D013927:Thrombosis / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077407:Cilostazol; C024555:ferric chloride