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 fn40a, one of several known β-pix 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 fn40a 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.

Cooperative defect is 1 of the earliest manifestations of disease patients with Alzheimer disease (AD) exhibit, but the underlying mechanism remains unclear.

Cutaneous mycoses, particularly tinea pedis caused by Trichophyton rubrum, are commonly known infections in humans. They are still considered as a major public health problem worldwide affecting the quality of life due to prolonged period of treatment and development of drug resistance, which leads to recurrence of infections. The objective of our study was to assess the effectiveness of miconazole in the presence and absence of urea, as a penetration enhancer, against T. rubrum and to formulate both of them in a water-soluble film to be applied topically for the purpose of treating tinea pedis caused by this fungus. Drug combination revealed synergism where miconazole minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) (0.5 and 1 mg/L) were considerably declined to 0.001 and 0.004 mg/L, respectively, when combined with 20% urea. This enhanced drug interaction activity against the test strain was explained by the alterations raised on the morphology and ultrastructures observed microscopically. Minimal fungicidal dose of miconazole/urea combination displayed plasmolysis and shrink cytoplasm; however, necrotic cells with punctured walls and degraded cytoplasmic content were observed at high fungicidal dose. Water-soluble films, prepared using increasing values of miconazole MFC and urea, were transparent, smooth, uniform, and flexible. Their physicochemical characters showed homogeneity in weight, thickness, drug content, and folding endurances with normal surface pH values, indicating the reproducibility of the preparation method. The novel simulation model for the film mechanism of action supported the idea and the suggested application method of the new dosage form. Evaluation of these films was carried in vitro using disk diffusion assay as well as in vivo using guinea pig dermatophytosis model. The in vitro assessment revealed an increase in the inhibition zone diameters in a concentration-dependent manner upon using 10 or 20% of urea combined with miconazole. In vivo test showed that combination of 0.004 mg/L miconazole with 20% urea (M + U20) showed the highest efficacy percentage (95.83%), which was statistically superior to the infected untreated control (p < 0.001) in fungal burden reduction as well as improvement in clinical scores (p < 0.001). This work supports the hypothesis and suggests a new promising dosage form for the treatment of T. rubrum infections.

Miconazole nitrate (MCNR) is a BCS class II antifungal drug with poor water solubility. Although numerous attempts have been made to increase its solubility, formulation researchers struggle with this significant issue. Transethosomes are promising novel nanocarriers for improving the solubility and penetration of drugs that are inadequately soluble and permeable. Thus, the objective of this study was to develop MCNR-loaded transethosomal gel in order to enhance skin permeation and antifungal activity. MCNR-loaded transethosomes (MCNR-TEs) were generated using the thin film hydration method and evaluated for their zeta potential, particle size, polydispersity index, and entrapment efficiency (EE%). SEM, FTIR, and DSC analyses were also done to characterize the optimized formulation of MCNR-TEs (MT-8). The optimized formulation of MCNR-TEs was incorporated into a carbopol 934 gel base to form transethosomal gel (MNTG) that was subjected to ex vivo permeation and drug release studies. In vitro antifungal activity was carried out against Candida albicans through the cup plate technique. An in vivo skin irritation test was also performed on Wistar albino rats. MT-8 displayed smooth spherical transethosomal nanoparticles with the highest EE% (89.93 ± 1.32%), lowest particle size (139.3 ± 1.14 nm), polydispersity index (0.188 ± 0.05), and zeta potential (-18.1 ± 0.10 mV). The release profile of MT-8 displayed an initial burst followed by sustained release, and the release data were best fitted with the Korsmeyer-Peppas model. MCNR-loaded transethosomal gel was stable and showed a non-Newtonian flow. It was found that ex vivo drug permeation of MNTG was 48.76%, which was significantly higher than that of MNPG (plain gel) (p ≤ 0.05) following a 24-h permeation study. The prepared MCNR transethosomal gel exhibited increased antifungal activity, and its safety was proven by the results of an in vivo skin irritation test. Therefore, the developed transethosomal gel can be a proficient drug delivery system via a topical route with enhanced antifungal activity and skin permeability.

To investigate the antimycotic activity of the plant alkaloid berberine (BBR), alone and in combination with antifungal azoles, against planktonic and biofilm Candida cultures.

