New therapeutic effects of cilostazol in patients with ischemic disorders

Cilostazol (CIL) is effective for the treatment of patients with peripheral arterial disease (PAD). CIL is an orally administered drug with multiple effects, including anti-platelets aggregation, favorable functions on plasmatic lipids and vasodilator ones, but how these effects might be related to improvement in patients walking affected by PAD is not fully understood. The latest data demonstrate that nitric oxide (NO) is induced by CIL through endothelial nitric oxide synthase (eNOS) activation via a cyclic-AMP (cAMP)/ protein kinase A (PKA)- and PI3K/Akt- dependent mechanism. This mechanism is also responsible for the vasodilatation dependent on endothelium which characterized patients receiving CIL. Other investigators have found that CIL notably reduces the exercise-induced host-inflammatory response in PAD patients, and consequently it improves lipid hydroperoxides and cell-adhesion molecule levels. We recently reported that CIL is able to cause neoangiogenesis in vivo by stimulating the production of proangiogenic proteins, such as vascular endothelial growth factor (VEGF), that increase levels of Endothelial progenitor cells (EPCs) and the formation of new blood vessels. The mechanisms of action of this drug are several and are not clear and established. The objective of the present review is to analyze the existing data about the therapeutic effects of CIL, with the purpose of providing practical indications about this topic for the management of subjects affected by ischemic disorders.