Studies on the antifungal effects of Hinokitiol on Candida albicans: inhibition of germ tube formation and synergistic pharmacological effects of miconazole.

One of the goals of oral healthcare management is to manage dry mouth. Thus, moisturizers containing antimicrobial ingredients, such as hinokitiol (HT), are applied to the oral mucosa after oral care. In this study, we investigated the preventive effect of HT against the growth of Candida albicans (C. al) and its synergistic effect when combined with miconazole (MCZ), an oral treatment for candidiasis. As the concentration of HT increased, the length and percentage of germ tubes (GT) decreased. Larger inhibition circles were observed for MCZ concentrations of 2.0 and 4.0 µg/disc compared to the HT medium without HT. The increased inhibitory effect was observed in both aerobic and anaerobic cultures. This suggests that the production of reactive oxygen species (ROS) by C. al cells increased with the combination of HT and MCZ. The length and percentage of GT increased, whereas the amount of ROS decreased when ROS scavengers were used in combination with the drug. HT led to morphological changes that inhibited the GT associated with pathogenic C. al, exhibited a complementary action against MCZ, and showed a possible association with hydrogen peroxide and superhydroxy anion radicals. These effects suggest that HT is a promising candidate for inhibiting C. al. In conclusion, HT demonstrated a prophylactic effect by inhibiting C. al and a synergistic effect with MCZ, a drug used to treat oral candidiasis. HT may also be useful for suppressing the onset and reducing the severity of oral candidiasis.

Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement.

Miconazole is an antimycotic drug showing anti-cancer effects in several cancers. However, little is known on its effects in melanoma. A375 and SK-MEL-28 human melanoma cell lines were exposed to miconazole and clotrimazole (up to 100 mM). Proliferation, viability with MTT assay and vascular mimicry were assayed at 24 h treatment. Molecular effects were measured at 6 h, namely, ATP-, ROS-release and mitochondria-related cytofluorescence. A metabolomic profile was also investigated at 6 h treatment. Carnitine was one of the most affected metabolites; therefore, the expression of 29 genes involved in carnitine metabolism was investigated in the public platform GEPIA2 on 461 melanoma patients and 558 controls. After 24 h treatments, miconazole and clotrimazole strongly and significantly inhibited proliferation in the presence of 10% serum on either melanoma cell lines; they also strongly reduced viability and vascular mimicry. After 6 h treatment, ATP reduction and ROS increase were observed, as well as a significant reduction in mitochondria-related fluorescence. Further, in A375, miconazole strongly and significantly altered expression of several metabolites including carnitines, phosphatidyl-cholines, all amino acids and several other small molecules, mostly metabolized in mitochondria. The expression of 12 genes involved in carnitine metabolism was found significantly modified in melanoma patients, 6 showing a significant impact on patients' survival. Finally, miconazole antiproliferation activity on A375 was found completely abrogated in the presence of carnitine, supporting a specific role of carnitine in melanoma protection toward miconazole effect, and was significantly reversed in the presence of caspases inhibitors such as ZVAD-FMK and Ac-DEVD-CHO, and a clear pro-apoptotic effect was observed in miconazole-treated cells, by FACS analysis of Annexin V-FITC stained cells. Miconazole strongly affects proliferation and other biological features in two human melanoma cell lines, as well as mitochondria-related functions such as ATP- and ROS-release, and the expression of several metabolites is largely dependent on mitochondria function. Miconazole, likely acting via carnitine and mitochondria-dependent apoptosis, is therefore suggested as a candidate for further investigations in melanoma treatments.

Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment.

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.

Tailored Sticky Solutions: 3D-Printed Miconazole Buccal Films for Pediatric Oral Candidiasis.

In this research, 3D-printed antifungal buccal films (BFs) were manufactured as a potential alternative to commercially available antifungal oral gels addressing key considerations such as ease of manufacturing, convenience of administration, enhanced drug efficacy and suitability of paediatric patients. The fabrication process involved the use of a semi-solid extrusion method to create BFs from zein-Poly-Vinyl-Pyrrolidone (zein-PVP) polymer blend, which served as a carrier for drug (miconazole) and taste enhancers. After manufacturing, it was determined that the disintegration time for all films was less than 10 min. However, these films are designed to adhere to buccal tissue, ensuring sustained drug release. Approximately 80% of the miconazole was released gradually over 2 h from the zein/PVP matrix of the 3D printed films. Moreover, a detailed physicochemical characterization including spectroscopic and thermal methods was conducted to assess solid state and thermal stability of film constituents. Mucoadhesive properties and mechanical evaluation were also studied, while permeability studies revealed the extent to which film-loaded miconazole permeates through buccal tissue compared to commercially available oral gel formulation. Histological evaluation of the treated tissues was followed. Furthermore, in vitro antifungal activity was assessed for the developed films and the commercial oral gel. Finally, films underwent a two-month drug stability test to ascertain the suitability of the BFs for clinical application. The results demonstrate that 3D-printed films are a promising alternative for local administration of miconazole in the oral cavity.