Osteoclasts are responsible for bone erosion in diseases as diverse as osteoporosis, periodontitis, and rheumatoid arthritis. Antifungal products have received recent attention as potential therapeutic and preventative drugs in human disease. Since little is known about the action of miconazole, an antifungal imidazole, on bone metabolism, we investigated the effects of miconazole on osteoclast formation using mouse bone marrow macrophages (BMMs). Miconazole inhibited RANKL-induced osteoclast formation in a dose-dependent manner without cytotoxicity. Furthermore, miconazole inhibited the bone resorptive activity of osteoclasts. Miconazole suppressed RANKL-induced expression of c-Fos and NFATc1, two essential transcription factors for osteoclast differentiation. Miconazole seemed to inhibit osteoclast formation MAPK pathways as well as Blimp1 through MafB expression. Miconazole also inhibited RANKL-induced expression of the pro-inflammatory cytokines, COX-2 and iNOS. In accordance with the in vitro study, miconazole reduced lipopolysaccharide-induced osteoclast formation in vivo. Therefore, miconazole exerted an inhibitory effect on osteoclast formation in vitro and in vivo. It could be useful for the treatment of bone diseases associated with excessive bone resorption.

Novel and new therapeutic strategies capable of enhancing the efficacy of existing antimicrobials is an attractive proposition to meet the needs of society.

The rising prevalence of multidrug-resistant hospital-acquired infections has increased the need for new antibacterial agents. In this study, a library of 1586 FDA-approved drugs was screened against A. calcoaceticus, a representative of the Acinetobacter calcoaceticus-baumannii complex. Three compounds were found to have previously undiscovered antibacterial properties against A. calcoaceticus: antifungal Miconazole, anthelminthic Dichlorophen, and Bithionol. These three drugs were tested against a wide range of Gram-positive and Gram-negative bacteria and confirmed to have broad-spectrum antibacterial properties. Combinations of these three drugs were also tested against the same bacteria, and two novel combination therapies with synergistic effects were discovered. In the future, antibacterial properties of these three drugs and two combination therapies will be evaluated against pathogenic bacteria using an animal model.

We performed a whole-transcriptome analysis of miconazole-treated Candida albicans biofilms, using RNA-sequencing. Our aim was to identify molecular pathways employed by biofilm cells of this pathogen to resist action of the commonly used antifungal miconazole. As expected, genes involved in sterol biosynthesis and genes encoding drug efflux pumps were highly induced in biofilm cells upon miconazole treatment. Other processes were affected as well, including the electron transport chain (ETC), of which eight components were transcriptionally downregulated. Within a diverse set of 17 inhibitors/inducers of the transcriptionally affected pathways, the ETC inhibitors acted most synergistically with miconazole against C. albicans biofilm cells. Synergy was not observed for planktonically growing C. albicans cultures or when biofilms were treated in oxygen-deprived conditions, pointing to a biofilm-specific oxygen-dependent tolerance mechanism. In line, a correlation between miconazole's fungicidal action against C. albicans biofilm cells and the levels of superoxide radicals was observed, and confirmed both genetically and pharmacologically using a triple superoxide dismutase mutant and a superoxide dismutase inhibitor N-N'-diethyldithiocarbamate, respectively. Consequently, ETC inhibitors that result in mitochondrial dysfunction and affect production of reactive oxygen species can increase miconazole's fungicidal activity against C. albicans biofilm cells.

Oropharyngeal candidiasis is a very common localized infection of the mucus membranes of the oropharynx that is most commonly caused by the patient's own commensal Candida albicans. It is the most common opportunistic infection affecting patients with the human immunodeficiency virus (HIV) and is also quite common in patients with hematological malignancies. Effective treatment options are of high importance given the worldwide incidence of these disease states and the potential for development of oropharyngeal candidiasis in these patients. Various systemic and topical treatment options for patients with oropharyngeal candidiasis have existed for many years. Miconazole buccal tablets have recently been approved by the US Food and Drug Administration for the treatment of oropharyngeal candidiasis. Clinical trials have demonstrated noninferiority in the treatment of oropharyngeal candidiasis when compared with clotrimazole troches in patients with HIV and against miconazole gel in patients with head and neck cancer. Miconazole buccal tablets exhibit few drug interactions because of low systemic absorption and are generally well tolerated with a safety profile similar to comparators. The once-daily dosing schedule may improve patient adherence compared with topical alternatives; however, the cost of therapy may be a barrier for some patients and should be considered by prescribers compared with alternative treatments.

