Cilostazol Group Research Articles

Abstract 473: Cilostazol Decreases Venous Outflow Inflammation And Improves Avf Patency Inmurine Arteriovenous Fistula

Background: Arteriovenous fistula (AVF) have high failure rates, and no pharmacotherapeutics can improve AVF patency. The most common cause of AVF failure is inflammation-driven neointimal hyperplasia and thrombosis. Limited observational data suggests that cilostazol (CIL), an FDA-approved phosphodiesterase-3 inhibitor that inhibits platelet activation and smooth muscle cell proliferation, could help improve AVF maturation. Here, we investigated the effects of cilostazol on murine AVF patency, and further assessed the fibrinogenesis and anti-inflammatory effects using intravital fluorescence molecular imaging. Methods: One week prior to fistula creation, mice were randomized to CIL (40mg/kg/day) or PBS group (n=20 each). AVF was created using an end-to-side external jugular vein and carotid artery anastomosis. AVF blood flow was measured post-operatively (Transonic) and then every 7 days until AVF was occluded (<0.1 ml/min). Macrophages and fibrin were imaged after 10mg/kg FMX-AF555 and/or 4.5nmol FTP11CyAm7 i.v. injection prior to imaging on day 7 or day 14, respectively. The target-to-background ratio (TBR) was calculated as mean signal intensity (MSI) of the fistula divided by the MSI of the contralateral vein. Results: Post-operative AVF blood flow was similar between CIL and PBS treated groups (p=0.3). Average AVF patency was significantly longer in CIL group compared to PBS group (42 vs 21 days, p<0.01, figure 1A). Both day 7 and day 14 venous outflow fibrinogenesis signal assessed by IVM was significantly lower in CIL group compared to PBS group (ps<0.05, Figure 1B). On day 14, CIL significantly lower venous outflow FMX signals compared to PBS group (p<0.05). Conclusion: Oral cilostazol therapy prolongs AVF patency, and decreases venous outflow inflammation and fibrinogenesis in experimental AVF in vivo. The current data supports investigating cilostazol as a clinical pro-AVF patency pharmacotherapeutic strategy in dialysis patients.

Cilostazol attenuates cardiac oxidative stress and inflammation in hypercholesterolemic rats.

Atherosclerosis is a multifactorial chronic disease associated with pro-inflammatory and pro-oxidative cardiovascular states. Cilostazol, a selective phosphodiesterase 3 inhibitor (PDE3), is clinically used in the treatment of intermittent claudication and secondary prevention of cerebral infarction. The aim of this study was to evaluate the cardioprotective effects of cilostazol and the molecular mechanisms involved in hypercholesterolemic rats. Male Wistar rats were divided into four groups: control group (C) and control + cilostazol group (C+CILO), that were fed a standard chow diet, and hypercholesterolemic diet group (HCD) and HCD + cilostazol (HCD+CILO) that were fed a hypercholesterolemic diet. Cilostazol treatment started after 30 days for C+CILO and HCD+CILO groups. Animals were administered cilostazol once a day for 15 days. Subsequently, serum and left ventricles were extracted for evaluation of lipid profile, inflammatory, and oxidative biomarkers. The HCD group displayed increased serum lipid levels, inflammatory cytokines production, and cardiac NF-kB protein expression and decreased cardiac Nrf2-mediated antioxidant activity. Conversely, the cilostazol treatment improved all these cardiac deleterious effects, inhibiting NF-kB activation and subsequently decreasing inflammatory mediators, reestablishing the antioxidant properties through Nrf2-mediated pathway, including increased SOD, GPx, and catalase expression. Taken together, our results indicated that cilostazol protects hypercholesterolemia-induced cardiac damage by molecular mechanisms targeting the crosstalk between Nrf2 induction and NF-kB inhibition in the heart.

Pharmacodynamic of cilostazol for anti-altitude hypoxia.

