Cilostazol protects against changes caused by streptozotocin-induced diabetic retinopathy / Cilostazol protege contra as alterações causadas pela retinopatia diabética induzida por estreptozotocina

ABSTRACT Purpose: This study investigates the protective effect of cilostazol on the development and evolution of diabetic retinopathy in rats. Methods: Sixty male rats were divided into four groups: untreated nondiabetic rats, untreated diabetic rats, cilostazol-treated nondiabetic rats, and cilostazol-treated diabetic rats. The thickness of the internal limiting membrane to the outer limiting membrane, inner plexiform layer, inner nuclear layer, and outer nuclear layer were measured. The number of cell nuclei per 50-μm length in retinal sections was counted to quantify the degree of retinal cell loss. Results: The number of nuclei in the ganglion cell layer was significantly higher in untreated nondiabetic rats (p<0.05). The mean number of nuclei in the cilostazol-treated nondiabetic rats was significantly higher than that in the cilostazol-treated diabetic rats (p<0.05). The cilostazol-treated nondiabetic rats had a significantly higher mean nuclei count in the inner nuclear layer and inner plexiform layer as compared with the other groups (p<0.05). The total mean retinal thickness of the cilostazol-treated nondiabetic rats was significantly higher than that of cilostazol-treated diabetic rats and untreated diabetic rats (p<0.05). Conclusion: By decreasing the loss of ganglion cells and reducing the sensorineural atrophy in the internal retinal layers, cilostazol had a protective effect against changes caused by diabetic retinopathy in diabetic rats.

RESUMO Objetivo: O objetivo deste estudo foi investigar o efeito protetor do cilostazol no desenvolvimento e na evolução da retinopatia diabética em ratos. Métodos: Sessenta ratos machos foram divididos em 4 grupos: ratos não-diabéticos não-tratados, ratos diabéticos não-tratados, ratos não-diabéticos tratados com cilostazol e ratos diabéticos tratados com cilostazol. A espessura da membrana limitante interna à membrana limitante externa, a camada plexiforme interna, a camada nuclear interna e a camada nuclear externa foram medidas. Para quantificar o grau de perda de células da retina, foi contado o número de núcleos de células por 50 μm de comprimento em secções retinianas. Resultados: O número de núcleos no GCL foi significativamente maior em Ratos não-diabéticos não-tratados com cilostazol (p<0,05). O número médio de núcleos em Ratos não-diabéticos tratados com cilostazol foi significativamente maior do que em Ratos diabéticos tratados com cilostazol (p<0,05). A contagem média de núcleos em camada nuclear interna e camada plexiforme interna de ratos não-diabéticos tratados com cilostazol foi significativamente maior do que nos outros grupos (p<0,05). A espessura retiniana média total de Ratos não-diabéticos tratados com cilostazol foi significativamente maior do que em Ratos diabéticos tratados com cilostazol e Ratos diabéticos não-tratados (p<0,05). Conclusão: Os resultados demonstraram que o cilostazol teve um efeito protetor contra as alterações causadas pela retinopatia diabética em ratos diabéticos, diminuindo a perda de células ganglionares e reduzindo a atrofia neurossensorial nas camadas retinianas internas.

The mechanism of cilostazole alleviating intestinal mucosal barrier dysfunction in type 2 diabetic mice / 西安交通大学学报(医学版)

【Objective】 To explore the effect of cilostazol on intestinal barrier function in type 2 diabetes (T2DM). 【Methods】 The GSE142153 dataset was downloaded from GEO database to analyze gene changes in diabetic patients. Eight-week-old male db/db mice and control m/m mice were randomly divided into m/m+cmc, m/m+cilo, db/db+cmc, and db/db+cilo groups. Mice in different groups were given cilostazol and corresponding solvents for 4 weeks. We detected the levels of serum sCD40L and the expression of CD40 in intestinal tissue, and evaluated the mice’s intestinal barrier function by examining intestinal permeability, water content, bacterial number, and tight junction protein expression in different groups. 【Results】 Differential expressed genes were enriched in platelet activation and endothelial barrier function pathways in diabetic patients. Compared with those in the control group, the levels of serum sCD40L in db/db diabetic mice elevated significantly, and the CD40 expression, permeability, water content and bacterial number in intestinal tissue increased obviously, while the expression of tight junction protein decreased. Cilostazol treatment in diabetic mice decreased the levels of serum sCD40L and CD40, and alleviated significantly the intestinal barrier dysfunction. 【Conclusion】 Cilostazol attenuated the damage of intestinal barrier function in T2DM, and its protective effect may be related to the inhibition of platelet activation in diabetic mice.

