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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. [ABSTRACT FROM AUTHOR]

Objectives: This systematic review and meta‐analysis aimed to evaluate the clinical and mycological effectiveness of mucoadhesives as vehicles for drugs or natural products in the treatment of oral candidiasis. Materials and methods: The search for articles was carried out in the Medline/PubMed, SCOPUS, EMBASE, Web of Science, Cochrane Library, and SciELO databases before August 2023. We selected the studies, extracted the data, evaluated the study quality, graded the evidence, performed the risk of bias, and carried out meta‐analysis. Results: A total of 389 potentially relevant articles were identified, and 11 studies (1869 participants) met the inclusion criteria of the systematic review. The overall risk of bias was considered low. The most common presentation of mucoadhesives was tablets, with miconazole being the most frequently drug used in the delivery system. Mucoadhesives demonstrated comparable efficacy with topical or systemic antifungal agents, with no significant differences between treatments in terms of clinical (RR = 0.907; 95CI = 0.3–1.297; p = 0.591; I2 = 64.648) or mycological (RR = 0.95; 95CI = 0.667–1.360; p = 0.789; I2 = 73.271) efficacy. Conclusions: Mucoadhesives may be a suitable alternative to conventional treatments, with the advantage of reducing the frequency of application by up to 5 times and the daily dosage by up to 20 times. [ABSTRACT FROM AUTHOR]

Introduction: Vulvovaginal candidiasis (VVC) significantly impacts women's quality of life and often shows a high recurrence rate despite conventional antifungal therapies. This study evaluates the efficacy of Limosilactobacillus fermentum (LF5), a probiotic, as an alternative treatment option to conventional miconazole therapy in managing VVC. Methods: The randomized, single-blind clinical trial involved 100 premenopausal women diagnosed with VVC. Participants were assigned to either a vaginal capsule containing LF5 probiotic strain or miconazole. Treatments were administered once daily for three consecutive days. Microbiological eradication of Candida spp. and recurrence rates were assessed at 30 days post-treatment. The trial was registered with the Italian Ministry of Health. Results: Both treatments achieved a high rate of microbiological eradication of Candida spp. within the three-day treatment period (96% for LF5 and 94% for miconazole). Recurrence rates within 2 weeks post-treatment were low and similar between the groups (10% for LF5 and 17% for miconazole). LF5 was found to have a significantly lower incidence of local adverse reactions compared to miconazole (4 vs. 12%). Discussion: LF5 presents a viable alternative to miconazole for the treatment of VVC, offering comparable efficacy with fewer side effects. The results suggest that probiotic treatments can potentially enhance patient compliance and quality of life by reducing adverse reactions and recurrence rates. Further research is needed to confirm these findings in larger and more diverse populations. [ABSTRACT FROM AUTHOR]

The structures of three multicomponent crystals formed with imidazole‐based drugs, namely metronidazole, ketoconazole and miconazole, in conjunction with trithiocyanuric acid are characterized. Each of the obtained adducts represents a different category of crystalline molecular forms: a cocrystal, a salt and a cocrystal of salt. The structural analysis revealed that in all cases, the N—H...N hydrogen bond is responsible for the formation of acid–base pairs, regardless of whether proton transfer occurs or not, and these molecular pairs are combined to form unique supramolecular motifs by centrosymmetric N—H...S interactions between acid molecules. The complex intermolecular forces acting in characteristic patterns are discussed from the geometric and energetic perspectives, involving Hirshfeld surface analysis, pairwise energy estimation, and natural bond orbital calculations. [ABSTRACT FROM AUTHOR]

Developing drugs for brain infection by Naegleria fowleri is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential N. fowleri enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected in silico were tested against N. fowleri. Nine primary hits with EC50 ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound 2a. The S-enantiomer of 2a produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the S-configuration over the R-configuration and the advantage of an ether linkage over an ester linkage. The two compounds, S-8b and S-9b, had an improved EC50 and KD compared to 2a. Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of S-9b was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.

