Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction

Gotoh, Fumio; Tohgi, Hideo; Hirai, Shunsaku; Terashi, Akiro; Fukuuchi, Yasuo; Otomo, E; Shinohara, Yukito; Itoh, Eiichi; Matsuda, Tamotsu; Sawada, Tohru; Yamaguchi, Takenori; Nishimaru, Katsuya; Ohashi, Yasuo

doi:10.1053/jscd.2000.7216

Cited by 325 publications

(231 citation statements)

References 20 publications

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“…The agent is only administered orally because of its low water-solubility (6). However, most patients with cerebral infarction have serious secondary conditions, such as impaired consciousness or aphagia (7). Thus, sufficient blood concentration and effects cannot be obtained with commercially available CLZ tablets.…”

Section: Introductionmentioning

confidence: 99%

Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

2018

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Abstract. Cilostazol (CLZ), an anti-platelet agent, is primarily used following the onset of cerebral infarction. However, as CLZ is only marginally soluble in water, a strategy for patients with serious secondary conditions, such as impaired consciousness or aphagia, is required. In the present study, topical formulations containing CLZ nanocrystals (CLZ nano ) were designed to enhance percutaneous absorption. In addition, the mechanism of penetration of CLZ nano through rat skin was investigated. A topical formulation containing CLZ nanoparticles (CLZ nano gel patch) was prepared using a combination of recrystallization and ball milling of an aqueous gel. The particle size of CLZ nano was 74.5±6.2 nm (mean ± standard deviation). The concentration of permeated CLZ nano and penetration mechanism of the nanocrystals were measured in a percutaneous absorption experiment. The amount of penetrated CLZ, the penetration rate (J c ), the penetration coefficient through the skin (K p ) and the skin/preparation partition coefficient (K m ) for the CLZ nano gel patch were all significantly higher than those of the CLZ powder (CLZ micro ) gel patch, the CLZ nano ointment and the CLZ micro ointment. In in vitro percutaneous penetration experiments on the CLZ nano gel patches, there was a positive correlation between the number of CLZ nano . Following the application of the CLZ nano gel patch on rat skin, 98% of penetrated CLZ was observed in nanoparticle form; for the CLZ micro gel patch, this figure was 9%. In addition, the CLZ concentrations in the plasma of rats administered the CLZ nano gel patches were significantly higher than those of rats administered the CLZ nano CP gel and PEG ointments. It was suggested that CLZ nano (diameter <100 nm) were transferred through the intracellular spaces in the skin and then into peripheral blood vessels. To the best of our knowledge, this is the first report to elucidate the mechanism of the percutaneous penetration of nanocrystal medicines.

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Section: Introductionmentioning

confidence: 99%

Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

2018

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“…In the Cilostazol Stroke Prevention Study (CSPS) [3,4] , a randomized, double-blind, and placebo-controlled trial was conducted, involving more than 1 000 Japanese patients, who had been diagnosed with ischemic stroke during the previ- In the Trial of cilOstazol in Symptomatic intracranial Stenosis (TOSS) [5] , which is another multicenter double-blind placebo-controlled trial, 135 patients with acute symptomatic stenosis in the M1 segment of middle cerebral artery or the basilar artery are randomized to cilostazol medication (200 mg per day) or placebo for 6 months, during which all the patients also receive aspirin medication. The results have shown that cilostazol and aspirin are tolerable and the co-effect in preventing the progression of symptomatic intracranial arterial stenosis (IAS) is superior to that of aspirin mono-therapy.…”

Section: Introductionmentioning

confidence: 99%

Effect of cilostazol on cerebral arteries in secondary prevention of ischemic stroke

Guo

Lin

et al. 2009

Neurosci. Bull.

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Objective To compare the effects of cilostazol on cerebral arteries and cerebrovascular blood flow in secondary prevention of ischemic stroke, with those of aspirin. Methods Sixty-eight patients who had ischemic stroke during the recent 1-6 months were recruited and randomized into cilostazol or aspirin group. Cerebrovascular condition was assessed by magnetic resonance angiography (MRA) and transcranial doppler ultrasonography (TCD) at the beginning of the study and after 12-month medication. Results During the clinical follow-up, ischemic stroke recurred in 2 patients in cilostazol group, while in aspirin group, one case of ischemic stroke recurrence and one case of acute myocardial infarction were found. MRA revealed that in aspirin group, the percentages of patients experiencing aggravation and attenuation of cerebrovascular condition were 3.3% and 6.7%, respectively, while in aspirin group, they were 3.3% and 10%, respectively. Moreover, TCD revealed that 26.9% of the patients in aspirin group and 14.3% of the patients in cilostazol group experienced aggravation of cerebrovascular condition. However, the systolic peak flow velocity of the previously abnormal arteries increased by 42.9% after 12-month medication of cilostazol, which was significantly higher than that after aspirin medication (27.5%) (P = 0.04).Furthermore, as a major side effect of antiplatelet therapy, the frequrency of bleeding was much less in cilostazol group (0 case in cilostazol group vs 5 in aspirin, P < 0.05). Conclusion Cilostazol is as effective as aspirin in preventing the aggravation of cerebral arteries in secondary prevention of ischemic stroke. Besides, it is more safe. Cilostazol can increase the systolic peak flow velocity of cerebral arteries, which may improve the blood supply of focal ischemia.

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“…Cilostazol may also play a future role in the secondary prevention of ischemic stroke because it significantly decreases the risk of stroke recurrence in stroke patients (Gotoh et al, 2000) and has both neuroprotective and antithrombotic effects (Choi et al, 2002;Kohda et al, 1999).…”

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confidence: 99%

The Phosphodiesterase 3 Inhibitor Cilostazol Dilates Large Cerebral Arteries in Humans Without Affecting Regional Cerebral Blood Flow

Birk

Kruuse

Petersen

et al. 2004

Journal of Cerebral Blood Flow & Metabolism

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Summary:Cilostazol, an inhibitor of phosphodiesterase (PDE) type 3, is used clinically in peripheral artery disease. PDE3 inhibitors may be clinically useful in the treatment of delayed cerebral vasospasm after subarachnoid hemorrhage. The authors present the first results on the effect of cilostazol on cerebral hemodynamics in normal participants. In this double-blind, randomized, crossover study, 200 mg cilostazol or placebo was administered orally to 12 healthy participants. Cerebral blood flow was measured using During the 4-hour observation period, there was no effect on systolic blood pressure (P ‫ס‬ 0.28), but diastolic blood pressure decreased slightly compared with placebo (P ‫ס‬ 0.04). V MCA decreased 21.5 ± 5.7% after cilostazol and 5.5 ± 12.2% after placebo (P ‫ס‬ 0.02, vs. placebo), without any change in global or regional cerebral blood flow. The superficial temporal artery diameter increased 17.6 ± 12.3% (P < 0.001 vs. baseline) and radial artery diameter increased 12.6 ± 8.6% (P < 0.001 vs. baseline). Adverse events, especially headache, were common. The findings suggest that cilostazol is an interesting candidate for future clinical trials of delayed cerebral vasospasm.

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Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction

Cited by 325 publications

References 20 publications

Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

Enhanced percutaneous absorption of cilostazol nanocrystals using aqueous gel patch systems and clarification of the absorption mechanism

Effect of cilostazol on cerebral arteries in secondary prevention of ischemic stroke

The Phosphodiesterase 3 Inhibitor Cilostazol Dilates Large Cerebral Arteries in Humans Without Affecting Regional Cerebral Blood Flow

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