Cardioprotective Effect of Cilostazol on Ischemia-Reperfusion Injury Model

Abstract Introduction: To clarify the potential protective role of cilostazol on rat myocardial cells with ischemia-reperfusion injury (IRI) models. Methods: 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. Results: 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). Conclusion: 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.

Pharmacodynamic of cilostazol for anti-altitude hypoxia / 中南大学学报(医学版)

OBJECTIVES@#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.@*METHODS@#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.@*RESULTS@#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.@*CONCLUSIONS@#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.

Efecto del cilostazol en la enfermedad del nodo sinusal / Cilostazol and sick sinus syndrome

Resumen Se presenta el caso de una paciente de 60 años con enfermedad del nodo sinusal (ENS), sintomática con mareos y ángor, con electrocardiograma que evidenciaba episodios de pausas sinusales con escapes nodales. Durante la internación, a la espera de colocación de marcapaso definitivo, se indicó cilostazol (100 mg cada 12 h vía oral), observando a las 48 horas del inicio un incremento en la frecuencia cardíaca y la desaparición de las pausas sinusales en Holter de 24 horas. Nuestro objetivo ha sido demostrar que el cilostazol puede ser útil en pacientes con ENS, aunque es necesario evaluar los efectos cronotrópicos a largo plazo de este tratamiento.

Abstract Here we present the case of a 60-year-old patient with sinus node disease (NSS), symptomatic with dizziness and angor. The electrocardiogram showed episodes of sinus pauses with nodal escapes. During hospitalization, pending the placement of a definitive pacemaker, cilostazol (100 mg every 12 hours orally) was indicated, observing an increase in heart rate 48 hours after starting the medication, and the disappearance of sinus pauses in the 24 hours Holter. Our objective has been to show that cilostazol can be useful in patients with SNN, although long-term chronotropic effects of this treatment has yet to be evaluated.

A Comparison Study of Cilostazol and Aspirin on Changes in Volume of Cerebral Small Vessel Disease White Matter Changes: Protocol of a Multicenter, Randomized Controlled Trial

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) is the most common cause of vascular dementia and a major contributor to mixed dementia. CSVD is characterized by progressive cerebral white matter changes (WMC) due to chronic low perfusion and loss of autoregulation. In addition to its antiplatelet effect, cilostazol exerts a vasodilating effect and improves endothelial function. This study aims to compare the effects of cilostazol and aspirin on changes in WMC volume in CSVD.METHODS: The comparison study of Cilostazol and aspirin on cHAnges in volume of cerebral smaLL vEssel disease white matter chaNGEs (CHALLENGE) is a double blind, randomized trial involving 19 hospitals across South Korea. Patients with moderate or severe WMC and ≥ 1 lacunar infarction detected on brain magnetic resonance imaging (MRI) are eligible; the projected sample size is 254. Participants are randomly assigned to a cilostazol or aspirin group at a 1:1 ratio. Cilostazol slow release 200 mg or aspirin 100 mg are taken once daily for 2 years. The primary outcome measure is the change in WMC volume on MRI from baseline to 104 weeks. Secondary imaging outcomes include changes in the number of lacunes and cerebral microbleeds, fractional anisotropy and mean diffusivity on diffusion tensor imaging, and brain atrophy. Secondary clinical outcomes include all ischemic strokes, all vascular events, and changes in cognition, motor function, mood, urinary symptoms, and disability.CONCLUSIONS: CHALLENGE will provide evidence to support the selection of long-term antiplatelet therapy in CSVD.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932203

