Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans

Woo, Su Kyung; Kang, Woo-Geun; Kwon, Kwang Il

doi:10.1067/mcp.2002.122474

Cited by 64 publications

(61 citation statements)

References 7 publications

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“…In addition, we cannot exclude the possibility that the alterations in reactivity, in part, relate to changes in systemic blood pressure. However, long-term cilostazol treatment is not associated with changes in mean arterial blood pressure, either in preclinical studies (rats or mice: Woo et al, 2002;Yuzawa et al, 2008;Nonaka et al, 2009) or in humans (Woo et al, 2002), although changes in heart rate and, consequently, diastolic blood pressure were evident.…”

Section: Discussionmentioning

confidence: 99%

Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

Yamashiro

Milsom

Duchêne

et al. 2010

J Cereb Blood Flow Metab

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Hypercholesterolemia is associated with decreased nitric oxide (NO) bioavailability and endothelial dysfunction, a phenomenon thought to have a major role in the altered cerebral blood flow evident in stroke. Therefore, strategies that increase endothelial NO production have potential utility. Vascular reactivity of the middle cerebral artery (MCA) from C57BL/6J wild-type (WT) mice, apolipoprotein-E knockout (ApoE À/À ) mice, and mice treated with the phosphodiesterase inhibitor cilostazol (100 mg/kg) was analyzed using the tension myograph. Contractile responses to endothelin-1 were significantly enhanced in MCA from ApoE À/À mice compared with WT mice (P < 0.01), an effect absent in cilostazol-treated ApoE À/À mice. Acetylcholine-induced relaxation (which is entirely NO-dependent) was significantly impaired in MCA of ApoE À/À mice compared with WT mice (P < 0.05), again an effect prevented by cilostazol treatment. Endothelial NOS phosphorylation at Ser 1179 was decreased in the aorta of ApoE À/À mice compared with WT mice (P < 0.05), an effect normalized by cilostazol. Taken together, our data suggest that the endothelial dysfunction observed in MCA associated with hypercholesterolemia is prevented by cilostazol, an effect likely due to the increase in eNOS phosphorylation and, therefore, activity.

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Section: Discussionmentioning

confidence: 99%

Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

Yamashiro

Milsom

Duchêne

et al. 2010

J Cereb Blood Flow Metab

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show abstract

“…The pharmacodynamic effects were shown to be well correlated with the PK profile. [13] Therefore, the cilostazol CR formulation would be expected to provide effects in patients similar to those of the cilostazol IR formulation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic characteristics of cilostazol 200 mg controlled-release tablet compared with two cilostazol 100 mg immediate-release tablets (Pletal) after single oral dose in healthy Korean male volunteers

Son

Cho

Choi

et al. 2016

Transl Clin Pharmacol

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Cilostazol controlled-release (CR) tablets have recently been developed by Korea United Pharm (Seoul, Korea). The tablets use a patented double CR system, which improves drug compliance by allowing "once daily" administration and reduces adverse events by sustaining a more even plasma concentration for 24 h. We conducted an open, randomized, two-period, two-treatment, crossover study to compare the pharmacokinetic (PK) characteristics and tolerability of cilostazol when administered to healthy Korean male volunteers as CR or immediate release (IR) tablets (Pletal, Korea Otsuka Pharmaceutical Co., Gyeonggi-do, Korea). Each volunteer was randomly allocated to receive a single tablet of cilostazol CR (200 mg) or two tablets of cilostazol IR (100 mg) with a 7-day washout period between treatments. Plasma cilostazol, OPC-13015 (3,4-dehydrocilostazol), and OPC-13213 (4'-trans-hydroxycilostazol) were assayed using liquid chromatography-tandem mass spectrometry for PK analysis. Thirty participants completed the study with no clinically relevant safety issues. The peak concentrations (C max , mean ± SD) of cilostazol CR and cilostazol IR were 1414.6 ± 49.3 and 1413.1 ± 35.2 ng/mL, respectively, and the areas under the plasma concentrationtime curve from 0 to the last concentration (AUC last ) were 23928.7 ± 65.9 and 25312.0 ± 62.6 ng•h/ mL, respectively. The geometric mean ratios (cilostazol CR/ cilostazol IR, GMR) of the C max and AUC last values were 1.001 (90% CI: 0.822, 1.220) and 0.945 (90% CI: 0.814, 1.098), respectively. The frequencies of adverse events were similar. The present study showed that cilostazol PK and tolerability were comparable when administered to healthy Korean men, regardless of whether administered as cilostazol CR or IR.

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“…The investigators did not mention the time of blood sampling for platelet function measurement after the last-dose administration. In a healthy volunteer study using pharmacokinetic-pharmacodynamic model (a single dose of 100 mg cilostazol), 22 peak cilostazol concentration was achieved at 3.65 h, but maximal platelet inhibition was at 6.05 h after cilostazol administration. The maximum pharmacodynamic effect was observed ≈8 h after clopidogrel loading.…”

Section: Article P 2581mentioning

confidence: 99%

Cilostazol to Overcome High On-Treatment Platelet Reactivity in Korean Patients Treated With Clopidogrel and Calcium-Channel Blocker

Jeong

Tantry

Bliden

et al. 2011

Circ J

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Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans

Abstract: This pharmacokinetic-pharmacodynamic model successfully described the relation between plasma concentration of cilostazol and the antiplatelet and cardiovascular effects of the drug.

Cited by 64 publications

References 7 publications

Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

Alterations in Nitric Oxide and Endothelin-1 Bioactivity Underlie Cerebrovascular Dysfunction in ApoE-Deficient Mice

Pharmacokinetic characteristics of cilostazol 200 mg controlled-release tablet compared with two cilostazol 100 mg immediate-release tablets (Pletal) after single oral dose in healthy Korean male volunteers

Cilostazol to Overcome High On-Treatment Platelet Reactivity in Korean Patients Treated With Clopidogrel and Calcium-Channel Blocker

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