The plateau environment is characterized by low oxygen partial pressure, leading to the reduction of oxygen carrying capacity in alveoli and the reduction of available oxygen in tissues, and thus causing tissue damage. Cilostazol is a phosphodiesterase III inhibitor that has been reported to increase the oxygen release of hemoglobin (Hb) in tissues. This study aims to explore the anti-hypoxic activity of cilostazol and its anti-hypoxic effect. A total of 40 male BALB/C mice were randomly divided into a low-dose cilostazol (6.5 mg/kg) group, a medium-dose (13 mg/kg) group, a high-dose (26 mg/kg) group, and a control group. The atmospheric airtight hypoxia experiment was used to investigate the anti-hypoxic activity of cilostazol and to screen the optimal dosage. Twenty-four male Wistar rats were randomly divided into a normoxia control group, a hypoxia model group, an acetazolamide (22.33 mg/kg) group, and a cilostazol (9 mg/kg) group. After 3 days of hypoxia in the 4 010 m high altitude, blood from the abdominal aorta was collected to determine blood gas indicators, the levels of IL-6 and TNF-α in plasma were determined by enzyme-linked immunosorbent assay, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutataione (GSH) were measured. The degree of pathological damage for rat tissues was observed with HE staining. Compared with the control group, the survival time of mice in the low, medium, and high dose group of cilostazol was significantly prolonged, and the survival time of mice in the medium dose group was the longest, with an extension rate at 29.34%, so the medium dose was the best dose. Compared with the hypoxia model group, the P50 (oxygen partial pressure at Hb oxygen saturation of 50%) value of rats in the cilostazol group was significantly increased by 1.03%; Hb and Hct were significantly reduced by 8.46% and 8.43%, and the levels of IL-6 and TNF-α in plasma were reduced by 50.65% and 30.77%. The MDA contents in heart, brain, lung, liver, and kidney tissues were reduced by 37.12%, 29.55%, 25.00%, 39.34%, and 21.47%, respectively. The SOD activities were increased by 94.93%, 9.14%, 9.42%, 13.29%, and 20.80%, respectively. The GSH contents were increased by 95.24%, 28.62%, 28.57%, 20.80%, and 44.00%, respectively. The results of HE staining showed that compared with the hypoxia model group, cilostazol significantly improved the damage of heart, lung, and kidney tissues in rats after hypoxia. Cilostazol can significantly improve the oxidative stress and inflammatory reaction caused by rapid altitude hypoxia, and it has a significant protective effect on tissue damage caused by hypoxia, suggesting that it has obvious anti-hypoxic activity.

Cilostazol combined with P2Y12 receptor inhibitors: A substitute antiplatelet regimen for aspirin-intolerant patients undergoing percutaneous coronary stent implantation.

BackgroundCilostazol combined with P2Y12 receptor inhibitor has been used as a substitute regimen for aspirin‐intolerant patients undergoing percutaneous coronary stent implantation on a small scale. Its exact impact on platelet functions and clinical benefits of aspirin‐intolerant patients is unknown.HypothesisCilostazol combined with P2Y12 receptor inhibitors could be used as a substitute antiplatelet regimen for aspirin‐intolerant patients undergoing percutaneous coronary stent implantation.MethodsIn this multicenter prospective cohort trial, patients undergoing elective percutaneous coronary stent implantation were assigned to the cilostazol group (cilostazol plus P2Y12 receptor inhibitors), based on aspirin intolerance criteria, or the aspirin group (aspirin plus P2Y12 receptor inhibitors). Platelet PAC‐1, CD62p, and vasodilator‐stimulated phosphoprotein phosphorylation (VASP‐P) were detected by flow cytometry. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE) including all‐cause death, acute myocardial infarction, emerging arrhythmia, nonfatal stroke, and heart failure. The secondary endpoints were the Bleeding Academic Research Consortium (BARC) bleeding events.ResultsOne hundred and fifty‐four aspirin‐intolerant percutaneous coronary stent implantation patients and 154 matched aspirin‐tolerant patients from a total of 2059 percutaneous coronary stent implantation patients were enrolled. The relative activation level of PAC‐1, CD62p, and platelet reaction index reflected by the VASP‐P test were similar in the two groups (p > .05). After 12 months of follow‐up, the incidence of all‐cause death was 1.9% in the cilostazol group and 1.3% in the aspirin group (risk ratio [RR], 1.500; 95% confidence interval [CI], 0.254–8.852; p = 1.000); the incidence of acute myocardial infarction was 0.6% in the cilostazol group and 1.3% in the aspirin group (RR, 0.500; 95% CI, 0.046–5.457; p = 1.000). No significant difference was seen in other MACCE events, or in any types of BARC bleeding events.ConclusionsCilostazol combined with P2Y12 inhibitors was not inferior to aspirin‐based standard therapy and could be used as a reasonable substitute antiplatelet regimen for aspirin‐intolerant patients undergoing percutaneous coronary stent implantation, but again with limitations, which required a larger sample and longer follow‐up to confirm its efficacy.

