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We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

Plasminogen activator inhibitor 1 (PAI-1), the primary inhibitor of fibrinolysis and C-reactive protein (CRP), is a predictor of myocardial infarction. Both are upregulated by tumor necrosis factor-alpha (TNF-α) within the obese population. This pilot study tested the hypothesis that TNF-α blockade with pentoxifylline lowers PAI-1 and high-sensitivity CRP (hsCRP) in obese individuals. Twenty participants were treated with pentoxifylline for 8 weeks. A proportional odds model was used to compare the change in PAI-1 and CRP in the pentoxifylline and placebo groups. Plasminogen activator inhibitor 1, but not hsCRP levels, decreased over the 8-week period of the study (P = .025 and P = NS). There was significant dropout of participants due to drug tolerability. These findings suggest that these markers of cardiovascular risk are differentially regulated in obesity and that PAI-1 levels can be reduced by pentoxifylline in this population.

Peripheral arterial disease may lead to lower limb claudication and increased risk of systemic vascular dysfunction. In this article, the authors have investigated the peripheral vascular dysfunction evaluating forearm blood flow using venous occlusion plethysmography, lipid profile, and C-reactive protein in 60 patients with moderate intermittent claudication treated during 20 weeks with placebo (n = 16), cilostazol (200 mg/d; n = 17), or pentoxifylline (1200 mg/d; n = 15) in a randomized double-blinded clinical trial, taking into account smoking. Forearm blood flow after reactive hyperemia response (FBF(h) ) or oral nitroglycerine spray to evaluate endothelial-dependent and endothelial-independent vasodilation, respectively, pain-free and maximal walking distance, levels of C-reactive protein, triglycerides, cholesterol, low-density lipoprotein, and high-density lipoprotein-cholesterol in plasma were determined. The results showed that there was an improvement in the high-density lipoprotein-cholesterol, pain-free and maximal walking distance, and FBF(h) independent of treatment in nonsmoking patients. Cilostazol increased high-density lipoprotein-cholesterol level, maximal walking distance, and FBF(h), whereas pentoxifylline reduced C-reactive protein level and increased maximal walking distance in total and nonsmoking groups. No treatment was effective in smokers.

Although endovascular therapy has revolutionized the management of patients with peripheral arterial disease (PAD), noninterventional regimens, such as structured exercise therapy, atherosclerotic risk factor modification, and pharmacotherapy, are effective in patients suffering from mild-to-moderate PAD and intermittent claudication (IC). For more than a decade, the only pharmacologic therapy for IC available in the United States was pentoxifylline, which had demonstrated superiority in improving walking distances but offered minimal clinical benefit. Recently, basic research into the pathophysiology of IC has led to the development of cilostazol, a new pharmacologic agent approved for treatment of this condition in 1999. Ongoing research in the use of angiogenic growth factors has further broadened the range of potential alternatives to treatment in patients with PAD. Revascularization procedures, including nonsurgical and surgical techniques, can thus be reserved to improve patency and reduce the risk of limb loss in patients with PAD and IC with more severe impairment.

Peripheral artery disease is associated with altered blood rheologic properties, including increased viscosity and decreased red blood cell (RBC) deformability. Pentoxifylline and cilostazol are available therapies for intermittent claudication. Improvement of blood viscosity and erythrocyte deformability have been cited as potential mechanisms of action for pentoxifylline. Cilostazol is a new drug with antiplatelet and vasodilating activity, but the mechanism by which it promotes an improvement in walking is not known. This study was performed to evaluate and compare the hemorheologic effects of pentoxifylline and cilostazol on viscosity, fibrinogen levels, and erythrocyte deformability when administered to adults with moderate to severe claudication. A double-blind, controlled study was conducted and included 59 patients (46 male, 13 female; mean age 65 yr) randomized to pentoxifylline 400 mg orally thrice daily (n=20), cilostazol 100 mg orally twice daily (n=19), or placebo (n=20); all subjects were observed for 24 weeks. Walking ability was assessed before, during, and at the conclusion of treatment by standard constant speed, variable grade treadmill testing. Erythrocyte deformability was measured by passage of washed RBCs, 10% hematocrit in phosphate buffered saline (PBS), through a polycarbonate membrane with 4.7 to 5.0 microm pores. Whole blood and plasma viscosity were measured using a cone/plate viscometer at variable shear rates (from 4.5 to 450 sec(-1)). Erythrocyte sedimentation rate was measured by a modified Westergren technique. Fibrinogen was assayed by a commercial reference laboratory. Plasma viscosities did not change significantly in any treatment group. Within-group comparisons demonstrated a significant (p<0.01) drop in whole blood viscosity (week 24 compared with week 0) for cilostazol-treated subjects (at shear rates of 45, 90, 225, and 450 sec(-1)), but these changes were not significantly different from those in the placebo group. There were no significant changes in whole blood viscosity for subjects treated with pentoxifylline or placebo. There were no significant changes in erythrocyte deformability, fibrinogen, or erythrocyte sedimentation rate. A trend toward improved walking distances was noted for both pentoxifylline and cilostazol in comparison with placebo. This trend was not correlated with changes in any underlying rheologic parameter. Ex vivo rheologic characteristics of blood from patients with intermittent claudication are not significantly affected by long-term administration of pentoxifylline or cilostazol. Pentoxifylline did not modulate viscosity or red cell deformability, a finding at variance with its putative mechanism of action. Pentoxifylline cannot be differentiated from cilostazol based on specific hemorheologic effects evaluated in this study. Different mechanisms of action for these medications should be considered.

