Cilostazol (Pletal®): A Dual Inhibitor of Cyclic Nucleotide Phosphodiesterase Type 3 and Adenosine Uptake

• Published in: Cardiovascular drug reviews Vol. 19; no. 4; pp. 369 - 386
• Main Authors: Liu, Yongge, Shakur, Yasmin, Yoshitake, Masuhiro, Kambayashi, Jun‐ichi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2001; Blackwell
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Adenosine - antagonists & inhibitors; Adenosine - metabolism; Adenosine uptake; Angioplasty, Balloon, Coronary - adverse effects; Animals; Arterial Occlusive Diseases - drug therapy; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Cell Division - drug effects; Cilostazol; Coronary Restenosis - prevention & control; Coronary Thrombosis - prevention & control; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 3; Fibrinolytic Agents - pharmacology; Humans; Hypolipidemic Agents - pharmacology; Intermittent claudication; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; PDE3; Peripheral arterial disease; Pharmacology. Drug treatments; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase Inhibitors - therapeutic use; Platelet aggregation; Platelet Aggregation Inhibitors - pharmacology; Pletal(r); Randomized Controlled Trials as Topic; Stroke - prevention & control; Tetrazoles - chemistry; Tetrazoles - pharmacology; Tetrazoles - therapeutic use; Vasodilation; Vasodilator Agents - pharmacology; Claudication; Vasodilator agent; Cardiovascular disease; Review; Arterial disease; Vascular disease; Randomization; Intermittent; Limb; Mechanism of action; Human; Adenosine; Treatment efficiency; Enzyme inhibitor; Controlled therapeutic trial; Cilostazol; Biological activity; Quality of life; Chemotherapy; Treatment; Placebo; Double blind study; Cyclic nucleotide; Occlusive arterial disease; Fibrinolytic
• ISSN: 0897-5957; 1527-3466
• DOI: 10.1111/j.1527-3466.2001.tb00076.x

ABSTRACT Cilostazol (Pletal®), a quinolinone derivative, has been approved in the U.S. for the treatment of symptoms of intermittent claudication (IC) since 1999 and for related indications since 1988 in Japan and other Asian countries. The vasodilatory and antiplatelet actions of cilostazol are due mainly to the inhibition of phosphodiesterase 3 (PDE3) and subsequent elevation of intracellular cAMP levels. Recent preclinical studies have demonstrated that cilostazol also possesses the ability to inhibit adenosine uptake, a property that may distinguish it from other PDE3 inhibitors, such as milrinone. Elevation of interstitial and circulating adenosine levels by cilostazol has been found to potentiate the cAMP‐elevating effect of PDE3 inhibition in platelets and smooth muscle, thereby augmenting anti‐platelet and vasodilatory effects of the drug. In contrast, elevation of interstitial adenosine by cilostazol in the heart has been shown to reduce increases in cAMP caused by the PDE3‐inhibitory action of cilostazol, thus attenuating the cardiotonic effects. Cilostazol has also been reported to inhibit smooth muscle cell proliferation in vitro and has been demonstrated in a clinical study to favorably alter plasma lipids: to decrease triglyceride and to increase HDL‐cholesterol levels. One, or a combination of several of these effects may contribute to the clinical benefits and safety of this drug in IC and other disease conditions secondary to atherosclerosis. In eight double‐blind randomized placebo‐controlled trials, cilostazol significantly increased maximal walking distance, or absolute claudication distance on a treadmill. In addition, cilostazol improved quality of life indices as assessed by patient questionnaire. One large randomized, double‐blinded, placebo‐controlled, multicenter competitor trial demonstrated the superiority of cilostazol over pentoxifylline, the only other drug approved for IC. Cilostazol has been generally well‐tolerated, with the most common adverse events being headache, diarrhea, abnormal stools and dizziness. Studies involving off‐label use of cilostazol for prevention of coronary thrombosis/restenosis and stroke recurrence have also recently been reported.