Cilostazol as an adjunctive treatment in major depressive disorder: a pilot randomized, double-blind, and placebo-controlled clinical trial

Cilostazol, a phosphodiesterase-3 inhibitor, has been reported to improve depressive-like behavior in experimental studies of depression. We investigated the safety and efficacy of cilostazol combination therapy with sertraline in treating patients with major depressive disorder (MDD) in a 6-week, parallel, randomized controlled trial. Among patients referred to the outpatient clinic of a tertiary hospital, those with a diagnosis of MDD with moderate to severe severity (a score of >19 on the Hamilton depression rating scale (HAM-D)) were enrolled. A total of 54 MDD patients aged 18-65 years were randomly assigned to either the cilostazol (100 mg daily) or the placebo group. Both groups received sertraline 100 mg per day similarly. Changes in HAM-D at weeks 2, 4, and 6 were the primary outcome. Participants and outcome assessors were blinded. At week 6, patients in the cilostazol group had significantly lower HAM-D score (p value= 0.015). General linear model repeated-measure analysis showed significant effect for treatment in improving MDD severity (p value <0.001). The remission rate at the study endpoint and number of responders at week 4 were significantly higher in the cilostazol group (p value= 0.047, p value= 0.032, respectively). The cilostazol group demonstrated a significantly shorter time to response. No significant difference was observed in treatment response at the study endpoint, and there were no serious adverse effects. Our study supports safety and efficacy of cilostazol in treating MDD patients. This trial was registered at the Iranian registry of clinical trials (IRCT: www.irct.ir ; registration number: IRCT20090117001556N130).

Cilostazol for Aneurysmal Subarachnoid Hemorrhage: An Updated Systematic Review and Meta-Analysis

Background and Purpose: Delayed cerebral ischemia is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH). Cilostazol, a selective inhibitor of phosphodiesterase 3, was reported to reduce cerebral vasospasm and improve outcomes. We aimed to conduct an updated systematic review and meta-analysis of the efficacy and safety of cilostazol in aSAH. Methods: We systematically searched PubMed, Embase, MEDLINE, and the Cochrane Library for articles published in English with the latest publishing time in August 2020. Articles reporting favorable outcome as the primary outcome and reporting severe angiographic vasospasm (aVS), symptomatic vasospasm (sVS), new cerebral infarction, or mortality as the secondary outcome were included in this review. Furthermore, we examined whether clinical outcomes were associated with the dosage of cilostazol (300 mg/day vs. 100–200 mg/day). Results: Data from 405 patients in 4 randomized controlled trials (RCTs) and 461 patients in 4 observational studies (OSs) were included. In RCT studies, cilostazol was associated with significant favorable outcomes at discharge or 1 month (risk ratio [RR] 1.41, 95% confidence interval [CI] 1.01–1.97, p = 0.04) or 3 or 6 months (RR 1.16, 95% CI 1.05–1.28, p = 0.002). However, in OSs, no significant difference was indicated in favorable outcomes at discharge or 1 month (RR 1.22, 95% CI 0.94–1.60, p = 0.14) nor 3 or 6 months (RR 1.29, 95% CI 0.92–1.81, p = 0.14). The analyses found that cilostazol significantly reduced the incidences of severe aVS (RCT: RR 0.64, 95% CI 0.41–1.01, p = 0.05; OS: RR 0.61, 95% CI 0.43–0.88, p = 0.007), sVS (RCT: RR 0.46, 95% CI 0.31–0.70, p = 0.0002; OS: RR 0.38, 95% CI 0.21–0.68, p = 0.001), and new cerebral infarction (RCT: RR 0.40, 95% CI 0.24–0.67, p = 0.0005; OS: RR 0.38, 95% CI 0.23–0.64, p = 0.0002). However, no significant difference in mortality (RCT: RR 0.86, 95% CI 0.23–3.21, p = 0.82; OS: RR 0.16, 95% CI 0.02–1.24, p = 0.08) was found. In 3 OSs which reported different doses of cilostazol (300 mg/day vs. 100–200 mg/day) for aSAH, the 300-mg/day cilostazol groups showed decreased delayed cerebral infarction (RR 0.27, 95% CI 0.09–0.81, p = 0.02) but no significant difference in shunt-dependent hydrocephalus (RR 0.92, 95% CI 0.33–2.60, p = 0.88) or functional outcomes (RR 1.14, 95% CI 0.74–1.75, p = 0.56) compared with the 100–200 mg/day cilostazol groups. Conclusions: The meta-analyses suggest the credible efficacy and safety of cilostazol in treating aSAH. Furthermore, 300-mg/day cilostazol treatment appeared to be more effective than 100–200 mg/day treatment.

