patients over 30 years of age with type 2 diabetes , diabetic retinopathy , and a visual acuity of 20 / 50 or better were enrolled in this prospective observational study . all participants were seen at seoul national university hospital from october 2011 to march 2012 . the baseline pobf analyses were performed in conjunction with a transcranial doppler ( tcd ) examination and blood pressure ( bp ) measurements . ophthalmic evaluations of best - corrected visual acuity ( bcva ) , iop , and cirrus hd optical coherence tomography ( oct ; carl zeiss meditec , dublin , ca , usa ) measurements were performed . one week after the administration of cilostazol ( pletal ; otsuka pharmaceutical , tokyo , japan ) , all examinations were repeated . all pobf examinations were performed by a single trained examiner ( djh ) to reduce inter - examiner bias . the central foveal thickness ( cft , the mean retinal thickness of the central 1 mm circle ) , the macular cube volume , and the macular cube average thickness were measured using a cirrus hd oct unit . when both eyes were eligible for the study , each eye was individually evaluated ; however , a computer algorithm randomly selected only one eye for use in the statistical analysis . the type of diabetic retinopathy was also classified into two subgroups : a non - proliferative diabetic retinopathy ( npdr ) group and a panretinal photocoagulation ( prp)-treated proliferative diabetic retinopathy ( pdr ) group . upon enrollment , the clinical history of each patient was thoroughly evaluated . after screening , patients were administered cilostazol twice daily at a dose of 100 mg for 1 week ( 200 mg per day ) . patients who were taking aspirin at the time of enrollment in this study were asked to stop aspirin treatment for 2 weeks before beginning the cilostazol regimen . the 200-mg cilostazol dose was continued for 1 week if no complication or severe event was observed . the administration of any other anti - platelet drugs that could strongly influence the effect of cilostazol was prohibited during the study period . however , pre - existing prescription drugs for chronic diseases such as hypertension and diabetic mellitus were continued throughout the study period . patients with the following conditions were excluded from the study : a history of retinal surgery ; ocular diseases , excluding diabetic retinopathy ; new retinal vessels observed with fluorescein angiography ; macular edema with a cft exceeding 300 m ; severe hypertension ( defined as having a systolic bp greater than 180 mmhg or a diastolic bp greater than 110 mmhg ) ; hypersensitivity to the cilostazol treatment ; pregnancy or the possibility of pregnancy ; uncontrolled diabetes ( hemoglobin a1c > 8% ) ; angina pectoris , myocardial infarction , or heart failure . a pobf analyzer was used to assess blood flow according to methods previously described . this noninvasive technique assessing ocular blood flow is based on the iop pulse . a modified applanation prism with distensible film at the contact surface is used to measure blood velocity . a pneumotonometer is used to create a waveform representing the ocular pulse . the amplitude and pulse rate ( pr ) of this waveform the pobf analyzer has been found to be reliable and reproducible in measuring ocular pulse amplitude ( pa ) , pulse volume ( pv ) , pr , and pobf . the tcd studies were performed using a tcd150 m device ( spencer technologies , seattle , wa , usa ) ( fig . 1b ) , which calculates a power m - mode doppler image and provides a single - gate spectrogram . the peak systolic velocity ( psv ) , mean flow velocity ( mfv ) , end diastolic velocity ( edv ) , and pulsatility index ( pi ) of the ophthalmic artery were evaluated at baseline and 1 week after the administration of cilostazol . the ophthalmic artery can be situated above or below the optic nerve in the posterior orbit and passes forward into the nasal orbit in a horizontal plane slightly superior to that of the optic nerve . these vessels were examined at a point approximately 25 mm behind the globe in the nasal orbit . at this point , the pi was calculated using the following formula ( psv  edv ) / ( mfv ) , which was used to characterize the peripheral vascular resistance . changes between values measured at baseline and those measured 1 week after the administration of cilostazol were evaluated using the paired t - test and wilcoxon signed - rank test for normally distributed data and data that were not normally distributed , respectively . significant differences in the pobf analyzer and tcd values between the subgroups ( npdr group vs. prp - treated pdr group ) were evaluated using the mann - whitney test for nonparametric data . analysis of covariance was performed to adjust for age , gender , and the duration of diabetes mellitus in the subgroup analysis . spearman 's nonparametric regression analysis was used to determine the correlation between pobf and tcd at the ophthalmic artery . a p - value less than 0.05 was considered to be statistically significant . the study was approved by the institutional review board of seoul national university hospital ( no . 