Effect of cilostazol in experimental model of degloving injuries in rat limbs

Abstract Purpose: To evaluate the effect of the cilostazol on the evolution of partially avulsed flaps, using experimental model of cutaneous degloving in rat limbs. Methods: A controlled and randomized experimental study was carried out in which the blood flow and the percentage of flap necrosis were evaluated. We compared the study group, which received cilostazol, and the control group, which received enteral saline solution in the postoperative period. The blood flow in the flap was evaluated through Laser Doppler flowmetry, and a planimetry using the IMAGE J® software was employed for the calculation of the area of necrosis. Results: Enteral administration of cilostazol was associated with a higher mean blood flow in all regions of the flap, with a statistically significant difference in the proximal and middle regions (p<0.001) and a lower percentage of necrotic area in the flap (p<0.001). Conclusion: Postoperative enteral administration of cilostazol increased blood flow and decreased the total area of necrosis of avulsed cutaneous flaps of rat limbs.

Population pharmacodynamics of cilostazol in healthy Korean subjects

Cilostazol is used for the treatment of intermittent claudication, ulceration and pain. This study was conducted to develop a population pharmacodynamic (PD) model for cilostazol's closure time (CT) prolongation effect in healthy Korean subjects based on a pharmacokinetic (PK) model previously developed. PD data were obtained from 29 healthy subjects who participated in a study conducted in 2009 at Severance Hospital. The PK model used was a two-compartment model with first order absorption. CT data were best described by a turnover model with a fractional turnover rate constant (K(out)) inhibited by drug effects (Eff), which were represented by a sigmoid E(max) model [Eff = E(max) · C(γ) / (EC₅₀(γ)+C(γ))] with E(max) being maximum drug effect, EC₅₀ drug plasma concentration at 50% of E(max), C drug plasma concentrations, and γ the Hill coefficient. For the selected PD model, parameter estimates were 0.613 hr⁻¹ for K(out), 0.192 for E(max), 730 ng/ml for EC₅₀ and 5.137 for γ. Sex and caffeine drinking status significantly influenced the baseline CT, which was 85.36 seconds in male non-caffeine drinkers and increased by 15.5% and 16.4% in females and caffeine drinkers, respectively. The model adequately described the time course of CT. This was the first population PD study for cilostazol's CT prolongation effect in a Korean population.

Cilostazol attenuates kainic acid-induced hippocampal cell death

Cilostazol is a selective inhibitor of type 3 phosphodiesterase (PDE3) and has been widely used as an antiplatelet agent. Cilostazol mediates this activity through effects on the cyclic adenosine monophosphate (cAMP) signaling cascade. Recently, it has attracted attention as a neuroprotective agent. However, little is known about cilostazol's effect on excitotoxicity induced neuronal cell death. Therefore, this study evaluated the neuroprotective effect of cilostazol treatment against hippocampal neuronal damage in a mouse model of kainic acid (KA)-induced neuronal loss. Cilostazol pretreatment reduced KA-induced seizure scores and hippocampal neuron death. In addition, cilostazol pretreatment increased cAMP response element-binding protein (CREB) phosphorylation and decreased neuroinflammation. These observations suggest that cilostazol may have beneficial therapeutic effects on seizure activity and other neurological diseases associated with excitotoxicity.

Antithrombotic effects of cilostazol combined with clopidogrel and aspirin in senile patients with cerebrovas-cular disease after PCI surgery / 中国基层医药