Cardioprotective Effect of Cilostazol on Ischemia-Reperfusion Injury Model.

To clarify the potential protective role of cilostazol on rat myocardial cells with ischemia-reperfusion injury (IRI) models. The study was conducted with three groups of 10 Wistar rats (control group, rats without any coronary ischemia; sham group, rats with coronary ischemia but without cilostazol administration; and cilostazol group, rats with coronary ischemia and cilostazol administration). The level of myocardial injuries was measured by analyzing cardiac troponin T and creatine kinase MB levels in blood samples. In tissue samples, adenosine triphosphate (ATP), nitric oxide, superoxide dismutase (SOD), and malondialdehyde were used to determine the amount of tissue damage. Tissues were stained with hematoxylin-eosin method, and samples were examined under light microscope. The mean level of ATP was 104.4 in the cilostazol group and 149.1 in the sham group (P=0.044). SOD level was significantly higher in the cilostazol group than in the sham group (2075.3 vs. 1783.7, P=0.043). According to histopathological examination, all samples were classified as G0 in the control group. In the sham group, one sample was categorized as G1, six samples as G2, and three samples as G3. In the cilostazol group, nine samples and one sample were categorized as G1 and G2, respectively (P=0.011). Cilostazol has beneficial effects on Wistar rats' myocardial cells in regard to decreasing inflammatory process, necrosis, and fibrosis. Our findings revealed that the use of cilostazol significantly decreased ATP and increased SOD levels in Wistar rats' myocardial cells after IRI.

Efficacy and safety of cilostazol in decreasing progression of cerebral white matter hyperintensities-A randomized controlled trial.

Cerebral small vessel disease (SVD) is an important cause of dementia that lacks effective treatment. We evaluated the efficacy and safety of cilostazol, an antiplatelet agent with potential neurovascular protective effects, in slowing the progression of white matter hyperintensities (WMHs) in stroke- and dementia-free subjects harboring confluent WMH on magnetic resonance imaging (MRI). In this single-center, randomized, double-blind, placebo-controlled study, we randomized stroke- and dementia-free subjects with confluent WMHs to receive cilostazol or placebo for 2 years in a 1:1 ratio. The primary outcome was change in WMH volume over 2 years. Secondary outcomes were changes in brain volumes, lacunes, cerebral microbleeds, perivascular space, and alterations in white matter microstructural integrity, cognition, motor function, and mood. We recruited 120 subjects from October 27, 2014, to January 21, 2019. A total of 55 subjects in the cilostazol group and 54 subjects in the control group were included for intention-to-treat analysis. At 2-year follow-up, the changes in WMH volume were not statistically different between cilostazol treatment and placebo (0.3±1.0mL vs -0.1±0.8mL, p = 0.167). Secondary outcomes, bleeding and vascular events, were also not statistically different between the two groups. In this trial with stroke- and dementia-free subjects with confluent WMHs, cilostazol did not impact WMH progression but demonstrated an acceptable safety profile. Future studies should address the treatment effects of cilostazol on subjects at different clinical stages of SVD.

Cilostazol induces angiogenesis and regulates oxidative stress in a dose-dependent manner: A chorioallantoic membrane study.

