Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxyge...Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxygenase1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol （30 mg/kg） for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semiquantitative PCR and western blot analysis showed that hypoxiainducible factorla and heme oxygenase1 expression levels in creased after chronic cerebral ischemia, with hypoxiainducible factorla expression peaking at 3 weeks and heme oxygenase1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxiainducible factorla may upregulate heine oxygenase1 expression fol lowing chronic cerebral ischemia and that the hypoxiainducible factor1/heme oxygenase1 sig naling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxiainducible factorla and heme oxygenase1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an antiapoptotic mechanism.展开更多
OBJeCTIve：To assess the efifcacy and safety of cilostazol on the progression and regression of symptomatic intracranial artery stenosis. DATA ReTRIvAL： We searched the main databases for eligible trials including Me...OBJeCTIve：To assess the efifcacy and safety of cilostazol on the progression and regression of symptomatic intracranial artery stenosis. DATA ReTRIvAL： We searched the main databases for eligible trials including Medline （from 1966 to June 2014）, Embase （from 1980 to June 2014）, Cochrane Library （Issue 6, 2014）, Chinese National Knowledge Infrastructure （from 1995 to June 2014）, Current Controlled Trials （http：//controlled-trials.com）, Clinical Trials.gov （http：//clinicaltrials.gov）, and Chinese Clinical Trial Registry （http：//www.chictr.org）. All studies regarding prevention and treatment of symptomatic intracranial arterial stenosis by cilostazol were collected. The Mesh or text keywords were the En-glish words： “cilostazol, phosphodiesterase 3 inhibitor, atherosclerosis, and ischemic stroke.” No restrictions were put on publications or publication language. SeLeCTION CRITeRIA：Grade A or B randomized controlled trials were selected according to the quality of evaluation criteria from the Cochrane Collaboration, in which cilostazol and aspi-rin were used to evaluate the effects of cilostazol in the treatment of patients with symptomatic intracranial artery stenosis. The quality of study methodology was evaluated based on criteria de-scribed in Cochrane Reviewer’s Handbook 5.0.1. RevMan 5.2 software was used for data analysis. MAIN OUTCOMe MeASUReS： Clinical efifcacy and safety of cilostazol in stopping progression and promoting regression of symptomatic intracranial artery stenosis were measured by magnet-ic resonance angiography and transcranial Doppler. ReSULTS：Two randomized controlled trials with a total of 203 patients were included in this study. The results showed that while cilostazol was associated with a significantly reduced progression of intracranial artery stenosis （OR = 0.21, 95%CI： 0.09–0.47,P 〈 0.01）, it had no beneifcial effect on symptom regression （OR = 1.42, 95%CI： 0.80–2.51,P = 0.24）. During the follow-up period, although some adverse effects developed, including headache, gastrointestinal disturbance, and dizziness, incidences of bleeding were lower than in aspirin-treated patients. CONCLUSION：Cilostazol may prevent the progression of symptomatic intracranial artery ste-nosis, which could reduce the incidence of ischemic stroke.展开更多
A simple,rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry（UPLC-MS/MS） method has been developed for the simultaneous determination of cilostazol and its pharmacologically active m...A simple,rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry（UPLC-MS/MS） method has been developed for the simultaneous determination of cilostazol and its pharmacologically active metabolite 3,4-dehydro cilostazol in human plasma using deuterated analogs as internal standards（ISs）.Plasma samples were prepared using solid phase extraction and chromatographic separation was performed on UPLC BEH C18（50 mm × 2.1 mm.1.7 μm） column.The method was established over a concentration range of 0.5-1000 ng/mL for cilostazol and 0.5-500 ng/mL for 3.4-dehydro cilostazol.Intra- and inter-batch precision（%CV） and accuracy for the analytes were found within 0.93-1.88 and 98.8-101.7% for cilostazol and 0.91-2.79 and 98.0-102.7% for the metabolite respectively.The assay recovery was within 95-97% for both the analytes and internal standards.The method was successfully applied to support a bioequivalence study of 100 mg cilostazol in30 healthy subjects.展开更多
Cilostazol, a potent inhibitor of type 3 phosphodiesterase (PDE3), has recently been reported to exert neuroprotective effects during acute cerebral ischemic injury. These effects are, at least in part, mediated by th...Cilostazol, a potent inhibitor of type 3 phosphodiesterase (PDE3), has recently been reported to exert neuroprotective effects during acute cerebral ischemic injury. These effects are, at least in part, mediated by the inhibition of oxidative cell death. However, the effects of cilostazol on glucose metabolism in brain cells have not been determined. In the present study, we examined the effects of cilostazol on the oxidative metabolism of glucose and the resultant formation of reactive oxygen species (ROS) in cultured neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with cilostazol (0 – 30 μM) for 48 hours prior to the assay. L-[U-14C]lactate ([14C]lactate) or [1-14C]pyruvate ([14C]pyruvate) oxidation was measured. ROS production was determined using an H2DCFDA assay with a microplate reader. Forty-eight hours of exposure to cilostazol resulted in dose-dependent increases in [14C]lactate and [14C]pyruvate oxidation in both the neurons and astroglia. Dibutyryl cyclic AMP (0 – 0.5 mM) also increased [14C]lactate oxidation, indicating cAMP-mediated PDH activation. In contrast, free radical formation was not affected by cilostazol in either the neurons or astroglia. Cilostazol enhanced the oxidative metabolism of glucose in both neurons and astroglia, while it did not augment ROS production.展开更多