Antifungal resistance and antifungal tolerance are two distinct terms that describe different cellular responses to drugs. Antifungal resistance describes the ability of a fungus to grow above the minimal inhibitory concentration (MIC) of a drug. Antifungal tolerance describes the ability of drug susceptible strains to grow slowly at inhibitory drug concentrations. Recent studies indicate antifungal resistance and tolerance have distinct evolutionary trajectories. Superficial candidiasis bothers millions of people yearly. Miconazole has been used for topical treatment of yeast infections for over 40 years. Yet, fungal resistance to miconazole remains relatively low. Here we found different clinical isolates of Candida albicans had different profile of tolerance to miconazole, and the tolerance was modulated by physiological factors including temperature and medium composition. Exposure of non-tolerant strains with different genetic backgrounds to miconazole mainly induced development of tolerance, not resistance, and the tolerance was mainly due to whole chromosomal or segmental amplification of chromosome R. The efflux gene CDR1 was required for maintenance of tolerance in wild type strains but not required for gain of aneuploidy-mediated tolerance. Heat shock protein Hsp90 and calcineurin were essential for maintenance as well as gain of tolerance. Our study indicates development of aneuploidy-mediated tolerance, not resistance, is the predominant mechanism of rapid adaptation to miconazole in C. albicans, and the clinical relevance of tolerance deserves further investigations. [ABSTRACT FROM AUTHOR]

Background: Miconazole nitrate, a BCS class II drug which is used for treatment of fungal infections. To minimize the disadvantages of sticky creams and ointments and their tendency to rub off, an intelligent dosage regimen needs to be designed as a film-forming spray formulation. The aim of this investigation was to develop a film-forming spray formulation containing 0.5% Miconazole nitrate for the treatment of fungal infections on the skin. Materials and Methods: The Miconazole nitrate film-forming spray formulation was prepared using different concentrations of Eudragit RL-100, Ethylcellulose, Camphor and Menthol crystals (Eutectic mixture), Polyethene glycol 400 and Ethanol by simple solvent dissolving method using a statistical tool, 23 full factorial design to optimize the film forming spray formulation. The film-forming spray underwent thorough testing to evaluate its formulation characteristics, including pH, viscosity, evaporation time, density, drug release and container-related factors such as spray angle, spray diameter and amount of spray solutions released per actuation at valve assembly. To carry out an antifungal activity test on an optimized spray formulation and compare it with a commercially available cream. Results and Discussion: From the study, the ethyl cellulose concentration has a greater influence on the viscosity and density, 45 cps and 0.8472 g/mL of the spray formulation respectively. Eudragit RL-100 and the eutectic mixture have a higher impact on the drug release 92.44% at 8 hr in pH 6.8 phosphate buffer. Conclusion: The topical treatment of fungal infections proved to be suitable for the Miconazole nitrate film-forming spray formulation. Longer, continuous medication administration is facilitated by the skin's longer retention period. The medication exhibits good antifungal effectiveness in preventing fungal infections, according to antifungal investigations. The Miconazole nitrate film-forming spray is a considerably better alternative to current dosage forms for treating topical fungal infections, as evidenced by its good stability, simplicity of administration and action. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The main objective of this study was to investigate the metabolism of miconazole, an azole antifungal drug. Miconazole was subjected to incubation with human liver microsomes (HLM) to mimic phase I metabolism reactions for the first time. Employing a combination of an HLM assay and UHPLC-HRMS analysis enabled the identification of seven metabolites of miconazole, undescribed so far. Throughout the incubation with HLM, miconazole underwent biotransformation reactions including hydroxylation of the benzene ring and oxidation of the imidazole moiety, along with its subsequent degradation. Additionally, based on the obtained results, screen-printed electrodes (SPEs) were optimized to simulate the same biotransformation reactions, by the use of a simple, fast, and cheap electrochemical method. The potential toxicity of the identified metabolites was assessed using various in silico models. [ABSTRACT FROM AUTHOR]

IntroductionVulvovaginal candidiasis (VVC) significantly impacts women’s quality of life and often shows a high recurrence rate despite conventional antifungal therapies. This study evaluates the efficacy of Limosilactobacillus fermentum (LF5), a probiotic, as an alternative treatment option to conventional miconazole therapy in managing VVC.MethodsThe randomized, single-blind clinical trial involved 100 premenopausal women diagnosed with VVC. Participants were assigned to either a vaginal capsule containing LF5 probiotic strain or miconazole. Treatments were administered once daily for three consecutive days. Microbiological eradication of Candida spp. and recurrence rates were assessed at 30 days post-treatment. The trial was registered with the Italian Ministry of Health.ResultsBoth treatments achieved a high rate of microbiological eradication of Candida spp. within the three-day treatment period (96% for LF5 and 94% for miconazole). Recurrence rates within 2 weeks post-treatment were low and similar between the groups (10% for LF5 and 17% for miconazole). LF5 was found to have a significantly lower incidence of local adverse reactions compared to miconazole (4 vs. 12%).DiscussionLF5 presents a viable alternative to miconazole for the treatment of VVC, offering comparable efficacy with fewer side effects. The results suggest that probiotic treatments can potentially enhance patient compliance and quality of life by reducing adverse reactions and recurrence rates. Further research is needed to confirm these findings in larger and more diverse populations.

