the current investigation was a prospective , multicenter , cohort study conducted at third referral hospitals in south korea , between december 2009 and october 2010 .
patients who met the following criteria were included in this study : 1 ) between 18 and 90 years of age ; 2 ) an established diagnosis of dm ; 3 ) lower limb discomfort for longer than six months ; 4 ) a diagnosis of pad established by the absence of one or more foot pulses of the involved foot or an ankle brachial pressure index ( abi ) less than 0.9 .
patients were excluded from the study if they had critical limb ischemia , defined as the presence of rest pain requiring analgesics for a duration of more than 2 weeks , the presence of non - healing ischemic ulcer , or gangrene ; a stroke or myocardial infraction within the last 3 months ; a tendency towards hemorrhage ; severe liver or kidney disease ; having undergone endovascular intervention of the coronary artery or a peripheral artery ; or having undergone operative revascularization within the last 3 months . with these strict inclusion and exclusion criteria , 100 diabetic patients with pad
were enrolled in this study , 6 of whom were excluded because they chose to discontinue the medication .
all patients who were eligible for the study agreed to participate and signed a written informed consent .
this study was performed according to the declaration of helsinki and was approved by the respective local institutional review boards from the institutions participating in the study .
patients were administered oral beraprost ( 40 g ) 3 times daily ( 120 g / day ) for 12 weeks .
use of other drugs with significant effects on peripheral vessels , hemostasis , or platelet function during the study was prohibited . among these
included pentoxifylline , heparin , warfarin , aspirin , persantine , ticlopidine , and prostaglandin e1 analogs .
all other medical care regimens were continued throughout the course of the study in all the patients .
the following safety assessments were made before treatment , as well as 6 weeks and 12 weeks thereafter , or at drug discontinuation : serum chemistry , hematology , electrocardiogram , vital signs , concomitant medication changes , and adverse events .
first , a list of descriptors was chosen on the basis of our experience and analysis of the literature .
following discussions and approval of content validity by a panel of 4 korean diabetic foot experts , we included 8 descriptors ( burning , coldness , edema , exertional pain , throbbing , shooting , stabbing , and paresthesias ) in the initial version of the questionnaire .
a pilot study was performed in all patients who participated in this study at their first visit in order to verify the face validity of the questionnaire .
the patients were asked to complete the questionnaire and to rate each descriptor for clarity in wording , understanding , and relevance to their current symptoms .
after the pilot study , the " throbbing " descriptor was excluded because it was considered irrelevant by a majority of patients .
in addition , the " shooting " descriptor was excluded because of very low prevalence ( < 30% of the patients reported the symptom ) as compared to the other descriptors .
thus , the final version of the disease - specific symptom questionnaire included 6 descriptors : burning , coldness , edema , exertional pain , stabbing , and paresthesias .
each subjective symptom was ranked from 0 to 4 , according to the severity of the symptoms felt by the patient ; 0 reflected asymptomatic status and 4 reflected the greatest severity .
patients were asked for their subjective assessment of their symptoms in the written questionnaire before treatment and at 12 weeks .
in addition to the assessment of subjective symptoms , patients were evaluated serially for new complaints , changes in symptoms , and functional status .
statistical analyses were consequently performed with the spss ver . 18.0 ( ibm co. , armonk , ny , usa ) .
differences between pretreatment and the last follow - up were analyzed by the wilcoxon matched - paired signed - ranks test .
first , a list of descriptors was chosen on the basis of our experience and analysis of the literature .
following discussions and approval of content validity by a panel of 4 korean diabetic foot experts , we included 8 descriptors ( burning , coldness , edema , exertional pain , throbbing , shooting , stabbing , and paresthesias ) in the initial version of the questionnaire .
a pilot study was performed in all patients who participated in this study at their first visit in order to verify the face validity of the questionnaire .
the patients were asked to complete the questionnaire and to rate each descriptor for clarity in wording , understanding , and relevance to their current symptoms .
after the pilot study , the " throbbing " descriptor was excluded because it was considered irrelevant by a majority of patients .
in addition , the " shooting " descriptor was excluded because of very low prevalence ( < 30% of the patients reported the symptom ) as compared to the other descriptors .
thus , the final version of the disease - specific symptom questionnaire included 6 descriptors : burning , coldness , edema , exertional pain , stabbing , and paresthesias .
each subjective symptom was ranked from 0 to 4 , according to the severity of the symptoms felt by the patient ; 0 reflected asymptomatic status and 4 reflected the greatest severity .
patients were asked for their subjective assessment of their symptoms in the written questionnaire before treatment and at 12 weeks .
in addition to the assessment of subjective symptoms , patients were evaluated serially for new complaints , changes in symptoms , and functional status .
statistical analyses were consequently performed with the spss ver . 18.0 ( ibm co. , armonk , ny , usa ) .
