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International Journal of Molecular... May 2022Triazole and imidazole fungicides represent an emerging class of pollutants with endocrine-disrupting properties. Concerning mammalian reproduction, a possible causative...
Synergistic Activity of Ketoconazole and Miconazole with Prochloraz in Inducing Oxidative Stress, GSH Depletion, Mitochondrial Dysfunction, and Apoptosis in Mouse Sertoli TM4 Cells.
Triazole and imidazole fungicides represent an emerging class of pollutants with endocrine-disrupting properties. Concerning mammalian reproduction, a possible causative role of antifungal compounds in inducing toxicity has been reported, although currently, there is little evidence about potential cooperative toxic effects. Toxicant-induced oxidative stress (OS) may be an important mechanism potentially involved in male reproductive dysfunction. Thus, to clarify the molecular mechanism underlying the effects of azoles on male reproduction, the individual and combined potential of fluconazole (FCZ), prochloraz (PCZ), miconazole (MCZ), and ketoconazole (KCZ) in triggering in vitro toxicity, redox status alterations, and OS in mouse TM4 Sertoli cells (SCs) was investigated. In the present study, we demonstrate that KCZ and MCZ, alone or in synergistic combination with PCZ, strongly impair SC functions, and this event is, at least in part, ascribed to OS. In particular, azoles-induced cytotoxicity is associated with growth inhibitory effects, G0/G1 cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, imbalance of the superoxide dismutase (SOD) specific activity, glutathione (GSH) depletion, and apoptosis. N-acetylcysteine (NAC) inhibits ROS accumulation and rescues SCs from azole-induced apoptosis. PCZ alone exhibits only cytostatic and pro-oxidant properties, while FCZ, either individually or in combination, shows no cytotoxic effects up to 320 µM.
Topics: Animals; Apoptosis; Glutathione; Imidazoles; Ketoconazole; Male; Mammals; Mice; Miconazole; Mitochondria; Oxidative Stress; Reactive Oxygen Species
PubMed: 35628239
DOI: 10.3390/ijms23105429 -
Resurgence and Repurposing of Antifungal Azoles by Transition Metal Coordination for Drug Discovery.Pharmaceutics Sep 2023Coordination compounds featuring one or more antifungal azole (AA) ligands constitute an interesting family of candidate molecules, given their medicinal polyvalence and... (Review)
Review
Coordination compounds featuring one or more antifungal azole (AA) ligands constitute an interesting family of candidate molecules, given their medicinal polyvalence and the viability of drug complexation as a strategy to improve and repurpose available medications. This review reports the work performed in the field of coordination derivatives of AAs synthesized for medical purposes by discussing the corresponding publications and emphasizing the most promising compounds discovered so far. The resulting overview highlights the efficiency of AAs and their metallic species, as well as the potential still lying in this research area.
PubMed: 37896159
DOI: 10.3390/pharmaceutics15102398 -
Molecules (Basel, Switzerland) Dec 2021Resistance to antifungal agents represents a major clinical challenge, leading to high morbidity and mortality rates, especially in immunocompromised patients. In this...
Resistance to antifungal agents represents a major clinical challenge, leading to high morbidity and mortality rates, especially in immunocompromised patients. In this study, we screened soil bacterial isolates for the capability of producing metabolites with antifungal activities via the cross-streak and agar cup-plate methods. One isolate, coded S6, showed observable antifungal activity against ATCC 10231 and clinical isolate. This strain was identified using a combined approach of phenotypic and molecular techniques as sp. MK212927. The purified metabolite displayed fungicidal activity, reserved its activity in a relatively wide range of temperatures (up to 60 °C) and pH values (6-7.8) and was stable in the presence of various enzymes and detergents. As compared to fluconazole, miconazole and Lamisil, the minimum inhibitory concentration of the metabolite that showed 90% inhibition of the growth (MIC) was equivalent to that of Lamisil, half of miconazole and one fourth of fluconazole. Using different spectroscopic techniques such as FTIR, UV spectroscopy, 1D NMR and 2D NMR techniques, the purified metabolite was identified as terbinafine, an allylamine antifungal agent. It is deemed necessary to note that this is the first report of terbinafine production by sp. MK212927, a fast-growing microbial source, with relatively high yield and that is subject to potential optimization for industrial production capabilities.
Topics: Antifungal Agents; Bacillaceae; Biological Products; Humans; Microbial Sensitivity Tests; Phylogeny; Soil Microbiology; Spectrum Analysis; Terbinafine
PubMed: 35011429
DOI: 10.3390/molecules27010201 -
The Journal of Veterinary Medical... Mar 2023Canine Malassezia dermatitis and otitis externa are generally treated by antifungal drugs. However, multi-drug-resistant strains of Malassezia pachydermatis have been...