Background In this study, we aimed to investigate the effects of cilostazol on angiogenesis and oxidative stress using the chorioallantoic membrane model. Methods In this experimental study, the Ross 308 chick embryos were used. The negative control group (n=10) received no intervention. The positive control group (n=10) consisted of eggs treated with epidermal growth factor for inducing angiogenesis. Three cilostazol groups were designed with 10-7 (n=10), 10-6 (n=10), and 10-5 (n=10) M concentrations. Each egg was punctured on the sixth day of incubation, and drug pellets were introduced to the positive control and drug groups at the prespecified doses. Vascular development was evaluated on the eighth day of application. The total oxidant status, total antioxidant capacity, and oxidative stress index levels were determined from albumen liquids obtained with a syringe before and after drug application. Results Lower oxidative stress index levels were obtained from the positive control and cilostazol groups compared to the negative control albumens (p=0.001). The increments in vascular junctions and newly developed vascular nodules were evaluated in drug-free and drug-applied chorioallantoic membranes. The highest activity was obtained in the 10-7 M concentration cilostazol group. An increased angiogenic activity was detected in all drug groups in each concentration compared to the negative control group (p=0.001). Angiogenic activity was similar in all the cilostazol-treated groups (p=0.43). Conclusion Cilostazol has a positive stimulant effect on angiogenesis and it seems to suppress oxidative stress during embryonic growth. Cilostazol exerts these effects significantly and similarly at different doses.

Double-blind, randomized, placebo-controlled pilot study of the phosphodiesterase-3 inhibitor cilostazol as an adjunctive to antidepressants in patients with major depressive disorder.

AimsCilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post‐stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double‐blind, randomized, placebo‐controlled pilot study.Methods80 participants with MDD (DSM‐IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5‐HT, TNF–α, NF‐ κB, and FAM19A5 were assessed pre‐ and post‐treatment.ResultsCo‐administration of CLS had markedly decreased HDRS score at all‐time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers.ConclusionCLS is safe and effective short‐term adjunctive therapy in patients with MDD with no other comorbid conditions.Trial registration ID:NCT04069819.

POS-569 EFFECT OF CILOSTAZOL ON ARTERIOVENOUS FISTULA IN HEMODIALYSIS PATIENTS

The maturation and patency of permanent vascular access are critical in patientsrequiring hemodialysis. Although numerus trials have been attempted to achieve permanently patentvascular access, little have been noticeable. Cilostazol, a phosphodiesterase-3 inhibitor, has beenshown to be effective in peripheral arterial disease including vascular injury-induced intimalhyperplasia. We therefore aimed to determine the effect of cilostazol on the patency and maturation ofpermanent vascular access. This single-center, retrospective study included 194 patients who underwent arteriovenousfistula surgery to compare vascular complications between the cilostazol (n = 107) and control (n =87) groups. The rate of vascular complications was lower in the cilostazol group than in the controlgroup (36.4% vs. 51.7%; p = 0.033), including maturation failure (2.8% vs. 11.5%; p = 0.016). Therate of reoperation due to vascular injury after hemodialysis initiation following fistula maturationwas also significantly lower in the cilostazol group than in the control group (7.5% vs. 28.7%; p&lt;0.001). However, there were no significant differences in the requirement for percutaneoustransluminal angioplasty (PTA), rate of PTA, and the interval from arteriovenous fistula surgery toPTA between the cilostazol and control groups. Cilostazol might be beneficial for the maturation of permanent vascular access inpatients requiring hemodialysis.

The Role of Cilostazol and Inflammation in Cognitive Impairment After Ischemic Stroke.

The aim of this study is to examine the potential effect of cilostazol and inflammation on cognitive impairment after stroke in an Asian population. Forty-five patients with cognitive impairment after ischemic stroke using cilostazol were enrolled as the study group and 45 patients using aspirin or clopidogrel were enrolled as the control group. Neuropsychiatric assessments were administered at the start of the study and after 6 months. Multiple logistic regression analysis was used to estimate the association between the cognitive change and cilostazol use. Macrophage polarization were assessed using flow cytometry in 7 patients. There were a significantly higher number of patients with peripheral arterial occlusive disease in the cilostazol group. No significant differences were observed in the cognitive change between the cilostazol and control groups. M1 macrophage subset increment were observed in the patient having a declined cognitive change. Cilostazol did not make a significant difference in cognitive change after ischemic stroke. M1 macrophage subset increment may indicate post stroke cognitive decline. Due to limited number of subjects, these findings should be examined further in large-scale randomized clinical trials.

