Licofelone, an inhibitor of cyclooxygenase and 5-lipoxygenase, specifically inhibits cyclooxygenase-1-dependent platelet activation.
5-Lipoxygenase/cyclooxygenase inhibitors, possessing anti-inflammatory action and gastric safety due to cyclooxygenase-2 and 5-lipoxygenase inhibition and antiplatelet activity due to cyclooxygenase-1 blockade, would be beneficial in the treatment of ischemic disease because they may reduce, at the same time, inflammation, underlying the atherosclerotic process, and platelet activation, responsible for acute thrombotic events. In this study, we characterized the antiplatelet effects of the new 5-lipoxygenase/cyclooxygenase inhibitor licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3,dihydro-1H-pyrrolizine-5-yl]-acetic acid. Licofelone completely prevented platelet aggregation induced in platelet-rich plasma by threshold aggregating concentrations of arachidonic acid (0.87+/-0.14 mM) at threshold inhibitory concentrations of 0.75+/-0.35 microM (n=5). Platelet-rich plasma aggregation induced by threshold aggregating concentrations of collagen/adrenalin (0.3+/-0.05 microg/ml and 0.4+/-0.1 microM, respectively) was reduced to 3.2+/-2% of control at licofelone 100 microM, (P<0.05, n=6). Washed platelet aggregation induced by threshold aggregating concentrations of thrombin (0.07+/-0.01 U/ml) was only partially affected by licofelone at concentrations one or two order of magnitude higher than those fully preventing arachidonic acid-induced aggregation (44+/-11% of control at 100 microM, P<0.05, n=7). Failure to prevent aggregation triggered by high concentrations of collagen/adrenalin in aspirin-treated platelets supports cyclooxygenase-1 as a specific target of licofelone. In fact, licofelone inhibited thromboxane B(2) (TxB(2)) production by all the agonists tested at concentrations between 0.5 and 50 microM. At this concentration, TxB(2) production was reduced at values similar to those of unstimulated platelets. These results indicate that, at clinically relevant concentrations, licofelone exerts a potent antiplatelet effect mediated by the inhibition of cyclooxygenase-1 activity.
Rotondo
Serenella
S
Laboratory of Vascular Biology and Pharmacology, Consorzio Mario Negri Sud, Via Nazionale, 66030 Santa Maria Imbaro, Italy. rotondo@negrisud.it
Krauze-Brzósko
Katarzyna
K
Manarini
Stefano
S
Evangelista
Virgilio
V
Cerletti
Chiara
C
D000085:Acetates / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D003094:Collagen / Q000494:pharmacology; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008565:Membrane Proteins; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011758:Pyrroles / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood
D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; D011804:Quinolines; C079315:2-(4-(quinolin-2-yl-methoxy)phenyl)-2-cyclopentylacetic acid; D016718:Arachidonic Acid; D013929:Thromboxane B2; D003094:Collagen; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D013917:Thrombin; C088092:licofelone; D001241:Aspirin; D004837:Epinephrine