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Antibiotics (Basel, Switzerland) May 2024(1) Background: Although accounts for the majority of fungal infections, therapeutic options are limited and require alternative antifungal agents with new targets; (2)...
(1) Background: Although accounts for the majority of fungal infections, therapeutic options are limited and require alternative antifungal agents with new targets; (2) Methods: A biofilm formation assay with RPMI1640 medium was performed with extract. A combination antifungal assay, dimorphic transition assay, and adhesion assay were performed under the biofilm formation condition to determine the anti-biofilm formation effect. qRT-PCR analysis was accomplished to confirm changes in gene expression; (3) Results: extract significantly reduces biofilm formation by 51.65% at 1.56 μg/mL use and therefore increases susceptibility to miconazole. extract also inhibited the dimorphic transition of Candida; nearly 50% of the transition was inhibited when 1.56 μg/mL of the extract was treated. The extract of inhibited the expression of genes related to hyphal development and extracellular matrix of 34.4% and 36.0%, respectively, as well as genes within the Ras1-cAMP-PKA, Cph2-Tec1, and MAP kinase signaling pathways of 25.58%, 7.1% and 15.8%, respectively, at 1.56 μg/mL of extract treatment; (4) Conclusions: extract significantly reduced Candida biofilm formation, which lead to induced antifungal susceptibility to miconazole. It suggests that extract is a promising anti-biofilm candidate of since the biofilm formation of is an excellent target for candidiasis regulation.
PubMed: 38786162
DOI: 10.3390/antibiotics13050434 -
Molecules (Basel, Switzerland) May 2024The main objective of this study was to investigate the metabolism of miconazole, an azole antifungal drug. Miconazole was subjected to incubation with human liver...
Identification of New Hepatic Metabolites of Miconazole by Biological and Electrochemical Methods Using Ultra-High-Performance Liquid Chromatography Combined with High-Resolution Mass Spectrometry.
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.
Topics: Miconazole; Humans; Chromatography, High Pressure Liquid; Microsomes, Liver; Mass Spectrometry; Electrochemical Techniques; Antifungal Agents; Biotransformation
PubMed: 38731651
DOI: 10.3390/molecules29092160 -
The Journal of Antibiotics Jul 2024Antibiotic resistance is a major health problem worldwide. Pseudomonas aeruginosa is a Gram-negative pathogen with an arsenal of virulence factors and elevated...
Antibiotic resistance is a major health problem worldwide. Pseudomonas aeruginosa is a Gram-negative pathogen with an arsenal of virulence factors and elevated antimicrobial resistance. It is a leading cause of nosocomial infections with high morbidity and mortality. The significant time and effort required to develop new antibiotics can be circumvented using alternative therapeutic strategies, including anti-virulence targets. This study aimed to investigate the anti-virulence activity of the FDA-approved drugs miconazole and phenothiazine against P. aeruginosa. The phenotypic effect of sub-inhibitory concentrations of miconazole and phenothiazine on biofilm, pyocyanin, protease, rhamnolipid and hemolysin activities in PAO1 strain was examined. qRT-PCR was used to assess the effect of drugs on quorum-sensing genes that regulate virulence. Further, the anti-virulence potential of miconazole and phenothiazine was evaluated in silico and in vivo. Miconazole showed significant inhibition of Pseudomonas virulence by reducing biofilm-formation approximately 45-48%, hemolytic-activity by 59%, pyocyanin-production by 47-49%, rhamnolipid-activity by approximately 42-47% and protease activity by 36-40%. While, phenothiazine showed lower anti-virulence activity, it inhibited biofilm (31-35%), pyocyanin (37-39%), protease (32-40%), rhamnolipid (35-40%) and hemolytic activity (47-56%). Similarly, there was significantly reduced expression of RhlR, PqsR, LasI and LasR following treatment with miconazole, but less so with phenothiazine. In-silico analysis revealed that miconazole had higher binding affinity than phenothiazine to LasR, RhlR, and PqsR QS-proteins. Furthermore, there was 100% survival in mice injected with PAO1 treated with miconazole. In conclusion, miconazole and phenothiazine are promising anti-virulence agents for P. aeruginosa.