Objective To analyze the antithrombotic effects of cilostazol combined with aspirin and clopi-dogrel in elderly patients with cerebrovascular disease after PCI .Methods 100 elderly patients with cerebrovascular diseases who treated with coronary artery interventional therapy ( PCI) were randomly divided into the control group and the observation group according to the digital table ,50casess in each group.The two groups were given control of blood pressure ,blood lipids ,blood sugar ,improve circulation and other conventional treatment .The control group was treated with aspirin combined with clopidogrel ,the observation group was treated with cilostazol based on the treatment of control group.Before and after treatment for 1,4 and 8 weeks,the platelet aggregation degree was detected by PL-11 automatic platelet analyzer .During 2 months of follow-up,the degree of platelet aggregation ,the volume of platelets,the efficacy of treatment and the incidence of adverse reactions were compared .Results The platelet aggre-gation rate between the two groups had no statistically significant difference before treatment (t0 =2.782,P>0.05). After treatment,the platelet aggregation rate of the two groups decreased significantly ,but after treatment for 1,4 and 8 weeks,the platelet aggregation rates of the observation group were significantly lower than those of the control group [(51.87 ±9.65)％,(40.85 ±10.24)％,(38.52 ±9.64)％;(69.25 ±8.41)％,(62.43 ±9.22)％,(58.46 ± 10.18)％],the differences were statistically significant (t1 =5.693,t4 =4.846,t8 =6.719,all P<0.05).Before treatment,the mean platelet volume between the two groups had statistically significant difference ( t0 =2.146,P>0.05).After treatment,the platelet volume of the two groups decreased significantly ( t1 =1.656,t4 =1.438,t8 =2.189,all P<0.05).There were no statistically significant differences between the observation group and the control group (t1 =3.716,t4 =1.271,t8 =2.523,all P>0.05).The effective rate of the observation group was 94.00％(47/50),which was significantly higher than that of the control group [82.00％(41/50)],the difference was statis-tically significant (χ2 =4.683,P<0.05).The incidence rates of adverse reactions in the observation group and the control group were 10.00％(5/50) and 8.00％(4/50),respectively,there was no statistically significant difference between the two groups (χ2 =1.947,P=0.136).Conclusion Cilostazol combined with clopidogrel and aspirin in the treatment of elderly patients with cerebrovascular disease after PCI can significantly reduce platelet aggregation rate,improve clinical curative effect ,and has certain clinical value .

Clinical Observation of Cilostazol Combined with Alprostadil in the Treatment of Peripheral Arterial Disease / 中国药房

OBJECTIVE:To investigate the clinical efficacy and safety of cilostazol combined with alprostadil in the treatment of peripheral arterial disease(PAD). METHODS:A total of 68 PAD patients in our hospital from Jan. 2015 to Jan. 2016 were di-vided into observation group(34 cases)and control group(34 cases)according to random number table. Control group was given basical treatment,and Alprostadil injection 2 mL+0.9% Sodium chloride injection 100 mL,ivgtt,qd. Observation group was addi-tionally given Cilostazol tablets 100 mg,po,bid,on the basis of control group. Both groups were treated for 30 days. Clinical effi-cacies of 2 groups were observed. The hemorheology indexes(hematocrit,whole blood high-shearing viscosity,erythrocyte aggre-gation index,erythrocyte deformation index,plasma viscosity),inflammatory factor indexes(TNF-α,IL-6,IL-8, hs-CRP),oxida-tion stress indexes(GSH-Px,SOD,T-Aoc,MDA),arteriosclerosis indexes(ABI,TBI,dorsalis pedis artery blood flow)were de-termined before and after treatment. The occurrence of ADR was recorded. RESULTS:Total response rate of observation group (91.18%)was significantly higher than that of control group(79.41%),with statistical significance(P0.05). After treatment,hematocrit,whole blood high-shearing viscosity,erythrocyte aggregation index,erythrocyte deformation index,plasma viscosity,the levels of TNF-α,IL-6,IL-8,hs-CRP and MDA in 2 groups were de-creased significantly;while the levels of GSH-Px,SOD,T-Aoc,ABI,TBI and dorsalis pedis artery blood flow were increased sig-nificantly;the improvement of above indexes in observation group was significantly better than control group,with statistical signif-icance(P0.05). CONCLUSIONS:For PAD,cilostazol combined with alprostadil can effectively improve hemorheolo-gy indexes,inflammatory factor indexes,oxidation stress indexes and arteriosclerosis indexes with good safety.

