***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Administration of L-arginine improves nitric oxide ( NO ) formation and endothelium-dependent vasodilation in atherosclerotic patients . OBJECTIVES We investigated in this double-blind , controlled study whether prolonged intermittent infusion therapy with L-arginine improves the clinical symptoms of patients with intermittent claudication , as compared with the endothelium-independent vasodilator prostagl and in E1 , and control patients . METHODS Thirty-nine patients with intermittent claudication were r and omly assigned to receive 2 x 8 g L-arginine/day , or 2 x 40 microg prostagl and in E1 (PGE1)/day or no hemodynamically active treatment , for 3 weeks . The pain-free and absolute walking distances were assessed on a walking treadmill at 3 km/h , 12 % slope , and NO-mediated , flow-induced vasodilation of the femoral artery was assessed by ultrasonography at baseline , at 1 , 2 and 3 weeks of therapy and 6 weeks after the end of treatment . Urinary nitrate and cyclic guanosine-3 ' , 5'-monophosphate ( GMP ) were assessed as indices of endogenous NO production . RESULTS L-Arginine improved the pain-free walking distance by 230+/-63 % and the absolute walking distance by 155+/-48 % ( each p < 0.05 ) . Prostagl and in E1 improved both parameters by 209+/-63 % and 144+/-28 % , respectively ( each p < 0.05 ) , whereas control patients experienced no significant change . L-Arginine therapy also improved endothelium-dependent vasodilation in the femoral artery , whereas PGE1 had no such effect . There was a significant linear correlation between the L-arginine/asymmetric dimethylarginine ( ADMA ) ratio and the pain-free walking distance at baseline ( r=0.359 , p < 0.03 ) . L-Arginine treatment elevated the plasma L-arginine/ADMA ratio and increased urinary nitrate and cyclic GMP excretion rates , indicating normalized endogenous NO formation . Prostagl and in E1 therapy had no significant effect on any of these parameters . Symptom scores assessed on a visual analog scale increased from 3.51+/-0.18 to 83+/-0.4 ( L-arginine ) and 7.0+/-0.5 ( PGE1 ; each p < 0.05 ) , but did not significantly change in the control group ( 4.3+/-0.4 ) . CONCLUSIONS Restoring NO formation and endothelium-dependent vasodilation by L-arginine improves the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease In a r and omized open study , the combination of either prostagl and in E1 ( PGE1 ) or pentoxifylline with controlled vascular training was compared with vascular training alone in patients with peripheral arterial occlusive disease in stage IIb . Forty-four patients were r and omly assigned to treatment either of intensive vascular training alone ( n = 15 ) or in combination with either i.v . pentoxifylline ( 200 mg over 2 hours BID , n = 15 ) or PGE1 ( 40 micrograms over 2 hours BID , n = 14 ) . The basic therapy was a well-defined routine for vascular training , which was identical for all groups . The duration of therapy was 4 weeks . In all three test groups , there was a significant increase in the walking distance . There was a 119 % increase in symptom-free walking distance in the exercise-only group . In comparison with exercise alone , the additional administration of pentoxifylline produced no greater effect ; the increase was 105 % . In contrast , administration of PGE1 combined with exercise achieved a remarkable improvement of 604 % . Between-group comparison revealed the significant superiority of treatment with PGE1 ( P < .05 ) . During the 1-year follow-up , there was a reduction in the walking performance in all groups , albeit of variable extent . In the exercise-only and the pentoxifylline groups , the maintained increase in walking distance was only 30 % compared with baseline values before the beginning of therapy . In the PGE1 group , on the other h and , the maintained improvement was 149 % . Nine of 14 patients were still in stage IIa of peripheral arterial occlusive disease 1 year after PGE1 therapy For the first time efficacy and safety of a new prostagl and in E1 ( PGE1 ) regimen in the treatment of intermittent claudication were evaluated in a r and omized , double-blind , placebo-controlled multicenter clinical trial . The study involved 213 out patients with a maximum walking distance of 50 to 200 m measured on the treadmill ( 3 km/hr , 12 % grade ) . After a 2-week run-in phase they received a 2-hour intravenous infusion of 60 micrograms PGE1 or placebo 