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The purpose of this work was to develop a novel topical formulation of econazole nitrate based on gel that can be easily scaled up in one pot for the potential treatment of fungal and yeast infections. Econazole nitrate, a topical antifungal, is used to treat tinea versicolor, tinea pedis, and tinea cruris. Compared to applying cream or ointment, topical gels offer numerous advantages, one of which is that the drug is released more quickly to the intended site of action. A viscous mixture of propylene glycol, Capmul® MCM C8, methyl and propyl paraben, and econazole nitrate were mixed together before being formulated into the optimized Carbopol® gel bases. The gel's color, appearance, and homogeneity were assessed visually. For every formulation, the drug content, pH, viscosity, spreadability, and gel strength were characterized. The cup plate diffusion method was used to evaluate the anti-fungal activity of the prepared formulations. To assess the behavior of the developed system, studies on in vitro release and mechanism were conducted. The manufactured formulations were transparent, pale yellow, and exhibited excellent homogeneity. The pH of each formulation was roughly 6.0, making them suitable for topical use. The concentration of Carbopol® 940 resulted in a significant increase in viscosity and gel strength but a significant decrease in spreadability. It was demonstrated that the prepared formulations inhibited the growth of Candida albicans and Aspergillus fumigatus. In contrast, the standard blank gel showed no signs of antifungal action. By increasing the concentration of Carbopol® 940, the in vitro release profile of econazole nitrate significantly decreased. Following the Korsmeyer–Peppas model fitting, all formulations exhibited n values greater than 0.5 and less than 1, indicating that diffusion and gel swelling control econazole nitrate release. [ABSTRACT FROM AUTHOR]

Background/purpose: Econazole is an antifungal drug. Antifungal activity of econazole against non-dermatophyte molds was reported. Econazole inhibited Ca2+ channels and stimulated cytotoxicity in lymphoma and leukemia cells. Ca2+ cations are crucial second envoy that triggers various processes. This research was aimed to investigate action of econazole on Ca2+ levels and cytotoxicity in OC2 human oral cancer cells. Materials and methods: Cytosolic Ca2+ levels ([Ca2+]i) were detected employing fura-2 as a probe in a RF-5301PC spectrofluorophotometer (Shimadzu). Cytotoxicity was determined using 4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] (WST-1) to detect fluorescence changes. Results: Econazole at 10–50 μmol/L provoked [Ca2+]i raises. Forty % of 50 μml//L econazole-induced signal was diminished when external Ca2+ was eliminated. The Ca2+ influx provoked by econazole was suppressed by different degrees by store-induced Ca2+ influx suppressors SKF96365 and nifedipine; GF109203X (a protein C [PKC] inhibitor); an extracellular signaling pathway (ERK) 1/2 blocker PD98059, and phospholipase A2 suppressor aristolochic acid, but was enhanced by phorbol 12-myristate 13 acetate (PMA; a PKC activator) by 18%. Without external Ca2+, econazole-caused [Ca2+]i raises were abolished by thapsigargin. In contrast, econazole partially suppressed the [Ca2+]i raises caused by thapsigargin. U73122 fell short to change econazole-caused [Ca2+]i responses. Econazole (10–70 μmol/L) elicited cytotoxicity in a dose-dependent fashion. Blockade of 50 μmol/L econazole-induced [Ca2+] rises with BAPTA/AM enhanced econazole-induced cytotoxicity by 72%. Conclusion: Econazole evoked [Ca2+]i raises and provoked cytotoxicity in a concentration-dependent manner in OC2 human oral cancer cells. In Ca2+-containing solution, BAPTA/AM enhanced 50 μmol/L econozole-induced cytotoxicity.

Econazole is an antifungal drug. Antifungal activity of econazole against non-dermatophyte molds was reported. Econazole inhibited Ca2+ channels and stimulated cytotoxicity in lymphoma and leukemia cells. Ca2+ cations are crucial second envoy that triggers various processes. This research was aimed to investigate action of econazole on Ca2+ levels and cytotoxicity in OC2 human oral cancer cells. Cytosolic Ca2+ levels ([Ca2+] i) were detected employing fura-2 as a probe in a RF-5301PC spectrofluorophotometer (Shimadzu). Cytotoxicity was determined using 4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] (WST-1) to detect fluorescence changes. Econazole at 10–50 μmol/L provoked [Ca2+] i raises. Forty % of 50 μml//L econazole-induced signal was diminished when external Ca2+ was eliminated. The Ca2+ influx provoked by econazole was suppressed by different degrees by store-induced Ca2+ influx suppressors SKF96365 and nifedipine; GF109203X (a protein C [PKC] inhibitor); an extracellular signaling pathway (ERK) 1/2 blocker PD98059, and phospholipase A2 suppressor aristolochic acid, but was enhanced by phorbol 12-myristate 13 acetate (PMA; a PKC activator) by 18%. Without external Ca2+, econazole-caused [Ca2+] i raises were abolished by thapsigargin. In contrast, econazole partially suppressed the [Ca2+] i raises caused by thapsigargin. U73122 fell short to change econazole-caused [Ca2+] i responses. Econazole (10–70 μmol/L) elicited cytotoxicity in a dose-dependent fashion. Blockade of 50 μmol/L econazole-induced [Ca2+] rises with BAPTA/AM enhanced econazole-induced cytotoxicity by 72%. Econazole evoked [Ca2+] i raises and provoked cytotoxicity in a concentration-dependent manner in OC2 human oral cancer cells. In Ca2+-containing solution, BAPTA/AM enhanced 50 μmol/L econozole-induced cytotoxicity. [ABSTRACT FROM AUTHOR]