0620113380 ) and followed the guidelines of good clinical practice . written informed consent for participation was obtained from all patients after they had been given a thorough explanation of this study . the study was carried out in accordance with the tenets of the declaration of helsinki . patients over 30 years of age with type 2 diabetes , diabetic retinopathy , and a visual acuity of 20 / 50 or better were enrolled in this prospective observational study . all participants were seen at seoul national university hospital from october 2011 to march 2012 . the baseline pobf analyses were performed in conjunction with a transcranial doppler ( tcd ) examination and blood pressure ( bp ) measurements . ophthalmic evaluations of best - corrected visual acuity ( bcva ) , iop , and cirrus hd optical coherence tomography ( oct ; carl zeiss meditec , dublin , ca , usa ) measurements were performed . one week after the administration of cilostazol ( pletal ; otsuka pharmaceutical , tokyo , japan ) , all examinations were repeated . all pobf examinations were performed by a single trained examiner ( djh ) to reduce inter - examiner bias . the central foveal thickness ( cft , the mean retinal thickness of the central 1 mm circle ) , the macular cube volume , and the macular cube average thickness were measured using a cirrus hd oct unit . when both eyes were eligible for the study , each eye was individually evaluated ; however , a computer algorithm randomly selected only one eye for use in the statistical analysis . the type of diabetic retinopathy was also classified into two subgroups : a non - proliferative diabetic retinopathy ( npdr ) group and a panretinal photocoagulation ( prp)-treated proliferative diabetic retinopathy ( pdr ) group . upon enrollment , the clinical history of each patient was thoroughly evaluated . after screening , patients were administered cilostazol twice daily at a dose of 100 mg for 1 week ( 200 mg per day ) . patients who were taking aspirin at the time of enrollment in this study were asked to stop aspirin treatment for 2 weeks before beginning the cilostazol regimen . the 200-mg cilostazol dose was continued for 1 week if no complication or severe event was observed . the administration of any other anti - platelet drugs that could strongly influence the effect of cilostazol was prohibited during the study period . however , pre - existing prescription drugs for chronic diseases such as hypertension and diabetic mellitus were continued throughout the study period . patients with the following conditions were excluded from the study : a history of retinal surgery ; ocular diseases , excluding diabetic retinopathy ; new retinal vessels observed with fluorescein angiography ; macular edema with a cft exceeding 300 m ; severe hypertension ( defined as having a systolic bp greater than 180 mmhg or a diastolic bp greater than 110 mmhg ) ; hypersensitivity to the cilostazol treatment ; pregnancy or the possibility of pregnancy ; uncontrolled diabetes ( hemoglobin a1c > 8% ) ; angina pectoris , myocardial infarction , or heart failure . a pobf analyzer was used to assess blood flow according to methods previously described . this noninvasive technique assessing ocular blood flow is based on the iop pulse . a modified applanation prism with distensible film at the contact surface is used to measure blood velocity . a pneumotonometer is used to create a waveform representing the ocular pulse . the amplitude and pulse rate ( pr ) of this waveform the pobf analyzer has been found to be reliable and reproducible in measuring ocular pulse amplitude ( pa ) , pulse volume ( pv ) , pr , and pobf . the tcd studies were performed using a tcd150 m device ( spencer technologies , seattle , wa , usa ) ( fig . 