Background Cilostazol is a newly developed antiplatelet drug that has been widely applied for clinical use. Its antiplatelet action appears to be mainly related to inhibition of intracellular phosphodiesterase activit...Background Cilostazol is a newly developed antiplatelet drug that has been widely applied for clinical use. Its antiplatelet action appears to be mainly related to inhibition of intracellular phosphodiesterase activity. Recently, cilostazol has been used for antiplatelet therapy after coronary bare metal stent implantation for thrombosis and restenosis prevention. This prospective randomized and double blind trial was designed to investigate the safety and efficacy of cilostazol for the prevention of late restenosis and acute or subacute stent thrombosis. Methods One hundred and twenty patients who underwent elective stent were randomly assigned to treatment group with cilostazol 200 mg/d （n = 60）, clopidogrel 75 mg/d and aspirin 100 mg/d or to control group with clopidogrel treatment 75 mg/d （n = 60） and aspirin 100 mg/d. Follow-up coronary angiography was performed 6--9 months later. Results Nine months major adverse cardio-cerebral event （MACCE） were lower in treatment groups （P〈0.05）. The quantitative coronary angiography （QCA） at 6 months follow-up showed that minimum lumen diameter （MLD） was higher in treatment group than that of control group [（2.14 ± 0.52）mm vs （1.82 ± 0.36）mm, P〈0.05]. Late lumen loss （LL） [（0.82 ± 0.42）mm vs （1.31 ± 0.58）mm; P〈0.01 ], restenosis rate （RR） （14% vs 32%; P〈0.05） and target lesion revascularizaion （TLR） rate （5% vs 17%; P〈0.05） were lower in treatment group than in control group. Conclusion Cilostazol therapy is an effective regimen for prevention not only stent thrombosis but also RR and TLR through reducing MLD without the risk of increasing bleeding.展开更多
Diabetic nephropathy （DN） is the most common microvascular complication of diabetes and is one of the major causes of end-stage renal disease （ESRD）. Cilostazol, an antiplatelet drug, plays an important role in t...Diabetic nephropathy （DN） is the most common microvascular complication of diabetes and is one of the major causes of end-stage renal disease （ESRD）. Cilostazol, an antiplatelet drug, plays an important role in the prevention and treatment of the chronic complications of diabetes through a series of mechanisms, including anti-inflammation, the inhibition of vascular smooth muscle proliferation, the protection of nerve cells, and the regulation of blood lipids.展开更多
Background Stroke is one of the leading causes of death worldwide.Cilostazol,an antiplatelet and phosphodiesterase 3 inhibitor,has not been clearly established for ischaemic stroke use.We aim to determine the efficacy...Background Stroke is one of the leading causes of death worldwide.Cilostazol,an antiplatelet and phosphodiesterase 3 inhibitor,has not been clearly established for ischaemic stroke use.We aim to determine the efficacy and safety of cilostazol for secondary stroke prevention.Methods MEDLINE,EMBASE,Cochrane Library,Web of Science and ClinicalTrials.gov were searched from inception to 25 September 2020,for randomised trials comparing the efficacy and safety of cilostazol monotherapy or dual therapy with another antiplatelet regimen or placebo,in patients with ischaemic stroke.Version 2 of the Cochrane risk-of-bias tool for randomised trials(RoB 2)was used to assess study quality.This meta-analysis was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)statement.Results Eighteen randomised trials comprising 11429 participants were included in this meta-analysis.Most trials possessed low risk of bias and were of low heterogeneity.Cilostazol significantly reduced the rate of ischaemic stroke recurrence(risk ratio,RR=0.69,95%CI 0.58 to 0.81),any stroke recurrence(RR=0.64,95%CI 0.54 to 0.74)and major adverse cardiovascular events(RR=0.67,95%CI 0.56 to 0.81).Cilostazol did not significantly decrease mortality(RR=0.90,95%CI 0.64 to 1.25)or increase the rate of good functional outcome(Modified Rankin Scale score of 0–1;RR=1.07,95%CI 0.95 to 1.19).Cilostazol demonstrated favourable safety profile,significantly reducing the risk of intracranial haemorrhage(RR=0.46,95%CI 0.31 to 0.68)and major haemorrhagic events(RR=0.49,95%CI 0.34 to 0.70).Conclusions Cilostazol demonstrated superior efficacy and safety profiles compared with traditional antiplatelet regimens such as aspirin and clopidogrel for secondary stroke prevention but does not appear to affect functional outcomes.Future randomised trials can be conducted outside East Asia,or compare cilostazol with a wider range of antiplatelet agents.展开更多
基金supported by the Natural Science Fundation of Jilin Province in China, No.200705272
文摘Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxygenase1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol （30 mg/kg） for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semiquantitative PCR and western blot analysis showed that hypoxiainducible factorla and heme oxygenase1 expression levels in creased after chronic cerebral ischemia, with hypoxiainducible factorla expression peaking at 3 weeks and heme oxygenase1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxiainducible factorla may upregulate heine oxygenase1 expression fol lowing chronic cerebral ischemia and that the hypoxiainducible factor1/heme oxygenase1 sig naling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxiainducible factorla and heme oxygenase1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an antiapoptotic mechanism.