Topics: Pseudomonas aeruginosa; Quorum Sensing; Miconazole; Phenothiazines; Biofilms; Virulence; Anti-Bacterial Agents; Animals; Microbial Sensitivity Tests; Pyocyanine; Pseudomonas Infections; Virulence Factors; Mice; Molecular Docking Simulation; Glycolipids
PubMed: 38724627
DOI: 10.1038/s41429-024-00731-5 -
Acta Dermatovenerologica Alpina,... Jun 2024Hailey‒Hailey disease is a rare chronic autosomal-dominant blistering disease characterized by erosions, fissures, and vegetations occurring in intertriginous regions....
Hailey‒Hailey disease is a rare chronic autosomal-dominant blistering disease characterized by erosions, fissures, and vegetations occurring in intertriginous regions. To date, there is no specific treatment and there are no therapeutic guidelines, which makes management of the disease challenging. We present the case of a 43-year-old man unsuccessfully treated for Hailey‒Hailey disease with topical and systemic corticosteroids, antibiotics, and surgical debridement. At presentation he had erosions, vegetations, and infection in the axillae and groin. We introduced oral methotrexate, 10 mg weekly, and complete remission was achieved in 3 weeks. After 8 weeks, we decided to discontinue methotrexate due to lesion absence. Over 3 years of follow-up, mild flares were effectively managed with topical miconazole or mild steroid creams. We conclude that oral methotrexate is safe and effective for achieving long-term remission in Hailey‒Hailey disease.
Topics: Humans; Pemphigus, Benign Familial; Male; Adult; Methotrexate; Administration, Oral; Dermatologic Agents; Immunosuppressive Agents; Treatment Outcome
PubMed: 38708770
DOI: No ID Found -
BMJ Open May 2024To evaluate the efficacy of topical miconazole or amorolfine compared to placebo for mild to moderately severe onychomycosis. (Randomized Controlled Trial)
Randomized Controlled Trial
How effective is topical miconazole or amorolfine for mild to moderately severe onychomycosis in primary care: the Onycho Trial - a randomised double-blind placebo-controlled trial.
OBJECTIVES
To evaluate the efficacy of topical miconazole or amorolfine compared to placebo for mild to moderately severe onychomycosis.
DESIGN
Randomised, double-blind, placebo-controlled trial, with computer-generated treatment allocation at a 1:1:1 ratio.
SETTING
Primary care, recruitment from February 2020 to August 2022.
PARTICIPANTS
193 patients with suspected mild to moderately severe onychomycosis were recruited via general practices and from the general public, 111 of whom met the study criteria. The mean age of participants was 51 (SD 13.1), 51% were female and onychomycosis was moderately severe (mean OSI 12.1 (SD 8.0)).
INTERVENTIONS
Once-daily miconazole 20 mg/g or once-weekly amorolfine 5% nail lacquer solution was compared with placebo (denatonium benzoate solution).
MAIN OUTCOME MEASURES
Complete, clinical and mycological cure at 6 months. Secondary outcomes were clinical improvement, symptom burden, quality of life, adverse effects, compliance, patient-perceived improvement and treatment acceptability.
RESULTS
Based on intention-to-treat analysis, none of the participants receiving miconazole or amorolfine reached complete cure compared with two in the placebo group (OR not estimable (n.e.), p=0.493 and OR n.e., p=0.240, respectively). There was no evidence of a significant difference between groups regarding clinical cure (OR n.e., p=0.493 and OR 0.47, 95% CI 0.04 to 5.45, p=0.615) while miconazole and amorolfine were less effective than placebo at reaching both mycological cure (OR 0.25, 95% CI 0.06 to 0.98, p=0.037 and OR 0.23, 95% CI 0.06 to 0.92, p=0.029, respectively) and clinical improvement (OR 0.26, 95% CI 0.08 to 0.91, p=0.028 and OR 0.25, 95% CI 0.07 to 0.85, p=0.021, respectively). There was no evidence of a significant difference in disease burden, quality of life, adverse reactions, compliance, patient-perceived improvement or treatment acceptability.
