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Veterinary Medicine and Science Nov 2023Fungal and yeast infections, including those caused by Malassezia spp., are becoming increasingly difficult to treat, likely due to the occurrence of drug resistance.
BACKGROUND
Fungal and yeast infections, including those caused by Malassezia spp., are becoming increasingly difficult to treat, likely due to the occurrence of drug resistance.
OBJECTIVES
This study aimed to evaluate the antifungal effects of omeprazole (OME), a proton pump inhibitor, against antifungal-resistant Malassezia pachydermatis and to investigate the potential synergistic effects between OME and other antifungal compounds.
METHODS
In total, 15 samples of M. pachydermatis isolated from the skin of dogs were tested. The susceptibility of M. pachydermatis to itraconazole, ketoconazole, miconazole, terbinafine and OME was assessed using a modified broth microdilution (BM) method. The in vitro efficacy of OME alone and in combination with other antifungal compounds was evaluated for all isolates using the BM chequerboard method. The data obtained were analysed using the fractional inhibitory concentration index (FICI).
RESULTS
The minimum inhibitory concentration (MIC) values of antifungal compounds and OME against quality control strain (M. pachydermatis CBS1879) were lower than the MIC values of same drugs against clinically collected strains. There was no significant difference in MIC values between drugs alone and combination. According to the analysis by the FICI method, no interaction was observed with OME and antifungal compounds.
CONCLUSIONS
Most M. pachydermatis strains were resistant to azole antifungal compounds. OME exerted antifungal effects against Malassezia spp. and even showed good effects on antifungal-resistant strains. No synergistic effects were observed between the antifungal compounds and OME.
Topics: Animals; Dogs; Antifungal Agents; Malassezia; Omeprazole; Drug Resistance, Fungal
PubMed: 37872836
DOI: 10.1002/vms3.1305 -
International Journal of Molecular... Sep 2019Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is...
Derivatives of tirapazamine and other heteroaromatic oxides (ArN→O) exhibit promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN→O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase/adrenodoxin (ADR/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR/ADX-catalyzed single-electron reduction, the reactivity of ArN→O ( = 9) increased with their single-electron reduction midpoint potential (), and correlated with the reactivity of quinones. NQO1 reduced ArN→O at low rates with concomitant superoxide production. The cytotoxicity of ArN→O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their , being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 α-naphthoflavone, isoniazid and miconazole statistically significantly ( < 0.02) decreased the toxicity of ArN→O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN→O is higher than that of quinones. This is partly attributed to ArN→O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN→O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.
Topics: Antineoplastic Agents; Biomarkers; Humans; Molecular Structure; NAD(P)H Dehydrogenase (Quinone); NADP; Oxidants; Oxidation-Reduction; Reactive Oxygen Species; Tirapazamine
PubMed: 31533349
DOI: 10.3390/ijms20184602 -
Pharmaceutics Jun 2020Opportunistic fungal infections are responsible for over 1.5 million deaths per year. This has created a need for highly effective antifungal medication to be as potent...
Opportunistic fungal infections are responsible for over 1.5 million deaths per year. This has created a need for highly effective antifungal medication to be as potent as possible. In this study, we improved the efficacy of a common over the counter (OTC) antifungal skin medication, miconazole, by encapsulating nano-molecules of the drug in cholesterol/sodium oleate nano-vesicles. These nano-vesicles were characterized to optimize their size, zeta potential, polydispersity index and encapsulation efficiency. Furthermore, these nano-vesicles were compared to a conventional miconazole-based commercially available cream to determine potential improvements via permeation through the stratum corneum, cytotoxicity, and antifungal capabilities. Our results found that the vesicle size was within the nano range (~300 nm), with moderate polydispersity and stability. When compared with the commercially available cream, Actavis, as well as free miconazole, the miconazole nano-vesicle formulation displayed enhanced fungal inhibition by a factor of three or more when compared to free miconazole. Furthermore, with smaller nanoparticle (NP) sizes, higher percentages of miconazole may be delivered, further enhancing the efficacy of miconazole's antifungal capability. Cytotoxicity studies conducted with human dermal fibroblast cells confirm its biosafety and biocompatibility, as cell survival rate was observed to be twofold higher in nano-vesicle formulation than free miconazole. This formulation has the potential to treat fungal infections through increasing the retention time in the skin, improving the treatment approach, and by enhancing the efficacy via the use of nano-vesicles.
PubMed: 32517047
DOI: 10.3390/pharmaceutics12060516 -
Journal of Medicinal Chemistry Dec 2023Developing drugs for brain infection by is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to...