文摘OBJeCTIve：To assess the efifcacy and safety of cilostazol on the progression and regression of symptomatic intracranial artery stenosis. DATA ReTRIvAL： We searched the main databases for eligible trials including Medline （from 1966 to June 2014）, Embase （from 1980 to June 2014）, Cochrane Library （Issue 6, 2014）, Chinese National Knowledge Infrastructure （from 1995 to June 2014）, Current Controlled Trials （http：//controlled-trials.com）, Clinical Trials.gov （http：//clinicaltrials.gov）, and Chinese Clinical Trial Registry （http：//www.chictr.org）. All studies regarding prevention and treatment of symptomatic intracranial arterial stenosis by cilostazol were collected. The Mesh or text keywords were the En-glish words： “cilostazol, phosphodiesterase 3 inhibitor, atherosclerosis, and ischemic stroke.” No restrictions were put on publications or publication language. SeLeCTION CRITeRIA：Grade A or B randomized controlled trials were selected according to the quality of evaluation criteria from the Cochrane Collaboration, in which cilostazol and aspi-rin were used to evaluate the effects of cilostazol in the treatment of patients with symptomatic intracranial artery stenosis. The quality of study methodology was evaluated based on criteria de-scribed in Cochrane Reviewer’s Handbook 5.0.1. RevMan 5.2 software was used for data analysis. MAIN OUTCOMe MeASUReS： Clinical efifcacy and safety of cilostazol in stopping progression and promoting regression of symptomatic intracranial artery stenosis were measured by magnet-ic resonance angiography and transcranial Doppler. ReSULTS：Two randomized controlled trials with a total of 203 patients were included in this study. The results showed that while cilostazol was associated with a significantly reduced progression of intracranial artery stenosis （OR = 0.21, 95%CI： 0.09–0.47,P 〈 0.01）, it had no beneifcial effect on symptom regression （OR = 1.42, 95%CI： 0.80–2.51,P = 0.24）. During the follow-up period, although some adverse effects developed, including headache, gastrointestinal disturbance, and dizziness, incidences of bleeding were lower than in aspirin-treated patients. CONCLUSION：Cilostazol may prevent the progression of symptomatic intracranial artery ste-nosis, which could reduce the incidence of ischemic stroke.
文摘A simple,rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry（UPLC-MS/MS） method has been developed for the simultaneous determination of cilostazol and its pharmacologically active metabolite 3,4-dehydro cilostazol in human plasma using deuterated analogs as internal standards（ISs）.Plasma samples were prepared using solid phase extraction and chromatographic separation was performed on UPLC BEH C18（50 mm × 2.1 mm.1.7 μm） column.The method was established over a concentration range of 0.5-1000 ng/mL for cilostazol and 0.5-500 ng/mL for 3.4-dehydro cilostazol.Intra- and inter-batch precision（%CV） and accuracy for the analytes were found within 0.93-1.88 and 98.8-101.7% for cilostazol and 0.91-2.79 and 98.0-102.7% for the metabolite respectively.The assay recovery was within 95-97% for both the analytes and internal standards.The method was successfully applied to support a bioequivalence study of 100 mg cilostazol in30 healthy subjects.