Cilostazol increases adenosine plasma concentration in patients with acute coronary syndrome

Cilostazol is a specific and strong inhibitor of phosphodiesterase (PDE) type III which can suppress the platelet aggregation by increasing cyclic adenosine monophosphate (cAMP) levels. The clinical benefit of cilostazol in ACS patients suggested that the drug may have non-platelet-directed properties. Some in vitro and animal studies also indicated that the 'pleiotropic' properties of cilostazol might be related to the interaction with adenosine metabolism. Adenosine is an important regulatory metabolite and an inhibitor of platelet activation. However, no human study has been conducted to determine whether cilostazol could increase the adenosine plasma concentration in vivo. As a result, this study aimed to investigate the impact of cilostazol on adenosine plasma concentration (APC) in acute coronary syndrome (ACS) patients. We prospectively analysed 149 ACS patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents. The included patients were divided into two groups according to the presence (cilostazol group, n=64) or absence (aspirin group, n=85) of aspirin intolerance. The inhibition of platelet aggregation (IPA), APC and cAMP concentration was measured. Patient characteristics, medications and 30-day clinical outcomes were examined. Patients receiving cilostazol had a significantly higher adenosine and cAMP plasma concentration than patients receiving aspirin (3.00±0.67 vs 2.56±0.74mol/L, P<.001; 28.10±14.74 vs 20.48±11.35pmol/mL, P=.0014). Cilostazol was associated with a higher inhibition rate of ADP induced platelet aggregation than aspirin (63.35±26.71 vs 52.2±28.35, P=.036). The plasma levels of adenosine and cAMP showed a positive correlation with ADP induced platelet aggregation. Cilostazol increases adenosine concentration compared with aspirin. Its potent antiplatelet effect in ACS patients may be partly mediated by adenosine.

Effect of cilostazol on carotid plaque volume measured by three‐dimensional ultrasonography in patients with type 2 diabetes: The FANCY study

To conduct a prospective randomized study to evaluate cilostazol, a phosphodiesterase 3 inhibitor, and compare it with aspirin for the prevention of the progression of atherosclerosis in patients with type 2 diabetes (T2D). Fifty patients with T2D and carotid atherosclerotic plaques were randomly assigned to either a 200 mg/d cilostazol (CTZ) group or a 100 mg/d aspirin (ASA) group for 6 months. The primary endpoint was change in plaque volume measured by carotid three-dimensional ultrasonography. The secondary endpoints were changes in carotid intima-media thickness (IMT) and endothelial function, assessed by laser Doppler. Twenty-four patients in the CTZ group and 23 in the ASA group were included in the final analysis. The mean ± SD age of male (n = 20) and female (n = 16) patients was 62.2 and 59.1 years, respectively. The total plaque volume was slightly decreased in the CTZ group (from 183.8 ± 52.5 to 181.5 ± 54.0 mm3 ; P = .567), but significantly increased in the ASA group (from 112.9 ± 21.2 to 128.5 ± 23.3 mm3 ; P = .043). A significant regression in the maximum IMT was observed only in the CTZ group (right: from 2.19 ± 0.17 to 1.96 ± 0.12 mm; left: from 2.02 ± 0.20 to 1.72 ± 0.19 mm). The CTZ group exhibited an increase in HDL cholesterol and a decrease in triglycerides and liver enzymes. Cilostazol treatment for 6 months significantly attenuated the progression of carotid plaque compared with aspirin in patients with T2D (NCT03248401).

Influence of Cilostazol on Changes in Cyclin D1 Expression in Cerebral Cortex of Rats with Chronic Cerebral Ischemia.

The influence of cilostazol on learning and memory, and cyclin D1 expression in the cerebral cortex of rats with chronic cerebral ischemia were investigated. A chronic cerebral ischemia model was established using the permanent bilateral common carotid artery occlusion method (2VO), learning and memory capacity was detected using the Morris water maze, and expression changes in apoptosis regulating gene cyclin D1 were tested by RT-PCR. Results of the Morris water maze indicated that significant extensions were found in the escape latent period and swimming path of rats in the ischemia group (2VO group), learning and memory results in the cilostazol group was obviously superior compared to the 2VO group (P<0.05), and the expression of cyclin D1 was observed to increase in both the ischemia and cilostazol intervention groups at the 9th week of ischemia. A significant difference was observed, compared with the sham operation group (P<0.05), the expression level decreased in the ischemia group compared with the cilostazol group, and a significant difference was identified compared with the ischemia group (P<0.05). Cilostazol can reduce nerve function impairment and improve learning and memory functions by affecting changes in apoptosis regulating genes.