The efficacy, safety, and cost of pentoxifylline (PXF) in long-range (>400 m interval) intermittent claudication was studied comparing PXF and placebo in a 12-month study. A standardized treadmill test was performed at inclusion and at 6 and 12 months. A training plan based on walking was associated with the control of risk factor levels. Of the 194 included patients, 135 completed the study: 75 in the PXF group and 60 in the placebo group. There were 59 dropouts (due to low compliance). The authors observed a 148% increase in total walking distance (TWD) at 6 months with PXF (vs 110% with placebo; p<0.05); at 12 months, the increase was 170% with PXF (vs 131% with placebo; p<0.02). There was a 38% difference at 6 months and 39% at 12 months in favor of PXF. Treatment was well tolerated. In conclusion, PXF improved walking distance significantly better than placebo.

The efficacy, safety and cost of pentoxifylline (PXF) in severe intermittent claudication was studied comparing PXF and placebo in a 12-month study. A treadmill test and microcirculatory evaluation with laser Doppler flowmetry were performed at inclusion and at the end of 6 and 12 months. A physical training plan (based on walking) and reduction in risk factor levels plan was used in both groups. Of the 120 included patients, 101 completed the study: 56 in the PXF group and 45 in the placebo group. There were 19 dropouts (due to low compliance). The two groups were comparable for age, sex distribution, walking distance, and the presence of risk factors and smoking. Intention-to-treat analysis indicated a 268% increase in walking distance in the PXF group (vs 198% in the placebo group; p<0.05) at 6 months and an increase of 404% (vs 280% in the placebo group; p<0.02) at 12 months. The absolute and percent increase in pain-free walking distance (PFWD) was greater in the PXF group (p<0.05). Treatment was well tolerated. No serious drug-related side effects were observed. Microcirculatory evaluation indicated an increase in flux (p < 0.05) in the PXF group (not significant in the placebo group); the after-exercise flux (AEF) was increased (p<0.05) in both groups at 6 months but the increase in AEF was greater in the PXF group at 12 month. In conclusion, between-group analysis favors PXF considering walking distance and microcirculatory parameters. Results indicate good efficacy and tolerability.

The efficacy of Pentoxifylline in vascular inner ear disease (VIED) was studied comparing PXF and placebo in a 4-week study; 40 patients with vascular disease and monolateral loss of hearing, vertigo, dizziness, tinnitus (analyzed with an analogue scale line), and cochlear flow reduction were included. The aims of the study were to study the effects of PXF (1600 mg daily) in VIED considering clinical outcome and cochlear flow. Of the 20 included patients, 19 completed the study. One dropout in the placebo group was due to low compliance. Intention-to-treat analysis indicated an improvement in cochlear flow (p<0.05) and a decrease in score in both groups. The cochlear flow increase was 287.5% in the PXF group vs 168% in the placebo group (119.5% difference; p<0.02). There was a difference in score decrease (44.1% larger) in the PXF group (p<0.05).Between-group analysis favors PXF considering blood flow and symptoms. Results indicate good efficacy and tolerability of PXF in VIED.

The aim of this study was the evaluation of treatment with pentoxifylline in patients with venous ulcers in a 6-month, randomized, controlled trial. Treatment with placebo or pentoxifylline (PXF; 400 mg, 3 times daily) lasted 6 months and was associated to elastic bandaging. The endpoints were the number of limbs with complete healing and the variation in the area of ulceration. A group of 172 patients were included: 82 in the PXF group and 88 in the placebo group; 82 completed the study in the PXF group and 78 in the placebo group. Results. The two groups were comparable for age and sex distribution. The treatment was well tolerated. Complete healing was obtained in 67% of patients in the PXF group and 30.7% in the placebo group (p<0.02). The variations in the average area of ulceration were 86.7% (decrease) in the PXF group and 47% in the placebo group. The cost of treatment increased 21% with PXF but the cost due to non-healing of the ulcer was equivalent to a 44% increase (in comparison with the PXF group). In conclusion PXF is effective and cost-effective in improving ulcer healing in patients with chronic venous hypertension.

The efficacy of pentoxifylline (PXF) in severe intermittent claudication was studied comparing PXF and placebo. Patients were randomized into two treatment plans: PXF (2400 mg, four 600-mg tablets daily) or equivalent placebo was administered for 10 days. The exercise protocol associated with treatment was conducted under supervision. Skin flux (RF) was measured at rest and after 1 minute of exercise (AEF = after exercise flux; 3 km/hr, 12% inclination) with laser Doppler. PO2 and PCO2 were measured at the dorsum of the foot. All 20 included patients completed the study. The two groups were comparable. In the PXF group there was a significant increase in RF, AEF, and in PO2 (p<0.05); PCO2 was decreased (p<0.05). There were also changes in the placebo group, significantly lower than those observed in the PXF group (p<0.05). In conclusion high-dose PXF treatments improved all microcirculatory parameters in subjects with short-range claudication even with a short period of treatment.

The efficacy of pentoxifylline (PXF) in vascular inner ear disease (VIED) was studied comparing PXF and placebo in a 4-week study; 60 patients with unilateral loss of hearing, vertigo, dizziness, tinnitus (analyzed with an analogue scale line), and cochlear flow reduction were included. The aim of the study was to study the effect of PXF (1800 mg/day) in VIED considering clinical outcome and cochlear flow. All patients completed the study. Improvement in cochlear flow (p<0.05) and a decrease in score in both groups were observed. The cochlear flow increase was 287.5% in the PXF group vs 168% in the placebo group (119.5% difference; p<0.02). There was a difference in score decrease (44.1% larger) in the PXF group (p<0.05). PXF was more effective considering flow and symptoms.

The aim of this study was to evaluate PXF (pentoxifylline; 1600 mg daily vs placebo) in patients with retinal vein thrombosis (RVT) in a 4-week trial, evaluating clinical outcome and retinal flow. Inclusion criteria were sudden loss of vision (SLV); retinal vein thrombosis (RVT); decrease in retinal vein flow; asymmetry between retinal veins (>40%) documented by duplex scanning (retinal vein thrombosis flow = RVTF). All 18 included patients completed the study. The groups were comparable. No side effect was observed. An improvement in arterial flow (p<0.05) and a decrease in analogue score (p<0.05) were observed in both groups (due to the spontaneous evolution with partial thrombus lysis in 4 weeks). The increase in arterial flow (PSF and EDF) were greater (p<0.05) in the PXF group. The RVFV increase was better in the PXF group (350% increase vs 200% increase in the placebo group; p<0.05). There was a significant difference in the analogue score decrease (4 vs 7) in the PXF group (p<0.05). In conclusion, PXF improved retinal flow after RVT better than placebo. It should be considered as an important treatment option.