Comparison of efficacy of cilostazol and aspirin in the treatment of vascular dementia with white matter lesions / 中国基层医药

Objective To compare the efficacy of cilostazol and aspirin in the treatment of vascular dementia with white matter lesions.Methods 50 patients with vascular dementia with white matter lesions were randomly divided into control group (aspirin and nimodipine group)and observation group (cilostazol and nimodipine group). The control group was orally given aspirin enteric -coated tablets and nimodipine tablets,the observation group was treated with cilostazol tablets and nimodipine tablets.Then,the patients were followed up,compared the cognitive function and adverse events of the two groups after treatment 6 months and 1 2 months.Results 6 months and 1 2 months after treatment,MMSE score and MoCA score of the control group were significantly improved[the MMSE score and MoCA score before treatment were (20.1 2 ±4.25)points,(1 4.25 ±4.25)points,6 months after treatment were (21 .22 ±4.68)points,(1 6.45 ±3.25)points,1 2 months after treatment were (22.38 ±5.64),(1 6.95 ± 4.68);6 months after treatment,t =0.87,2.06;1 2 months after treatment,t =1 .96,2.1 4,all P <0.05].6 months and 1 2 months after treatment,MMSE score and MoCA score of the observation group were significantly improved than before treatment [before treatment the MMSE score and MoCA score were (1 9.85 ±5.1 4)points,(1 3.98 ± 6.28)points,6 months after treatment were (23.76 ±4.1 5)points,(1 8.75 ±4.28)points,1 2 months after treatment were (25.26 ±3.72)points,(23.95 ±5.43 )points,6 months after treatment t =2.96,3.1 4;1 2 months after treatment,t =4.26,6.00,all P <0.05].6,1 2 months after treatment,the MMSE score between the two groups had significant difference (t =2.03,2.1 3,all P <0.05),MoCA score between two groups had significant difference(t =2.1 4,4.88,all P <0.05).The incidence rates of cerebral hemorrhage in the observation group and control group were 0.00%,1 2.00%,the difference was significant (χ2 =3.1 9,P <0.05).Conclusion Cilostazol and nimodipine in the treatment of vascular dementia with white matter lesions,can significantly improve cognitive function of patients, and has less cerebral hemorrhage,significantly clinical effect,good security.

Clinical study on hyperbaric oxygen combined with cilostazol foot in treating diabetic foot / 国际检验医学杂志

Objective To study the clinicalvalue of hyperbaric oxygen combined with cilostazol in treating diabetic foot .Methods 90 patients with diabetic foot in our hospital from June 2014 to July 2016 were selected and randomly divided into the observation group and control group according to the random number table method ,45 cases in each group .The control group was given the cilostazol treatment on the basis of basic treatment ,while on the basis of control group treatment ,the observation group was added with the hyperbaric oxygen therapy .The clinical efficacy and the changes of hemorheology ,blood parameters and plasma fibrinolytic indicators of the two groups were observed .Results The total effective rate in the observation group was 91 .11% ,which was sig-nificantly higher than 71 .11% in the control group ,the difference was statistically significant(P<0 .05);the whole blood viscosity (high shear and low shear ) ,hematocrit after treatment in the observation group were significantly lower than those in the control group(P<0 .05);the levels of HbA1c ,homocysteine(Hcy) and plasma high-sensitivity C reactive protein(hs-CRP) after treatment in the observation group were significantly lower than those in the control group (P<0 .05) ,the levels of plasma fibrinogen andtis-sue-type plasminogen activator(TPA) after treatment in the observation group were significantly superior to those in the control group(P<0 .05) .Conclusion Hyperbaric oxygen combined with cilostazol can effectively improve the levels of HbA 1c ,Hcy and hs-CRP in thee patients with diabetic foot ,promotesthe wound healing and improves the clinical treatment effect .

