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Pharmacology: Antiplatelet Action: In vitro studies: Cilostazol inhibited platelet aggregation induced by ADP, collagen, arachidonic acid, epinephrine, and thrombin in humans. The drug also inhibited shear stress-induced platelet aggregation.
Cilostazol inhibited ADP- and epinephrine-induced primary aggregation and exhibited a dispersing effect on human platelet aggregates induced by various aggregating agents.
Cilostazol inhibited thromboxane A2 production in activated human platelets.
Cilostazol inhibited the procoagulant activity of human platelets.
In vivo studies: Cilostazol inhibited ADP- and collagen-induced platelet aggregation when orally administered to beagle dogs and pigs.
The inhibitory effect of cilostazol on ADP-induced platelet aggregation was unchanged during repeated oral administration in rats.
Cilostazol prevented platelet aggregation induced by ADP, collagen, arachidonic acid, and epinephrine when orally administered to patients with chronic arterial occlusion or cerebral infarction.
The onset of cilostazol's platelet aggregation inhibitory effect was prompt in humans, and the effect persisted during repeated administration.
Following discontinuation of cilostazol administration, as the plasma concentration of the drug declined, platelet aggregability returned to baseline levels with no rebound phenomenon (no increase of platelet aggregation).
Antithrombotic Action: Cilostazol reduced mortality due to pulmonary embolism induced experimentally in mice by intravenous administration of ADP or collagen.
Cilostazol suppressed the progression of peripheral thrombotic circulatory insufficiency in the hind limbs induced by intra-arterial injection of sodium laurate solution into the femoral artery of dogs.
Cilostazol inhibited thrombotic occlusion of prosthetic artificial grafts placed in the femoral artery of dogs.
Cilostazol inhibited electrical stimulation-induced thrombus formation in the carotid artery of pigs.
Cilostazol reduced the size of cerebral infarction induced by injection of arachidonic acid into the internal carotid artery of rabbits.
Cilostazol reduced the frequency of ischemic attacks in patients with transient ischemic attacks.
Vasodilating Action: Cilostazol inhibited KCl- and prostaglandin F2α-induced contraction of the isolated femoral, middle cerebral, and basilar arteries in dogs.
Cilostazol increased blood flow in the femoral, vertebral, common carotid, and internal carotid arteries in anesthetized dogs.
Cilostazol increased blood flow in the cerebral cortex in anesthetized dogs and cats.
Cilostazol increased blood flow in the cerebral cortex and hypothalamus in conscious rats.
Results of plethysmographic study showed that cilostazol increased blood flow in the occluded ankle and calf region in patients with chronic arterial occlusion, and results of a thermographic plethysmographic study demonstrated that the drug induced an increase in skin temperature of the extremities and increased cutaneous blood flow in patients with chronic arterial occlusion.
Cilostazol increased cerebral blood flow in patients with ischemic cerebrovascular diseases, as determined by the xenon-inhalation method.
Effect on Vascular Cells: Cilostazol suppressed 3H-thymidine uptake in cultured human vascular smooth muscle cells.
Cilostazol suppressed the depletion of lactated dehydrogenase from cultured human endothelial cells stimulated with homocysteine or lipopolysaccharide.
Mechanism of Action: Experiments in rabbits showed that cilostazol suppressed serotonin release from platelets without affecting serotonin and adenosine uptake by platelets. The drug inhibited platelet aggregation induced by thromboxane A2 (TXA2).
Cilostazol exerts its antiplatelet and vasodilating actions by selectively inhibiting PDE3 (cGMP-inhibited PDE) in platelets and vascular smooth muscle.
Cilostazol's antiaggregation effect in human platelets was augmented in the presence of vascular endothelial cells or prostaglandin E1.
Cilostazol's antiaggregation effect in canine platelets was augmented in the presence of prostaglandin I2 or adenosine.
Clinical Studies: RHEA Cilostazol Tablets were studied in a total of 226 patients with chronic arterial occlusive disease in open and double-blind studies. Based on global assessment, for ischemic symptoms, including ulceration, pain, and coldness of the extremities, the drug was judged to be either effective or very effective in 66.1% (119/180) and slightly effective or better in 85.0% (153/180) of patients with peripheral circulatory insufficiency.