P1348EFFECT OF CILOSTAZOL ON ARTERIOVENOUS FISTULA IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Permanent vascular access is important in patients requiring hemodialysis. However, among patients requiring hemodialysis, even if arteriovenous fistula surgery is performed, many are unable to undergo hemodialysis with vascular access due to maturation failure. Method Using 194 patients who underwent arteriovenous fistula surgery, a cilostazol group (n = 107) and a control group (n = 87) were compared and analyzed for the occurrence of vascular complications. Results In the cilostazol group, there were less vascular complications (36.4% vs. 52.9%; p = 0.022), especially maturation failure (2.8% vs. 11.5%; p = 0.016). However, there was no significant difference between the cilostazol group and control group regarding percutaneous transluminal angioplasty (PTA) requirement nor frequency and interval to PTA after vascular surgery. The frequency of reoperations due to vascular injury after the start of hemodialysis after maturation was also significantly lower in the cilostazol group. Conclusion These results suggest that vascular access patients may benefit from postoperative cilostazol therapy.

Adjunctive Cilostazol to Dual Antiplatelet Therapy to Enhance Mobilization of Endothelial Progenitor Cell in Patients with Acute Myocardial Infarction: A Randomized, Placebo-Controlled EPISODE Trial

Background: Endothelial progenitor cells (EPCs) have the potential to protect against atherothrombotic event occurrences. There are no data to evaluate the impact of cilostazol on EPC levels in high-risk patients. Methods: We conducted a randomized, double-blind, placebo-controlled trial to assess the effect of adjunctive cilostazol on EPC mobilization and platelet reactivity in patients with acute myocardial infarction (AMI). Before discharge, patients undergoing percutaneous coronary intervention (PCI) were randomly assigned to receive cilostazol SR capsule (200-mg) a day (n = 30) or placebo (n = 30) on top of dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Before randomization (baseline) and at 30-day follow-up, circulating EPC levels were analyzed using flow cytometry and hemostatic measurements were evaluated by VerifyNow and thromboelastography assays. The primary endpoint was the relative change in EPC levels between baseline and 30-day. Results: At baseline, there were similar levels of EPC counts between treatments, whereas patients with cilostazol showed higher levels of EPC counts compared with placebo after 30 days. Cilostazol versus placebo treatment displayed significantly higher changes in EPC levels between baseline and follow-up (ΔCD133+/KDR+: difference 216%, 95% confidence interval (CI) 44~388%, p = 0.015; ΔCD34+/KDR+: difference 183%, 95% CI 25~342%, p = 0.024). At 30-day follow-up, platelet reactivity was lower in the cilostazol group compared with the placebo group (130 ± 45 versus 169 ± 62 P2Y12 Reaction Unit, p = 0.009). However, there were no significant correlations between the changes of EPC levels and platelet reactivity. Conclusion: Adjunctive cilostazol on top of clopidogrel and aspirin versus DAPT alone is associated with increased EPC mobilization and decreased platelet reactivity in AMI patients, suggesting its pleiotropic effects against atherothrombotic events (NCT04407312).

Cilostazol and peripheral artery disease-specific health status in ambulatory patients with symptomatic PAD

BackgroundImprovement of symptoms and functional status is one of the main peripheral artery disease (PAD) treatment goals but pharmacological options are limited. The objective of this study was to assess the use of cilostazol and its association with patient-reported health status quantified by the Peripheral Artery Questionnaire (PAQ). MethodsInitiation of cilostazol therapy was assessed in 567 patients in the US cohort of PORTRAIT between June 2011 and December 2015. Patients with heart failure history, on cilostazol prior to enrollment, with no baseline or follow-up PAQ scores were excluded. Health status over time was quantified using linear mixed models adjusting for baseline PAQ scores and patient characteristics. ResultsOf the 567 cilostazol-naïve patients, 65 (11%) were started on cilostazol. Mean age was 68.5 ± 9.6 years, 43% were female and 71.1% white. There was no significant difference in the mean PAQ score changes from baseline to 12 months between the cilostazol and non-cilostazol group, with difference of 3.8 [CI (−2.6, 10.1), p = .24] for summary scores, 1.6 [CI (−5.5, 8.6), p = .66] for quality of life, 3.6 [CI (−4.3, 11.6), p = .37] for symptoms, 6.2 [CI (−3.1, 15.5), p = .19] for physical limitation and 3.2 [CI (−3.9, 10.2), p = .38] for social limitation scores. ConclusionsWe found a low rate of cilostazol use and while there was no significant association between cilostazol initiation and subsequent health status, the ability to define small differences in health status was limited due to the small sample size.