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or NRF2, a transcription factor capable of upregulating antioxidant response element (ARE)-mediated expression and cytoprotective proteins, plays critical roles in chemoprevention, inflammation and aging. NRF2 has recently been proposed as a novel target for cancer chemoprevention. The fungicide miconazole has shown promising antiproliferative effects in cancer cells.

Imipramine, a tricyclic antidepressant widely used clinically, has other pharmacological effects, such as antileishmanial activity. Tricyclic antidepressants interact with lipid bilayers, and some studies have shown that imipramine inhibits methyltransferases. Leishmania spp. produces compounds with an ergostane skeleton instead of a cholesterol skeleton, and the inhibition of enzymes of the sterol biosynthesis pathway is an interesting therapeutic target. Among these enzymes, C-24 methyltransferase has been suggested to play an essential role, as its inhibition kills the parasites. In this context, we investigated whether imipramine alters the biosynthesis of sterols in L. amazonensis and evaluated the efficacy of imipramine alone and in combination with miconazole, a classical inhibitor of another step in this pathway.

Miconazole is effective in treating inflammatory skin conditions and has well-established antifungal effects. To elucidate the underlying mechanisms mediating its additional beneficial effects, we assessed whether miconazole influences the inflammation induced by 27-hydroxycholesterol (27OHChol), an oxygenated cholesterol derivative with high proinflammatory activity, using THP-1 monocytic cells. Miconazole dose-dependently inhibited the expression of proinflammatory markers, including CCL2 and CCR5 ligands such as CCL3 and CCL4, and impaired the migration of monocytic cells and CCR5-positive T cells. In the presence of 27OHChol, miconazole decreased CD14 surface levels and considerably weakened the lipopolysaccharide response. Furthermore, miconazole blocked the release of soluble CD14 and impaired the transcription of the matrix metalloproteinase-9 gene and secretion of its active gene product. Additionally, it downregulated the expression of ORP3 and restored the endocytic function of THP-1 cells. Collectively, these findings indicate that miconazole regulates the 27OHChol-induced expression of proinflammatory molecules in monocytic cells, thereby suppressing inflammation in an oxysterol-rich milieu.

A simple extractive spectrophotometric technique has been developed and validated for the determination of miconazole nitrate in pure and pharmaceutical formulations. The method is based on the formation of a chloroform-soluble ion-pair complex between the drug and bromocresol green (BCG) dye in an acidic medium. The complex showed absorption maxima at 422 nm, and the system obeys Beer's law in the concentration range of 1-30 µg/mL with molar absorptivity of 2.285 × 104 L/mol/cm. The composition of the complex was studied by Job's method of continuous variation, and the results revealed that the mole ratio of drug : BCG is 1 : 1. Full factorial design was used to optimize the effect of variable factors, and the method was validated based on the ICH guidelines. The method was applied for the determination of miconazole nitrate in real samples.

Miconazole is an antifungal agent that is used for the treatment of superficial mycosis. However, recent studies have indicated that miconazole also exhibits potent anticancer effects in various types of cancer via the activation of apoptosis. The main aim of the present study was to observe the effect of miconazole on autophagic cell death of cancer cells. Cytotoxicity was measured by viable cell counting after miconazole treatment in glioblastoma cell lines (U343MG, U87MG and U251MG). Induction of autophagy was analyzed by examining microtubule-associated protein light chain 3 (LC3)-II expression levels using western blotting and by detecting GFP-LC3 translocation using a fluorescence microscope. Intracellular ROS production was measured using a fluorescent probe, 2',7'-dichlorodihydrofluorescein diacetate. It was found that miconazole induced autophagic cell death in the U251MG glioblastoma cell line via the generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress response. An association between miconazole-induced ROS production and autophagy was also identified; in particular, pretreatment of the cells with a ROS scavenger resulted in a reduction in the levels of LC3-II. Miconazole-induced ER stress was associated with increases in binding immunoglobulin protein (BiP), inositol-requiring enzyme 1α (IRE1α) and CHOP expression, and phospho-eIF2α levels. The inhibition of ER stress via treatment with 4-phenylbutyric acid or BiP knockdown reduced miconazole-induced autophagy and cell death. These findings suggest that miconazole induces autophagic cell death by inducing an ROS-dependent ER stress response in U251MG glioma cancer cells and provide new insights into the potential antiproliferative effects of miconazole.

Fungal otitis extern or otomycosis, is common worldwide, and resistance of fungal organisms to antifungal drugs has been reported in otomycosis and other fungal infections. This study aimed to evaluate the clinical efficacy of sertaconazole versus placebo, as well as miconazole and clotrimazole topical creams in otomycosis patients.