5 days a week for 4 weeks . It was followed by a 4-week interval treatment with the same medication administered only twice a week . Patients were monitored for 3 months when they received no study medication . In the PGE1 group the intention-to-treat analysis ( n = 208 ) revealed an increase in walking distance after 4 weeks of 75 % ( placebo , 43 % ) . At the end of the interval treatment the walking distance had improved to 101 % ( placebo , 60 % ) . The results remained virtually constant during follow-up ( PGE1 , 104 % , placebo , 63 % ) . Between-group comparisons showed significant differences in favor of PGE1 for all three time points of measurement ( p < 0.05 , p < 0.01 , and p < 0.05 ) . PGE1 was well tolerated ; the rate of adverse reactions related to the treatment was 12.8 % ( placebo , 7.7 % ) . In summary , these results show that the new PGE1 regimen is effective and safe in the treatment of out patients with intermittent claudication Summary In a r and omized patient-blind study iloprost or hydroxy-ethyl starch 200/0.5 were given i.v . 5 h daily for 2 weeks to 24 patients suffering from severe intermittent claudication due to peripheral vascular disease . An increase in pain-free walking distance of more than 50 % occurred in 6 of 11 patients after the iloprost infusions and in 7 of 12 patients after HES treatment . No significant effects on haemodynamic or clinical chemistry tests were observed Beraprost sodium is an orally active prostagl and in (PG)I(2 ) analogue , which has antiplatelet and vasodilating properties . In this study , we investigated the effects of beraprost on the expression of vascular cell adhesion molecule-1 ( VCAM-1 ) , one of the key molecules involved in atherosclerosis , in cultured vascular endothelial cells . In addition , we examined the effects of beraprost on circulating VCAM-1 level and atherosclerosis progression in patients with type 2 diabetes mellitus .  Beraprost significantly decreased tumor necrosis factor-alpha (TNF-alpha)-induced VCAM-1 expression in human vascular endothelial cells . Beraprost also repressed human monocytoid U937 cell adhesion to the vascular endothelial cells . Twenty-five patients with type 2 diabetes mellitus who had atherosclerotic change of carotid arteries were enrolled for an open prospect i ve study : 11 patients received beraprost for 3 years , while the other 14 did not . The 3-year changes of circulating VCAM-1 level , as well as those of carotid arterial intima-media thickness ( IMT ) were significantly lower in the patients receiving the beraprost treatment than that in the patients without the treatment . Thus , beraprost had an ability to repress the expression of VCAM-1 in human vascular endothelial cells . In addition , beraprost lowered circulating VCAM-1 level and prevented the increase of carotid IMT in patients with type 2 diabetes mellitus . Considering that circulating VCAM-1 and IMT are predictive of future vascular events , beraprost may have a beneficial effect on progression of atherosclerosis in diabetic patients We compared the efficacy and safety of three doses of beraprost sodium , an epoprostenol analogue , with placebo in the treatment of intermittent claudication ( Fontaine 's stage II ) . One hundred sixty-four patients were r and omized to receive either placebo , 20 micrograms beraprost sodium ( BPS60 group ) , 40 micrograms beraprost sodium ( BPS120 group ) , or 60 micrograms beraprost sodium ( BPS180 group ) three times daily administered orally in a double-blind manner for 12 weeks . Treadmill exercise tests were performed twice during an initial selection phase ( D-28 and D0 ) at week 10 ( at trough beraprost concentration ) and week 12 ( at peak beraprost concentration ) of the treatment phase . At week 10 , all groups showed an increase in pain-free walking distance , and this distance was greatest in the BPS60 and BPS120 groups ( p = 0.055 ) . At week 12 , a similar pattern was observed , and the difference was significant between the groups ( p = 0.023 ) . The most frequent adverse events reported were gastrointestinal disorders , headaches , skin disorders , and flushes . Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance . Further studies are required to investigate why the highest dose used ( 180 micrograms daily ) showed lower efficacy . Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term , beraprost sodium is a promising drug for the treatment of intermittent claudication Iloprost , a stable carbaprostacyclin analog , was infused ( up to 2 - 4 ng/kg/min ) for 12 h daily on 5 consecutive days into the forearm vein of 13 patients with peripheral arterial occlusive disease ( PAOD ) of legs ( stages IIb-III ) . All vasodilatory and antiplatelet drugs were stopped three weeks earlier . For comparison , dextran was infused in a r and omized , crossover , double-blind manner with an average interval of 3 months . Iloprost increased significantly ankle systolic pressure and ankle/arm pressure ratio for the follow-up period of one month . Foot skin temperature increased insignificantly . Pain-free walking distance was prolonged up to 1.51 times by iloprost and 1.14 times by dextran ( p less than 0.05 ) . Venous occlusion plethysmography showed no improvement in the blood flow of legs . Eight patients experienced a subjective improvement in their clinical status with iloprost . Ten patients suffered from mild to severe headache , nausea , transient rest pain of legs , and hypotension . One patient with gastric ulcer history was withdrawn because of mild hematemesis , not definitely drug-related . No significant changes occurred in st and ard laboratory safety control or in hemostasis . The results suggest that a 5-day iloprost infusion exerts a mild favourable effect on patients with PAOD This study aims to evaluate the reliability of repeated grade d workload treadmill testing ( G-test ; 2 mph ; 0 % grade , increasing 2 % every 2 min ) and to compare the reliability of a constant workload treadmill protocol ( C-test ; 2 mph ; 12 % grade ) versus the grade d workload treadmill protocol in patients with intermittent claudication , studied longitudinally . A clinical trial investigating an orally stable prostacycline derivative that included 330 patients with intermittent claudication was performed . The trial employed three active treatment groups and one placebo group . Because there were no significant inter-group differences at baseline or after treatment , data from all groups were pooled for the evaluation of treadmill test reliability . Treadmill data were obtained from a 2-week run-in phase where three G-tests were performed , as well as from the beginning and the end of a 3-month double-blind phase where a G-test and a C-test were performed in r and om order . Treadmill test reliability was described through test process-related and between-subject variances and also using variance-derived parameters such as the reliability coefficient ( RC ) and the relative precision ( RP ) . A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to between-subject variance and not to test process-related variance . Estimates of variance were described for both the maximal or absolute claudication distance ( ACD ) and the initial claudication distance ( ICD ) with each treadmill test . Reliability estimates are reported for the total study sample and for patients with baseline claudication distances < 300 feet and .300 feet ( approximately < 100 m ; .100 m ) , as measured with the C-test . The cut-off value was empirically chosen to separate severely diseased from mild to moderately diseased claudicants . Theoretical considerations suggest that reliability measures may differ in these subgroups . With repeated testing during the run-in phase for the measure of ACD , the G-test had an RC of 0.952 and an RP of 21.9 % . With the comparison of both test protocol s in the entire study population for the measurement of ACD , the G-test had an RC of 0.902 and an RP of 31.3 % , while the C-test had an RC of 0.876 and an RP of 35.2 % . The results for ICD on the G-test were an RC of 0. 
    Output:
    
Compared with pentoxifylline , PGE1 was associated with a higher final PFWD and MWD but these results were based on final walking distances rather than changes in walking distance from baseline .
In one study using three different dosages of iloprost  , PFWD and MWD appeared to increase in a dose-dependent manner ; iloprost was associated with headache , pain , nausea and diarrhoea , leading to a higher rate of treatment withdrawal .
Beraprost sodium was associated with an increased incidence of drug-related adverse events .
Whilst results from some individual studies suggested a beneficial effect of PGE1 , the quality of these studies and of the overall evidence available is insufficient to determine whether or not patients with intermittent claudication derive clinical ly meaningful benefit from the administration of prostanoids .