Efficacy and safety of ticagrelor plus cilostazol in the treatment of patients with low body weight after percutaneous coronary intervention / 中国介入心脏病学杂志

Objective To explore the efficacy and safety of ticagrelor plus cilostazol of different dosage in the treatment of low-weight patients after PCI.Methods A total of 148 consecutive ACS patients (body weight ≤ 65 kg) past PCI and with aspirin intolerance were enrolled and randomly divided into four groups.Patients given cilostazol 50mg twice daily plus clopidogrel 75 mg daily were named as the CC50 mg group.Patients in the CC100 mg group were given cilostazol 100 mg twice daily plus clopidogrel 75 mg daily.The TCS0 mg group were given cilostazol 50 mg twice daily plus standard ticagrelor 90mg twice daily and the TC100 mg group were given cilostazol 50 mg twice daily plus standard ticagrelor 90 mg twice daily.All patients were followed up clinically for 6 months.The clinical endpoints were MACEs and bleeding events.Platelet aggregation at 7 and 30 days after treatment the incidence of clinical endpoints during followup were compared between the four groups.Results Patients in the TC100mg group had the lowest platelet aggregation rates tested on both the 7th and 30th day after treatment among all the 4 groups.After 6 months of follow up,the MACEs rate was not significantly different between the four groups (P =0.930).Bleeding events rates in the TC100 mg group the highest among the 4 but without groups significant differences.Conclusions In ACS patients with low body weight ≤ 65 kg) past PCI and with aspirin intolerance,cilostazol 50mg twice daily plus ticagrelor is a safe and efficacious therapeutic regimen.

Oral Administration of Cilostazol Increases Ocular Blood Flow in Patients with Diabetic Retinopathy

PURPOSE: To investigate the effect of cilostazol on ocular hemodynamics and to determine whether the administration of cilostazol increases the ocular blood flow in patients with diabetic retinopathy. METHODS: This prospective observational study investigated the effect of orally administered cilostazol on diabetic retinopathy. Before and after administration for 1 week, pulsatile ocular blood flow (POBF) and retrobulbar hemodynamics were measured using a POBF analyzer and transcranial Doppler imaging, respectively. Visual acuity, intraocular pressure, and blood pressure were also evaluated before and after treatment. RESULTS: Twenty-five eyes of 25 patients were included in this study. POBF increased significantly (16.8 ± 4.6 µL/sec vs. 19.6 ± 6.2 µL/sec, p < 0.001) after administration of cilostazol, while no significant change was identified in visual acuity, intraocular pressure, and blood pressure. Mean flow velocity in the ophthalmic artery as measured with transcranial Doppler imaging also increased significantly after medication (23.5 ± 5.6 cm/sec vs. 26.0 ± 6.9 cm/sec, p = 0.001). The change in POBF directly correlated with the change in mean flow velocity (r = 0.419, p = 0.007). CONCLUSIONS: Cilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy, possibly by modulating retrobulbar circulation.

Therapeutic effect and safety of cilostazol combined clopidogrel and aspirin on aged patients after PCI / 心血管康复医学杂志

Objective:To explore therapeutic effect and safety of cilostazol combined clopidogrel +aspirin on aged pa‐tients after percutaneous coronary intervention (PCI) .Methods :A total of 100 aged patients with coronary heart disease undergoing PCI were randomly divided into routine treatment group (n=52 ,received aspirin and clopidogrel antiplatelet therapy) and cilostazol group (n= 48 ,received cilostazol therapy based on routine treatment group ) . Turbidimetry was used to measure platelet aggregation rate (PAR );PAR and mean platelet volume (MPV ) were compared between two groups before ,one week and one month after PCI .All subjects were followed up for six months ,incidence rates of major adverse cardiovascular events (MACE) and hemorrhage events were compared be‐tween two groups .Results:There were no significant difference in MPV and PAR between two groups before PCI . Compared with routine treatment group ,PAR significantly reduced [one week after PCI :(48.7 ± 6.3)% vs .(43.5 ± 5.7)% ,one month after PCI :(46.8 ± 5.8)% vs .(42.4 ± 5.4)% ] in cilostazol group , P0.05;incidence rate of hemorrhage in cilostazol group was significantly lower than that of routine treatment group (6.25% vs .19.23% , P< 0.01) .Conclusion:Compared with clopidogrel+aspirin therapy ,cilostazol combined clopidogrel+aspirin can more significantly inhibit platelet ag‐gregation ,and significantly reduce hemorrhage events ,so they are safe and effective in aged patients with coronary heart disease undergoing PCI .

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 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 concentration-time 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.

