Failure of Pentoxifylline or Cilostazol to Improve Blood and Plasma Viscosity, Fibrinogen, and Erythrocyte Deformability in Claudication

Abstract

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.

Peripheral Artery Disease: Current Insight Into the Disease and Its Diagnosis and Management

“…[118][119][120] However, a recent study failed to support this hypothesis in blood samples taken from patients with moderate to severe claudication. 121 The beneficial response to pentoxifylline is small in most patients, and the overall data are insufficient to support its widespread use in patients with claudication. 12 Pentoxifylline should be reserved for patients who cannot take cilostazol, have not responded adequately to an exercise program, and/or are not candidates for revascularization procedures or clinical trials.…”

The efficacy of the bio-electro-magnetic-regulation therapy and pentoxifylline treatment in peripheral arterial stenosis

“…Haemorrheologiai kezelés a vér és a plazma viszkozitá-sát csökkentő isovolaemiás haemodilutio is. Emellett a thrombosisprofi laxis céljából thrombocytagátló gyógy-szereket (aszpirin, clopidogrel) alkalmazhatunk [1, 2, 3, 4, 5, 6,7,8,9,10,11,12].…”

“…Hatására szignifi káns mértékben nő a vörösvérsejtek deformabilitása, csökken a vörösvérsejtek és a thrombocyták aggregabilitása [1, 6,7,8,10,12]. Bár van olyan vizsgálat is, amely a pentoxifi llin kedvező haemorrheologiai hatását nem tudta igazolni [2].…”

Pharmacologic treatment for intermittent claudication

“…Though the CAPRIE trial demonstrated clopidogrel's superiority to aspirin (acetylsalicyclic acid) in reducing ischemic vascular events in 6452 PAD patients (relative risk reduction 24%), there is no medical evidence to date that clopidogrel relieves the symptoms of intermittent claudication. 6 2…”

“…However, these purported effects may no longer be valid since a recent investigation revealed no signi cant difference in whole blood viscosity, erythrocyte deformability, or brinogen levels in patients receiving pentoxifylline over a 24-week period of time. 6 Pentoxifylline's mechanism(s) of action may be white blood cellmediated since other articles have documented subsequent changes in the function, 7 adhesion, 8 and cytoskeleton 9 of the leukocyte.…”