The aims of this study were to evaluate the effect of PXF (1600 mg daily) in diabetic patients with intermittent claudication. Of the 60 included patients, 53 completed the study (27 in the PXF group). There were seven dropouts. The groups were comparable for age, sex distribution, and total walking distance (TWD), and risk factors. There was an increase in TWD at 3 and 6 months in both groups (p<0.05) possibly due to exercise. However the increase (both absolute and percentage) in TWD was significantly larger in the PXF group. At 6 months, PXF produced a 292% increase in TWD (vs 180% produced by placebo) (p<0.02). The excess increase produced by PXF treatment was 112% at 6 months in comparison with placebo (p<0.02). Treatment was well tolerated. Between-group analysis favors PXF considering TWD, and results indicate good efficacy and tolerability.

The aim of this study was the evaluation of the treatment of venous ulcers with pentoxifylline (PXF) in 12 months. This double-blind, placebo-controlled trial was conducted in GCP. Patients were included after consent and randomized for PXF (400 mg three times daily) or placebo. The number of healed ulcers, the variation in the area of ulceration, and the variation in microcirculatory parameters (laser-Doppler flux and skin PO2) were considered as endpoints. Of the 85 patients included, 80 completed the study (41 in the PXF and 39 in the placebo group). The groups were comparable. Healing occurred in 88% of limbs in the PXF and in 44% in the placebo group (44% difference; p<0.02). The average area reduction was 93% in the PXF and 56% in the placebo group. Microcirculation was significantly improved in both groups at 12 months. The decrease in flux and the increase in PO2 were greater in the PXF group (p<0.05). Considering the proportion of healed ulcers a better outcome was observed with PXF (p<0.02; 12% of nonhealed ulcers in the PXF vs 56% in the placebo group). The ulcerated area decreased 93% in the PXF vs 56% in the placebo group (40% difference; p<0.02). Tolerability was comparable (6% in the PXF group and 5% in the placebo group complained for treatment). No important side effects were observed. In conclusion, treatment with PXF in venous ulcers improves healing and microcirculation and should be considered in slow-healing venous ulcers.

The efficacy, safety, and cost of pentoxifylline (PXF) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a randomized 40-week study. A treadmill test was performed at inclusion and at the end of weeks 20 and 40. A progressive training plan and the control of risk factors (with antiplatelet treatment) were used in both groups. Of the 200 included patients, 178 completed the study: 88 in the PXF group and 90 in the placebo group. There were 22 dropouts. The two groups were comparable for age, sex distribution, and for the presence of risk factors and smoking. There was a significant increase in pain-free walking distance (PFWD) in both groups. The absolute and percent increase in PFWD was significantly greater in the PXF group (p<0.05). At 20 weeks, the increase was 360.5% in the PXF vs 252% in the placebo group. At 40 weeks, the increase was 386% in the PXF and 369% in the placebo group (p<0.02). Total walking distance (TWD) increased at 20 weeks (up to 254%) and up to 329% at 40 weeks. In the placebo groups the increase was 158% at 20 weeks and 183% at 40 weeks. The excess increase produced by PXF treatment was 30% at 20 weeks and 38% at 40 weeks (p<0.02). Unwanted effects treatment was well tolerated. No serious drug-related side effects were observed. In summary, between-group analysis favors PXF considering walking distance and costs. Results indicate good efficacy and tolerability.

The aim of this study was to evaluate the effect of PXF (1800 mg daily) in patients with sudden loss of vision (SLV) in a 4-week trial, evaluating clinical outcome and retinal flow parameters. Inclusion criteria were SLV associated with thrombosis of the retinal artery; decrease in retinal blood flow (PSF: peak-systolic flow; EDF: end-diastolic flow velocity) and asymmetry between the two retinal arteries (>40%) documented by duplex scanning. All 10 included patients completed the study. The groups were comparable. No side effects were reported. A significant improvement in flow velocity (p<0.05) and a decrease in analogue score in both groups were observed. PSF increase was 550% in the PXF group vs 288% in the placebo group (262% difference). EDF increase was 400% in the PXF group vs 200% in the placebo group (200% difference). There was a significant difference in the analogue score decrease (33.3% difference larger in the PXF group; p<0.05). In conclusion, PXF treatment improved retinal flow after retinal artery occlusion better than placebo and should be considered as an important option in this condition.

Seventy-one patients with peripheral arterial occlusive disease (PAOD) were randomized into two groups of different treatment modalities. The diagnosis of PAOD was established by history of intermittent claudication, clinical examination, and by Doppler pressure assessment or lower extremity arteriography. After a three-month washout period, 35 patients (Group 1) started treatment with indobufen (400 mg per day) and 36 patients (Group 2) with pentoxifylline (600 mg per day). Twenty-nine patients from each group completed six months of treatment. Both of the drugs significantly improved maximal and pain-free walking distances, but the effect of indobufen was more pronounced than that of pentoxifylline. Patients with PAOD exhibited signs of hypercoagulation. Fibrinogen, D-dimer, and b-thromboglobulin concentrations did not change significantly following treatment in both of the groups. The authors observed a decrease of platelet aggregation after treatment with indobufen and a decrease of F1 + 2 fragment and PAI-1 antigen after treatment with pentoxifylline.

