Cilostazol as a unique antithrombotic agent.
Cilostazol (CLZ) was originally developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). PDE3 inhibition in platelets and vascular smooth muscle cells (VSMC) was expected to provide an antiplatelet effect and vasodilation. Recent preclinical studies have demonstrated that CLZ also possesses the ability to inhibit adenosine uptake by various cells, a property that distinguishes CLZ from other PDE3 inhibitors, such as milrinone. After extensive preclinical and clinical studies, CLZ has been shown to have unique antithrombotic and vasodilatory properties based upon these novel mechanisms of action. CLZ was approved in 1988 for the treatment of symptoms related to peripheral arterial occlusive disease in Japan (Pletaal) and in 1999 in the U.S. and in 2001 in the U.K. (Pletal) for the treatment of intermittent claudication symptoms. Despite its remarkable antiplatelet properties, CLZ is not generally considered an antithrombotic agent in Western countries, perhaps due to the bulk of its antithrombotic preclinical and clinical development being conducted in Japan. In this review, the unique properties of CLZ are reviewed with the focus on CLZ as a unique antiplatelet agent targeting platelets and VSMC, demonstrating synergy with endogenous mediators and showing lowered risk of bleeding risk compared to other antiplatelet drugs.
Kambayashi
Junichi
J
Otsuka Maryland Research Institute, Inc. Rockville, MD 20850, USA. junichik@otsuka.com
Liu
Yongge
Y
Sun
Bing
B
Shakur
Yasmin
Y
Yoshitake
Masuhiro
M
Czerwiec
Frank
F
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D000077407:Cilostazol; D002986:Clinical Trials as Topic; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D013777:Tetrazoles; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000077407:Cilostazol