Developing drugs for brain infection by 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 enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected were tested against . Nine primary hits with EC ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound . The -enantiomer of produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the -configuration over the -configuration and the advantage of an ether linkage over an ester linkage. The two compounds, - and -, had an improved EC and compared to . Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of - was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.
Topics: Miconazole; 14-alpha Demethylase Inhibitors; Naegleria fowleri; Drug Discovery
PubMed: 38085955
DOI: 10.1021/acs.jmedchem.3c01898 -
Pharmaceutics Aug 2019Amphotericin B possesses high activity against spp. with low risk of resistance. However, Amphotericin B's high molecular weight compared to other antifungal drugs,...
Amphotericin B possesses high activity against spp. with low risk of resistance. However, Amphotericin B's high molecular weight compared to other antifungal drugs, such as miconazole and clotrimazole, and poor water solubility hampers its efficacy at the physiological conditions of the oropharyngeal cavity (saliva pH, limited volume for dissolution) and thereby limits its clinical use in oropharyngeal candidiasis. We have prepared fast-dissolving orodispersible films with high loading (1% ) using solvent casting that enables amphotericin B to remain solubilised in saliva in equilibrium between the monomeric and dimeric states, and able to produce a local antifungal effect. Optimisation of the amphotericin B-loaded orodispersible films was achieved by quality by design studies combining dextran and/or maltodextrin as dextrose-derived-polymer film formers with cellulose-derived film formers (hydroxypropylmethyl/hydroxypropyl cellulose in a 1:4 weight ratio), sorbitol for taste masking, microcrystalline cellulose (Avicel 200) or microcrystalline cellulose-carboxymethylcellulose sodium (Avicel CL-611) for enhancing the mechanical strength of the film, and polyethylene glycol 400 and glycerol (1:1 ) as plasticizers. The optimised amphotericin B orodispersible films (containing 1% AmB, 25% dextran, 25% maltodextrin, 5% sorbitol, 10% Avicel 200, 10% polyethylene glycol 400, 10% glycerol, 3% hydroxypropylmethyl cellulose acetate succinate, 12% hydroxypropyl cellulose) possessed a fast disintegration time (60 ± 3 s), quick release in artificial saliva (>80% in 10 min), high burst strength (2190 mN mm) and high efficacy against several spp. (, and ) (>15 mm inhibition halo). Amphotericin B orodispersible films are stable for two weeks at room temperature (25 °C) and up to 1 year in the fridge. Although further toxicological and in vivo efficacy studies are required, this novel Amphotericin B orodispersible films is a promising, physicochemically stable formulation with potential wide application in clinical practice, especially for immunocompromised patients suffering from oropharyngeal candidiasis.
PubMed: 31374879
DOI: 10.3390/pharmaceutics11080369 -
BMC Chemistry Dec 2023Two accurate, sensitive, and selective methods for simultaneous determination of miconazole nitrate (MIC), nystatin (NYS), and metronidazole (MET) in pure state or drug...
Two accurate, sensitive, and selective methods for simultaneous determination of miconazole nitrate (MIC), nystatin (NYS), and metronidazole (MET) in pure state or drug product were established and verified. First, RP-HPLC-DAD was designed. Separation was accomplished using a ZOBRAX Eclipse Plus RP-C column that was running under an isocratic elution of methanol: 0.05% aqueous solution of sodium dodecyl sulphate (40: 60 v/v), with a flow rate that was regulated at 0.8 mL/min. The column temperature was adjusted at 25 °C and diode array detector was monitored at 220 nm. The linearity range of the proposed method was achieved at the concentration of 5-50, 4-50, and 4-40 µg/mL and the attained retention time for the studied drugs was 2.52, 3.52 and 4.99 min for MIC, NYS, and MET, correspondingly. Second, a TLC-densitometric approach was used to resolve the three compounds. Resolution of the three cited drugs was carried out using TLC aluminum plates pre-coated with 0.25 mm silica gel 60 F. A developing solvent comprised ethyl acetate: toluene: methanol: triethyl amine: formic acid (3: 1: 7: 0.3: 0.1 by volume) (pH = 5.5) was utilized and scanning of the resolved bands at 215 nm. Linearity of the developed TLC method was evaluated and evident to be 0.4-2, 0.4-2.2, and 0.4-2 μg/band for MIC, NYS, and MET, in that order. The suggested chromatographic methods were verified according to ICH directives. The findings of the developed chromatographic procedures were statistically compared with the results of the reported ones using student's t-test and F-test. Furthermore, two green assessment tools evaluated the indicated methods' level of greenness (GAPI and AGREE).
