Licofelone, a balanced inhibitor of cyclooxygenase and 5-lipoxygenase, reduces inflammation in a rabbit model of atherosclerosis.
Licofelone, a dual anti-inflammatory drug that inhibits 5-lipoxygenase (LOX) and cyclooxygenase (COX) enzymes, may have a better cardiovascular profile that cycloxygenase-2 inhibitors due to cycloxygenase-1 blockade-mediated antithrombotic effect and a better gastrointestinal tolerability. We examined the anti-inflammatory effect of licofelone on atherosclerotic lesions as well as in isolated neutrophils from whole blood of rabbits compared with a selective inhibitor of COX-2, rofecoxib. We also assessed the antithrombotic effect of licofelone in rabbit platelet-rich plasma. For this purpose, 30 rabbits underwent injury of femoral arteries, and they were randomized to receive 10 mg/kg/day licofelone or 5 mg/kg/day rofecoxib or no treatment during 4 weeks with atherogenic diet in all cases. Ten healthy rabbits were used as controls. Neutrophils and platelets were isolated from peripheral blood of rabbits for ex vivo studies. Licofelone reduced intima/media ratio in injured arteries, the macrophages infiltration in the neointimal area, monocyte chemoattractant protein-1 (MCP-1) gene expression, and the activation of nuclear factor-kappaB in rabbit atheroma. Moreover, licofelone inhibited COX-2 and 5-LOX protein expression in vascular lesions. Rofecoxib only diminished COX-2 protein expression and MCP-1 gene expression in vascular atheroma. Prostaglandin E(2) in rabbit plasma was attenuated by both drugs. Licofelone almost abolished 5-LOX activity by inhibiting leukotriene B4 generation in rabbit neutrophils and prevented platelet thromboxane B2 production from whole blood. Licofelone reduces neointimal formation and inflammation in an atherosclerotic rabbit model more markedly than rofecoxib. This effect, together with the antiplatelet activity of licofelone, suggests that this drug may have a favorable cardiovascular profile.
Vidal
Cristina
C
Department of Vascular Research, Fundación Jiménez Díaz, Autónoma University, Madrid, Spain. cvidal@fjd.es
Gómez-Hernández
Almudena
A
Sánchez-Galán
Eva
E
González
Alejandro
A
Ortega
Luis
L
Gómez-Gerique
Juan Antonio
JA
Tuñón
José
J
Egido
Jesús
J
D000085:Acetates / Q000627:therapeutic use*; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D018932:Chemokine CCL2 / Q000235:genetics; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000097:blood; D004195:Disease Models, Animal; D007975:Leukotriene B4 / Q000096:biosynthesis; D008055:Lipids / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008264:Macrophages / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology
D000085:Acetates; D018932:Chemokine CCL2; D016861:Cyclooxygenase Inhibitors; D008055:Lipids; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D011758:Pyrroles; D012333:RNA, Messenger; D007975:Leukotriene B4; D013929:Thromboxane B2; D015232:Dinoprostone; C088092:licofelone