Cilostazol for Chinese Patients with Aspirin Intolerance after Coronary Drug-Eluting Stent Implantation

Cilostazol-based dual antiplatelet therapy (DAPT) is widely used in patients with aspirin intolerance after coronary drug-eluting stent (DES) implantation in China. However, this empirical strategy is not recommended or even mentioned in Chinese or international guidelines due to a lack of evidence from large-scale studies. We aimed to explore the efficacy and safety of cilostazol-based DAPT in this special population. In this cohort study, patients were grouped according to the DAPT strategy that they received after coronary DES implantation. The primary efficacy endpoint was major adverse cardiovascular and cerebrovascular events (MACCEs). Angiographic follow-up and major bleeding events were also recorded. A total of 918 patients receiving cilostazol-based DAPT due to aspirin intolerance were enrolled, matched with 918 patients receiving aspirin-based DAPT. After 15-month prospective follow-up, the cilostazol group had lower risk of MACCE (5.1% vs. 7.6%, propensity score adjusted hazard ratio = 0.671 [95% confidence interval 0.462-0.974], p = 0.036) compared with the aspirin group. Lower rate of coronary lesion progression was also found through follow-up angiography in the cilostazol group (17.4% vs. 23.6%, p = 0.022), especially in nontarget lesions (12.1% vs. 17.6%, p = 0.019). The two groups had the same risk of major bleeding events (0.8% vs. 0.4%, p = 0.364). In the current study, cilostazol is a good substitute for aspirin in patients who have aspirin intolerance but need DAPT after coronary DES implantation in China. However, large-scale randomized controlled trials were still required to further confirm its efficacy and safety.

Suppression of experimental atrial fibrillation in a canine model of rapid atrial pacing by the phosphodiesterase 3 inhibitor cilostazol

ObjectiveAtrial fibrillation (AF) represents the most common arrhythmia encountered in cardiology department. The purpose of this study was designed to investigate whether cilostazol, an oral phosphodiesterase 3 inhibitor (PDE3) could have protective effects on atrial remodeling in a canine model of AF and explore the potential molecular mechanisms. MethodsDogs were randomly assigned to Sham, Paced, Paced + cilostazol group, 7 dogs in each group. In Sham group, pacemaker was instrumented but without pacing. Rapid atrial pacing (RAP) at 600 or 500 bpm/min was maintained in Paced group and Paced + cilo group for 2 h or 2 weeks in acute or chronic experiment, respectively. The Paced + cilo group of dogs were pretreated with cilostazol orally (10 mg·kg−1·d−1, cilo) for 1 h or 2 days prior RAP induction and served as treatment group. Atrial effective refractory periods (AERP) at different basic cycle lengths (BCLs), inducibility, and duration time of AF were measured after pacing for 2 h. The blood sample, echocardiography, histopathology, inflammation and oxidative stress makers, protein and mRNA expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 were detected after 2 weeks pacing in each group. ResultsSignificant changes in electrophysiological parameters were observed in the acute RAP canine model, the AERPs shortened with increased inducibility and duration of AF, which was attenuated by cilostazol (P < 0.05). The serum inflammation makers as interleukin-8 (IL-8) and toll like receptor 4 (TLR 4) levels and oxidative stress indicators like xanthine oxidative (XO) and reactive oxygen species (ROS) in the Paced group was significantly higher than that in Sham group (P < 0.01), and was significantly reduced by cilostazol treatment (P < 0.01). The level of mean platelet volume (MPV) which is one of the platelet indices was significantly elevated in Paced group (P < 0.01). While after cilostazol treated for 2 weeks, the level of MPV was obviously decreased than Paced group (P < 0.01). Pathology and echocardiography studies showed that cilostazol can also prevent RAP induced cardiac fibrosis and structural remodeling. The MPV level has close correlations with IL-8, TLR4, XO and ROS (all P < 0.01). MMP-2 and MMP-9 expression were significantly increased in Paced group (all P < 0.01), which can be attenuated by cilostazol. ConclusionsCilostazol may have protective effects on RAP-induced atrial remodeling by anti-inflammatory, anti-oxidative stress action and regulate the extracellular collagen matrix in a canine model. Moreover, MPV level is associated with inflammation and oxidative stress response of RAP, which might be an important predictors of new-onset and recurrent AF.