Triazole and imidazole fungicides are an emerging class of contaminants with an increasing and ubiquitous presence in the environment. In mammals, their reproductive toxicity has been reported. Concerning male reproduction, a combinatorial activity of tebuconazole (TEB; triazole fungicide) and econazole (ECO; imidazole compound) in inducing mitochondrial impairment, energy depletion, cell cycle arrest, and the sequential activation of autophagy and apoptosis in Sertoli TM4 cells (SCs) has recently been demonstrated. Given the strict relationship between mitochondrial activity and reactive oxygen species (ROS), and the causative role of oxidative stress (OS) in male reproductive dysfunction, the individual and combined potential of TEB and ECO in inducing redox status alterations and OS was investigated. Furthermore, considering the impact of cyclooxygenase (COX)-2 and tumor necrosis factor-alpha (TNF-α) in modulating male fertility, protein expression levels were assessed. In the present study, we demonstrate that azoles-induced cytotoxicity is associated with a significant increase in ROS production, a drastic reduction in superoxide dismutase (SOD) and GSH-S-transferase activity levels, and a marked increase in the levels of oxidized (GSSG) glutathione. Exposure to azoles also induced COX-2 expression and increased TNF-α production. Furthermore, pre-treatment with N-acetylcysteine (NAC) mitigates ROS accumulation, attenuates COX-2 expression and TNF-α production, and rescues SCs from azole-induced apoptosis, suggesting a ROS-dependent molecular mechanism underlying the azole-induced cytotoxicity. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

The purpose of this work was to develop a novel topical formulation of econazole nitrate based on gel that can be easily scaled up in one pot for the potential treatment of fungal and yeast infections. Econazole nitrate, a topical antifungal, is used to treat tinea versicolor, tinea pedis, and tinea cruris. Compared to applying cream or ointment, topical gels offer numerous advantages, one of which is that the drug is released more quickly to the intended site of action. A viscous mixture of propylene glycol, Capmul® MCM C8, methyl and propyl paraben, and econazole nitrate were mixed together before being formulated into the optimized Carbopol® gel bases. The gel’s color, appearance, and homogeneity were assessed visually. For every formulation, the drug content, pH, viscosity, spreadability, and gel strength were characterized. The cup plate diffusion method was used to evaluate the anti-fungal activity of the prepared formulations. To assess the behavior of the developed system, studies on in vitro release and mechanism were conducted. The manufactured formulations were transparent, pale yellow, and exhibited excellent homogeneity. The pH of each formulation was roughly 6.0, making them suitable for topical use. The concentration of Carbopol® 940 resulted in a significant increase in viscosity and gel strength but a significant decrease in spreadability. It was demonstrated that the prepared formulations inhibited the growth of Candida albicans and Aspergillus fumigatus. In contrast, the standard blank gel showed no signs of antifungal action. By increasing the concentration of Carbopol® 940, the in vitro release profile of econazole nitrate significantly decreased. Following the Korsmeyer–Peppas model fitting, all formulations exhibited n values greater than 0.5 and less than 1, indicating that diffusion and gel swelling control econazole nitrate release.

Vulvovaginal Candidiasis (VVC) is a fungal infection of the genital mucosa caused by Candida spp. This is an investigation on the isolation of Candida krusei from cervical-VVC patients in Erbil hospitals, Iraqi Kurdistan, and its identification using Chromagar medium. In this study the Susceptibility test of antifungal medications and plant extracts against C. krusei isolates were assessed by disc diffusion and agar well diffusion method, respectively. In disc diffusion method C. krusei showed various susceptibility ranges against the tested antifungal drugs: Econazole (8mm), Ketoconazole (12mm), Miconazole (10mm) and Nystatin (14mm), while in agar well diffusion method it has been showed higher susceptibilities values against ethanol and aquatic pomegranate peel extract, (15mm) when compared to antifungal drugs. As a result Pomegranate peel is an antifungal alternative that can be used to treat C. krusei. According to the LC–MS/MS Technique, both ethanolic and aquatic pomegranate peel extracts were analyzed by Mass Spectrometry and yielded many compounds such as high amount Quinic acid (ethanol: 114.574, water 97.94) mg. analyte/g. extract and Ellagic acid (Ethanol 14.604, Water 48.314) mg/g. extract, while very low amount of Luteolin (E0.005, W0.005) mg/g. extract, Naringenin (E0.007, W0.005) mg/g. extract and Apigenin (E0.003, W0.002) mg/g. extract.