Abstract 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

The crystal structure of the new triclinic polymorph of miconazole {MIC; C18H14Cl4N2O; systematic name: (RS)-1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole} is reported and compared with the monoclinic form of solvent-free miconazole previously reported [Kaspiaruk & Chęcińska (2022). Acta Cryst. C78, 343–350]. A comparison shows a different orientation of imidazole and one dichlorophenyl ring between polymorphic molecules. In the crystal structure of the title compound, only weak halogen bonds and C—H...π(arene) interactions are found. Hirshfeld surface analysis and energy framework calculations complement the comparison of the two polymorphic forms of the miconazole drug.

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. [ABSTRACT FROM AUTHOR]

Creams are among the most analytically challenging dosage forms both in product analysis and in cleaning validation. This is especially true when highly lipophilic drugs are the active ingredients. The case is getting more challenging with the greenness emerges as an evaluation criterion where solvents and wastes should be minimized. Green methods are difficult to achieve with lipophilic drugs and creams that may encounter high carry-over tendency. In this study, an ecofriendly RP-HPLC-DAD method was developed for the determination of hydrocortisone acetate (HCA), mometasone furoate (MOM), betamethasone valerate (BTM), clotrimazole (CLT) and oxytetracycline (OXT) in the presence of miconazole as examples of lipophilic drugs commonly formulated in creams. The separation was performed on a C18 (5 µm, 150 × 4.6 mm ID) column using methanol–water (80 : 20, v/v) as a mobile phase and a photo-diode array detector. The method was validated according to ICH guidelines. Greenness and whiteness were assessed by NEMI, GAPI, AGREE, Eco-scale, and the RGB 12 model and compared to currently available methods. The developed method was found linear with r2 > 0.99 within the range of 0.05–9.00 HCA, 0.1–9.0 MOM, 0.2–9.0 BTM, 0.6–9.0 CLT, and 5.0–9.0 µg/mL OXT. The accuracy (98.4 ± 1.7)–(102.3 ± 1.5) and precision (CV < 10%) were in acceptable ranges while retaining high sensitivity (LOD down to 15 ng). The proposed method proved to be environmentally friendly by applying different greenness and whiteness algorithms and was successfully applied to different cream formulations. In conclusion, the developed method outperforms currently available methods for the determination of tested lipophilic compounds in creams. [ABSTRACT FROM AUTHOR]

BACKGROUND Onychomycosis is a common fungal nail infection with a low cure rate. While dermatophytes are the most common causal agent for onychomycosis, the incidence of Candida and nondermatophyte mold (NDM) onychomycosis is increasing. This study aimed to analyze the clinical and microbiological characteristics of patients with onychomycosis. METHODS Patients who visited the Department of Dermatology and Venereology, Cipto Mangunkusumo Hospital, and were diagnosed with onychomycosis from 2017 to 2022 were included. Diagnosis was established through clinical examination, supported by the result of direct microscopic examination with potassium hydroxide. RESULTS Of 171 patients, 93.6% had onychodystrophy, 65.5% were females, and 62.0% were aged 19-59 years. Most patients had onychodystrophy in more than three nails, affecting fingernails (31.6%) and toenails (34.5%). Interestingly, 84.8% of patients had no history of nail diseases. The median onset of disease was 24.0 (1-1,040) weeks, while the median onychomycosis severity index was 10.0 (2-40). Most cases were caused by Candida albicans (48.3%). Fusarium was the only NDM documented (2.3%). Some patients were resistant to itraconazole (11.4%) and miconazole (4.5%). Overall, 49.1% of the patients were declared not cured. CONCLUSIONS Candida was the predominant cause of onychomycosis, and onychodystrophy was the dominant feature. Current treatment regimens with systemic or topical antifungal agents did not yield satisfactory results, with more than half of the patients deemed not cured. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The objective of this research was to develop a mucoadhesive delivery system that improves permeation for the administration of poorly absorbed oral medications. Thiolation of xanthan gum (XGM) was carried out by esterification with mercaptobutyric acid. Fourier-transformed infrared spectroscopy was used to confirm thiol-derivatization. Using Ellman's technique, it was revealed that the xanthan-mercaptobutyric acid conjugate had 4.7 mM of thiol groups in 2 mg/mL of polymeric solution. Using mucosa of sheep intestine, the mucoadhesive properties of XGM and thiolated xanthan gum (TXGM) nanoparticles were investigated and we found that TXGM had a longer bioadhesion time than XGM. The disulfide link that forms between mucus and thiolated XGM explains why it has better mucoadhesive properties than XGM. A study on in vitro miconazole (MCZ) release using phosphate buffer (pH 6.8) found that TXGM nanoparticles released MCZ more steadily than MCZ dispersion did. A 1-fold increase in the permeation of MCZ was observed from nanoparticles using albino rat intestine compared to MCZ. Albino rats were used to test the pharmacokinetics of MCZ, and the results showed a 4.5-fold increase in bioavailability. In conclusion, the thiolation of XGM enhances its bioavailability, controlled release of MCZ for a long period of time, and mucoadhesive activity. [ABSTRACT FROM AUTHOR]