Peripheral vascular disease (PVD) commonly presents with leg claudication during walking and eventually limits the walking distance and daily activities. Aspirin or pentoxifylline are commonly prescribed to improve blood flow. Aspirin works through its antiplatelet aggregation mechanism, and pentoxifylline increases the red blood cell flexibility, which leads to increased tissue perfusion. Data on comparative studies of these drugs for improving claudication in the elderly are limited. The objective of this study was to compare pain relief offered by either aspirin or pentoxifylline for walking leg pain in the elderly with PVD. Patients sixty-five years or older with claudication were randomly assigned to receive aspirin or pentoxifylline. Their reported level of walking claudication pain with use of the visual analogue scale (0-5) and the distance walked during exercises were recorded. Six weeks later the same parameters were recorded and results were compared with Student's t test, and a P value less than 0.05 was considered a statistically significant difference. Of the 90 patients who participated, 45 received aspirin (325 mg daily) and 45 were prescribed pentoxifylline (400 mg tid) for six weeks. Both the aspirin and the pentoxifylline groups reported a moderate level of pain (2/5) and remained about the same (2/5 for aspirin and 1/5 for pentoxifylline, P = 0.9, NS) after six weeks. However, the pentoxifylline group reported a farther walking distance of 2 miles compared with the aspirin group of 1.2 miles (P < 0.05). The level of pain did not change significantly with either aspirin or pentoxifylline, but the walking distance was farther with the pentoxifylline group.

In the light of the current controversy surrounding the use of hemorheologic and vasodilator drugs in the treatment of peripheral arteriosclerosis, a comparative study was designed in order to evaluate the efficacy of pentoxifylline, buflomedil, and nifedipine in 45 patients with peripheral arterial disease (Fontaine stage II). The patients in this prospective randomized study were divided into three groups: 15 patients received pentoxifylline treatment (1,200 mg/day), 15 were treated with buflomedil (600 mg/day), and 15 with nifedipine (60 mg/day). Response to treatment was assessed at the start of the study and after forty-five and ninety days, by clinical examination, Doppler test, strain test, and digital occlusion plethysmography using a strain gauge ring. Pentoxifylline was significantly more effective (P < 0.05) than buflomedil and nifedipine at ninety days in improving walking performance, resting toe pressure, resting and postexercise ankle/brachial pressure ratio, and basal/postischemic toe-pulse ratio. Significant differences within groups were also noted for initial claudication, toe peak-flow time, pulse reappearance time (PRT/2), and maximum postischemic flow time, together with significant intergroup variables. In conclusion, pentoxifylline proved more effective than the other drugs tested in: 1. improving distal pressure and resting microcirculatory blood flow; 2. increasing postexercise distal flow, ratios, and pressures and enabling faster recuperation of basal pulse rates; 3. increasing initial claudication distance in the strain test within the test group and achieving a greater absolute subjective claudication distance than that obtained using the other treatments.

Pentoxifylline was first introduced in Germany twenty years ago. Today it is the best researched oral drug for intermittent claudication. A total of seventeen placebo-controlled trials could be retrieved from the world literature. The majority of these studies show that pentoxifylline will prolong the walking distance in a statistically significant way. Even though these trials are conducted with considerable scientific rigor, important flaws can be identified. Whether the symptomatic improvement is clinically relevant is difficult to say and may depend on the patient's individual situation. These collective data show that pentoxifylline prolongs the walking distance in patients with intermittent claudication.

A sixty-six-year-old man with known severe atherosclerosis was admitted with painful feet and nonblanching purpuric lesions of his toes. He had undergone cardiac catheterization and coronary artery bypass five and three months, respectively, prior to admission. Initial treatment included: stopping the patient's lisinopril, increasing his nifedipine dose, and adding pentoxifylline 400 mg po tid. Within twenty-four hours pain was markedly decreased. Skin biopsy confirmed a diagnosis of cholesterol embolism. Pentoxifylline was stopped and intravenous heparin therapy was initiated. Within twenty-four hours, pain returned. Nitrol paste applied to the top of each foot had no effect. After forty-eight hours, pentoxifylline was restarted. Once again, pain relief was noted within twenty-four hours, and after forty-eight hours both feet were visibly improved. Heparin and analgesics were discontinued. On the ninth hospital day, the patient was able to walk and was discharged to home. The innocuous nature of the intervention combined with the prompt nature of the therapeutic response support a short trial of pentoxifylline in patients with cholesterol emboli who are not responding to other therapy.

This literature survey of the medical treatment of venous ulcers of the lower extremities discusses five classes of agents: (1) fibrinolytics, (2) hydroxyrutosides, (3) prostaglandins, (4) methylxanthines, and (5) others. The authors conclude that all these agents require further research.

There are several anecdotal reports of improvement in diabetic sensory neuropathy following a course of pentoxifylline therapy. Pentoxifylline theoretically could improve skin blood flow, thus reducing ischemia at axonal endings. The authors used laser Doppler techniques to measure skin blood flow and measured sine wave current perception thresholds (CPTs) in pentoxifylline-treated diabetic patients with sensory neuropathy. Twenty-four patients completed a six-month course of treatment. These patients had a predominantly "stocking" neuropathy; all the major abnormalities on clinical, laser Doppler, and current perception testing were found on the lower extremity. Seventeen of the 24 patients reported symptomatic improvement. A careful, graded neurologic examination confirmed that improvement, with a decrease in symptom score on the lower extremity (SSDW) from a baseline of 5.0 +/- 0.7 to 3.5 +/- 0.7 (p < 0.01) and of physical score (PSDW) from baseline 22.0 +/- 2.0 to 16.0 +/- 1.9 (p < 0.01) after six months. On the lower extremity, there was an increase in laser Doppler measured flow score (FS) both at 35 degrees and at 44 degrees C. FSDW (35 degrees) increased from 10 +/- 2 to 14 +/- 3 at six months (p < 0.05). FSDW (44 degrees) increased from 58 +/- 5 to 77 +/- 7 at six months (p < 0.01). There was an improvement in sine wave current perception measured by current perception threshold score (TS). TSDW dropped from 150 +/- 32 to 84 +/- 28 at six months (p < 0.03). In patients with diabetic sensory neuropathy, pentoxifylline appears to improve skin blood flow. Current perception thresholds improve in tandem, corroborating improvement in clinical neurologic findings.(ABSTRACT TRUNCATED AT 250 WORDS)

The possible healing effect of deferoxamine and pentoxifylline on persisting lower limb ulcers was studied in 51 patients with thalassemia major. The results indicated that the regular use of deferoxamine at an intravenous dose of 20 mg/kg did not affect the healing progress and the recurrence rate of these ulcers significantly. On the contrary, the oral administration of pentoxifylline at a dose of 1,200 mg daily during the ulcer's healing time and at a low long-term maintenance dose of 400 mg daily during the ulcer-free intervals improved their healing ability impressively and diminished their recurrence rate significantly.