CONCLUSIONS
Topical miconazole and amorolfine were not effective in achieving a complete, clinical or mycological cure of mild to moderately severe onychomycosis, nor did they significantly alleviate the severity or symptom burden. These treatments should, therefore, not be advised as monotherapy to treat onychomycosis.
TRIAL REGISTRATION NUMBER
WHO ICTRP NL8193.
Topics: Humans; Miconazole; Onychomycosis; Female; Double-Blind Method; Male; Middle Aged; Antifungal Agents; Administration, Topical; Treatment Outcome; Adult; Primary Health Care; Quality of Life; Aged; Severity of Illness Index; Morpholines
PubMed: 38702077
DOI: 10.1136/bmjopen-2023-081914 -
European Journal of Pharmaceutical... Jun 2024Cytochrome P450 (CYP) system is a critical elimination route to most pharmaceuticals in human, but also prone to drug-drug interactions arising from the fact that...
Cytochrome P450 (CYP) system is a critical elimination route to most pharmaceuticals in human, but also prone to drug-drug interactions arising from the fact that concomitantly administered pharmaceuticals inhibit one another's CYP metabolism. The most severe form of CYP interactions is irreversible inhibition, which results in permanent inactivation of the critical CYP pathway and is only restored by de novo synthesis of new functional enzymes. In this study, we conceptualize a microfluidic approach to mechanistic CYP inhibition studies using human liver microsomes (HLMs) immobilized onto the walls of a polymer micropillar array. We evaluated the feasibility of these HLM chips for CYP inhibition studies by establishing the stability and the enzyme kinetics for a CYP2C9 model reaction under microfluidic flow and determining the half-maximal inhibitory concentrations (IC) of three human CYP2C9 inhibitors (sulfaphenazole, tienilic acid, miconazole), including evaluation of their inhibition mechanisms and nonspecific microsomal binding on chip. Overall, the enzyme kinetics of CYP2C9 metabolism on the HLM chip (K = 127 ± 55 µM) was shown to be similar to that of static HLM incubations (K = 114 ± 14 µM) and the IC values toward CYP2C9 derived from the microfluidic assays (sulfaphenazole 0.38 ± 0.09 µM, tienilic acid 3.4 ± 0.6 µM, miconazole 0.54 ± 0.09 µM) correlated well with those determined using current standard IC shift assays. Most importantly, the HLM chip could distinguish between reversible (sulfaphenazole) and irreversible (tienilic acid) enzyme inhibitors in a single, automated experiment, indicating the great potential of the HLM chip to simplify current workflows used in mechanistic CYP inhibition studies. Furthermore, the results suggest that the HLM chip can also identify irreversible enzyme inhibitors, which are not necessarily resulting in a time-dependent inhibition (like suicide inhibitors), but whose inhibition mechanism is based on other kind of covalent or irreversible interaction with the CYP system. With our HLM chip approach, we could identify miconazole as such a compound that nonselectively inhibits the human CYP system with a prolonged, possibly irreversible impact in vitro, even if it is not a time-dependent inhibitor according to the IC shift assay.
Topics: Humans; Microsomes, Liver; Cytochrome P-450 CYP2C9; Kinetics; Cytochrome P-450 Enzyme Inhibitors; Miconazole; Enzymes, Immobilized; Cytochrome P-450 CYP2C9 Inhibitors; Lab-On-A-Chip Devices; Microfluidic Analytical Techniques; Sulfaphenazole; Microfluidics
PubMed: 38641124
DOI: 10.1016/j.ejps.2024.106773 -
International Journal of Molecular... Mar 2024Miconazole 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...
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.
Topics: Humans; Melanoma; Miconazole; Clotrimazole; Reactive Oxygen Species; Mitochondria; Carnitine; Adenosine Triphosphate
PubMed: 38612401
DOI: 10.3390/ijms25073589 -
Pharmaceutics Feb 2024Curcumin (CUR) is a natural compound that can be combined with miconazole (MCZ) to improve vulvovaginal candidiasis (VVC) caused by treatment's efficacy. This study...