The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca2+, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca2+ reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels. The econazole-bound TRPV5 structure adopts a closed conformation with a distinct lower gate that occludes Ca2+ permeation through the channel. Structural comparisons between TRPV5 and other TRPV channels, complemented with molecular dynamics (MD) simulations of the econazole-bound TRPV5 structure, allowed us to gain mechanistic insight into TRPV5 channel inhibition by small molecules.

Zhen Liang, Zhen Zhang, Jingjing Yang, Ping Lu, Tianyang Zhou, Jingguo Li, Junjie Zhang Henan Eye Hospital, Henan Provincial People’s Hospital & People’s Hospital of Zhengzhou University, Zhengzhou, People’s Republic of ChinaCorrespondence: Jingguo Li; Junjie ZhangHenan Eye Hospital, Henan Provincial People’s Hospital & People’s Hospital of Zhengzhou University, Number 7 Weiwu Road, Zhengzhou, People’s Republic of ChinaEmail lijingguo@zzu.edu.cn; zhangjunjie@zzu.edu.cnIntroduction: Fungal keratitis (FK) remains a severe sight-threatening disease, and case management is difficult due to ocular intrinsic barriers and drug shortages. Econazole (ECZ), a broad-spectrum antifungal agent, is limited in ocular applications due to the poor water solubility and strong irritant property.Methods: We successfully prepared solid-lipid nanoparticle-based ECZ eye drops (E-SLNs) by microemulsion method, and the physicochemical properties of E-SLNs were investigated. Corneal permeability, antifungal ability against Fusarium spp., irritation and bioavailability compared to ECZ Suspension (E-Susp) were evaluated in vitro and in vivo.Results: E-SLNs were a uniform and stable system which had an average particle size of 19 nm and a spherical morphology. E-SLNs also exhibited controlled release, enhanced antifungal activity without irritation. The pharmacokinetic analysis in vivo confirmed that E-SLNs showed an improved ocular bioavailability and the drug concentration in the cornea were above minimum inhibitory concentration (MIC) for 3 h after single administration.Conclusion: The E-SLNs colloid system is a promising therapeutic approach for fungal keratitis and could serve as a candidate strategy for other ocular diseases.Keywords: fungal keratitis, solid-lipid nanoparticles, econazole, topical administration, corneal penetration

Fungal keratitis, a disease in which the cornea becomes inflamed due to an invasive fungal infection, remains difficult to treat due in part to limited choices of available treatments. Topical eye drops are first-line treatment, but can be ineffective as low levels of drug reach the target site due to precorneal losses and the impenetrability of the cornea. The aim of this study was to determine the corneal delivery of econazole using a novel topical enhancement approach using a composite delivery system based upon cyclodextrins and soft hydrogel contact lenses. Excess econazole nitrate was added to hydroxypropyl-α-cyclodextrin (HP-α-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions, and the solubility determined using HPLC. Proprietary soft hydrogel contact lenses were then impregnated with saturated solutions and applied to freshly enucleated porcine eyeballs. Econazole nitrate 'eye drops' at the same concentrations served as the control. After 6 h, the corneas were excised and drug-extracted, prior to quantification using HPLC. Molecular dynamic simulations were performed to examine econazole–HP-β-CD inclusion complexation and dissociation. The minimum inhibitory concentration (MIC) of econazole was determined against four fungal species associated with keratitis, and these data were then related to the amount of drug delivered to the cornea, using an average corneal volume of 0.19 mL. The solubility of econazole increased greatly in the presence of HP-β-CD and more so with HP-α-CD (p < 0.001), with ratios >> 2. Hydrogel contact lenses delivered ×2.8 more drug across the corneas in comparison to eye drops alone, and ×5 more drug delivered to the cornea when cyclodextrin was present. Molecular graphics demonstrated dynamic econazole release, which would create transient enhanced drug concentration at the cornea surface. The solution-only drops achieved the least satisfactory result, producing sub-MIC levels with factors of ×0.81 for both Fusarium semitectum and Fusarium solani and ×0.40 for both Scolecobasidium tshawytschae and Bipolaris hawaiiensis. All other treatments delivered econazole at > MIC for all four fungal species. The efficacies of the delivery platforms evaluated were ranked: HP-α-CD contact lens > HP-β-CD contact lens > contact lens = HP-α-CD drops > HP-β-CD drops > solution-only drops. In summary, the results in this study have demonstrated that a composite drug delivery system based upon econazole–HP-β-CD inclusion complexes loaded into contact lenses can achieve significantly greater corneal drug delivery with the potential for improved clinical responses. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth. Econazole stimulates autophagy initiation by the modulation of ATF3/ID-1/AKT axis while compromises lysosomal biogenesis, therefore inducing excessive autophagosome accumulation and ER stress-mediated apoptosis in PDAC cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Econazole has been found efficacious as antitubercular in in vitro and in vivo animal studies. However, limited information is available for its safety and pharmacokinetics in humans. In our present study we have conducted single ascending dose, safety, and pharmacokinetic evaluation in healthy human volunteers with the purpose of enabling translation for tuberculosis. This study was conducted as a single-center, ascending-dose, placebo-controlled, double blind design. Three ascending dose were chosen (250 , 500 , and 1000 mg) to be administered as a single oral dose. The volunteers were screened for potential eligibility. Participants were randomized to receive either Econazole or Placebo in a 6:2 design. Safety assessments and pharmacokinetic evaluations were carried out for each cohort. Econazole was found to be safe at all dose levels. No serious or severe adverse events occurred during the study. The AUC (0–∞) showed a response relationship with a value of 49 ± 3.47 h* µg/ml, 17. 86 ± 8.40 hr* µg/ml, 35.54 ± 13.94 hr* µg/ml for 250 mg, 500 mg, and 1000 mg, respectively. Based on the findings of our study, a dose of 500 mg Econazole, once a day orally was considered as appropriate for further evaluation. [ABSTRACT FROM AUTHOR]