Pentoxifylline, a hemorheologic drug reputed to reduce blood viscosity, can be used to improve the microcirculation in peripheral vascular disease. The authors report on 2 patients who were being followed up for possible glaucoma and whose visual field constriction became worse at about the same time as their peripheral vascular symptoms began to increase in severity. Following initiation of treatment with oral pentoxifylline, their peripheral vascular complaints decreased and their visual fields gradually expanded over the next several months. This dual effect seemed more than a coincidence. It may in fact indicate that the same mechanism said to aggravate the peripheral ischemia (ie, increased blood viscosity) in patients with peripheral vascular disease may also have been the basis for the visual field contraction in these 2 patients, possibly by producing retinal ischemia. The reversal of the contracted visual fields would then seem to be due to the ameliorative effect of the pentoxifylline treatment on the blood viscosity.

The aim of this study was to test whether in claudicants oral pentoxifylline, given for twelve weeks in addition to physical exercise, prolongs the walking distance more than placebo plus exercise. Forty outpatients were randomized into group A (2 x 600 mg oral pentoxifylline per day) or group B (placebo). Both groups received the same exercise program in addition. The maximal and painfree walking distances and blood viscosity were measured. Intergroup differences in terms of blood viscosity reached the level of significance only after twelve weeks (p = 0.006 at shear rate of 94.5 s-1), but values of group A continuously decreased and those of group B continuously increased. After one and eight weeks, but not after twelve weeks, the maximal walking distances were significantly longer in group A than in group B. At no point were there significant intergroup differences in terms of painfree walking distance. The data suggest that pentoxifylline is clinically effective in claudicants even when given in addition to exercise. The benefit of drug plus physical therapy compared with exercise alone could be observed mainly in the first weeks of treatment and may wear off during long-term therapy.

Painful diabetic distal sensory neuropathy is a disabling and common complication of diabetes mellitus. There is evidence that microvascular changes resulting in ischemia to the vasa nervorum may contribute to this problem. Pentoxifylline has been shown to improve circulation through partially occluded peripheral vessels and has been postulated to be of potential benefit. Forty adult type II diabetics were enrolled in a double-blind, placebo-controlled study utilizing pentoxifylline for six months. Visual analog scores, nerve conduction studies, and physical examinations were used to evaluate response to treatment. At the end of the six-month trial, there was no significant difference in the patients' pain between the pentoxifylline- and placebo-treated groups. The authors conclude that pentoxifylline is not useful in the treatment of painful distal diabetic neuropathy.

Vascular impotence is a common medical problem for which available therapies are limited. Three impotent patients observed in the authors' practice who were receiving pentoxifylline for treatment of claudication of the lower extremities spontaneously reported improved sexual function. A controlled trial of pentoxifylline for vascular impotence may be warranted.

Abnormal blood rheology is a known characteristics of coronary artery disease. The authors evaluated the effects of pentoxifylline on the exercise capacity ejection fraction and symptoms of 9 patients with ischemic cardiomyopathy. All patients had signs and symptoms of left ventricular dysfunction. All had at least two major vessels obstructed as determined by coronary angiography. Pentoxifylline 400 mg three times daily was administered for twelve weeks. Seven of 9 patients responded with increases in ejection fraction and exercise tolerance. Exercise tolerance correlated with improvement or lack of improvement in ejection fraction. For all patients at twelve weeks post-therapy mean ejection fraction increased 9.8% over baseline (p = .07), total treadmill time increased 15% (p = .27), and mean double product increased 13% (p = .03). Anginal symptoms were significantly improved over baseline at twelve weeks of therapy (p greater than .001), as well as dyspnea on exertion (p = .03). Pentoxifylline was well tolerated. Pentoxifylline may benefit ischemic cardiomyopathy by improving coronary perfusion owing to favorable alterations in hemorheologic properties.

In recent years double-blind trials have proved the effectiveness of nonsurgical therapy in the treatment of peripheral obstructive arterial disease (POAD). Among the non-pharmacologic measures taken, walking distance was increased by 40% in subjects who stopped smoking and by more than 100% in those who undertook physical exercise. Drug treatment reduces the atherosclerotic process and brings about an improvement in the symptoms of the disease. In subjects given hypolipidemic treatment the progression of the disease was reduced by two thirds. Two separate studies suggest that antiplatelet drugs, taken over a period of two to four years, significantly slow the progression of atherosclerosis in lower extremity arteries. In the treatment of claudication, two vasodilating drugs, naftidrofuryl and buflomedil, have shown a significant improvement in painfree walking distance and/or total walking distance, compared with treatment with placebo. Another effective approach is in the treatment of blood rheology through drugs such as pentoxifylline or by hemodilution. Double-blind trials with pentoxifylline demonstrated an average increase of 66% in maximum walking distance as compared with 22% with placebo. The effectiveness of hemodilution was demonstrated by two controlled trials, during which the reduction of the hematocrit to values of 40-42 for periods of four to six weeks increased both walking distance and resting blood flow. When introduced intraarterially in low doses in the vicinity of the occluding thrombus, thrombolytic agents have been found to be helpful in the treatment of acute and chronic POAD. This therapy should, however, be regarded as a substitute for surgical treatment only in high-risk patients. Further, after having produced the lysis of thrombi, the treatment permits the underlying parietal lesions to be accurately identified; at this point the appropriate therapy can be decided upon, either an operative procedure or a balloon dilation. In conclusion the many controlled clinical trials carried out over the past few years have clearly demonstrated that conservative treatment can alleviate clinical signs and symptoms in patients with claudication and pain at rest.