PubMed: 38041191
DOI: 10.1186/s13065-023-01083-1 -
Marine Drugs Feb 2021Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant at 10 μg/mL (15.4 μM). The... (Comparative Study)
Comparative Study
Oceanapiside (OPS), a marine natural product with a novel bifunctional sphingolipid structure, is fungicidal against fluconazole-resistant at 10 μg/mL (15.4 μM). The fungicidal effect was observed at 3 to 4 h after exposure to cells. Cytological and morphological studies revealed that OPS affects the budding patterns of treated yeast cells with a significant increase in the number of cells with single small buds. In addition, this budding morphology was found to be sensitive in the presence of OPS. Moreover, the number of cells with single medium-sized buds and cells with single large buds were decreased significantly, indicating that fewer cells were transformed to these budding patterns, suggestive of inhibition of polarized growth. OPS was also observed to disrupt the organized actin assembly in , which correlates with inhibition of budding and polarized growth. It was also demonstrated that phytosphingosine (PHS) reversed the antifungal activity of oceanapiside. We quantified the amount of long chain-bases (LCBs) and phytoceramide from the crude extracts of treated cells using LC-ESI-MS. PHS concentration was elevated in extracts of cells treated with OPS when compared with cells treated with miconazole and amphotericin B. Elevated levels of PHS in OPS-treated cells confirms that OPS affects the pathway at a step downstream of PHS synthesis. These results also demonstrated that OPS has a mechanism of action different to those of miconazole and amphotericin B and interdicts fungal sphingolipid metabolism by specifically inhibiting the step converting PHS to phytoceramide.
Topics: Amphotericin B; Antifungal Agents; Biological Products; Candida glabrata; Chromatography, Liquid; Drug Resistance, Fungal; Fluconazole; Glycolipids; Mass Spectrometry; Miconazole; Sphingolipids; Sphingosine
PubMed: 33652774
DOI: 10.3390/md19030126 -
Frontiers in Veterinary Science 2021(formerly ) belongs to geophilic dermatophytes, fungi involved in keratin degradation in the soil; however, they are also found in dogs and cats. Transmission to humans...
(formerly ) belongs to geophilic dermatophytes, fungi involved in keratin degradation in the soil; however, they are also found in dogs and cats. Transmission to humans can occur directly by contact with soil, but indirect transmission domestic animals is reported too. The exact source of the infection is usually difficult to assess and in most cases only hypothesised and rarely investigated. This case report describes a kerion caused by in a 2-year-old boy, where the contagion was probably secondary to domestic healthy carrier dogs. A "One-Health" approach involving human dermatologists and veterinarians, combined with the use of conventional and molecular-based techniques, allowed tracing of the epidemiological chain and managing of not only the treatment but also the prevention of a recurrence. The child's lesion began to regress after about 8 weeks of treatment with both systemic and topical therapy, while the dogs were given chlorhexidine and miconazole baths. No recurrences nor new infections occurred, demonstrating the effectiveness of the strategies used.
PubMed: 34504889
DOI: 10.3389/fvets.2021.718766 -
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 -
Pakistan Journal of Medical Sciences 2022To study prevalence and resistance pattern to azoles of candida species causing vulvovaginitis in reproductive age women.
OBJECTIVES
To study prevalence and resistance pattern to azoles of candida species causing vulvovaginitis in reproductive age women.
METHODS
Samples were collected from Hayatabad Medical Complex from November 2018 to May 2019. This cross-sectional study was conducted at the department of Microbiology, Institute of Pathology and Diagnostic Medicine, Khyber Medical University Peshawar, Pakistan. A total of 369 high vaginal swabs were collected. Candida was isolated by vaginal swabs inoculation on Sabouraud's dextrose agar (SDA). Colonies on SDA were inoculated on Candida CHROM agar to identify candida species. Wet film microscopy and Gram staining were performed. Biochemical identification was done with 20C AUX. Antifungal susceptibility testing was done by disc diffusion and broth micro-dilution methods to find the resistance pattern of azole drugs. Fluconazole, Clotrimazole, Miconazole, Voriconazole and Itraconazole were the azoles drugs used.
RESULTS
Among 43%(n=158) positive candida cases, 44%(n=85) were non pregnant women while 41%(n=73) were pregnant. The Candida species distribution of 158 isolates was as follow; 46.2%(n=73), 29.1%(n=46), 19%(n=30) and 5.7%(n=9). Overall Candida isolates were highly resistant 72%(n=113) to Fluconazole while least resistant 21.5 % (n=34) to Itraconazole.
CONCLUSION
is the most prevalent specie involved in Vulvovaginal candidiasis. Candida species were found to be least resistant to Itraconazole followed by Voriconazole, Miconazole, Clotrimazole and Fluconazole.
PubMed: 36415248
DOI: 10.12669/pjms.38.8.5984