1b ) , which calculates a power m - mode doppler image and provides a single - gate spectrogram . the peak systolic velocity ( psv ) , mean flow velocity ( mfv ) , end diastolic velocity ( edv ) , and pulsatility index ( pi ) of the ophthalmic artery were evaluated at baseline and 1 week after the administration of cilostazol . the ophthalmic artery can be situated above or below the optic nerve in the posterior orbit and passes forward into the nasal orbit in a horizontal plane slightly superior to that of the optic nerve . these vessels were examined at a point approximately 25 mm behind the globe in the nasal orbit . at this point , the pi was calculated using the following formula ( psv  edv ) / ( mfv ) , which was used to characterize the peripheral vascular resistance . statistical analyses were performed using a commercially available software package pasw ver . 18.0 ( spss inc . , chicago , il , usa ) . changes between values measured at baseline and those measured 1 week after the administration of cilostazol were evaluated using the paired t - test and wilcoxon signed - rank test for normally distributed data and data that were not normally distributed , respectively . significant differences in the pobf analyzer and tcd values between the subgroups ( npdr group vs. prp - treated pdr group ) were evaluated using the mann - whitney test for nonparametric data . analysis of covariance was performed to adjust for age , gender , and the duration of diabetes mellitus in the subgroup analysis . spearman 's nonparametric regression analysis was used to determine the correlation between pobf and tcd at the ophthalmic artery . the study was approved by the institutional review board of seoul national university hospital ( no . 0620113380 ) and followed the guidelines of good clinical practice . written informed consent for participation was obtained from all patients after they had been given a thorough explanation of this study . the study was carried out in accordance with the tenets of the declaration of helsinki . the mean age was 62.5  12.0 years and 16 patients ( 64% ) were male . the pdr group ( 18.4  6.4 years ) had a longer duration of diabetes mellitus than the npdr group ( 11.6  6.0 years ) ( p = 0.001 ) . cilostazol was well tolerated by all of the patients , and no complications or severe adverse events were observed during the 1 week of administration . there were no significant changes in visual acuity , iop , or bp after medication . among the oct parameters , there were no significant changes in the cft ( 255.9  26.4 m vs. 254.0  27.4 m , p = 0.111 ) , macular cube volume ( 10.32  1.0 mm vs. 10.3  1.0 mm , p = 0.845 ) , or macular cube average thickness ( 286.7  29.0 m vs. 287.3  28.2 m , p = 0.111 ) , respectively . the pa , pr , and pobf measurements exhibited significant changes after cilostazol administration , as shown in table 1 . at 1 week after cilostazol administration , pa had decreased by 17.9% ( 2.8  1.3 mmhg vs. 2.3  0.9 mmhg , p < 0.001 ) , and pr had increased by 25.3% ( 72.8  14.3 times / min vs. 91.2  21.6 times / min , p < 0.001 ) . mean pobf was 16.8  4.6 l / sec at baseline and increased by 17.1% to 19.6  6.2 l / sec after 1 week of cilostazol medication ( p < 0.001 ) ( fig . mfv was 23.5  5.6 cm / sec at baseline and then increased significantly by 11.7% to 26.0  6.9 cm / sec with medication administration ( p = 0.001 ) ( fig . psv also increased by 12.8% ( 43.9  12.5 cm / sec vs. 49.5  15.1 cm / sec , p = 0.001 ) . edv and pi remained relatively constant throughout the study . a moderate correlation between changes in pobf and tcd the changes in the pobf were found to correlate with the changes in mfv ( absolute change : r = 0.404 , p = 0.010 ; percentage change : r = 0.419 , p = 0.007 , respectively ) , as shown in fig . the changes in the pobf also correlated with the changes in psv and edv ( r = 0.393 , p = 0.012 and r = 0.337 , p = 0.034 , respectively ) . after dividing the 25 patients into two groups ( a npdr group and prp - treated pdr group ) there was no significant difference in any of the pobf or tcd parameters between the two groups . the analysis of covariance revealed no significant inter - group differences after adjustment for age , sex , and duration of diabetes mellitus ( p > 0.05 ) . neither age nor gender was found to be a significant predictor of changes in pobf or mfv ( p = 0.275 and p = 0.114 , respectively ) . the pa , pr , and pobf measurements exhibited significant changes after cilostazol administration , as shown in table 1 . at 1 week after cilostazol administration , pa had decreased by 17.9% ( 2.8  1.3 mmhg vs. 2.3  0.9 mmhg , p < 0.001 ) , and pr had increased by 25.3% ( 72.8  14.3 times / min vs. 91.2  21.6 times / min , p < 0.001 ) . mean pobf was 