• Two silver(I) complexes with econazole were synthesized and characterized. • DFT was used for investigation of solution behaviour of the complexes. • Silver(I) complexes showed significant activity against the tested Candida species. • Silver(I) complexes reduced the amount of ergosterol in the fungal cell membrane. • Silver(I) complexes showed remarkable activity against the Staphylococcus aureus. Two new silver(I) complexes with the antifungal agent econazole (ecz) of the general formula [Ag(еcz) 2 ]X, X = CF 3 SO 3 − (Ag1) and PF 6 − (Ag2), were synthesized and structurally characterized by spectroscopic (1H NMR, IR and UV–Vis) and electrochemical methods. The crystal structure of Ag2 was determined by single crystal X-ray diffraction analysis, confirming an ideal linear geometry of the silver(I) ion in this complex. In addition, by utilising Hirshfeld surface analysis (HSA), it was verified that the crystal structure of Ag2 is stabilized by H⋯H, H⋯Cl, C⋯H, and H⋯F interactions. Density functional theory (DFT) calculations provided additional evidence for formation of the complexes in the solid state and their stability in solution. The coordination of ecz to the silver(I) ion endowed this agent with antibacterial activity against Gram-positive (Pseudomonas aeruginosa and Escherichia coli) and Gram-negative (Staphylococcus aureus and Listeria monocytogenes) bacteria. The most significant antibacterial activity of Ag1 and Ag2 was observed against S. aureus with 56- and 73-fold improvement, respectively, compared to the parent drug. Moreover, a study of the bacterial antibiofilm activity revealed that these complexes were able to prevent approximately 90 % of biofilm formation at their low concentrations. Also, both complexes have shown more pronounced anti- Candida activity than econazole itself, being less toxic on the human normal fibroblast cell line MRC-5. The total amount of ergosterol was reduced in the presence of the subinhibitory concentrations of Ag1 and Ag2 complexes, which was also confirmed by a molecular docking study with two isomers of cytochrome P450 sterol 14 α -demethylase, CYP51B and CYP130, as target receptors. Two silver(I) complexes with clinically used antifungal agent econazole have shown significantly improved anti- Staphylococcus and anti- Candida activities in comparison to organic-based drug itself, being less toxic on the human normal fibroblast cell line MRC-5. [Display omitted] [ABSTRACT FROM AUTHOR]

ABSTRACT Colistin is a last-line antibiotic which acts by causing membrane permeabilization in Gram-negative bacteria. However, its clinical value has been limited by its toxicity and the emergence of resistant organisms. In this study, we showed that econazole and colistin can act synergistically to produce a strong antimicrobial effect sufficient for eradication of starvation-induced tolerant and multidrug-resistant populations of Acinetobacter baumannii, a notorious pathogen causing recalcitrant infections, both in vitro and in mouse infection models. Investigation of the underlying mechanism showed that, while colistin disrupts the membrane structure, econazole causes the dissipation of proton motive force, eliciting a vicious cycle of membrane structural damages and disruption of membrane protein functions, and eventually cell death. This drug combination therefore achieves our goal of using a much smaller dosage of colistin to produce a much stronger antimicrobial effect to tackle the problems of toxicity and resistance associated with colistin usage. IMPORTANCE Findings described in this study constitute concrete evidence that it is possible to significantly enhance the antimicrobial activity of colistin by using an antifungal drug, econazole, as a colistin adjuvant. We showed that this drug combination can kill not only multidrug-resistant A. baumannii but also the tolerant subpopulation of such strains known as persisters, which may cause chronic and recurrent infections in clinical settings. The synergistic killing effect of the econazole and colistin combination was also observable in mouse infection models at a very low concentration, suggesting that such a drug combination has high potential to be used clinically. Findings in this study therefore have important implications for enhancing its clinical application potential as well as developing new approaches to enhance treatment effectiveness and reduce suffering in patients.