Previous studies demonstrated a high incidence of local thrombosis in patients in whom external arteriovenous shunts were used for vascular access. This procedure provides, therefore, a useful model for the evaluation of potential antithrombotic agents. The effect of the hemorheologically and hemostasiologically active drug Pentoxifylline on the incidence of thrombosis of arteriovenous shunts (Ramires shunt) was investigated in a long-term, double-blind, placebo-controlled study in 51 patients on chronic hemodialysis. The two treatment groups were comparable in age, sex, concomitant medication, and dialysis program (three times per week for four hours). Drugs known to affect platelet function or coagulation were excluded, with the exception of heparin, during the dialysis procedure. All shunts were placed in the forearm and inserted into the distal part of the radial artery and basilic antebrachial vein. Simultaneously, for medical reasons, in all patients an arteriovenous fistula was performed (proximal part of radial artery and cephalic antebrachial vein). Shunt thrombosis was assumed when the flow in the shunt discontinued under visual and auscultatory control. Thrombi were documented by physical removal from the arterial part of the shunt by use of gentle suction or by complete shunt thrombosis (both arterial and venous part of the shunt). Thereafter, the patients' trial period terminated. The total number of thrombi during the observation period was 44 in the pentoxifylline group (26 patients), compared with 82 in the placebo group (25 patients). The mean number of thrombi per patient was 1.69 +/- 1.29 in the pentoxifylline group, significantly lower than that in the placebo group (3.28 +/- 1.99/p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

In this trial of pentoxifylline, 15 patients with end-stage peripheral vascular disease had symptoms severe enough to warrant operation, but surgery was contraindicated because of anatomically noncorrectable disease, serious medical problems, or refusal. Their mean age was sixty-six years. Each patient received oral pentoxifylline, 400 mg tid, for twelve weeks. Pentoxifylline had no measurable clinical benefit in 14 of the patients. In addition, the authors noted an increased incidence of symptomatic coronary artery insufficiency during the trial period that may or may not have been drug related.

An up-dated synopsis is given on the antithrombotic potential of pentoxifylline. Pentoxifylline enhances the PGI2 release from the vascular wall and causes increasing platelet sensitivity to antiaggregating prostaglandins. By its PDE inhibiting effect pentoxifylline in high doses can also enhance PGI2-stimulated cAMP synthesis. These platelet aggregation inhibiting effects in combination with increases in fibrinolytic activity under pentoxifylline administration are suggested to be the main determinants of the compound's antithrombotic properties as evident from investigations in different animal models of thrombosis: Intravascular thrombus formation upon stimulation by both iontophoretically introduced ADP or laser injury of endothelium in the hamster cheek pouch and in the rat mesentery, respectively, was significantly reduced under pentoxifylline. Clinically these findings are corroborated by the regress of platelet aggregability, reduction in fibrinogen, increase in AT III and decrease in antiplasmin activity under treatment with pentoxifylline.

In a randomized, placebo-controlled, crossover study, 15 ambulatory patients with Raynaud's phenomenon, treated for three weeks with ketanserin 80 mg/day and pentoxiphylline 1,200 mg/day, were evaluated by subjective symptom scores, daily frequency and duration of attacks, and photoplethysmography, at room temperature and after cold test. Reduced subjective symptoms and duration of attacks, together with improved cold test plethysmography, were significant only after ketanserin. All subjective symptom scores also improved after ketanserin but only for cyanosis and paresthesia after pentoxiphylline. Excellent results were obtained in 4 cases after ketanserin and in 1 case with pentoxiphylline. The authors discuss the greater importance of antivasospastic action over antiaggregating and hemorheologic effects in Raynaud's phenomenon therapy, as well as the pathogenetic role of serotonin.

The effect of a 3 month daily administration of 800 mg pentoxifylline (Trental 400 bds) or placebo was assessed under double blind crossover design in 18 patients (12 males and 6 females) with peripheral occlusive arterial disease in respect of painfree walking distance and various hemorheological and hemostasiological variables, platelet aggregation, serum cholesterol and triglycerides. In first treatment period walking distance significantly increased with pentoxifylline by 46% from baseline 121 +/- 15 m and by 4% with placebo from baseline 134 +/- 18 m. Pentoxifylline administration furthermore yielded significant decrease in whole blood and plasma viscosity and significant increase in erythrocyte deformability. This was paralleled by distinct reduction of fibrinogen, platelet aggregation and euglobulin lysis time, also plethysmographic variables showed positive changes pointing to improvement of limb perfusion. The results of the study suggest that treatment of peripheral occlusive vascular disease by a drug improving blood fluidity through correction of hemorheological and hemostasiological factors turns especially promising and beneficial since the action centers finally on the languishing microcirculation in the ischemic tissue.

Recent investigations suggest an interdependence between blood fluidity and walking performance in patients with peripheral arterial occlusive disease (PAOD). Therefore, various blood fluidity variables (erythrocyte aggregation, erythrocyte flexibility, plasma viscosity, plasma proteins) were studied in groups of healthy subjects and claudicants with severe PAOD (exhausted perfusion reserve) receiving intravenous treatment with Trental (600 mg Pentoxifylline b.i.d., 21 days). Erythrocyte flexibility (expressed by filterability through micropore filters), red cell aggregation and plasma viscosity deteriorate with progression of disease especially in Stage IIb and III Fontaine classification, with walking distance below 150 m. Trental treatment resulted in patients with advanced POAD stages in improvement of red cell filterability, red cell aggregation, decrease of plasma viscosity, increase in absolute walking distance and relief from rest pain, suggesting that such patients are accessible to conservative treatment with hemorheologically active agents.