16.8  4.6 l / sec at baseline and increased by 17.1% to 19.6  6.2 l / sec after 1 week of cilostazol medication ( p < 0.001 ) ( fig . mfv was 23.5  5.6 cm / sec at baseline and then increased significantly by 11.7% to 26.0  6.9 cm / sec with medication administration ( p = 0.001 ) ( fig . psv also increased by 12.8% ( 43.9  12.5 cm / sec vs. 49.5  15.1 cm / sec , p = 0.001 ) . the changes in the pobf were found to correlate with the changes in mfv ( absolute change : r = 0.404 , p = 0.010 ; percentage change : r = 0.419 , p = 0.007 , respectively ) , as shown in fig . the changes in the pobf also correlated with the changes in psv and edv ( r = 0.393 , p = 0.012 and r = 0.337 , p = 0.034 , respectively ) . after dividing the 25 patients into two groups ( a npdr group and prp - treated pdr group ) , subgroup analyses were performed for the pobf and tcd parameters . there was no significant difference in any of the pobf or tcd parameters between the two groups . the analysis of covariance revealed no significant inter - group differences after adjustment for age , sex , and duration of diabetes mellitus ( p > 0.05 ) . neither age nor gender was found to be a significant predictor of changes in pobf or mfv ( p = 0.275 and p = 0.114 , respectively ) . in this study , ocular blood flow as assessed by the pobf analyzer increased with oral administration of cilostazol in patients with diabetic retinopathy patients . this increase in ocular blood flow was parallel to the increase in retrobulbar vessel blood flow velocity as measured with tcd . the same trend of increased ocular blood flow was observed irrespective of the degree of diabetic retinopathy . the average increase in pobf observed in this study was 17.1% . this change in ocular blood flow was significant even after considering the previously proven test / retest variability . furthermore , to minimize the interobserver variability , all measurements were performed by a single experienced operator , which is very important in measuring pobf . pobf values have a wide normal range and low discriminating power , so intra - individual comparisons with repeated examinations , as performed in this study , are more useful than inter - individual comparisons . pobf analysis also showed that cilostazol administration significantly decreased pa and increased pr , which have been reported to be negatively correlated with each other in healthy subjects , and pv did not change significantly . these trends may explain the increase in pobf , which is affected by pa , pr , and pv . however , the outcomes of the present study should be discussed with an awareness of the associated instrumental limitations . currently , there is no established gold standard for the assessment of ocular blood flow , and therefore validation of any given method is limited to comparison with other methods . although the measurement of ocular blood flow with the pobf analyzer has empirical validity , it is necessary to consider the accuracy of our results . this is important because the measurement of blood flow from the ocular pulse is based on specific assumptions , hence no single method may provide a complete description of ocular blood flow . we therefore performed tcd to also evaluate retrobulbar vessel velocity , and found that the mean velocity in the ophthalmic artery had increased by 11.7 % . these changes in the tcd parameters of retrobulbar hemodynamics suggest that cilostazol treatment may modulate the velocity of blood in the retrobulbar vessels . changes in pobf were found to moderately correlate with changes in mfv by tcd , although ocular blood flow accounts for only a small portion of blood flow through the ophthalmic artery . changes in pobf also correlated with changes in psv and edv as well as mfv . despite the fact that the pobf and tcd measure different phenomena , the simultaneous increase in pobf and retrobulbar blood flow , as measured by the tcd , raises the possibility that the increase in pobf may reflect an actual increase in ocular blood flow , which may be affected by the increase in retrobulbar blood flow . although cilostazol reportedly enhances cerebral blood flow in cases of chronic cerebral infarction , its effect on ocular blood flow has not been investigated , and its ability to increase ocular blood flow remains unknown , especially in the diabetic state . to the best of our knowledge , this is the first study designed to elucidate the effect of systemic medication on ocular blood flow in patients with diabetic retinopathy . it may be speculated that the increased