Canine Malassezia dermatitis and otitis externa are generally treated by antifungal drugs. However, multi-drug-resistant strains of Malassezia pachydermatis have been reported worldwide. Given the presence of these multi-drug-resistant strains, it is unclear which antifungal agent is the most effective for canine Malassezia dermatitis and canine otitis. In this study, we attempted to determine the most effective drug against azole-resistant M. pachydermatis. Susceptibility to azoles and terbinafine (TBF) was assessed using a modified broth microdilution method. In all tested isolates, the minimum inhibitory concentration at 90% of organisms (MIC) were 16 to >32 μg/mL for the azoles, and 2 μg/mL for TBF. All of the strains that showed low susceptibility to both itraconazole and miconazole were also relatively susceptible to TBF.
Topics: Animals; Dogs; Azoles; Terbinafine; Malassezia; Japan; Antifungal Agents; Microbial Sensitivity Tests; Dermatitis; Dog Diseases
PubMed: 36724970
DOI: 10.1292/jvms.22-0358 -
Current Medical Mycology Mar 2021Cutaneous fungal infections are the fourth most common health problem, which involves approximately one billion people worldwide. Drug delivery to the skin seems to be...
Cutaneous fungal infections are the fourth most common health problem, which involves approximately one billion people worldwide. Drug delivery to the skin seems to be the best choice for superficial fungal infections. Topical formulations can release a sufficient amount of drug in therapeutical concentrations and permeate higher layers of the skin like the stratum corneum. As the outermost layer of the epidermis, the stratum corneum prevents the drug from penetrating the skin. Liposomes, especially nanosized as topical drug delivery systems to the skin, can show various functions depending on their size, lipids and cholesterol components, the percent of ingredients, lamellarity, and surface charge. Nanoliposomes can increase permeation through the stratum corneum, decrease systemic effects with their localizing actions, and overcome many dermal drug delivery obstacles. Antifungal drugs, such as croconazole, econazole, fluconazole, ketoconazole, terbinafine hydrochloride, tolnaftate, and miconazole entrapped in liposomes have indicated improved skin penetration and localizing effects. According to the literature review summarized in this paper, many studies have identified liposomes as a powerful carrier for topical antifungal drug delivery to the skin. However, a few studies introduced new generations of liposomes like ethosomes and transfersomes. This paper was conducted on almost all liposomal studies of antifungal drugs with dermal application.
PubMed: 34553102
DOI: 10.18502/cmm.7.1.6247 -
Pharmaceutics Jun 2023The antifungal drug miconazole nitrate has a low solubility in water, leading to reduced therapeutic efficacy. To address this limitation, miconazole-loaded...
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/cm 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 compared with cream ( < 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 R 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.
PubMed: 37376085
DOI: 10.3390/pharmaceutics15061637 -
Frontiers in Pharmacology 2021Miconazole is effective in treating inflammatory skin conditions and has well-established antifungal effects. To elucidate the underlying mechanisms mediating its...
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.
PubMed: 34744703
DOI: 10.3389/fphar.2021.691019 -
Microbiology Spectrum Feb 2022Septation in filamentous fungi is a normal part of development, which involves the formation of cross-hyphal bulkheads, typically containing pores, allowing cytoplasmic...
Septation in filamentous fungi is a normal part of development, which involves the formation of cross-hyphal bulkheads, typically containing pores, allowing cytoplasmic streaming between compartments. Based on previous findings regarding septa and cell wall stress, we hypothesized that septa are critical for survival during cell wall stress. To test this hypothesis, we used known Aspergillus nidulans septation-deficient mutants (Δ, Δ, Δ, and Δ) and six antifungal compounds. Three of these compounds (micafungin, Congo red, and calcofluor white) are known cell wall stressors which activate the cell wall integrity signaling pathway (CWIS), while the three others (cycloheximide, miconazole, and 2,3-butanedione monoxime) perturb specific cellular processes not explicitly related to the cell wall. Our results show that deficiencies in septation lead to fungi which are more susceptible to cell wall-perturbing compounds but are no more susceptible to other antifungal compounds than a control. This implies that septa play a critical role in surviving cell wall stress. The ability to compartmentalize potentially lethal damage via septation appears to provide filamentous fungi with a facile means to tolerate diverse forms of stress. However, it remains unknown whether this mechanism is deployed in response to all forms of stress or is limited to specific perturbations. Our results support the latter possibility by showing that presence of septa promotes survival in response to cell wall damage but plays no apparent role in coping with other unrelated forms of stress. Given that cell wall damage is a primary effect caused by exposure to the echinocandin class of antifungal agents, our results emphasize the important role that septa might play in enabling resistance to these drugs. Accordingly, the inhibition of septum formation could conceivably represent an attractive approach to potentiating the effects of echinocandins and mitigating resistance in human fungal pathogens.