Triazole and imidazole fungicides are an emerging class of contaminants with an increasing and ubiquitous presence in the environment. In mammals, their reproductive toxicity has been reported. Concerning male reproduction, a combinatorial activity of tebuconazole (TEB; triazole fungicide) and econazole (ECO; imidazole compound) in inducing mitochondrial impairment, energy depletion, cell cycle arrest, and the sequential activation of autophagy and apoptosis in Sertoli TM4 cells (SCs) has recently been demonstrated. Given the strict relationship between mitochondrial activity and reactive oxygen species (ROS), and the causative role of oxidative stress (OS) in male reproductive dysfunction, the individual and combined potential of TEB and ECO in inducing redox status alterations and OS was investigated. Furthermore, considering the impact of cyclooxygenase (COX)-2 and tumor necrosis factor-alpha (TNF-α) in modulating male fertility, protein expression levels were assessed. In the present study, we demonstrate that azoles-induced cytotoxicity is associated with a significant increase in ROS production, a drastic reduction in superoxide dismutase (SOD) and GSH-S-transferase activity levels, and a marked increase in the levels of oxidized (GSSG) glutathione. Exposure to azoles also induced COX-2 expression and increased TNF-α production. Furthermore, pre-treatment with N-acetylcysteine (NAC) mitigates ROS accumulation, attenuates COX-2 expression and TNF-α production, and rescues SCs from azole-induced apoptosis, suggesting a ROS-dependent molecular mechanism underlying the azole-induced cytotoxicity.

Co-encapsulated econazole nitrate-triamcinolone acetonide loaded biocompatible, physically stable, and non-irritating mesoporous silica nanoparticles (EN-TA–loaded MSNs) were prepared and optimized by using a central composite rotatable design (CCRD) for providing better therapeutic efficacy against commonly prevailed resistant fungal infections. These drugs loaded MSNs can significantly overcome the deficiencies and problems like short duration of action, requirement of frequent administration, erythema, and burning sensation and irritation associated with conventional drug delivery systems. The stability of optimized drugs loaded MSNs prepared with 100 gm of oil at pH 5.6 with a stirring time of 2 h was confirmed from a zeta potential value of −25 mV. The remarkable compatibility of formulation ingredients was depicted by X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR) spectra while scanning electron microscopy (SEM) and size analysis represented a very fine size distribution of nanoparticles ranging from 450–600 nm. The CCRD clearly predicted that the optimized parameters of drugs loaded MSNs have better values of percentage yield (85%), EN release (68%), and TA release (70%). Compared to pure drugs, the decreased cytotoxicity of EN-TA–loaded MSNs was quite evident because they showed a cell survival rate of 90%, while in the case of pure drugs, the survival rate was 85%. During in vivo antifungal testing against Candida albicans performed on three different groups, each consisting of six rabbits, the EN-TA–loaded MSNs were relatively superior in eradicating the fungal infection as a single animal exhibited a positive culture test. Rapid recovery of fungal infection and a better therapeutic effect of EN-TA–loaded MSN were quite evident in wound healing and histopathology studies. Likewise, on the 14th day, a larger inhibitory zone was measured for optimized nanoparticles (15.90 mm) compared to the suspension of pure drugs (13.90 mm). In skin irritation studies, MSNs did not show a grade of erythema compared to pure drugs, which showed a four-fold grade of erythema. As a result, MSNs loaded with combination therapy seem to have the potential of improving patient compliance and tolerability by providing enhanced synergistic antifungal effectiveness at a reduced dose with accelerated wound healing and reduced toxicity of therapeutics.

Relevance. Empirical treatment of vaginitis is indicated due to its polymicrobial etiology and limited microbiological analysis. The aim of the study was to study the combination of ornidazoleneomycinprednisoloneeconazole (ONPE, Elzhina) as a first-line drug for local treatment of patients with various forms of non-specific vaginitis. Materials and methods. The study included 55 non-pregnant women aged 18 to 50 years (381.5 years) who had clinical and laboratory signs of acute vaginitis. Results. All patients at the initial treatment complained of pathological discharge, 47 (85.5%) noted itching, burning, pain in the genital area of various degrees of severity, 17 (30.9%) discomfort when urinating, 9 (16.4%) unpleasant smell, 8 (14.5%) dyspareunia, 4 (2.2%) complained of sensations of a foreign body in the vagina. The clinical and laboratory effectiveness of treatment was 89.1% (49). In 6 (10.9%) patients, clinical improvement was noted, with the remaining laboratory signs of aerobic vaginitis. Conclusion. The new combination of ornidazoleneomycinprednisoloneeconazole (ONPE, Elzhina ) has a good efficacy and safety profile and can be used to initiate empirical treatment of non-specific inflammatory diseases of the lower genital tract.

The aim of the present work is to formulate and characterize Econazole loaded transfersomal gel for antifungal activity. Econazole is a broad-spectrum imidazole antifungal agent that belongs to BCS Class II. Due to poor solubility, Econazole is incompletely absorbed after oral administration and bioavailability vary among individuals. Topical treatment of fungal infections is usually preferred, but the barrier is to cross stratum corneum, so formulating the drug in Transfersomes solved this problem. Prepared formulations of transfersomes were optimized on basis of vesicle size, shape, surface charge and entrapment efficiency. In order to predict and correlate the in vitro econazole permeation behavior from these transfersomes through semi-permeable membrane, it is necessary to fit into a suitable mathematical model. The in vitro drug permeation data from formulation F-12 containing econazole through semi-permeable membrane was evaluated kinetically by various mathematical models like zero-order, first-order, Higuchi, and Korsmeyer-Peppas Model. The results were obtained which showed that transfersomal gel was a promising candidate for transdermal delivery with targeted and prolonged release of a drug. [ABSTRACT FROM AUTHOR]

