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Miconazole has one chiral center, and consists of two enantiomers. In this study, a novel chiral liquid chromatography–tandem mass spectrometry method was developed for enantioselective separation and determination of miconazole in rat plasma. For the first time, the enantioselective pharmacokinetics of miconazole was investigated by the current method. Firstly, attempts were made to separate the enantiomers in reversed-phase mode with a mobile phase that was mass spectrometry compatible. Baseline separation was achieved on a Chiralpak IC column with a mobile phase composed of acetonitrile and aqueous ammonium hydrogen carbonate (5 mM; 80:20, v/v). Data were acquired in multiple reaction monitoring mode with positive electrospray ionization by triple-quadrupole mass spectrometry. Then, overall method validation regarding the linearity, accuracy, precision, extraction recovery, matrix effect, and stability of each enantiomer was performed, and acceptable results were obtained for all of these. Finally, the method developed was applied in an enantioselective pharmacokinetic study of miconazole enantiomers in rats after oral administration of racemic miconazole at doses of 5 and 10 mg/kg. The results demonstrated that (–)-( R )-miconazole had a higher concentration than (+)-( S )-miconazole in plasma, with a ratio of 1.3–1.7 for both doses. This is the first experimental evidence of enantioselective behavior of miconazole in vivo, and provides a reference for clinical practice and encourages further research into miconazole enantioselective metabolism and drug interactions. Graphical Abstract A stereoselective pharmacokinetic study of the miconazole enantiomers was investigated using a novel chiral liquid chromatography–tandem mass spectrometry method. Baseline separation was achieved on Chiralpak IC column, and Chiralcel OJ column was used to collect single enantiomer. A significant difference between the two enantiomers was observed in view of the plasma concentration

Purpose The effect of topical miconazole oral gel and systemic oral voriconazole on the pharmacokinetics of oral etoricoxib was studied in 12 healthy volunteers. Methods Plasma concentrations of etoricoxib, miconazole, voriconazole, and thromboxane B₂ generation were followed after ingestion of 60 mg etoricoxib without pretreatment, after topical administration of miconazole oral gel (85 mg x 3, 3 days), or after oral voriconazole (400 mg x 2, 1st day, 200 mg x 2, 2nd day). Results Etoricoxib area under the plasma concentration-time curve [graphic removed] and maximum plasma concentration (Cmax) geometric mean ratios (GMR) with/without miconazole were 1.69 {90% confidence interval (CI); 1.46-1.92} and 1.12 (90% CI; 0.99-1.25), respectively, and corresponding GMRs with/without voriconazole were 1.49 (90% CI; 1.37-1.61) and 1.19 (90% CI; 1.08-1.31), respectively. Conclusions Miconazole oral gel and oral voriconazole produced comparable increase in the exposure to etoricoxib, presumably via CYP3A inhibition.

Purpose To investigate if the ordinary use of a vaginal suppository containing miconazole results in systemic absorption that is sufficient to affect the activities of CYP1A2 and CYP3A4, which are major drug- and steroid-metabolising enzymes. Methods In 20 healthy non-pregnant women aged 18-45 years, the serum concentration of miconazole was determined following the use of a vaginal suppository containing 1,200 mg miconazole. Enzyme activities of CYP1A2 and CYP3A4 were determined as metabolic ratios of caffeine (CMR = (AFMU + 1MU + 1MX)/17DMU) and quinidine (QMR = 3-hydroxy-quinidine/quinidine) respectively before and 34 h after insertion of the suppository. Miconazole was analysed by LC-MS/MS, while caffeine and metabolites were analysed by HPLC-UV and quinidine and hydroxy-quinidine were analysed by HPLC fluorescence. Results All 20 women had measurable concentrations of miconazole in serum (mean ± SD: 12.9 ± 5.6 μg/L; range: 3.5-24.6 μg/L). Although not statistically significant, an association between the serum concentrations of miconazole and the inhibition of CYP1A2 activity was indicated. No relation was observed between the CYP3A4 activity and the miconazole serum concentration. Conclusions Miconazole is absorbed via the vaginal mucosa to the systemic circulation in measurable concentrations. Our data indicate a concentration-dependent inhibition of CYP1A2, but the effect is negligible compared with the variation in the activity of CYP1A2 and is regarded to be of no clinical significance to the women. However, further studies on the ability of miconazole to be transferred across the placenta or to interfere with the placental function are warranted to secure safe use during pregnancy.