ocular blood flow observed in this study was due to the vasodilatory effect of cilostazol , as cilostazol is known to act as a platelet inhibitor and vasodilator . the pi calculated from the parameters measured by tcd , which reflects vascular resistance , showed no significant change . the blood flow velocity was observed to increase , thereby increasing the retrobulbar blood flow . cilostazol may affect the autoregulatory function of ocular blood flow and cause the vascular resistance to remain constant despite increased cerebral blood flow , thereby allowing increased ocular blood flow . no significant change was identified in the iop , bp , bcva , and oct thickness parameters , such as the cft and the macular cube volume at 1 week after the administration of cilostazol . with the increased ocular blood flow induced by cilostazol additionally , cilostazol may have a direct effect on inducing vasodilation in the ocular vasculature . spectral domain - oct parameters do not represent retinal blood flow , and there are no reliable methods currently available to assess retinal blood flow . the challenge of evaluating the effects of cilostazol on retinal blood flow and its long - term clinical outcomes remains to be solved in future studies . previous studies on cilostazol reported a lower mean pobf in the prp - treated pdr group as compared to the npdr group . however , our results showed no significant difference in pobf values between the npdr group and pdr groups . in addition , the pobf of the npdr and pdr groups were higher than those reported in previous studies for patients with diabetic retinopathy . reported a mean value of 15.9 l / sec for the npdr group , which was lower than the values reported in this study . reported mean values of 15.7 l / sec for moderate to severe npdr and 10.3 l / sec for prp - treated pdr , both of which were also lower than the values reported in this study ( 16.8 l / sec for npdr and 19.6 l / sec for pdr ) . this may be due to variability in the conditions of the patients enrolled in these studies , as most related studies have reported a small sample size , and only patients with relatively good vision were enrolled in our study . in addition , the interpretation and comparison of the pobf values may be limited by differences in patient age , sex , and the classification of diabetic retinopathy . the clinical significance of this increase in ocular blood flow with the administration of cilostazol in patients with diabetic retinopathy remains to be evaluated . studies describing the role of altered ocular blood flow in patients with diabetic retinopathy report conflicting results . increased ocular blood flow does not directly correlate with either improved visual acuity or delayed progression of diabetic retinopathy . our understanding of the role of ocular blood flow in the pathophysiology of diabetic retinopathy is in its infancy , and attempts to pharmacologically modify the progression of diabetic retinopathy are also in their primitive stages . to the best of our knowledge , our study is the first to evaluate the effects of systemic medication on ocular blood flow in diabetic retinopathy . the results of this study suggest that cilostazol may have potential value in increasing ocular blood flow in patients with diabetic retinopathy , although the long - term benefits need to be elucidated . with regard to safety , none of the patients in this study showed any complications or severe adverse events during medication administration . moreover , in a recent report , the addition of cilostazol to a regimen of aspirin therapy did not increase the bleeding tendency when compared with a regimen consisting of aspirin alone . cilostazol treatment could therefore safely be added to an ongoing antiplatelet regimen without increasing the risk of bleeding in patients with diabetic retinopathy . there are some limitations to this study that should be considered when interpreting the results . a large - scale long - term comparative study with a control group will be necessary to confirm these findings . in this study , cilostazol increased ocular blood flow by more than 10% without any significant side effects in patients with diabetic retinopathy . this demonstrates its potential as a tool for increasing blood flow in diabetic retinopathy , although its long - term clinical benefit remains to be clarified . further studies are required to investigate whether increased ocular blood flow due to cilostazol can slow the progression of diabetic retinopathy or improve visual outcome .