Fungal keratitis, a disease in which the cornea becomes inflamed due to an invasive fungal infection, remains difficult to treat due in part to limited choices of available treatments. Topical eye drops are first-line treatment, but can be ineffective as low levels of drug reach the target site due to precorneal losses and the impenetrability of the cornea. The aim of this study was to determine the corneal delivery of econazole using a novel topical enhancement approach using a composite delivery system based upon cyclodextrins and soft hydrogel contact lenses. Excess econazole nitrate was added to hydroxypropyl-α-cyclodextrin (HP-α-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions, and the solubility determined using HPLC. Proprietary soft hydrogel contact lenses were then impregnated with saturated solutions and applied to freshly enucleated porcine eyeballs. Econazole nitrate ‘eye drops’ at the same concentrations served as the control. After 6 h, the corneas were excised and drug-extracted, prior to quantification using HPLC. Molecular dynamic simulations were performed to examine econazole–HP-β-CD inclusion complexation and dissociation. The minimum inhibitory concentration (MIC) of econazole was determined against four fungal species associated with keratitis, and these data were then related to the amount of drug delivered to the cornea, using an average corneal volume of 0.19 mL. The solubility of econazole increased greatly in the presence of HP-β-CD and more so with HP-α-CD (p < 0.001), with ratios >> 2. Hydrogel contact lenses delivered ×2.8 more drug across the corneas in comparison to eye drops alone, and ×5 more drug delivered to the cornea when cyclodextrin was present. Molecular graphics demonstrated dynamic econazole release, which would create transient enhanced drug concentration at the cornea surface. The solution-only drops achieved the least satisfactory result, producing sub-MIC levels with factors of ×0.81 for both Fusarium semitectum and Fusarium solani and ×0.40 for both Scolecobasidium tshawytschae and Bipolaris hawaiiensis. All other treatments delivered econazole at > MIC for all four fungal species. The efficacies of the delivery platforms evaluated were ranked: HP-α-CD contact lens > HP-β-CD contact lens > contact lens = HP-α-CD drops > HP-β-CD drops > solution-only drops. In summary, the results in this study have demonstrated that a composite drug delivery system based upon econazole–HP-β-CD inclusion complexes loaded into contact lenses can achieve significantly greater corneal drug delivery with the potential for improved clinical responses.

Imidazoles, together with triazoles, constitute azole sub-group of antifungal drugs which acts by inhibiting cytochrome P450-dependent enzyme, the lanosterol 14-a-demethylase. In addition to their primary use, when it comes to additional anti-cancer function, clotrimazole, econazole and ketoconazole have come to the fore among the imidazoles. Based on the findings up to now, although having different effects, disruption of the glycolytic pathway, blockage of Ca2+ influx and nonspecific inhibition of CYP450 enzymes can be regarded as the main ones responsible for the antineoplastic activities of the mentioned drugs, respectively. Considering the advantages of repurposing of drugs with known pharmacology compared to new drug development studies requiring labor, time and cost, it will be extremely important and valuable to continue the clarification of the different mechanisms of these antifungals on cancerous cells and benefit from them especially to increase drug efficacy and overcome drug resistance. In this review, the action mechanisms of imidazole antifungals on cancerous cells and consequently, their potential for use in cancer treatment alone or in combination with conventional therapeutics were discussed in detail. [ABSTRACT FROM AUTHOR]

Using antifungal medication econazole as the lead compound, a series of 1-[2-benzyloxy-2- (2,4-difluorophenyl) ethyl]-1H-1,2,4-triazole derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR and HRMS. The in vitro fungicidal activities of those compounds against 7 plant pathogenic fungi were evaluated to discover effective compounds preliminarily. The efficiencies of the most effective compounds were further tested against rice sheath blight and wheat stripe rust in greenhouse and field. Furthermore, the inhibitory effect on the ergosterol biosynthesis of R. solani also were determined. Most of the target compounds exhibited good fungicidal activities against the tested plant pathogenic fungi in vitro, especially against Rhizoctonia solani and Alternaria solani. By measuring their EC50 values, it was found that the EC50 values of the tested compounds against R. solani were less than 3 μmol/L, which were significantly higher than those of difenoconazole and econazole. The EC50 values of 4a, 4b, 4c, 4g, 4i and 4l against A. solani were all lower than 10 μmol/L. Compounds 4b and 4i showed higher than 70% control efficiencies against wheat stripe rust at 250 μmol/L in greenhouse. And the control efficiency of compound 4b against wheat stripe rust was 81.93% at 240 g a.i./hm2 in field. In addition, compounds 4b and 4i were found to be effective in inhibiting ergosterol biosynthesis of R. solani with the inhibition rate of around 80% at the concentration of 100 μmol/L. [ABSTRACT FROM AUTHOR]

Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1 +/- and NF1 -/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1 -/- but not NF1 +/- cell proliferation. We identify econazole nitrate as being effective against NF1 -/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1 -/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