RHEA Cilostazol Tablets were studied in a total of 1,034 patients with cerebral infarction in a placebo-controlled double-blind study. The annual incidence rates of cerebral infarction were 3.43% and 5.75% in the RHEA cilostazol and placebo groups, respectively, (total duration of observation: 873.8 and 973.7 person-years; incidence of recurrence: 30 and 56 respectively). The estimated risk reduction per person-year for RHEA cilostazol treatment relative to placebo treatment was 40.3%. Based on the number of "all-cause deaths" during the treatment period (one of the secondary endpoints) the annual mortality rate was estimated to be 0.92% in the RHEA cilostazol group and 0.82% in the placebo group, showing no significant difference between the two groups. In this study, occurrence of angina pectoris was reported in more patients in the RHEA cilostazol group (6/516) than in the placebo group (0/518).
Pharmacokinetics: Plasma Concentrations: Following single oral administration of cilostazol 100 mg to fasted normal health individuals, the plasma cilostazol concentration promptly rose to a maximum level of 763.9 ng/mL in 3 hours. The plasma half-life of the drug estimated using a two-compartment model was 2.2 hours in the β-phase and 18.0 hours in the α-phase. Two metabolites were found to be active: OPC-13015 (dehydrated metabolite) and OPC-13213 (hydroxylated metabolite).
Administration of a single oral dose of cilostazol 50 mg in a fed state was associated with a 2.3-fold increase in Cmax and 1.4-fold increase in AUCinf compared with administration in a fasted state.
Metabolizing Enzymes: Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly CYP3A4, and to a lesser extent, CYP2D6 and CYP2C19 (in vitro).
Protein Binding: Cilostazol: Greater than 95% (equilibrium dialysis in vitro, 0.1-6 μg/mL).
Active metabolite, OPC-13015: 97.4% (ultrafiltration in vitro, 1 μg/mL).
Active metabolite, OPC-13213: 53.7% (ultrafiltration in vitro, 1 μg/mL).
Pharmacokinetics in Patients with Renal Impairment (Outside Japan): Repeated oral administration of RHEA cilostazol at a daily dose of 100 mg for 8 days in patients with severe renal impairment showed decreases (Cmax by 29% and AUC by 39%) in plasma concentrations of cilostazol and marked increases (Cmax by 173% and AUC by 209%) in plasma concentrations of the active metabolite OPC-13213 compared with administration in normal healthy individuals. However, the concentrations of cilostazol and OPC-13213 in patients with mild to moderate renal impairment were similar to those in normal healthy individuals.
Pharmacokinetics in Patients with Hepatic Impairment (Outside Japan): Plasma concentrations of cilostazol following single oral administration of RHEA cilostazol 100 mg in patients with mild to moderate hepatic impairment were similar (Cmax decreased 7%, AUC increased by 8%) to those in normal healthy individuals.
Drug Interactions (Outside Japan): RHEA Cilostazol did not inhibit either the metabolism or pharmacological effects of R- and S-warfarin when administered in combination with single dose of warfarin 25 mg.
Coadministration of a single dose of cilostazol 100 mg during repeated administration of erythromycin 500 mg tid for 7 days increased cilostazol Cmax by 47% and AUC by 87% compared with administration of cilostazol alone. Coadministration of a single dose of ketoconazole 400 mg with a single dose of cilostazol 100 mg increased cilostazol Cmax by 94% and AUC by 129% compared with administration of cilostazol alone. Coadministration of diltiazem 180 mg with a single dose of cilostazol 100 mg increased cilostazol Cmax by 34% and AUC by 44% compared with administration of cilostazol alone.
Administration of a single dose of cilostazol 100 mg with 240 mL of grapefruit juice increased cilostazol Cmax by 46% and AUC by 14% compared with administration of cilostazol without grapefruit juice.
Coadministration of a single dose of cilostazol 100 mg during repeated administration of omeprazole 40 mg qd for 7 days increased cilostazol Cmax by 18% and AUC by 26% compared with administration of cilostazol alone.