Peripheral nerve injury (PNI) causes motor and sensory defects, has strong impact on life quality and still has no effective therapy. Miconazole is one of the most widely used antifungal drugs; the aims of the study were to investigate the effects of miconazole during sciatic nerve regeneration in a mouse model of sciatic nerve crush injury.

The aim of the present study was to investigate the protective effects of miconazole on myelin sheaths following cerebral white matter damage (WMD) in premature infant rats. Sprague Dawley rats (3-days-old) were randomly divided into four groups (n=30 each) as follows: Sham surgery group, WMD model group, 10 mg/kg/day treatment group and 40 mg/kg/day treatment group. A cerebral white matter lesion model was created by ligating the right common carotid artery for 80 min. Treatment groups were administered with 10 or 40 mg/kg miconazole at 4-8 days following birth (early treatment group) or 5-11 days following birth (late treatment group). Rats in the model group received the same concentration of dimethylsulfoxide. Myelin basic protein (MBP) immunohistochemical staining and western blotting were used to detect the expression of cerebral white matter-specific MBP, and changes in myelin structure were observed using transmission electron microscopy. No swelling or necrosis was observed in the corpus callosum of the sham group rats, whereas rats in the model group demonstrated edema, loose structure, fiber disorder, inflammatory gliocytes and selective white matter lesions. Following treatment with miconazole, MBP expression in the corpus callosum was significantly higher compared with the model group. Furthermore, in the model group, myelin sheaths in the corpus callosum were loose with small vacuoles, there was a marked decrease in thickness and structural damage was observed. Conversely, a marked improvement in myelination was observed in the treatment group. The results of the present study suggest that miconazole is able to promote formation of the myelin sheath to ameliorate premature cerebral white matter lesions caused by ischemia or hypoxia in rats.

Fungal biofilm-related infections are increasingly occurring. We previously identified a fungicidal antibiofilm combination, consisting of miconazole (MCZ) and the quaternary ammonium compound domiphen bromide (DB). DB eliminates tolerance rather than altering the susceptibility to MCZ of various Candida spp. Here we studied the mode of action of the MCZ-DB combination in more detail. We found that DB's action increases the permeability of the plasma membrane as well as that of the vacuolar membrane of Candida spp. Furthermore, the addition of DB affects the intracellular azole distribution. MCZ is a fungicidal azole that, apart from its well-known inhibition of ergosterol biosynthesis, also induces accumulation of reactive oxygen species (ROS). Interestingly, the MCZ-DB combination induced significantly more ROS in C. albicans biofilms as compared to single compound treatment. Co-administration of the antioxidant ascorbic acid resulted in abolishment of the ROS generated by MCZ-DB combination as well as its fungicidal action. In conclusion, increased intracellular MCZ availability due to DB's action results in excess of ROS and enhanced fungal cell killing.

The antifungal drug miconazole nitrate has a low solubility in water, leading to reduced therapeutic efficacy. To address this limitation, miconazole-loaded microemulsions were developed and assessed for topical skin delivery, prepared through spontaneous emulsification with oleic acid and water. The surfactant phase included a mixture of polyoxyethylene sorbitan monooleate (PSM) and various cosurfactants (ethanol, 2-(2-ethoxyethoxy) ethanol, or 2-propanol). The optimal miconazole-loaded microemulsion containing PSM and ethanol at a ratio of 1:1 showed a mean cumulative drug permeation of 87.6 ± 5.8 μg/cm2 across pig skin. The formulation exhibited higher cumulative permeation, permeation flux, and drug deposition than conventional cream and significantly increased the in vitro inhibition of Candida albicans compared with cream (p < 0.05). Over the course of a 3-month study conducted at a temperature of 30 ± 2 °C, the microemulsion exhibited favorable physicochemical stability. This outcome signifies its potential suitability as a carrier for effectively administering miconazole through topical administration. Additionally, a non-destructive technique employing near-infrared spectroscopy coupled with a partial least-squares regression (PLSR) model was developed to quantitatively analyze microemulsions containing miconazole nitrate. This approach eliminates the need for sample preparation. The optimal PLSR model was derived by utilizing orthogonal signal correction pretreated data with one latent factor. This model exhibited a remarkable R2 value of 0.9919 and a root mean square error of calibration of 0.0488. Consequently, this methodology holds potential for effectively monitoring the quantity of miconazole nitrate in various formulations, including both conventional and innovative ones.