• Duloxetine and econazole enantiomers were simultaneously separated by CE in 7.5 min. • Real concentrations determined by CE were used in stability and toxicity studies. • Stability of single drugs and their mixtures under abiotic and biotic conditions. • Single drugs and their mixture resulted very toxic for aquatic plant. • Toxicological interaction of drugs was studied in the whole range of effect levels. Stability and toxicity studies for duloxetine and econazole were achieved using individual solutions and their mixtures. Stability of drugs racemates and enantiomers was investigated under abiotic and biotic conditions. Toxicity was evaluated for the first time on Spirodela polyrhiza. EC50 values were calculated for each individual drug and for their binary mixture. Real (not nominal) concentrations determined by Capillary Electrophoresis were employed in the calculations of toxicity parameters. The use of a 25 mM phosphate buffer (pH 3.0) with 1.5% S-β-CD as chiral selector at a temperature of 30 °C and a separation voltage of −20 kV enabled the simultaneous enantiomeric separation of duloxetine and econazole in 7.5 min with enantiomeric resolutions of 7.9 and 6.5, respectively. For individual solutions, decay percentages under abiotic conditions were higher for duloxetine (80%) than for econazole (60%), while in presence of Spirodela polyrhiza they increased for duloxetine but not for econazole. Econazole showed the highest decay percentages under abiotic or biotic conditions (100%) in binary mixtures. EC50 values for duloxetine and econazole enabled to include both drugs within the group of very toxic compounds although econazole showed a higher toxicity than duloxetine and the binary mixture. [ABSTRACT FROM AUTHOR]

Abstract Enantiomer stability was investigated in this work for the first time for duloxetine and econazole in individual solutions and their mixtures under the standardized ecotoxicity test experimental conditions for Daphnia magna and abiotic conditions. Real (and not nominal) enantiomer concentrations were employed for calculations since their determination was achieved by Capillary Electrophoresis. Relevant differences were found in stability profiles for both drugs in any case. Toxicity was evaluated for the first time in this work for mixtures of duloxetine and econazole on Daphnia magna. Dose-effect parameters were calculated at different exposure times (24, 48, and 72 h) showing a significant inhibition of daphnids mobility when increasing the incubation time. Combination index values enabled to obtain the type and level of interaction of drugs with the organism. A strong synergism was observed at 48 h exposure time and any effect level, which demonstrated the high toxicity of the drug mixture compared with the individual drug solutions. These results were corroborated when evaluating the oxidative stress using fluorescence images. Graphical abstract Unlabelled Image Highlights • Stability of each drug or mixture was evaluated under abiotic and biotic conditions. • Toxicity of both drugs and their mixtures for Daphnia magna was established. • Real concentrations of drug enantiomers were determined by chiral CE. • Strong synergism observed for drug mixture at 48 h exposure and any effect level. [ABSTRACT FROM AUTHOR]

Background and Purpose: Candida species are the most common organisms involved in superficial fungal infections, worldwide. Although econazole is among the most frequently used topical formulations for the treatment of candidiasis, no information is available regarding the susceptibility profiles of Candida species in Iran. Materials and Methods: In vitro susceptibility of 100 clinical Candida isolates belonging to 6 species from superficial candidiasis of Iran towards to econazole was compared with three other common antifungal agents including itraconazole, fluconazole, and miconazole. Minimum inhibitory concentrations (MICs) values were analyzed according to the Clinical and Laboratory Standards Institute (CLSI) M38-A3 document. All isolates were previously identified to the species level, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on ITS region. Results: The MIC of econazole, itraconazole, miconazole, and fluconazole were within the range of 0.016-16, 0.032-16, 0.016-16, and 0.25-64 g/ml, respectively. In general, econazole and miconazole were more active against Candida isolates, compared to the other two agents. Conclusion: The present study demonstrated that for Candida albicans isolates, miconazole and econazole had the best effect, but in non-albicans Candida species, itraconazole and miconazole displayed more activity than other antifungal agents.

Econazole is a feasible alternative treatment in the management of fungal keratitis. Nevertheless, its low water solubility is considered the main limitation to the incorporation into ophthalmic formulations. In this work, econazole nitrate is solubilized by using cyclodextrins to achieve an optimum therapeutic concentration. Phase solubility diagrams suggest α-cyclodextrin as the most effective cyclodextrin and later the inclusion complex formed with this one was characterized in solution by 1D, 2D-NMR, and molecular modeling. Econazole-α-cyclodextrin inclusion complex was included in 2 types of ocular hydrogels: a natural polysaccharides ion-sensitive hydrogel and a hyaluronic acid hydrogel. Both of them show no ocular irritation in the hen's egg test on chorioallantoic membrane assay and a controlled econazole release over time. Permeability studies suggest that hydrogels do not modify the econazole nitrate permeability through bovine cornea in comparison with an econazole-α-cyclodextrin inclusion complex solution. Finally, ocular biopermanence studies performed using positron emission tomography show these hydrogels present a high retention time on the eye. Results suggest the developed formulations have a high potential as vehicles for the econazole topical ocular administration as fungal keratitis treatment. [ABSTRACT FROM AUTHOR]

