title: Effects of novel antifungal azole derivatives on the 5-lipoxygenase and cyclooxygenase pathway.
abstract: 5-Lipoxygenase and cyclooxygenase catalyze the first steps of the conversion of arachidonic acid into leukotrienes and prostanoids, respectively. Leukotrienes are important mediators of inflammation and thromboxanes are mainly involved in platelet functions. The effects of the new antimycotic drugs, itraconazole and fluconazole, on the 5-lipoxygenase pathway in human polymorphonuclear leukocytes (PMNL), on the eicosanoid metabolism in platelets, platelet aggregation and on cyclooxygenase activity were investigated and compared with miconazole and ketoconazole. Itraconazole inhibited the formation of 5-lipoxygenase metabolites in human PMNL (IC50 = 2 x 10(-6) mol/l), while it had no effect on cyclooxygenase and platelet aggregation at concentrations up to 10(-4) mol/l and 10(-5) mol/l, respectively. Fluconazole was ineffective in all assays. Miconazole inhibited thromboxane synthase (IC50 = 1 x 10(-5) mol/l) and platelet aggregation (IC50 = 3 x 10(-5) mol/l). Ketoconazole was less active in this respect (IC50 for platelet aggregation = 2 x 10(-4) mol/l). All compounds did not affect cyclooxygenase activity in concentrations up to 10(-4) mol/l in the pure enzyme assay. These results indicate that among the tested azoles two compounds show remarkable effects. Miconazole inhibits thromboxane synthesis and itraconazole is a potent inhibitor of leukotriene formation which has only minor effects on the cyclooxygenase pathway. This finding is of considerable interest regarding the application of itraconazole during immunosuppressive therapy and suggests further studies of its potential antiphlogistic properties.
authors: Pharmaceutical Institute, University of Tübingen, Fed. Rep. of Germany.
authors: D
authors: D
authors: Steinhilber
authors: K
authors: K
authors: Jaschonek
authors: J
authors: J
authors: Knospe
authors: O
authors: O
authors: Morof
authors: H J
authors: HJ
authors: Roth
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D001393:Azoles / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D016859:Lipoxygenase Inhibitors; D008825:Miconazole / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000097:blood / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D008825:Miconazole; D001094:Arachidonate 5-Lipoxygenase; D013930:Thromboxane-A Synthase