Ketoconazole Dotaz Zobrazit nápovědu
- Klíčová slova
- NIZORAL ŠAMPON,
- MeSH
- dermatózy skalpu terapie MeSH
- dospělí MeSH
- ketokonazol aplikace a dávkování terapeutické užití MeSH
- kosmetické přípravky terapeutické užití MeSH
- lidé MeSH
- mladiství MeSH
- seboroická dermatitida terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
Ketoconazole has been widely used as an antifungal drug that is formulated as tablets, cream and overthecounter ketoconazole shampoo. The aim of this research was to study and to standardize an ultraviolet spectrophotometric (UVS) method, potentiometric and a high performance liquid chromatographic (HPLC) method for the determination of ketoconazole in commercially available Oromycosal® tablets. These three methods were compared and discussed with respect to their sensitivity, selectivity and readyapplicability in routine analytical work. Absorption spectra and spectrophotometric determinations were carried out on the UVS spectrophotometer. Investigated concentrations were in range from 0.003 to 0.02mg?dm3. The absorbance was measured at 224 nm. In potentiometric titrations glass and saturated (KCl) calomel electrode were used. HPLC analyses of ketoconazole were carried in the presence of econazole as internal standard. It can be concluded that the described methods are simple, fast and reliable for determination of ketoconazole in pharmaceutical preparations. The preparation of the samples is easy, the excipients do not interfere in the methods, so they can be used in routine quality control analysis.
- Klíčová slova
- Oromycosal®,
- MeSH
- antifungální látky * chemie MeSH
- inhibitory 14-alfa-demethylasy chemie MeSH
- lékové formy MeSH
- lidé MeSH
- potenciometrie * MeSH
- řízení kvality MeSH
- senzitivita a specificita MeSH
- spektrofotometrie ultrafialová * MeSH
- vysokoúčinná kapalinová chromatografie * MeSH
- Check Tag
- lidé MeSH
Authors describe the frequency and properties of mutants resistant to ketoconazole, obtained from the dermatophytes Microsporum gypseum and Trichophyton mentagrophytes. Spontaneous mutants occurred with the frequency of 10(-9) to spore and nucleus. Ultraviolet radiation increased the frequency of mutants by two numeric orders. The resistance level was relatively small in both types of mutants (RL within the range of 2-5).
The presented study deals with the properties of two wild strains of dermatophyte Microsporum gypseum and of eleven mutants resistant to ketoconazole. The growth rate of spontaneous mutants is greater than that of the wild strain, the group of UV-induced mutants manifests in general lower growth rate. The resistance level varies in the interval 1.1-1.6 (spontaneous mutants), resp. 2.7-5.5 (UV-induced mutants). The phenomenon of cross-resistance to other imidazole drugs (miconazole, clotrimazole) has been observed in mutants. There is further given the characteristic of ergosterol synthesis influence by the three used antifungal drugs. The data obtained are discussed from the point of view of possible biochemical processes resulting in the formation of resistance to ketoconazole.
The ketoconazole-resistant mutants were isolated from four strains of the dermatophyte Microsporum gypseum. The frequency of spontaneous mutants ranged within 10(-8) to 10(-9) (per spore and nucleus). The method was established for obtaining the spontaneous mutants manifested as the faster growing sectors. By means of mutagenic effect of UV radiation, the frequency of mutants increased by one order. The method used for determination of ergosterol the biosynthesis of which could be associated with the mechanism of resistance to ketoconazole is described and evaluated.
Azole antifungal ketoconazole (KET) was demonstrated to activate aryl hydrocarbon receptor (AhR). Since clinically used KET is a racemic mixture of two cis-enantiomers (2R,4S)-(+)-KET and (2S,4R)-(-)-KET, we examined the effects of KET enantiomers on AhR signaling pathway. (+)-KET dose-dependently activated AhR in human gene reporter cell line AZ-AHR, and displayed 5-20× higher agonist activity (efficacy), as compared to (-)-KET; both enantiomers were AhR antagonists with equal potency (IC50). Consistently, (+)-KET strongly induced CYP1A1 mRNA and protein in human HepG2 cells, while (-)-KET exerted less than 10% of (+)-KET activity. In primary human hepatocytes, both enantiomers preferentially induced CYP1A2 over CYP1A1 mRNA and protein, and the potency of (+)-KET was slightly higher as compared to (-)-KET. Ligand binding assay with guinea pig liver cytosols revealed that both (+)-KET and (-)-KET are weak ligands of AhR that displaced [3H]-TCDD with comparable potency. Similarly, both enantiomers weakly transformed AhR to DNA-binding form with similar potency, as showed by EMSA, in guinea pig liver cytosolic extracts and nuclear extracts from mouse Hepa-1 cells. We also examined effects of KET on glucocorticoid receptor (GR), a regulator of AhR activity. Both KET enantiomers antagonized GR with similar potency, as revealed by gene reporter assay in AZ-GR cell line and down-regulation of tyrosine aminotransferase mRNA in human hepatocytes. Finally, we demonstrate enantiospecific antifungal activities of KET enantiomers in six Candida spp. strains. In conclusion, the significance of current study is providing the first evidence of enatiospecific effects of cis-enantiomers of ketoconazole on AhR-CYP1A pathway.
- MeSH
- antifungální látky chemie farmakologie MeSH
- buňky Hep G2 MeSH
- Candida účinky léků MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 genetika metabolismus MeSH
- genetická transkripce účinky léků MeSH
- hepatocyty účinky léků metabolismus MeSH
- ketokonazol chemie farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- morčata MeSH
- myši MeSH
- receptory aromatických uhlovodíků metabolismus MeSH
- senioři MeSH
- signální transdukce účinky léků MeSH
- stereoizomerie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- morčata MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