The anti-fungal effect of miconazole and miconazole-loaded chitosan nanoparticles gels in diabetic patients with Oral candidiasis-randomized control clinical trial and microbiological analysis.

BACKGROUND: Oral thrush is the most common occurring fungal infection in the oral cavity in uncontrolled diabetic patients, it is treated by various antifungal drugs according to each case. This study aimed to evaluate the therapeutic effects of topical application of miconazole and miconazole-loaded chitosan nanoparticles in treatment of diabetic patients with oral candidiasis. METHODS: In this randomized controlled clinical trial. A total of 80 diabetic patients presenting with symptomatic oral candidiasis were randomly assigned into two treatment groups: miconazole and miconazole-loaded chitosan nanoparticles. The patients were treated for 28 days, and clinical assessments were conducted at baseline, 7, 14, 21 and 28 days. Clinical parameters, including signs and symptoms of oral candidiasis were evaluated and microbiological analysis was performed to determine the Candida species and assess their susceptibility to the antifungal agents. Statistical analysis was done to the categorical and numerical data using chi-square test and Kruskal Wallis test. RESULTS: The antifungal efficacy between the miconazole and miconazole-loaded chitosan nanoparticles (CS-MCZ) groups insignificant difference (P >  0.05) was observed. Both treatment modalities exhibited comparable effectiveness in controlling oral candidiasis symptoms and reducing Candida colonization as miconazole-loaded chitosan nanoparticles group showed a significant difference in the clinical improvement in respect of both signs and symptoms from baseline (70%) until the end of study at 28 days (5%) (P <  0.05) Moreover, miconazole-loaded chitosan nanoparticles, there was a significant reduction in the number of colonies forming units of Candida albicans from baseline until the end of the study at 28-day with P value <  0.000. CONCLUSIONS: This randomized controlled clinical trial and microbiological analysis demonstrate that both miconazole and miconazole-loaded chitosan nanoparticles are effective in the treatment of oral candidiasis in diabetic patients with no adverse reactions. TRIAL REGISTRATION: NCT06072716 with first registration first registration in 10/10/2023.

Antagonist of transient receptor potential melastatin 2 suppresses mechanical hypersensitivity and activation of microglia induced by infraorbital nerve ligation in male rats.

Activation of microglia is known to be involved in neuropathic pain. However, the pathway that regulates the microglial activation is not completely understood. Transient receptor potential (TRP) melastatin 2 (TRPM2), which is part of the TRP superfamily, is reportedly expressed on microglia and is suggested to be involved in neuropathic pain. To explore the effect of a TRPM2 antagonist on orofacial neuropathic pain and the relationship between TRPM2 and the activation of microglia, experiments were conducted using male rats that underwent infraorbital nerve (ION) ligation as orofacial neuropathic pain models. TRPM2 expression was detected on microglia in the trigeminal spinal subnucleus caudalis (Vc). The immunoreactivity of TRPM2 in the Vc increased after ION ligation. Mechanical threshold for head-withdrawal response was measured using von Frey filament, and it decreased after ION ligation. When the TRPM2 antagonist was administered to the ION-ligated rats, the low mechanical threshold for head-withdrawal response increased, and the number of phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive cells in the Vc decreased. The number of CD68-immunoreactive cells in the Vc also decreased after the administration of the TRPM2 antagonist in the ION-ligated rats. These findings suggest that TRPM2 antagonist administration suppresses hypersensitivity to mechanical stimulation induced by ION ligation and microglial activation, and TRPM2 is also involved in microglial activation in orofacial neuropathic pain.

Chitosan-coated miconazole as an effective anti-inflammatory agent for the treatment of postoperative infections in obstetrics and vaginal yeast infection control on in vitro evaluations.