The crystal structure of the new triclinic polymorph of miconazole {MIC; C18H14Cl4N2O; systematic name: (RS)-1-[2-(2,4-dichlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole} is reported and compared with the monoclinic form of solvent-free miconazole previously reported [Kaspiaruk & Chęcińska (2022). Acta Cryst. C78, 343-350]. A comparison shows a different orientation of imidazole and one dichlorophenyl ring between polymorphic molecules. In the crystal structure of the title compound, only weak halogen bonds and C--H...p(arene) interactions are found. Hirshfeld surface analysis and energy framework calculations complement the comparison of the two polymorphic forms of the miconazole drug. [ABSTRACT FROM AUTHOR]

Abstract 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. Graphical Abstract

We have described one-pot multicomponent synthesis of 2-amino-3,5-dicyano-6-phenylthiopyridine incorporated1,2,3-triazole derivatives from triazolyl aldehydes, malononitrile and thiophenol in excellent yields. The antitubercular, antifungal and antioxidant activity for all the synthesized derivatives were evaluated. The antifungal activity results show that the compounds 12a, 12b and 12g were observed more potent than Miconazole with MIC value <25 µg/mL. Whereas, the antitubercular screening against MTB H37Rv strain did not produce any promising results. Furthermore, in silico ADME properties for all the compounds were also studied and exhibited the potential to be developed as an oral drug candidate. [ABSTRACT FROM AUTHOR]

A highly sensitive, accurate, and robust LC-MS/MS method was developed and validated for the simultaneous determination of ornidazole (ODZ) and miconazole (MCZ) in rat plasma using metronidazole (MTR) as an internal standard (IS). The analyte and IS were extracted from plasma by precipitating protein with acetonitrile and were chromatographed. The mobile phase was acetonitrile and 0.1% formic acid (75:25 v/v). The total run time was 3 min, and the injection volume was 5.0 μL. Multiple reaction monitoring (MRM) mode was used, in which the transitions of m/z 417.10→m/z 160.90 for MCZ, m/z 220.10→m/z 127.90 for ODZ, and m/z 172.10→m/z 128.1 for IS were monitored. The linearity range of MCZ was 0.15 -- 250.0 ng/mL and 3.0-250.0 ng/mL for ODZ. The lower limits of quantification (LLOQ) were found to be 0.05 ng/mL for MCZ and 1.0 ng/mL for ODZ in rat plasma. Recoveries of MCZ ranged between 75.33% -- 94.25% and ODZ ranged between 75.33% -- 95.54%. The quality control sample accuracy and precision (intra-day and inter-day) were -1.25% to 1.68% and 3.01% to 6.44% for MCZ and -1.31% to 1.88% and 3.34% to 6.98% for ODZ, respectively. The analytes and IS were stable during all sample storage and analysis procedures. [ABSTRACT FROM AUTHOR]

Hydrophilic drugs could be incorporated into the skin surface by manes of Lipogel. This study aimed to prepare miconazole lipogel with natural ingredients to enhance drug permeability using dimethyl Sulfoxide (DMSO). The miconazole lipogels, A1 (without DMSO) and A2 (with DMSO) were formulated and evaluated for organoleptic evaluation, pH, viscosity, stability studies, freeze-thawing, drug release profile and drug permeation enhancement. Results had stated that prepared lipogel's pH falls within the acceptable range required for topical delivery (4 to 6) while both formulations show good results in organoleptic evaluation. The A2 formulation containing DMSO shows better permeation of miconazole (84.76%) on the artificial skin membrane as compared to A1 lipogel formulation (50.64%). In in-vitro drug release studies, A2 for-mulation showed 87.48% drug release while A1 showed just 60.1% drug release from lipogel. Stability studies were performed on model formulations under environmental conditions and both showed good spreadibility, stable pH, free of grittiness and good consistency in formulation. The results concluded that A2 formulation containing DMSO shows better results as compared to DMSO-free drug lipogel. [ABSTRACT FROM AUTHOR]