differences between pretreatment and the last follow - up were analyzed by the wilcoxon matched - paired signed - ranks test .
four patients failed to qualify for the study because of adverse reactions to beraprost , the study medication .
the mean age was 63.5 years ( range , 30 to 83 years ) and the mean duration of dm was 9.3 years ( range , 1 to 30 years ) .
diabetic retinopathy , nephropathy , and neuropathy were present in 8 patients ( 8.9% ) , 11 patients ( 12.2% ) , 18 patients ( 20.0% ) , respectively , some of whom had more than one complication .
comorbidities , including hypertension , hyperlipidemia , and previous myocardial infarction were noted in 57 patients .
ten patients were either current smokers or had a history of smoking within the past 2 years .
no specific counseling on diet , smoking cessation or exercise was offered during the study period .
of 81 patients with coldness , 59 patients ( 72.8% ) showed improvement in their symptoms , 21 patients ( 25.9% ) remained the same , and one patient ( 1.2% ) worsened .
seventy - four patients had edema , and 39 patients ( 52.7% ) showed improvement in this symptom . stabbing , burning , and paresthesias were observed in 61 , 56 , and 67 patients , respectively , and 65.6% , 64.3% , and 55.2% of them showed improvement in the respective symptoms .
significant improvement in all estimated subjective symptoms ( coldness , edema , exertional pain , stabbing , burning , and paresthesias ) in the lower extremities was reported at 12 weeks ( p < 0.001 ) .
there were 18 patients with neuropathy that was determined by an absent protective threshold using a 5.07 ( 10 g ) semmes - weinstein monofilament . with the numbers available , these patients that had accompanying neuropathy showed significant improvement in all 6 subjective symptoms at 12 weeks ( p < 0.05 ) ( table 3 )
there were no reports of critical cardiovascular events , including myocardial infarction , transient ischemic attack or ischemic gangrene , during the treatment period with beraprost .
adverse reactions considered to be causally related to beraprost occurred in 4 of the 94 patients ( 4.3% ) , and all of these patients discontinued treatment prematurely .
insomnia ( one patient ) and dyspepsia ( one patient ) were reported as well .
treatment of pad can be considered to take part in 3 stages : lifestyle and risk factor modification , pharmacotherapies , and revascularization .
treatment of the patient 's lower extremity symptoms should be chosen on the basis of the severity of the symptoms .
pharmacotherapy includes vasodilating agents , calcium channel blockers , anticoagulants , antiplatelets , and prostaglandin analogs . a revascularization procedure , including surgical or endovascular intervention , is usually reserved for patients with disabling claudication that affects their quality of life , after medical therapy has failed to improve symptoms and critical limb ischemia symptoms .
. currently , 2 agents are available in the united states for the symptomatic treatment of pad : pentoxifylline and cilostazol .
both drugs have shown to increase pain - free walking time and total distance walked , although the data on pentoxifylline is conflicting.19,20 ) in comparison with the placebo , cilostazol improved the distance that patients with intermittent claudication were able to walk during standardized treadmill testing.21,22 ) however , its use is contraindicated in patients with heart failure , and a sizable minority discontinues treatment due to gastrointestinal upset or palpitations .
prostaglandins have also shown clinical benefit in reducing the symptoms of intermittent claudication and significant increase in walking distance.23,24 ) pgi2 which is synthesized in vascular endothelial and smooth muscle cells , shows antiplatelet action and vasodilating action.4,5 ) beraprost sodium is a stable , orally active pgi2 analogue , launched in japan in 1992 , and is currently used in several countries to treat ischemic symptoms in chronic arterial occlusion .
beraprost has favorable effects on maximal treadmill walking distance and quality of life , while reducing the incidence of critical cardiovascular events in patients with intermittent claudication at 6 months.9 ) however , another trial of beraprost that involved 897 patients in the united states showed no significant improvement in maximal walking distance.10 ) although the two trials were well designed , only a few patients with dm were included in these studies .
for that reason , it is necessary to test the efficacy of beraprost treatment in patients with dm specifically .
intermittent claudication has been considered the most characteristic manifestation of pad.12 ) however , in community - based epidemiologic studies , many people with pad have symptoms other than classic intermittent claudication.14 - 16 ) significant improvement of pain - free walking distance or maximum walking distance has been demonstrated . however , if the patients ' subjective symptoms assessment is not changed , there is no reason to consider the effect to be beneficial .
thus , we developed a new disease - specific symptom questionnaire , which evaluated the effects of pad on leg discomfort in daily life , to assess therapeutic responses . in this study , 6 subjective symptoms were evaluated as parameters of the drug effect .
oral administration of beraprost over a period of 12 weeks resulted in significant improvement in all measures of subjective symptoms in diabetic patients with pad ( p < 0.001 ) .