Topics: Antifungal Agents; Aspergillus nidulans; Cell Wall; Congo Red; Fungal Proteins; Hyphae; Micafungin; Microbial Viability; Stress, Physiological
PubMed: 35107348
DOI: 10.1128/spectrum.02063-21 -
BMC Chemistry Nov 2023Recently, green analytical chemistry (GAC) is a key issue towards the idea of sustainability, the analytical community is focused on developing analytical methods that...
Green chromatographic methods for determination of co-formulated lidocaine hydrochloride and miconazole nitrate along with an endocrine disruptor preservative and potential impurity.
Recently, green analytical chemistry (GAC) is a key issue towards the idea of sustainability, the analytical community is focused on developing analytical methods that incorporate green chemistry principles to minimize adverse impacts on the environment and humans. Herein, we present 2 sustainable, selective, and validated chromatographic methods. Initially, lidocaine hydrochloride (LDC) and miconazole nitrate (MIC) with two preservatives; methyl paraben (MTP) and saccharin sodium (SAC) were chromatographed via TLC-densitometric method which employed ethyl acetate: methanol: formic acid (9:1:0.1, by volume) as the mobile phase with UV detection at 220.0 nm, good correlation was obtained in the range of 0.3-3.0 µg/band for MIC and LDC. Following that, RP-HPLC was successfully applied for separating quinary mixture of LDC, MIC, MTP, SAC along with LDC impurity; dimethyl aniline (DMA) using C18 column, and a gradient green mobile phase composed of methanol and phosphate buffer (pH 6.0) in different ratios with a flow rate 1.5 mL/min and UV detection at 210.0 nm, linearity ranges from 1.00 to 100.00 µg/mL for MIC, 2.00-100.00 µg/mL for LDC and 1.00--20.00 µg/mL for MTP and DMA. No records to date regarding the determination of the two drugs, besides MTP and DMA. The proposed methods were validated according to the ICH guidelines and applied successfully to the analysis of the compounds. The methods' results were statistically compared to those obtained by applying the reported one, indicating no significant difference regarding both accuracy and precision. The methods' greenness profiles have been assessed and compared with those of the reported method using different assessment tools.
PubMed: 37941018
DOI: 10.1186/s13065-023-01065-3 -
Scientific Reports Dec 2022A green and simple method was proposed for the synthesis of silver nanoparticles (Ag-NPs) using Piper cubeba seed extract as a reducing agent for the first time. The...
Green synthesis, characterization, and antimicrobial applications of silver nanoparticles as fluorescent nanoprobes for the spectrofluorimetric determination of ornidazole and miconazole.
A green and simple method was proposed for the synthesis of silver nanoparticles (Ag-NPs) using Piper cubeba seed extract as a reducing agent for the first time. The prepared Ag-NPs were characterized using different spectroscopic and microscopic techniques. The obtained Ag-NPs showed an emission band at 320 nm when excited at 280 nm and exhibited strong green fluorescence under UV-light. The produced Ag-NPs were used as fluorescent nanosensors for the spectrofluorimetric determination of ornidazole (ONZ) and miconazole nitrate (MIZ) based on their quantitative quenching of Ag-NPs native fluorescence. The current study introduces the first spectrofluorimetric method for the determination of the studied drugs using Ag-NPs without the need for any pre-derivatization steps. Since the studied drugs don't exhibit native fluorescent properties, the importance of the proposed study is magnified. The proposed method displayed a linear relationship between the fluorescence quenching and the concentrations of the studied drugs over the range of 5.0-80.0 µM and 20.0-100.0 µM with limits of detection (LOD) of 0.35 µM and 1.43 µM for ONZ and MIZ, respectively. The proposed method was applied for the determination of ONZ and MIZ in different dosage forms and human plasma samples with high % recoveries and low % RSD values. The developed method was validated according to ICH guidelines. Moreover, the synthesized Ag-NPs demonstrated significant antimicrobial activities against three different bacterial strains and one candida species. Therefore, the proposed method may hold potential applications in the antimicrobial therapy and related mechanism research.
Topics: Humans; Silver; Metal Nanoparticles; Microbial Sensitivity Tests; Ornidazole; Miconazole; Anti-Infective Agents; Plant Extracts; Anti-Bacterial Agents
PubMed: 36496441
DOI: 10.1038/s41598-022-25830-x