Ten patients with acute stroke and impaired erythrocyte deformability received pentoxifylline parenterally in daily doses of 1.2-1.5 g for ten days (Study A). Hemorheologic parameters: erythrocyte aggregation, erythrocyte deformability, plasma viscosity, and yield shear stress were monitored. While plasma viscosity and erythrocyte aggregation did not change significantly, there was marked improvement in erythrocyte deformability and yield shear stress. Nine patients improved clinically, 1 died. In 40 patients with lacunar infarcts (Study B) clinical and hemorheologic data were recorded during a three-month treatment with 800 to 1,600 mg oral pentoxifylline per day. The above-quoted variables, being pathologically altered in comparison with healthy controls, were again monitored. Thirty-six patients completed the study (4 dropouts). Clinically, 34 patients improved during treatment, 2 worsened. Hemorheologic variables, which were pathologically altered at baseline, improved significantly. Improvement of accompanying disturbances in the retinal microcirculation (confirmed by video fluorescence angiography) during therapy indicated a close correlation between hemorheologic factors and microcirculation.

In vivo thrombolytic studies in stumptailed monkeys indicated that pentoxifylline potentiates thrombolysis induced by urokinase activated human plasmin. Pentoxifylline as well as prostaglandin E1 released plasminogen activators and activated the fibrinolysin system. From this point of view pentoxifylline and prostaglandin E1 synergized with each other. Pentoxifylline potentiated the thrombolytic effect of prostaglandin E1 in vivo.

Pentoxifylline has recently been reported to stimulate in vitro the synthesis of prostacyclin. However it is not known so far whether the drug is able to stimulate prostacyclin synthesis in man also in vivo. In the present study the effects of pentoxifylline on prostaglandin synthesis and several circulatory parameters were studied in 10 controls and 10 patients with occlusive arterial disease after acute i.v. and medium term oral treatment. Prostacyclin (as 6-keto-PGF1 alpha) and PGE2 plasma concentrations have been measured together with arterial blood flow, peripheral vascular resistance, platelet aggregation and red blood cell deformability. Pentoxifylline was found both in healthy subjects and patients to significantly increase prostacyclin plasma concentration after i.v. treatment. In medium term oral treatment prostacyclin concentration was found to increase only two hours after administration and not 8 hours after. No significant variations in PGE2 plasma concentration were found at any time in both groups. Pentoxifylline significantly enhanced resting and post-ischemic blood flow of the lower limbs and simultaneously decreased peripheral vascular resistance both in healthy subjects and patients. Different grades of delayed platelet aggregation and increased red blood cell deformability were also observed. In conclusion results of the present placebo controlled study show that pentoxifylline increases arterial blood flow in patients with occlusive arterial disease. Moreover pentoxifylline induces a temporary stimulation of prostacyclin synthesis which can be suggested to contribute to the clinical activity of the drug as far as an antithrombotic effect in terms of inhibition of platelet aggregation is concerned.

Diabetic neuropathy includes a heterogenous group of neuropathic syndromes associated with diabetes mellitus. One form of diabetic neuropathy is distal symmetric polyneuropathy, which is characterized at a late stage by intractable pain. This pain is generally refractory to present modalities of therapy except for narcotics. Pentoxifylline offers a new approach to therapy, reducing the blood viscosity and improving perfusion of ischemic microcirculation. A case report will be presented of intractable painful peripheral neuropathy responding dramatically to pentoxifylline therapy.

Physiology and pathophysiology of blood fluidity are reviewed focussing the clinical relevance of the different hyperviscosity syndromes with particular respect to the microcirculation and thromboembolic complications. A new therapeutical approach is presented with pentoxifylline, a drug which largely satisfies the complex requirements of a compound affecting most of the determinants of disturbed blood fluidity. The presented data of the multifunctional pharmacological properties of pentoxifylline on blood components and vessel wall suggest this drug as indicated for the treatment of the disorders of blood fluidity linked with many diseases. Its antihemostasiological and antithrombotic potential also offers the facility for prevention of postoperative thrombotic events and in vessel surgery to avoid reocclusion.

A group of 11 female patients (mean age 33.7 +/- 8 years) with a clearly proven primary Raynaud's syndrome of up to five years' duration were subjected to a two-month oral treatment with 3 X 400 mg pentoxifylline per day. The following parameters were studied without and with exposure to cold conditions: hemodynamics (finger photoplethysmography), red cell deformability (filtration test), various clotting variables (prothrombin activity, antithrombin III, plasma fibrinogen, partial thromboplastin time, thrombin time, thrombelastogram), and clinical symptomatology. After treatment 7 of the 11 patients showed a distinct improvement of peripheral blood flow and of symptoms (decrease or removal of asphyxia attacks, pain, color change) under basal conditions, as well as after exposure to cold. Red cell filtration was significantly (p less than 0.05) improved, increasing by 35% under normal conditions and by 30% after exposure to cold. Positive changes were also found in respect to antithrombin III (increase) and plasma fibrinogen (decrease). The thrombelastogram was unchanged. Clinical and instrumental improvements were probably ascribable to better microcirculatory flow due to increased red cell deformability, reduced viscosity, and decreased fibrinogen, all capable of influencing in various degrees the blood flow at the microcirculatory level.