文摘Cilostazol, a potent inhibitor of type 3 phosphodiesterase (PDE3), has recently been reported to exert neuroprotective effects during acute cerebral ischemic injury. These effects are, at least in part, mediated by the inhibition of oxidative cell death. However, the effects of cilostazol on glucose metabolism in brain cells have not been determined. In the present study, we examined the effects of cilostazol on the oxidative metabolism of glucose and the resultant formation of reactive oxygen species (ROS) in cultured neurons and astroglia. Cultures of neurons or astroglia were prepared from Sprague-Dawley rats. The cells were treated with cilostazol (0 – 30 μM) for 48 hours prior to the assay. L-[U-14C]lactate ([14C]lactate) or [1-14C]pyruvate ([14C]pyruvate) oxidation was measured. ROS production was determined using an H2DCFDA assay with a microplate reader. Forty-eight hours of exposure to cilostazol resulted in dose-dependent increases in [14C]lactate and [14C]pyruvate oxidation in both the neurons and astroglia. Dibutyryl cyclic AMP (0 – 0.5 mM) also increased [14C]lactate oxidation, indicating cAMP-mediated PDH activation. In contrast, free radical formation was not affected by cilostazol in either the neurons or astroglia. Cilostazol enhanced the oxidative metabolism of glucose in both neurons and astroglia, while it did not augment ROS production.
文摘Background Cilostazol is a newly developed antiplatelet drug that has been widely applied for clinical use. Its antiplatelet action appears to be mainly related to inhibition of intracellular phosphodiesterase activity. Recently, cilostazol has been used for antiplatelet therapy after coronary bare metal stent implantation for thrombosis and restenosis prevention. This prospective randomized and double blind trial was designed to investigate the safety and efficacy of cilostazol for the prevention of late restenosis and acute or subacute stent thrombosis. Methods One hundred and twenty patients who underwent elective stent were randomly assigned to treatment group with cilostazol 200 mg/d （n = 60）, clopidogrel 75 mg/d and aspirin 100 mg/d or to control group with clopidogrel treatment 75 mg/d （n = 60） and aspirin 100 mg/d. Follow-up coronary angiography was performed 6--9 months later. Results Nine months major adverse cardio-cerebral event （MACCE） were lower in treatment groups （P〈0.05）. The quantitative coronary angiography （QCA） at 6 months follow-up showed that minimum lumen diameter （MLD） was higher in treatment group than that of control group [（2.14 ± 0.52）mm vs （1.82 ± 0.36）mm, P〈0.05]. Late lumen loss （LL） [（0.82 ± 0.42）mm vs （1.31 ± 0.58）mm; P〈0.01 ], restenosis rate （RR） （14% vs 32%; P〈0.05） and target lesion revascularizaion （TLR） rate （5% vs 17%; P〈0.05） were lower in treatment group than in control group. Conclusion Cilostazol therapy is an effective regimen for prevention not only stent thrombosis but also RR and TLR through reducing MLD without the risk of increasing bleeding.
文摘Diabetic nephropathy （DN） is the most common microvascular complication of diabetes and is one of the major causes of end-stage renal disease （ESRD）. Cilostazol, an antiplatelet drug, plays an important role in the prevention and treatment of the chronic complications of diabetes through a series of mechanisms, including anti-inflammation, the inhibition of vascular smooth muscle proliferation, the protection of nerve cells, and the regulation of blood lipids.
文摘Background Stroke is one of the leading causes of death worldwide.Cilostazol,an antiplatelet and phosphodiesterase 3 inhibitor,has not been clearly established for ischaemic stroke use.We aim to determine the efficacy and safety of cilostazol for secondary stroke prevention.Methods MEDLINE,EMBASE,Cochrane Library,Web of Science and ClinicalTrials.gov were searched from inception to 25 September 2020,for randomised trials comparing the efficacy and safety of cilostazol monotherapy or dual therapy with another antiplatelet regimen or placebo,in patients with ischaemic stroke.Version 2 of the Cochrane risk-of-bias tool for randomised trials(RoB 2)was used to assess study quality.This meta-analysis was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)statement.Results Eighteen randomised trials comprising 11429 participants were included in this meta-analysis.Most trials possessed low risk of bias and were of low heterogeneity.Cilostazol significantly reduced the rate of ischaemic stroke recurrence(risk ratio,RR=0.69,95%CI 0.58 to 0.81),any stroke recurrence(RR=0.64,95%CI 0.54 to 0.74)and major adverse cardiovascular events(RR=0.67,95%CI 0.56 to 0.81).Cilostazol did not significantly decrease mortality(RR=0.90,95%CI 0.64 to 1.25)or increase the rate of good functional outcome(Modified Rankin Scale score of 0–1;RR=1.07,95%CI 0.95 to 1.19).Cilostazol demonstrated favourable safety profile,significantly reducing the risk of intracranial haemorrhage(RR=0.46,95%CI 0.31 to 0.68)and major haemorrhagic events(RR=0.49,95%CI 0.34 to 0.70).Conclusions Cilostazol demonstrated superior efficacy and safety profiles compared with traditional antiplatelet regimens such as aspirin and clopidogrel for secondary stroke prevention but does not appear to affect functional outcomes.Future randomised trials can be conducted outside East Asia,or compare cilostazol with a wider range of antiplatelet agents.