People with immune deficiency are at risk of developing infections caused by several bacterial and fungal species. In this work, chitosan-coated miconazole was developed by a simple sol-gel method. Miconazole is considered an effective drug to treat vaginal infection-causing bacteria and fungi. The coating of chitosan with miconazole nitrate showed the highest drug loading efficiency (62.43%) and mean particle size (2 µm). FTIR spectroscopic analysis confirmed the entrapment of miconazole nitrate into chitosan polymer. The antifungal result demonstrated that MN@CS microgel possessed notable anti-Aspergillus fumigatus and Candida albicans activity in lower doses. Antibacterial activity results revealed excellent bacterial growth inhibition of MN@CS microgel towards human skin infectious pathogens Escherichia coli and Staphylococcus aureus. The biocompatibility studies of In vitro cell viability and Artemia salina lethality assay suggested that MN@CS microgel is more biosafe and suitable for human external applications. In the future, it will be an efficient anti-inflammatory agent for the treatment of vaginal infections.

Does protocol miconazole administration improve mortality and morbidity on surgical necrotizing enterocolitis?

PURPOSE: Our previous clinical pilot study reported that miconazole (MCZ) prevented morbidity from surgical necrotizing enterocolitis (NEC). The present study re-investigated this effect in a long-term cohort over 20 years. METHODS: We conducted a retrospective cohort study from April 1998 to March 2020. A total of 1169 extremely low-birth-weight infants (ELBWIs) admitted to our neonatal intensive care unit, including 45 with NEC (3.8%), underwent surgery. Since 2002, protocol MCZ administration for 3 weeks has been applied for neonates born before 26 weeks' gestation or weighing under 1000 g. We compared the background characteristics and clinical outcomes between patients with and without MCZ administration. RESULTS: The morbidity rate decreased after applying the MCZ protocol, but no improvement in mortality was seen. A propensity score-matched analysis indicated that treated patients by MCZ showed a delay in developing surgical NEC by 12 days. The MCZ protocol also helped increase body weight at surgery. Prophylactic MCZ administration did not improve the neurological development of the language-social and postural-motor domains in the surgical NEC patients. But cognitive-adaptive domain caught up by a chronological age of 3 years old. CONCLUSIONS: Revising the protocol to extend the dosing period may improve the outcomes of surgical NEC after the onset.

Miconazole for the treatment of vulvovaginal candidiasis. In vitro, in vivo and clinical results. Review of the literature.

At concentrations achieved following systemic administration, the primary effect of imidazoles and triazoles on fungi is inhibition of 14-α-sterol demethylase, a microsomal cytochrome P450 (CYP) enzyme. Imidazoles and triazoles impair the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the accumulation of 14-α-methyl sterols. The synthetic imidazole miconazole is additionally able to increase intracellular reactive oxygen species, at least in part through inhibition of fungal catalase and peroxidase. This unique feature of miconazole is probably the basis for its fungicidal activity in C. albicans, in addition to the fungistatic mode of action. Studies show that miconazole is superior to nystatin treatment and demonstrate its impact as one of the best options in managing vulvovaginal candidiasis. Regarding recurrent vulvovaginal candidiasis, several new drugs are currently developed to ensure effective treatment also for this group of patients.

Development of miconazole nitrate nanoparticles loaded in nanoemulgel to improve its antifungal activity.

Miconazole is a synthetic derivative of imidazole, a medication with a broad-spectrum antifungal agent that is used to treat localized vaginal, skin, and nail infections. The aim of the study was to develop an innovative technique to improve the permeability and efficacy of topical miconazole nitrate. A nanoemulgel of miconazole nitrate was formulated by the incorporation of a nanoemulsion and a hydrogel. The nanoemulsion was first optimized using a self-emulsifying technique, and the drug was then loaded into the optimum formulation and evaluated prior to mixing with the hydrogel. Miconazole nitrate nanoemulgel formulations were evaluated for their physical characteristics and antifungal activity. Based on the results, the formulation with 0.4 % Carbopol showed the highest release profile (41.8 mg/ml after 2 h); thus, it was chosen as the optimum formulation. A cell diffusion test was performed to examine the ability of the Miconazole nitrate nanoemulgel to penetrate the skin and reach the bloodstream. Percentage cumulative drug releases of 29.67 % and 23.79 % after 6 h were achieved for the MNZ nanoemulgel and the commercial cream, Daktazol, respectively. The antifungal activity of the novel MNZ nanoemulgel formulation was tested against Candida albicans and compared to Daktazol cream and almond oil; the results were: 40.9 ± 2.3 mm, 25.4 ± 2.7 mm and 18 ± 1.9 mm, respectively. In conclusion, a novel MNZ nanoemulgel showing superior antifungal activity compared to that of the commercial product has been developed. This nanotechnology technique is a step toward making pharmaceutical dosage forms that has a lot of promise.

Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-κB pathway and iNOS production.

Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-κB pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-κB activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.

Miconazole Promotes Cooperative Ability of a Mouse Model of Alzheimer Disease.

