Failure of pentoxifylline or cilostazol to improve blood and plasma viscosity, fibrinogen, and erythrocyte deformability in claudication.
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.
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001809:Blood Viscosity / Q000187:drug effects*; D000077407:Cilostazol; D003627:Data Interpretation, Statistical; D004311:Double-Blind Method; D004907:Erythrocyte Deformability / Q000187:drug effects*; D005260:Female; D005340:Fibrinogen / Q000187:drug effects*; D006801:Humans; D007383:Intermittent Claudication / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D010919:Placebos; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016138:Walking
D010919:Placebos; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D005340:Fibrinogen; D000077407:Cilostazol; D010431:Pentoxifylline