coldness was the next commonly reported subjective symptom , occurring in 90.0% of the enrolled patients , and 72.8% of these patients reported improvement in this symptom .
neuropathies developing in patients with diabetes are known to be heterogeneous in respect to their symptoms , pathologic alterations , and pattern of neurologic involvement .
chronic neuropathic pain is present in 13% to 26% of diabetic patients.25 - 28 ) the symptom in diabetic painful neuropathy was most often described by the patients as " burning / hot , " " electric , " sharp , " " achy , " and " tingling".29 ) these symptoms are similar to those observed in pad patients .
therefore , when pad patients accompanied with neuropathy are treated with beraprost , it is difficult to predict the outcome . in this study , we observed improvement in all of the 6 symptom parameters in patients accompanied with neuropathy .
therefore , if pad is prevalent in patients suspected to have diabetic neuropathy , we may expect improvement in some symptoms by treating pad .
one study of beraprost demonstrated that beraprost increased blood flow significantly to the skin of the feet in patients with type 2 diabetes.30 ) consistent with an increase in abi , significant improvement in coldness of the limb , numbness , and paralysis was observed in diabetic patients with pad after treatment with beraprost.11 ) in this study , a 12-week treatment with beraprost significantly improved edema ( 39 of 74 patients , 52.7% ) and coldness ( 59 of 83 patients , 72.8% ) .
all of the above suggests that , in treatment of diabetic circulatory disorders , beraprost dilates peripheral vessels and increase blood flow to the skin , resulting in the improvement of various symptoms . in the current study
, adverse events considered by the investigators to be drug - related were observed in 4 patients ( 4.3% ) , including headache ( 2 patients , 2.1% ) , insomnia ( one patient , 1.1% ) , and dyspepsia ( one patient , 1.1% ) .
the incidence of adverse events in our study was relatively low compared to that in previous studies.9 - 11 ) this is probably because the period of medication was relatively short in our study .
the limitations of this study include the uncontrolled and nonrandomized design , as well as the relatively small sample size . in addition , the lack of placebo control limits the statistical power of the data . also , there was a limited ability to perform analyses of a subgroup with neuropathy because sample size could be decreased further . in the present study ,
various antipyretic analgesics , tricyclic antidepressants , the anticonvulsants gabapentin and pregabalin , as well as serotonin and norepinephrine reuptake inhibitors were used concomitantly with beraprost .
therefore , to verify the contributory effect of beraprost treatment , separate analyses should have been done before and after beraprost treatment for groups using and not using each concomitant drug .
no changes in activity or risk factor modification were recommended during the trial . by minimizing the biases coming from these factors , these similarities lent statistical power to our results .
finally , objective findings such as abi and transcutaneous oxygen saturation were not measured to assess the efficacy of beraprost . instead , this study focused on the effect of beraprost on subjective leg symptoms in diabetic patients with pad . in future prospective randomized studies ,
evaluation of abi or transcutaneous oxygen saturation are required to determine whether objective findings indeed improve .
diabetic patients with pad may have various symptoms that are generally reproducible during daily activities , resulting in a negative impact on quality of life .
beraprost is an agent with pharmacological actions unlike other drugs in respect to the treatment of pad .
this trial showed statistically significant improvement of subjective symptoms in diabetic patients with pad after 12 weeks of therapy with beraprost , even without specific risk - factor modification and a directed exercise program .
beraprost may present a new option for the treatment of various symptoms in diabetic patients with pad .
further studies are needed with a larger sample size and a placebo control to confirm our results .
 backgroundthis study evaluated the effects of beraprost sodium ( berasil ) on subjective leg symptoms in patients with peripheral arterial disease caused by diabetes mellitus.methodsninety-four diabetic patients with peripheral arterial disease were treated with beraprost in a fixed - dose , prospective , multicenter , cohort study . 
 beraprost ( 40 g ) was administered orally 3 times daily ( 120 g / day ) for 12 weeks . 
 we developed a new disease - specific symptom questionnaire , which evaluated the effect of peripheral arterial disease on leg discomfort in daily life and assessed therapeutic responses to treatment . 
 patients were asked for their subjective assessment of symptoms on a written questionnaire before treatment and after 12 weeks of therapy.resultsthere was significant improvement in all estimated subjective symptoms ( burning , coldness , edema , exertional pain , stabbing , and paresthesias ) in the lower extremities at 12 weeks ( p < 0.001 ) . 
 there were 18 patients with neuropathy in whom significant improvement was noted for 6 subjective symptoms at 12 weeks ( p < 0.05 ) . 
 adverse events considered to be drug - related were observed in 4 patients ( 4.3% ) , all of which were mild and resolved with discontinuation of the medication.conclusionsberaprost is effective as a treatment for improving various subjective symptoms in the lower extremities , such as burning , coldness , edema , exertional pain , stabbing , and paresthesias , in diabetic patients with peripheral arterial disease . 