Administration of miconazole to mice infected with Coccidioides immitis prevented death in all cases; the infecting doses killed 60%-1O0% of the untreated animals. The drug's anticoccidioidal influence was also demonstrated by its capacity to limit fungal proliferation in the lungs. The endospore phase of C. immitis, which predominates in lesions, was more susceptible to miconazole than were the saprophytic arthrospore and mycelial phases. The drug was lethal to endospores in vitro in the presence or absence of human plasma, but plasma decelerated the rate of killing. A sensitive quantitative assay (using endospores) for the drug in plasma was developed, and the inefficacy of determining the sensitivity of strains with mycelia was demonstrated.

Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ—metronidazole; MCZ—miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.

Two premature newborn infants with systemic candidiasis are reported; both were treated with miconazole. One died and the other made a complete recovery. Miconazole may be a useful addition to the drugs available for the treatment of systemic candidiasis in the neonate, but all of them have serious limitations.

Two drugs, miconazole and clobetasol, have functions that modulate differentiation of oligodendrocyte progenitor cells directly, enhance remyelination, and significantly reduce disease severity in mouse models of multiple sclerosis. Remyelination in multiple sclerosis Multiple sclerosis is characterized by an autoimmune response and failure of remyelination in the brain due to defects in differentiation of myelin-producing cells from oligodendrocyte progenitor cells. Most current treatments target the immune system. Paul Tesar and colleagues screened for compounds that can enhance oligodendrocyte maturation from mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitors. They found two drugs — miconazole (an antifungal) and clobetasol (a steroid) — that enhance myelin production in vivo in mouse models of multiple sclerosis and enhanced the differentiation of human oligodendrocytes progenitors in vitro . Mechanistically, these compounds appear to target both the immune response and oligodendrocyte progenitor cells. Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes 1 . These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention 2 . To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells 3 , 4 , 5 . Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro . Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro . Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

Hemorrhagic stroke accounts for 10-15% of all strokes and is strongly associated with mortality and morbidity worldwide, but its prevention and therapeutic interventions remain a major challenge. Here, we report the identification of miconazole as a hemorrhagic suppressor by a small-molecule screen in zebrafish. We found that a hypomorphic mutant , one of several known mutant alleles in zebrafish, had the major symptoms of brain hemorrhage, vessel rupture and inflammation as those in hemorrhagic stroke patients. A small-molecule screen with mutant embryos identified the anti-fungal drug miconazole as a potent hemorrhagic suppressor. Miconazole inhibited both brain hemorrhages in zebrafish and mesenteric hemorrhages in rats by decreasing matrix metalloproteinase 9 (MMP9)-dependent vessel rupture. Mechanistically, miconazole downregulated the levels of pErk and Mmp9 to protect vascular integrity in mutants. Therefore, our findings demonstrate that miconazole protects blood vessels from hemorrhages by downregulating the pERK-MMP9 axis from zebrafish to mammals and shed light on the potential of phenotype-based screens in zebrafish for the discovery of new drug candidates and chemical probes for hemorrhagic stroke.

Purpose. To assess the improvement in oral bioavailability and efficacy in systemic candidiasis treatment of miconazole nitrate (MN) formulations in murine models of candidiasis. Methods. Selected formulations containing 5% of Softisan+Phospholipon 90H lipid matrix with 3% of MN (A1), 5% of stearic acid+Phospholipon 90H lipid matrix with 3% of MN (B1), and 5% Softisan+stearic acid+Phospholipon 90H with 3% of MN (C1) from the in vitro investigation were used for the study. Their acute toxicity was assessed using Lorke’s method (with slight modification) while bioavailability was determined using the bioassay method. The optimized batch (A1) was tested in murine systemic candidiasis induced in cyclophosphamide-immunosuppressed mice. The mice were treated with a single oral dose (100 mg/kg) of the formulations for five days. Serum fungal counts (cfu/mL) were determined on days 1, 3, and 5 of the treatment period. Haematological assessments were done. Results. The lipid formulations were safer than MN powder with LD50 values of 3162.8 and 1118.3 mg/kg. Bioavailability determination revealed a higher area under the curve (AUC) value for formulations A1 (6.11 μg/hr/mL) and B1 (4.91 μg/hr/mL) while formulation C1 (1.80 μg/hr/mL) had a lower AUC than MN (4.46 μg/hr/mL). Fungi were completely cleared from the blood of animals treated with the optimized formulation by day 3 as opposed to the controls (MN and Tween® 20) which still had fungi on day 5. No significant increase (p>0.05) in haematological parameters was observed in mice treated with A1. Conclusion. Formulation A1 successfully cleared Candida albicans from the blood within a shorter period than miconazole powder. This research has shown the potential of orally administered MN-loaded SRMS-based microparticles in combating systemic candidaemia.