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 .
 purposeto 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.methodsthis 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.resultstwenty-five eyes of 25 patients were included in this study . 
 pobf increased significantly ( 16.8  4.6 l / sec vs. 19.6  6.2 l / 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).conclusionscilostazol was effective in increasing ocular blood flow in patients with diabetic retinopathy , possibly by modulating retrobulbar circulation 
 . 
Materials and Methods
Participants
POBF measurement
Retrobulbar vessel (ophthalmic artery) blood velocity
Statistical analyses
Ethics statement
Results
POBF analysis
Retrobulbar vessel (ophthalmic artery) blood velocities
Correlation between the POBF and TCD parameters
Comparison of the NPDR and PDR groups
Discussion