Search

The aim of this investigation was to ascertain possible inhibitory effects of the antimycotic agent croconazole on eicosanoid biosynthesis. Human polymorphonuclear leukocytes (PMN) and whole blood of healthy donors were pretreated with croconazole in different concentrations (0.8-100 microM) for 5 min followed by the addition of Ca ionophore A23187 (10 microM) and subsequent incubation for 10 min (PMN) and 30 min (whole blood), respectively. Thereupon the eicosanoids were determined by reversed-phase high-performance liquid chromatography. Croconazole exhibited dose-dependent inhibitory activity on the 5-lipoxygenase (5-LOX) of neutrophils. The mean half maximum inhibition concentration (IC50) of croconazole for synthesis of leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) was determined as 7.8 +/- 1.7 and 7.6 +/- 0.3 microM, respectively. The mean IC50 value for LTB4 estimated in whole blood was distinctly higher (27.0 +/- 3.1 microM) compared with that determined in PMN. Additionally, an inhibitory effect (IC50 9.8 +/- 2.0 microM) on the production of the cyclooxygenase (COX) product 12-hydroxyheptadecatrienoic acid (HHT) was demonstrated, whereas the production and/or releasing of 12-hydroxyeicosatetraenoic acid (12-HETE) was not attenuated by the azole. Our results in the cell-free 5-LOX system favor a direct inhibitory action of croconazole on 5-LOX, with a relatively high portion (45-77%) of reversibility. In spite of distinctly lower inhibitory potency compared with reference inhibitors such as nordihydroguaiaretic acid and indomethacin, croconazole is an effective inhibitor of arachidonic acid metabolism. Our results suggest that croconazole may be of some benefit in anti-inflammatory therapy.

Investigations on croconazole, a novel imidazole compound, suggested antiphlogistic properties in vitro. Hence, its anti-inflammatory capacity was tested in vivo using the arachidonic acid-induced mouse ear swelling test, which is a suitable model for screening inhibitors of the lipoxygenase and/or the cyclooxygenase. Topical application of croconazole (1%/0.01%) to the mouse ear induced a maximal inhibition of edema (inhibition: 39%/33%; p = 0.01) which was as strong as the reference nordihydroguaiaretic acid (inhibition: 38.9%; p = 0.01). These results justify further investigations on croconazole to study potential inhibitory effects on proinflammatory arachidonic acid metabolites.

Dapsone (4,4'-diaminodiphenylsulfone) is effective in treating inflammatory skin diseases. Several lines of evidence suggest that the anti-inflammatory properties of this sulfone are partially due to modulation of functions of polymorphonuclear leukocytes (PMN). The goal of the present investigation is therefore to ascertain possible inhibitory effects of dapsone upon human 5-lipoxygenase (5-LOX) pathway. PMN of healthy donors were pretreated with dapsone in different concentrations (1.6-100 microM) for 5 min following by adding Ca ionophore A 23187 (10 microM) and subsequent incubation for 10 min. Thereupon the eicosanoids were assessed by reversed-phase high-performance liquid chromatography (RP-HPLC). Dapsone exhibited dose-dependent inhibitory activity showing 50% inhibition at 15 microM for leukotriene B4 (LTB4) with 5 x 10(6) PMN. The IC50 (half maximum inhibition concentration) of dapsone for 5-hydroxyeicosatetraenoic acid (5-HETE) and omega-OH-LTB4 amounted to similar values (5-HETE: 9 microM; omega-OH-LTB4: 11 microM). The inhibition of the conversion of arachidonic acid to several eicosanoids mainly suggests an effect on the 5-LOX enzyme. The comparison of inhibition values between intact PMN and a cell-free system (by sonification) indicates an additional effect of dapsone upon enzymes other than 5-LOX. Since the concentrations used are comparable with therapeutic conditions, dapsone may exert part of its anti-inflammatory effect by prevention of the generation of 5-LOX metabolites.