Chiral β‐heteroaryl amino alcohols play a crucial role as intermediates in the synthesis of numerous bioactive pharmaceuticals, including cenobamate, oteseconazole, and miconazole. Nevertheless, there is a lack of literature documenting the establishment of a versatile approach for the synthesis of β‐heteroaryl amino alcohols and the aforementioned drugs. In this study, we successfully asymmetrically synthesized 50 pairs of chiral β‐heteroaryl amino alcohols using two engineered ketoreductases (KREDs) with opposite stereopreference. Based on this achievement, we developed a three‐step chemoenzymatic cascade route for synthesizing of chiral miconazole analogues from commercially available 2‐bromoacetophenone derivatives. By optimizing the solvent for the synthesis of α‐imidazolyl ketones in the first step, followed by the reduction of α‐imidazolyl ketones using KREDs in the second step and etherification in the third step, we obtained 20 chiral miconazole analogues with promising yields (26–84%) and impressive stereoselectivities (up to >99% ee). Notably, this route eliminates the need for the isolation of ketone and alcohol intermediates, and avoids the use of metal catalysts in the synthesis of chiral miconazole analogues. Furthermore, we successfully scaled up the preparation of (S)‐miconazole, achieving a 30% isolated yield and >99% ee. This method presents a novel synthetic approach for production chiral ether drugs and chiral β‐heteroaryl amino alcohols, offering new possibilities in pharmaceutical synthesis. [ABSTRACT FROM AUTHOR]

Enhancement of skin bioavailability through topical formulation is challenging due to the presence of the barrier stratum corneum. Elastic, deformable lipid vesicles are easily penetrated through the skin barrier. The present study involves unsaturated fatty acid for vesicular preparation, ufosomes of miconazole nitrate. Fatty acid acts as skin penetration enhancer and improves skin retention. The effect of formulation parameters on efficacy of formulation was studies using 32 full factorial design. The particle size and % entrapment efficiency was found to be in the range of 157 to 291.6 nm with irregular spherical shape and 54.14% to 85.84%, respectively. The in vitro drug release, ex vivo drug release and skin retention of optimized ufosomes were found to be 78.424 %, 20.793 % and 43.36 %, respectively. The optimized batch displayed Higuchi drug release kinetic model with desired physicochemical properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Several studies have investigated the safety and efficacy of antimicrobial peripherally inserted central catheters (PICCs), and the results are conflicting. Therefore, in this systematic review and meta-analysis, we aimed to summarize and identify the effect of antimicrobial PICCs on central line–associated bloodstream infection (CLABSI) risk. A systematic search of PubMed, Ovid MEDLINE, Ovid Embase, and Web of Science was performed to identify relevant studies up to December 2022. A total of 9 studies were included for analysis. There were 7 retrospective/prospective cohort studies and 2 randomized controlled trials. The 9 studies involved 51,373 patients with PICCs. Among these patients, 6,563 (12.8%) antimicrobial-coated/impregnated PICCs and 44,810 (87.2%) nonantimicrobial-impregnated PICCs were inserted. The meta-analysis showed that antimicrobial PICCs had a nonsignificant association with lower CLABSI risk compared with noncoated PICCs (relative risk [RR] = 0.67; 95% CI, 0.43-1.05). In the subgroup analysis, minocycline-rifampin–(RR = 0.30; 95% CI, 0.19-0.49) or chlorhexidine-coated (RR = 0.61; 95% CI, 0.04-8.55) PICCs showed an association with reduced risk of CLABSI. In the adult population, antimicrobial PICCs had a nonsignificant association with lower CLABSI risk (RR = 0.50; 95% CI, 0.20-1.22). This systematic review and meta-analysis suggested that antimicrobial PICCs had a nonsignificant association with lower CLABSI risk compared with noncoated PICCs. Minocycline-rifampin–or chlorhexidine-coated PICCs showed an association with reduced risk of CLABSI. • This systematic review and meta-analysis suggested that antimicrobial peripherally inserted central catheters (PICCs) had a nonsignificant association with lower central line–associated bloodstream infection (CLABSI) risk compared with noncoated PICCs. • Minocycline-rifampin- or chlorhexidine-coated PICCs had a nonsignificant association with lower CLABSI risk. • In the pediatric population, antimicrobial PICCs had a nonsignificant association with lower CLABSI risk compared with noncoated PICCs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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