title: Cilostazol and dipyridamole synergistically inhibit human platelet aggregation.
abstract: It has been previously shown that cilostazol (Pletal), a drug for relief of symptoms of intermittent claudication, potently inhibits cyclic nucleotide phosphodiesterase type 3 (PDE3) and moderately inhibits adenosine uptake. It elevates extracellular adenosine concentration, by inhibiting adenosine uptake, and combines with PDE3 inhibition to augment inhibition of platelet aggregation and vasodilation while attenuating positive chronotropic and inotropic effects on the heart. In the present study, we tested the hypothesis that cilostazol combined with a more potent adenosine uptake inhibitor, dipyridamole, synergistically inhibited platelet aggregation in human blood. In the presence of exogenous adenosine (1 microM), the combination of cilostazol and dipyridamole synergistically increased intra-platelet cAMP. Furthermore, cilostazol inhibited platelet aggregation in a washed platelet assay concentration-dependently with IC50s of 0.17 +/- 0.04 microM (P < 0.05 versus plus adenosine alone of 0.38 +/- 0.05 microM), 0.11 +/- 0.06 microM (P < 0.05), and 0.01 +/- 0.01 microM (P < 0.005) when combined with 1, 3, or 10 microM dipyridamole, respectively (n = 5). In whole blood, cilostazol (0.3 to 3 microM) and dipyridamole (1 or 3 microM) synergistically inhibited collagen- and ADP-induced platelet aggregation in vitro. Furthermore, the synergism was confirmed in an open-label, sequential study in healthy human subjects using ex vivo whole-blood collagen-induced platelet aggregation. Four hours after oral co-administration of cilostazol (100 mg) and dipyridamole (200 mg), platelet aggregation was inhibited by 45 +/- 17%, while no significant inhibition was observed from subjects treated with either drug alone. The combination may provide a potential treatment of arterial thrombotic disorders.
authors.affiliation: Otsuka Maryland Medicinal Laboratories, LLC, Rockville, MD 20850, USa.
authors.forename: Yongge
authors.initials: Y
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Cone
authors.forename: Sang N
authors.initials: SN
authors.lastname: Le
authors.forename: Miranda
authors.initials: M
authors.lastname: Fong
authors.forename: Lian
authors.initials: L
authors.lastname: Tao
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shoaf
authors.forename: Patricia
authors.initials: P
authors.lastname: Bricmont
authors.forename: Frank S
authors.initials: FS
authors.lastname: Czerwiec
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kambayashi
authors.forename: Masuhiro
authors.initials: M
authors.lastname: Yoshitake
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
mesh_terms: D000241:Adenosine / Q000097:blood / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D000077407:Cilostazol; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004176:Dipyridamole / Q000097:blood / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007425:Intracellular Membranes / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013777:Tetrazoles / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D004176:Dipyridamole; D000242:Cyclic AMP; D000241:Adenosine; D000077407:Cilostazol