BACKGROUND: Cooperative defect is 1 of the earliest manifestations of disease patients with Alzheimer disease (AD) exhibit, but the underlying mechanism remains unclear. METHODS: We evaluated the cooperative function of APP/PS1 transgenic AD model mice at ages 2, 5, and 8 months by using a cooperative drinking task. We examined neuropathologic changes in the medial prefrontal cortex (mPFC). Another experiment was designed to observe whether miconazole, which has a repairing effect on myelin sheath, could promote the cooperative ability of APP/PS1 mice in the early AD-like stage. We also investigated the protective effects of miconazole on cultured mouse cortical oligodendrocytes exposed to human amyloid ß peptide (Aß1-42). RESULTS: We observed an age-dependent impairment of cooperative water drinking behavior in APP/PS1 mice. The AD mice with cooperative dysfunction showed decreases in myelin sheath thickness, oligodendrocyte nuclear heterochromatin percentage, and myelin basic protein expression levels in the mPFC. The cooperative ability was significantly improved in APP/PS1 mice treated with miconazole. Miconazole treatment increased oligodendrocyte maturation and myelin sheath thickness without reducing Aß plaque deposition, reactive gliosis, and inflammatory factor levels in the mPFC. Miconazole also protected cultured oligodendrocytes from the toxicity of Aß1-42. CONCLUSIONS: These results demonstrate that mPFC hypomyelination is involved in the cooperative deficits of APP/PS1 mice. Improving myelination through miconazole therapy may offer a potential therapeutic approach for early intervention in AD.

Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

Effects of a miconazole oral patch on preventing development of oral candidiasis in patients with head and neck cancer undergoing radiotherapy: results of a preliminary study quantifying the prevalence of Candida albicans in saliva.

PURPOSE: Serious oral mucositis develops during radiation therapy (RT) for head and neck cancer, but there is no effective preventive method. We have used a steroid ointment to prevent oral mucositis during RT, but the use of steroid ointment is discontinued when oral candidiasis develops. Therefore, prevention of oral candidiasis is important. The purpose of this study was to examine whether administration of a miconazole oral patch reduced the amount of Candida albicans in saliva and prevented the development of oral candidiasis during RT. METHODS: Participants were patients with head and neck cancer receiving RT ≥ 60 Gy. Patients in the intervention group received miconazole oral patches for 14 days after the appearance of grade 2 oral mucositis. The control group received oral care only. Total bacteria and C. albicans counts in the saliva were analyzed by real-time polymerase chain reaction. The incidence of oral candidiasis was compared between the groups. RESULTS: Total bacterial counts did not change throughout RT in either the intervention or the control group. However, C. albicans count significantly increased at 30 Gy and 60 Gy in the control group but was suppressed in the intervention group. The saliva pH did not show a significant change throughout RT in either group. The incidence of oral candidiasis in the intervention group tended to be lower than that in the control group. CONCLUSION: This study suggested that prophylactic use of a miconazole oral patch was effective in suppressing the growth of C. albicans count in saliva during RT for head and neck cancer.

Miconazole and terbinafine induced reactive oxygen species accumulation and topical toxicity in human keratinocytes.

There are an estimated 1 billion cases of superficial fungal infection globally. Fungal pathogens form biofilms within wounds and delay the wound healing process. Miconazole and terbinafine are commonly used to treat fungal infections. They induce the accumulation of reactive oxygen species (ROS) in fungi, resulting in the death of fungal cells. ROS are highly reactive molecules, such as oxygen (O2), superoxide anion (O2•-), hydrogen peroxide (H2O2) and hydroxyl radicals (•OH). Although ROS generation is useful for killing pathogenic fungi, it is cytotoxic to human keratinocytes. To the best of our knowledge, the effect of miconazole and terbinafine on HaCaT cells has not been studied with respect to intracellular ROS stimulation. We hypothesized that miconazole and terbinafine have anti-wound healing effects on skin cells when used in antifungal treatment because they generate ROS in fungal cells. We used sulforhodamine B protein staining to investigate cytotoxicity and 2',7'-dichlorofluorescein diacetate to determine ROS accumulation at the 50% inhibitory concentrations of miconazole and terbinafine in HaCaT cells. Our preliminary results showed that topical treatment with miconazole and terbinafine induced cytotoxic responses, with miconazole showing higher cytotoxicity than terbinafine. Both the treatments stimulated ROS in keratinocytes, which may induce oxidative stress and cell death. This suggests a negative correlation between intracellular ROS accumulation in keratinocytes treated with miconazole or terbinafine and the healing of fungi-infected skin wounds.

