Differential effects of cilostazol and pentoxifylline on vascular endothelial growth factor in patients with intermittent claudication.
Cilostazol is a new phosphodiesterase inhibitor with anti-platelet and vasodilatory properties. Cilostazol and pentoxifylline are the only two drugs that have been approved for the treatment of patients with intermittent claudication. However, the mechanisms by which exercise tolerance is improved remain unclear. Vascular endothelial growth factor (VEGF) is a potent endothelial mitogen that results in angiogenesis when overexpressed in human subjects. To assess the potential role of VEGF in the improvement in exercise tolerance, we investigated plasma levels of VEGF in 50 patients with intermittent claudication who were allocated randomly to groups receiving cilostazol (n=17), pentoxifylline (n=17) or placebo (n=16). Patients given either cilostazol or pentoxifylline showed a significant improvements in maximal walking distance compared with the placebo group (34 m and 33 m respectively, compared with 5 m; both P<0.05). Neither cilostazol nor pentoxifylline increased the ankle-brachial index after treatment. Circulating VEGF levels were increased (from 116+/-29 to 169+/-45 pg/ml; P=0.002), and the levels of VEGF were correlated significantly with exercise tolerance in a positive direction (r=0.88, P=0.004), in those patients treated with cilostazol that did not have diabetes mellitus. In contrast, VEGF levels remained stable after the administration of pentoxifylline. These findings suggest that VEGF may contribute to the cilostazol-related improvement in exercise tolerance in non-diabetic patients. However, pentoxifylline did not affect VEGF levels, although a similar improvement in maximal walking distance was achieved. Thus the mechanisms involved in the pentoxifylline-treated group were different from those in the cilostazol-treated group, and require further study.
Lee
T M
TM
Department of Internal Medicine, Cardiology Section, College of Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan. tmlee@ha.mc.ntu.edu.tw
Su
S F
SF
Tsai
C H
CH
Lee
Y T
YT
Wang
S S
SS
D000368:Aged; D000077407:Cilostazol; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D004311:Double-Blind Method; D016228:Endothelial Growth Factors / Q000097:blood; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006801:Humans; D007383:Intermittent Claudication / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D008222:Lymphokines / Q000097:blood / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011446:Prospective Studies; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010726:Phosphodiesterase Inhibitors; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014665:Vasodilator Agents; D000077407:Cilostazol; D010431:Pentoxifylline