Ketoconazole

Ketoconazole (KET), an imidazole derivative with well-known antifungal properties, is lipophilic and practically insoluble in water, therefore its clinical use has some practical disadvantages. The aim of the present study was to investigate the influence of PAMAM-NH(2) and PAMAM-OH dendrimers generation 2 and generation 3 on the solubility and antifungal activity of KET and to design and evaluate KET hydrogel with PAMAM dendrimers. It was shown that the surface charge of PAMAM dendrimers strongly affects their influence on the improvement of solubility and antifungal activity of KET. The MIC and MFC values obtained by broth dilution method indicate that PAMAM-NH(2) dendrimers significantly (up to 16-fold) increased the antifungal activity of KET against Candida strains (e.g., in culture Candida albicans 1103059/11 MIC value was 0.008 μg/mL and 0.064 μg/mL, and MFC was 2 μg/mL and 32 μg/mL for KET in 10 mg/mL solution of PAMAM-NH(2) G2 and pure KET, respectively). Antifungal activity of designed KET hydrogel with PAMAM-NH(2) dendrimers measured by the plate diffusion method was definitely higher than pure KET hydrogel and than commercial available product. It was shown that the improvement of solubility and in the consequence the higher KET release from hydrogels seems to be a very significant factor affecting antifungal activity of KET in hydrogels containing PAMAM dendrimers.

BackgroundOxidized linoleic acid metabolites (OLAMs) are a class of endogenous agonists to the transient receptor potential V1 (TRPV1) receptor. Although TRPV1 mediates inflammatory heat hyperalgesia, it is not known if the OLAMs contribute to the peripheral activation of this receptor during tissue inflammation. In the present study, we evaluated whether the OLAM system is activated during inflammation and whether cytochrome P450 enzymes mediate OLAM contributions to heat hyperalgesia using the complete Freund's adjuvant (CFA) model of inflammation.ResultsOur results demonstrate that the intraplantar (ipl) injection of anti-OLAM antibodies significantly reversed CFA-induced heat hyperalgesia. Moreover, application of lipid extracts from inflamed rat skin to cultured sensory neurons triggered a significant release of iCGRP that is blocked by co-treatment with I-RTX, a TRPV1 antagonist. To determine the role of CYP enzymes in mediating OLAM effects, we used a broad spectrum CYP inhibitor, ketoconazole. Pretreatment with ketoconazole inhibited the release of TRPV1 agonists in lipid extracts from inflamed skin and significantly reversed CFA-induced heat hyperalgesia by a peripheral mechanism of action. Moreover, the ipl injection of linoleic acid to rats 24 hr after CFA evoked spontaneous nocifensive behaviors that were significantly reduced by capsazepine, by knockout of the TRPV1 gene, or by pretreatment with either anti-OLAM antibodies or ketoconazole.ConclusionsTaken together, our data suggests that OLAMs contribute to inflammatory nociception in the periphery and that cytochrome P450 enzymes play a crucial role in mediating OLAM contributions to inflammatory heat hyperalgesia.

Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography-mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as "flags" to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach.

Five simple, sensitive, and eco-friendly spectrophotometric techniques were developed for solving the highly overlapped spectra of Terbinafine HCl and Ketoconazole in their combined tablet formulation, for the first time without the common excipients interfering. The methods included third derivative spectrophotometry (D3) (Method I), ratio spectra difference spectrophotometry (Method II), first derivative of ratio spectra (Method III), induced dual-wavelength (Method IV), and dual-wavelength resolution (Method V). The evaluation of the developed methods was based on correlation coefficients, relative standard deviations, and limits of detection and quantitation. Statistical tests, including the variance ratio F-test and Student t-test, showed no significant differences between the results obtained from the developed methods and those from the established reference methods. The techniques were efficiently applied to analyze the cited drugs in commercial tablet formulations with high % recoveries and low % RSD values. An assessment of the methods' environmental impact, using the Analytical Eco-scale, the Green Analytical Procedure Index (GAPI), Analytical Greenness Approach (AGREE) and blue applicability grade index (BAGI) metrics demonstrated their sustainability. The developed spectrophotometric methods don't require prior separation steps, large volumes of organic solvents, or sophisticated instruments; therefore, they are well-suited for routine analysis and quality control of the specified drugs in their dosage forms.