Acne cream reduces the deep Cutibacterium acnes tissue load before elective open shoulder surgery: a randomized controlled pilot trial.

BACKGROUND: Cutibacterium acnes is the main pathogen in periprosthetic shoulder infections. In acne vulgaris therapy, benzoyl peroxide-miconazole nitrate cream effectively reduces the superficial C acnes burden of the skin. Its additional potential in the subcutaneous and capsular layers (eg, for prevention of future periprosthetic shoulder infections) is unknown. The aim of this study was to investigate the efficacy of a topical acne vulgaris cream (benzoyl peroxide-miconazole nitrate) to reduce subcutaneous and capsular C acnes in individuals with C acnes skin colonization undergoing open shoulder surgery. METHODS: A prospective randomized pilot trial was performed, allocating 60 adult patients (1:1) to either a 7-day preoperative application of a commercial acne cream (benzoyl peroxide-miconazole nitrate) on the preoperative skin (intervention group) or no cream (control group) from November 1, 2018, to May 31, 2020. The superficial skin of the shoulder was sampled at enrollment and before incision, and deep subcutaneous and capsular shoulder samples were taken during surgery. RESULTS: Sixty patients (mean age, 59 years; 55% female patients) undergoing primary open shoulder surgery (17 Latarjet procedures and 43 arthroplasties) were included in the study. At baseline, both randomized groups showed the presence of C acnes on the skin at a rate of 60% (18 of 30 patients in intervention group and 19 of 30 patients in control group, P = .79). In patients with C acnes skin colonization, the intervention resulted in a significant reduction in the overall number of intraoperative samples with positive findings compared with the control group (8 of 18 patients vs. 16 of 19 patients, P = .01), especially in capsular samples (0 of 18 patients vs. 4 of 19 patients, P = .04). CONCLUSION: The topical 7-day preoperative skin application of acne cream (benzoyl peroxide-miconazole nitrate) significantly reduced the intraoperative C acnes load in 56% of the patients in the intervention group compared with 16% of the control patients.

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.

Prophylactic efficacy of enteral antifungal administration of miconazole for intestinal perforation, especially for necrotizing enterocolitis: a historical cohort study at a single institution.

PURPOSE: Despite improvements in neonatal intensive care, the outcomes of extremely-low-birth-weight infants (ELBWIs) with surgical diseases remain to be improved. We started administering enteral miconazole (MCZ) to ELBWIs from 2002 to prevent fungal infection. Since then, the incidence of intestinal perforation has significantly decreased. We investigated this prophylactic effect of MCZ against necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) and explored a new prophylactic concept against intestinal perforation. METHODS: We designed a historical cohort study to evaluate the effect of MCZ for intestinal perforation in ELBWIs who underwent treatment in our neonatal intensive-care unit between January 1998 and December 2005. We divided these cases into two groups: the Pre-MCZ group and the Post-MCZ group. We compared the morbidity, clinical outcomes and pathological features of NEC and FIP. RESULTS: The rate of intestinal perforation with NEC was significantly reduced after the introduction of MCZ (p = 0.007, odds ratio; 3.782, 95% confidence interval; 1.368-12.08). The pathological findings of NEC specimens showed that the accumulation of inflammatory cells was significantly reduced in the Post-MCZ group when compared with the Pre-MCZ group (p < 0.05). CONCLUSIONS: The efficacy of the enteral administration of MCZ on intestinal perforation with NEC highlights a new prophylactic concept in the clinical management of ELBWIs.

Inhibitory Effect of Eugenol and trans-Anethole Alone and in Combination with Antifungal Medicines on Candida albicans Clinical Isolates.

One of the most common pathogens among yeasts is Candida albicans, which presents a serious health threat. The study aimed to check the antifungal properties of trans-anethole and eugenol with selected antifungal medicines (AMs) against C. albicans clinical isolates. The checkerboard method was used to tests of interactions between these compounds. Achieved results indicated that eugenol showed synergistic and additive activities with miconazole and econazole against investigated clinical isolates, respectively. Moreover, the combination - trans-anethole - miconazole also showed an additive effect against two clinical isolate. We tried to relate the results to changes in C. albicans cell sheaths under the influence of essential oils compounds (EOCs) performing the Fourier transform infrared spectra analysis to confirm the presence of particular chemical moieties in C. albicans cells. Nevertheless, no strong relationships was observed between synergistic and additive actions of used EOC-AMs combinations and chemical moieties in C. albicans cells.

Miconazole induces protective autophagy in bladder cancer cells.

Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.