ABSTRACT
BACKGROUND AND PURPOSE: Licofelone is a dual inhibitor of the cyclooxygenase and 5-lipoxygenase (5-LO) pathway, and has been developed for the treatment of inflammatory diseases. Here, we investigated the molecular mechanisms underlying the inhibition by licofelone of the formation of 5-LO products. EXPERIMENTAL APPROACH: The efficacy of licofelone to inhibit the formation of 5-LO products was analysed in human isolated polymorphonuclear leukocytes (PMNL) or transfected HeLa cells, as well as in cell-free assays using respective cell homogenates or purified recombinant 5-LO. Moreover, the effects of licofelone on the subcellular redistribution of 5-LO were studied. KEY RESULTS: Licofelone potently blocked synthesis of 5-LO products in Ca(2+)-ionophore-activated PMNL (IC(50)=1.7 microM) but was a weak inhibitor of 5-LO activity in cell-free assays (IC(50)>>10 microM). The structures of licofelone and MK-886, an inhibitor of the 5-LO-activating protein (FLAP), were superimposable. The potencies of both licofelone and MK-886 in ionophore-activated PMNL were impaired upon increasing the concentration of arachidonic acid, or under conditions where 5-LO product formation was evoked by genotoxic, oxidative or hyperosmotic stress. Furthermore, licofelone prevented nuclear redistribution of 5-LO in ionophore-activated PMNL, as had been observed for FLAP inhibitors. Finally, licofelone as well as MK-886 caused only moderate inhibition of the synthesis of 5-LO products in HeLa cells, unless FLAP was co-transfected. CONCLUSIONS AND IMPLICATIONS: Our data suggest that the potent inhibition of the biosynthesis of 5-LO products by licofelone requires an intact cellular environment and appears to be due to interference with FLAP.
Subject(s)
Acetates/pharmacology , Carrier Proteins/antagonists & inhibitors , Lipoxygenase Inhibitors , Membrane Proteins/antagonists & inhibitors , Pyrroles/pharmacology , 5-Lipoxygenase-Activating Proteins , Acetates/chemistry , Arachidonate 5-Lipoxygenase/genetics , Arachidonate 5-Lipoxygenase/metabolism , Arachidonic Acid/chemistry , Arachidonic Acid/pharmacology , Arsenites/pharmacology , Bridged Bicyclo Compounds/pharmacology , Calcimycin/pharmacology , Calcium/pharmacology , Carrier Proteins/biosynthesis , Cell-Free System , Cells, Cultured , Dithiothreitol/pharmacology , Dose-Response Relationship, Drug , HeLa Cells , Humans , Indoles/chemistry , Indoles/pharmacology , Leukotriene Antagonists/pharmacology , Leukotrienes/biosynthesis , Leukotrienes/chemistry , Lipoxygenase Inhibitors/pharmacology , Membrane Proteins/biosynthesis , Molecular Structure , Neutrophils/cytology , Neutrophils/drug effects , Neutrophils/metabolism , Nuclear Envelope/drug effects , Nuclear Envelope/metabolism , Pyrroles/chemistry , Quinolines/pharmacology , Sodium Compounds/pharmacology , TransfectionABSTRACT
In an open, prospective, randomized study, the quality and duration of analgesia and the side effects associated with tramadol were compared with those of metimazole in acute ureteral colic in 60 patients. The results revealed that tramadol (100 mg) is as effective as metimazole (2.5 g) with respect to analgesia. No serious side effects were observed in either group.
