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      Pharmacokinetic comparison of sustained- and immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

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          A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers.


          This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUC T ), the measured peak plasma concentration at steady state ( C max,ss), and the time to reach C max,ss ( t max,ss) were analyzed using a noncompartmental method.


          A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUC T (96–120 hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) C max,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median t max,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863–1.017), 0.960 (0.883–1.043), and 0.935 (0.859–1.017) for AUC T and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized C max,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4′-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated.


          At steady state, the AUC T of cilostazol SR 200 mg is comparable to that of cilostazol IR 100 mg twice a day in healthy male Korean subjects. Both formulations are well tolerated.

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          Most cited references 14

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          Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis.

          Cilostazol, a phosphodiesterase inhibitor, has been reported to reduce restenosis rate after coronary angioplasty and stenting. This study was performed to investigate the effect of cilostazol on the progression of intracranial arterial stenosis (IAS). We randomized 135 patients with acute symptomatic stenosis in the M1 segment of middle cerebral artery or the basilar artery to either cilostazol 200 mg per day or placebo for 6 months. Aspirin 100 mg per day was also given to all patients. Patients with potential embolic sources in the heart or extracranial arteries were excluded. IAS was assessed by magnetic resonance angiogram (MRA) and transcranial Doppler (TCD) at the time of recruitment and 6 months later. The primary outcome was the progression of symptomatic IAS on MRA and secondary outcomes were clinical events and progression on TCD. Thirty-eight patients were prematurely terminated. Dropout rates and reasons for dropouts were similar between the cilostazol and placebo groups. There was no stroke recurrence in either cilostazol or placebo group, but there was 1 death and 2 coronary events in each group. In cilostazol group, 3 (6.7%) of 45 symptomatic IAS progressed and 11 (24.4%) regressed. In placebo group, 15 (28.8%) of symptomatic IAS progressed and 8 (15.4%) regressed. Progression of symptomatic IAS in cilostazol group was significantly lower than that in placebo group (P=0.008) Our study suggests that symptomatic IAS is a dynamic lesion and cilostazol may prevent its progression.
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            Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction.

             F Gotoh,  H Tohgi,  S Hirai (2015)
            Cilostazol, an antiplatelet drug that increases the cyclic adenosine monophosphate (AMP) levels in platelets via inhibition of cyclic AMP phosphodiesterase, has been used in chronic arterial occlusive disease. The purpose of the present study was to examine the effects of cilostazol on the recurrence of cerebral infarction using a multicenter, randomized, placebo-controlled, double-blind clinical trial method. Patients who suffered from cerebral infarction at 1 to 6 months before the trial were enrolled between April 1992 and March 1996. Oral administration of cilostazol (100 mg twice daily) or placebo was randomly assigned to the patients and continued until February 1997. The primary endpoint was the recurrence of cerebral infarction. In total, 1,095 patients were enrolled. An analysis based on 1,052 eligible patients (526 given cilostazol and 526 given placebo) showed that the cilostazol treatment achieved a significant relative-risk reduction (41.7%; confidence interval [CI], 9.2% to 62.5%) in the recurrence of cerebral infarction as compared with the placebo treatment (P=.0150). Intention-to-treat analysis of 1,067 patients also showed a significant relative-risk reduction (42.3%; CI, 10.3% to 62.9%, P=.0127). No clinically significant adverse drug reactions of cilostazol were encountered. Long-term administration of cilostazol was effective and safe in the secondary prevention of cerebral infarction. Copyright © 2000 National Stroke Association. Published by Elsevier Inc. All rights reserved.
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              Usefulness of Nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study). NIsoldipine in COronary artery disease in LEuven.

              The NIsoldipine in COronary artery disease in LEuven (NICOLE) study investigates (1) whether nisoldipine, a dihydropyridine calcium antagonist, reduces the progression of minor coronary arterial lesions in the long term, and (2) whether it reduces the restenosis rate after successful percutaneous transluminal coronary angioplasty (PTCA). The NICOLE study is a single-center, randomized, double-blind trial in 826 patients, who underwent a successful PTCA. Nisoldipine 40 mg coat-core or placebo was started the morning after the procedure and continued for 3 years. All coronary arterial segments were measured on preprocedural angiogram and on the second follow-up angiogram at 3 years. On the first follow-up angiogram at 6 months only the dilated segments were measured. Although the study is still ongoing until the primary end point is reached, we report in this study the angiographic restenosis data as well as the clinical events observed at 6-month follow-up. The per-protocol population consisted of 646 patients. Restenosis, defined as a > or =50% loss of the initial gain (National Heart, Lung, and Blood Institute criterion IV) occurred in 49% and 55% of the 308 nisoldipine-treated and the 338 placebo-treated patients, respectively (p = NS). At follow-up, the rates of death and myocardial infarction were low and similar in both groups, but in the nisoldipine group, less patients required early coronary angiography (18% vs 26%, p = 0.006) and subsequent revascularization procedures (32% vs 41%, p = 0.057). Thus, nisoldipine did not significantly reduce the angiographic restenosis rate after PTCA, but reduced the number of repeat revascularization procedures, which may be due to its antianginal action.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                09 July 2015
                : 9
                : 3571-3577
                [1 ]Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea
                [2 ]Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, Republic of Korea
                [3 ]Department of Clinical Pharmacology, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea
                [4 ]Clinical Trials Center, Pusan National University Hospital, Busan, Republic of Korea
                Author notes
                Correspondence: Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, College of Medicine, University of Ulsan, Asan Medical Center, 88 Olympic-ro 43-gil, Songpagu, Seoul, 138-736, Republic of Korea, Tel +82 2 3010 4622, Fax +82 2 3010 4623, Email mdlhs@ 123456amc.seoul.kr
                © 2015 Kim et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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