Fungal keratitis is an infectious disease caused by pathogenic fungi with a high blindness rate. Econazole (ECZ) is an imidazole antifungal drug with insoluble ability. Econazole-loaded solid lipid nanoparticles (E-SLNs) were prepared by microemulsion method, then modified with positive and negative charge. The mean diameter of cationic E-SLNs, nearly neutral E-SLNs and anionic E-SLNs were 18.73±0.14, 19.05±0.28, 18.54±0.10 nm respectively. The Zeta potential of these different charged SLNs formulations were 19.13±0.89, -2.20±0.10, -27.40±0.67 mV respectively. The Polydispersity Index (PDI) of these three kinds of nanoparticles were all about 0.2. The Transmission Electron Microscopy (TEM) and Differential Scanning Calorimetry (DSC) analysis showed that the nanoparticles were a homogeneous system. Compared with Econazole suspension (E-Susp), SLNs exhibited sustained release capability, stronger corneal penetration and enhanced inhibition of pathogenic fungi without irritation. The antifungal ability was further improved after cationic charge modification compared with E-SLNs. Studies on pharmacokinetics showed that the order of the AUC and t 1/2 of different preparations was cationic E-SLNs > nearly neutral E-SLNs > anionic E-SLNs > E - Susp in cornea and aqueous humor. It was shown that SLNs could increase corneal penetrability and ocular bioavailability while these capabilities were further enhanced with positive charge modification compared with negative charge ones. [Display omitted] [ABSTRACT FROM AUTHOR]

This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.

Objective: : The aim of this study was to determine the inhibitory effect of eight antifungal drugs on S. mutans growth, biofilm formation and virulence factors. Methods: The actions of antifungal drugs on S. mutans were determined by recovery plates and survival kinetic curves. Biofilms were observed by scanning electron microscopy and the viable cells were recovered on BHI plates, meanwhile biofilms were stained by BacLight live/dead kit to investigate the biofilm viability. Bacteria/extracellular polysaccharides staining assays were performed to determine the EPS production of S. mutans biofilms. Acidogenicity and acidurity of S. mutans were determined using pH drop and acid tolerance assays, and the expression of ldh gene was evaluated using qPCR. Results: We found that clotrimazole (CTR) and econazole (ECO) showed antibacterial activities on S. mutans UA159 and S. mutans clinical isolates at 12.5 and 25 mg/L, respectively. CTR and ECO could also inhibit S. mutans biofilm formation and reduce the viability of preformed biofilm. CTR and ECO affected the live/dead ratio and the EPS/bacteria ratio of S. mutans biofilms. CTR and ECO also inhibited the pH drop, lactate acid production, and acid tolerance. The abilities of CTR and ECO to inhibit S. mutans ldh expression were also confirmed. Conclusions: We found that two antifungal azoles, CTR and ECO, had the abilities to inhibit the growth and biofilm formation of S. mutans and more importantly, they could also inhibit the virulence factors of S. mutans. [ABSTRACT FROM AUTHOR]

Background/purpose: Econazole is an antifungal drug. Antifungal activity of econazole against non-dermatophyte molds was reported. Econazole inhibited Ca 2+ channels and stimulated cytotoxicity in lymphoma and leukemia cells. Ca 2+ cations are crucial second envoy that triggers various processes. This research was aimed to investigate action of econazole on Ca 2+ levels and cytotoxicity in OC2 human oral cancer cells., Materials and Methods: Cytosolic Ca 2+ levels ([Ca 2+ ] i ) were detected employing fura-2 as a probe in a RF-5301PC spectrofluorophotometer (Shimadzu). Cytotoxicity was determined using 4-[3-[4-lodophenyl]-2-4(4-nitrophenyl)-2H-5-tetrazolio-1,3-benzene disulfonate] (WST-1) to detect fluorescence changes., Results: Econazole at 10-50 μmol/L provoked [Ca 2+ ] i raises. Forty % of 50 μml//L econazole-induced signal was diminished when external Ca 2+ was eliminated. The Ca 2+ influx provoked by econazole was suppressed by different degrees by store-induced Ca 2+ influx suppressors SKF96365 and nifedipine; GF109203X (a protein C [PKC] inhibitor); an extracellular signaling pathway (ERK) 1/2 blocker PD98059, and phospholipase A2 suppressor aristolochic acid, but was enhanced by phorbol 12-myristate 13 acetate (PMA; a PKC activator) by 18%. Without external Ca 2+ , econazole-caused [Ca 2+ ] i raises were abolished by thapsigargin. In contrast, econazole partially suppressed the [Ca 2+ ] i raises caused by thapsigargin. U73122 fell short to change econazole-caused [Ca 2+ ] i responses. Econazole (10-70 μmol/L) elicited cytotoxicity in a dose-dependent fashion. Blockade of 50 μmol/L econazole-induced [Ca 2+ ] rises with BAPTA/AM enhanced econazole-induced cytotoxicity by 72%., Conclusion: Econazole evoked [Ca 2+ ] i raises and provoked cytotoxicity in a concentration-dependent manner in OC2 human oral cancer cells. In Ca 2+ -containing solution, BAPTA/AM enhanced 50 μmol/L econozole-induced cytotoxicity., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8 + T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy., (© 2023 Wiley-VCH GmbH.)