Monitoring the Antiplatelet Effect of Cilostazol with Light Transmission Aggregometer: Two Cases of Possible Cilostazol Resistance

BACKGROUND: Coronary artery disease is an important cause of death in adults and stent insertion is one of the treatment modalities. The most severe adverse effect of a stent insertion is the formation of a thrombus; therefore, antiplatelet agents are used. The addition of cilostazol to low-dose aspirin and clopidogrel results in a better antiplatelet effect. However, laboratory tests to monitor the effect of cilostazol are insufficient. METHODS: We tested the inhibitory effect of cilostazol using maximal platelet aggregation in 20 healthy volunteers. Conditions for incubation and concentrations of cilostazol and prostaglandin E1 (PGE1) were established and aggregation was induced by 5'-adenosine diphosphate (ADP) and measured with light transmission aggregometry (LTA). Blood samples were incubated with 1 µM and 2 µM cilostazol for 10 minutes at room temperature, and 80 nM PGE1 was added and incubated for an additional 10 minutes. Aggregation was induced by ADP and reactivity was evaluated. RESULTS: The average maximum aggregation (MA) was 58.1% at 1 µM cilostazol and 22.0% when PGE1 was added. The average MA was 42.8% when cilostazol concentration was increased to 2 µM and 21.2% when PGE1 was added. Average inhibition of aggregation at 1 µM cilostazol was not statistically significant (P=0.085), but was significant (P=0.004) at 2 µM cilostazol. Aggregation was not inhibited even with 2 µM cilostazol and PGE1 in 2 volunteers, which suggests possible resistance to cilostazol. CONCLUSIONS: We designed a method to monitor the effect of cilostazol using in vitro incubation with PGE1.

Successful sequential desensitization in a patient with drug hypersensitivity to three kinds of antiplatelet agents

Antiplatelet agents, such as aspirin, clopidogrel, and cilostazol, are essential for the treatment and prevention of cardiovascular, cerebrovascular, and peripheral vascular diseases. A 53-year-old male with aspirin hypersensitivity developed dizziness, which was caused by severe stenosis of the left vertebral artery. Clopidogrel was administerted, but discontinued due to generalized urticaria and angioedema. As an alternative drug, cilostazol was administered, but discontinued again because of the same adverse reactions. Desensitization was planned as other alternative antiplatelet agents were not available. Initially, aspirin desensitization was successfully performed. One day after aspirin desensitization, clopidogrel desensitization was sequentially done successfully. After a few months, cilostazole desensitization was performed. During the follow-up period, he had to stop aspirin and cilostazol twice to prevent the risk of bleeding after a procedure and an operation. After discontinuing medicines, sequential desensitization of aspirin and cilostazol was successfully performed. Physicians should be aware that drug hypersensitivity could be induced by various kinds of antiplatelet agents and that desensitization could be the treatment of choice unless alternative medicines are available.

A simple spectrophotometric quantitative determination of Cilostazol in bulk and pharmaceutical dosage forms using DNPH reagent.

A simple, sensitive, cost effective spectrophotometric method developed and validated for the determination of Cilostazol (CIL), in bulk drug and its pharmaceutical formulations. The method is rely on the formation of a hydrazone with 2,4-dinitrophenylhydrazine (DNPH); the reaction of drug with reagent gives a bright yellow colour. The obtained coloured species absorbance was measured at its absorption maximum (λmax) 355 nm. The Beer’s law has been obeyed in the concentration range 2-20 μg/ml. The optical parameters were calculated as 2.2980x104 (L mol-1 cm-1), 0.0161 (μg/cm2), molar absorptivity and Sandell sensitivity respectively. The analytical parameters of interest LOD and LOQ of the proposed method were calculated 0.1079 (μg/ml), 0.3594 (μg/ml) respectively. All the variables were examined to optimize the reaction conditions. There was no interference observed in the presence of common pharmaceutical excipients. The validity of the method was established by analyzing CIL in its pharmaceutical formulations and critically tested for its accuracy by statistical tests. Good recoveries were obtained by the developed method; the obtained results were critically analyzed and successfully employed for the determination of CIL in its pharmaceutical dosage forms.