Curcumin (CUR) is a natural compound that can be combined with miconazole (MCZ) to improve vulvovaginal candidiasis (VVC) caused by treatment's efficacy. This study aimed to develop ureasil-polyether (U-PEO) vaginal ovules loaded with CUR and MCZ for the treatment of VVC. Physicochemical characterization was performed by thermogravimetry (TGA), differential thermal analysis (DTA), Fourier transform infrared spectroscopy (FTIR), and in vitro release. Antifungal assays were used to determine minimum inhibitory concentrations (MICs) and synergism between CUR and MCZ, and the activity of U-PEO ovules were performed by microdilution and agar diffusion. TGA results showed high thermal stability of the hybrid ovules. In DTA, the amorphous character of U-PEO and a possible interaction between CUR and MCZ were observed. FTIR showed no chemical incompatibility between the drugs. In vitro release resulted in 80% of CUR and 95% of MCZ released within 144 h. The MICs of CUR and MCZ were 256 and 2.5 µg/mL, respectively. After combining the drugs, the MIC of MCZ decreased four-fold to 0.625 µg/mL, while that of CUR decreased eight-fold to 32 µg/mL. Synergism was confirmed by the fractional inhibitory concentration index (FICI) equal to 0.375. U-PEO alone showed no antifungal activity. U-PEO/MCZ and U-PEO/CUR/MCZ ovules showed the greatest zones of inhibition (≥18 mm). The results highlight the potential of the ovules to be administered at a lower frequency and at reduced doses compared to available formulations.
PubMed: 38543206
DOI: 10.3390/pharmaceutics16030312 -
Alternative Therapies in Health and... Mar 2024To evaluate the impact of clotrimazole suppositories on the distribution of vaginal pathogens and oxidative stress in patients with vaginitis.
OBJECTIVE
To evaluate the impact of clotrimazole suppositories on the distribution of vaginal pathogens and oxidative stress in patients with vaginitis.
METHODS
A total of 120 patients with vaginitis were recruited from our hospital between January 2021 and December 2022 and were divided into an observation group and a control group using a random envelope method. The control group received treatment with miconazole tablets alone, while the observation group received combined treatment with miconazole tablets and clotrimazole suppositories. Vaginal secretions were collected from the subjects for pathogenic microbial testing. The clinical efficacy of the patients was evaluated, and indicators related to vaginal microecology and microbial imbalance were examined. Serum levels of IL-8, CRP, TNF-α, IL-6, PCT, P, LH, FSH, SOD, MDA, NO, and ET-1 were measured in the subjects.
RESULTS
Among patients with vaginitis, bacteria, fungi, and gram-negative cocci accounted for a relatively high proportion, with bacterial infections accounting for more than 30% and fungal and gram-negative cocci infections both exceeding 10%. Pathogenic infections such as Chlamydia and Trichomonas were less than 10%. The observation group showed significantly higher clinical efficacy compared to the control group, with a statistically significant difference (P < .05). Following treatment, the observation group exhibited significantly lower scores for itching, vaginal discharge, and burning sensation compared to the control group, with a statistically significant difference (P < .05). After treatment, the observation group had significantly lower bacterial density and Nugent score, higher cleanliness, positive lactobacilli rate, and pH value compared to the control group, and the difference was statistically significant (P < .05). After treatment, the observation group demonstrated significantly lower blood levels of IL-8, CRP, TNF-α, IL-6, and PCT compared to the control group, with a statistical significance of P < .05. Similarly, the levels of P, LH, and FSH hormones in the observation group were significantly lower than those in the control group, also with a statistical significance of P < .05. In contrast, the levels of SOD and NO in the observation group were significantly higher, while the levels of MDA and ET-1 were significantly lower compared to the control group, with a statistical significance of P < .05.
CONCLUSION
Clotrimazole suppositories have been shown to significantly enhance therapeutic outcomes for patients with vaginitis by alleviating inflammation, rebalancing vaginal microecology, regulating hormone secretion, and mitigating oxidative stress.
PubMed: 38430151
DOI: No ID Found