A double-blind, randomized, placebo-controlled long-term clinical study of Trental 400 was carried out, partly under cross-over design, partly as a parallel-group study, in 36 patients suffering from chronic arterial obstructive disorders in the lower limbs, associated with intermittent claudication, in order to evaluate the effectiveness and the safety of this drug administered t.i.d. over a period of 6 months. This controlled period was preceded by a placebo run-in period of 3 months. The clinical results under Trental 400 showed a statistically significant within group improvement of painfree and maximum walking parameters (p less than 0.05) corresponding to an increase to baseline by +96% to +139% respectively and also in comparison to placebo (p less than 0.05). The alterations of walking parameters within the placebo groups, ranging between -25% and +28% were not significant. The subjective parameters (rest pain, paraesthesias, muscular cramps and sensation of heaviness in the legs) paralleled the course of the walking parameters. Under Trental 400, 24 out of 36 patients reported an improvement of these symptoms compared to 7 under placebo. Trental 400 was well tolerated. Minor side effects were mentioned by 7 out of 36 patients. One patient had to stop the drug treatment because of persisting prickling sensation and subsequent insomnia. Drug-related changes in the laboratory findings could not be detected; vital signs varied in function of age, concomitant drug treatments and seasonal factors. The results obtained in these studies suggest Trental 400 as a drug of choice for treating patients with intermittent claudication due to peripheral arterial obstruction according to stage II or III after Fontaine.

The general pathophysiological basis in occlusive arterial disease is the reduced flow rate of blood in the microcirculation. Blood flow in the ischemic tissue can be increased by improving the flow properties of blood. The fibrinogen concentration of blood and the deformability of red cells are two main factors determining the flow properties of blood. Ancrod, a fibrinogen-lowering substance, improves the flow properties of blood by decreasing the viscosity of blood and plasma and by desaggregation of erythrocyte aggregates. Treatment of patients suffering from severe occlusive arterial diseases with Ancrod exhibits surprisingly good results. Disappearance of rest pains and reduction in the use of analgetic drugs has been proved statistically. In the exercising muscles a local hyperosmolarity exists, which is able to decrease the deformability of red cells thereby impairing the flow in narrow capillaries. The addition of Pentoxifyllin to blood in-vitro reduces the rigidity of red cells in hyperosmolar blood samples by increasing their cellular ATP-content. Thus the reduced flow rate of hyperosmolar blood through 8 mu-capillaries could be increased twice (p less than 0.0005) by the addition of Pentoxifyllin. These in-vitro results could be the starting point of a new idea for the treatment of patients with intermittent claudication.

Pentoxifylline is the prototype of a new class of drugs that improve peripheral blood flow mainly by increasing red blood cell flexibility. Few studies have been performed to objectively evaluate the effect of the drug in a routine clinical setting. In 11 patients with intermittent claudication, photoplethysmography was used to monitor the effect of pentoxifylline on the microcirculation in the lower extremities. Values obtained improved significantly (p less than .0001) under therapy. Concomitant measurements of ankle-brachial indices showed no significant changes despite clinical improvement. Diabetic patients in this study seemed to benefit from treatment with pentoxifylline at least as much as nondiabetic patients. Photoplethysmography proved to be a very efficient and inexpensive method of studying the effects of pentoxifylline. Ankle-brachial indices are not a suitable method of detecting flow changes attributable to the mechanism of action of this drug.

The effect of oral pentoxifylline, administered 1,200 mg/day (400 mg slow-release tablets tid) through six weeks, was studied in 10 patients with established deep venous incompetence and persisting venous ulcers. The following parameters were used for verification of the therapeutic result: venous patency (VP) and valvular competence (VC) assessed by means of Doppler ultrasound; venous refilling time (VRT) assessed by photoplethysmography; skin blood flow (SBF) at rest and after tiptoeing exercise, as well as skin perfusion pressure (SPP), both assessed by means of 99mtechnetium clearance technique. Finally, photo documentation of the tissue lesion was obtained, using a two-dimensional (max and min diameter = Dmax, Dmin) metered scale photo. There was an overall good response to the treatment, the studied parameters showing the following changes: VP and VC remained unchanged; VRT improved in 8 patients, SBF increased in 10; SPP slightly improved in 5; and Dmax and Dmin in all 10 patients. Removal or substantial diminution of the ulcers was obtained in 8 patients. These findings indicate that oral administration of pentoxifylline over a period of six weeks supports the conservative treatment and improves considerably the condition of patients with persisting venous ulcers.

A double-blind study was performed on 40 physically trained patients with stage II peripheral arterial insufficiency. Daily doses of 450 mg buflomedil were administered for 90 days and eventual improvements were compared to the effects of pentoxifylline given in daily doses of 300 mg. After treatment with buflomedil and also with pentoxifylline, significant increases were achieved in walking distances during these tests, the increase was not significant. Nor uniform findings were noted in oscillograms and in ultrasonic Doppler investigations.

Pentoxifylline, a methyl xanthine analogue was evaluated for treatment of intermittent claudication in a double-blind placebo controlled parallel group study in seven centers in the United States. Tests were performed on 128 cases, including 42 who took pentoxifylline (600 mg by mouth daily, increased stepwise to 1200 mg daily at the end of one month) and 40 who took placebo for 24 weeks. Twenty-five patients on pentoxifylline and 21 on placebo were dropped from the study for reasons unrelated to the drug. Walking ability on a treadmill was increased significantly after 2 weeks and remained so throughout the study in the pentoxifylline vs. the placebo group. Ability to walk until first experiencing intermittent claudication was a more sensitive index than the maximum ability to walk. The drug did not cause changes in blood pressure or in heart rate. Other than mild nausea, there were no significant side effects.

The red blood cell flexibility was studied in the blood of twenty patients with severe peripheral vascular disease and twenty matched controls. Patients exhibited significantly less red cell flexibility than controls. In both groups there was an inverse relationship between age and red cell flexibility. No correlation was found between red cell flexibility and sex or smoking history. Pentoxifylline, a xanthine derivative which inhibits phosphodiesterases and platelet aggregation, was found to increase red cell flexibility. This effect of the drug was greater on red cells with imparied flexibility than on normal cells. Various prostaglandins by contrast were found to decrease red cell flexibility, this could be compensated for by pentoxifylline. Forty patients with COAD were treated intravenously with PgE1. Significant inhibition of platelet aggregation and clinical improvement was noticed. It is suggested that combinations of PgE1 and pentoxifylline should be explored in clinical studies.