• Korean Journal of Clinical Pharmacy
• /
• v.34 no.1
• /
• pp.71-78
• /
• 2024

Background: Oral cancer drugs, particularly tyrosine kinase inhibitors (TKIs), are increasingly popular due to their convenience. However, they pose challenges like drug interactions, especially with medications like azole antifungals. While the FDA provides some guidance, more detailed information is needed to manage these interactions effectively. A meta-analysis was conducted to understand the impact of interactions between TKIs and azole antifungals on adverse events during clinical studies. Methods: A meta-analysis followed PRISMA guidelines. Data from PubMed, EMBASE, and references were searched until November 30, 2021. Inclusion criteria encompassed studies on TKI-antifungal interactions in English. Study selection and quality assessment were conducted by two independent investigators. Results: Out of 158 articles, 11 were selected for analysis. Combination therapy showed a slight increase in adverse events but was not statistically significant (OR 1.02, 95% CI 0.49-2.13, p=0.95). AUC and Cmax fold changes did not significantly impact adverse event development. Both itraconazole and ketoconazole showed no significant difference in adverse event development compared to TKI alone. Conclusions: Study finds TKI-DDI not significantly linked to AE increase; azole antifungal types not related to AE. Future DDI research crucial for drug development.

• Proceedings of the Korean Society for Bioinformatics Conference
• /
• 2005.09a
• /
• pp.139-143
• /
• 2005

Cytochrome P450 14${\alpha}$-sterol demethylase enzyme (CYP51) is the target a of azole type antifungals. The azole blocks the ergosterol synthesis and thereby inhibits fungal growth. A three-dimensional (3D) homology model of CYP51 from Candida albicans was constructed based on the X-ray crystal structure of CYP51 from Mycobacterium tuberculosis. Using this model, the binding modes for the substrate (24-methylene-24, 25-dihydrolanosterol) and the known inhibitors (fluconazole, voriconazole, oxiconazole, miconazole) were predicted from docking. Virtual screening was performed employing Structure Based Focusing (SBF). In this procedure, the pharmacophore models for database search were generated from the protein-ligands interactions each other. The initial structure-based virtual screening selected 15 compounds from a commercial available 3D database of approximately 50,000 molecule library, Being evaluated by a cell-based assay, 5 compounds were further identified as the potent inhibitors of Candida albicans CYP51 (CACYP51) with low minimal inhibitory concentration (MIC) range. BMD-09-01${\sim}$BMD-09-04 MIC range was 0.5 ${\mu}$g/ml and BMD-09-05 was 1 ${\mu}$g/ml. These new inhibitors provide a basis for some non-azole antifungal rational design of new, and more efficacious antifungal agents.

• Animal cells and systems
• /
• v.10 no.4
• /
• pp.203-209
• /
• 2006

Azoles are widely used antifungal agents, which inhibit the biosynthesis of fungal cell-membrane ergosterol. In this study, using an amphibian follicle culture system, the effects of azoles on follicular steroidogenesis in frogs were examined. Itraconazole (ICZ), clotrimazole (CTZ) and ketoconazole (KCZ) suppressed pregnenolone ($P_5$) production by the follicles ($ED_{50};\;0.04_{\mu}M,\;0.33_{\mu} M,\;and\;0.91_{\mu}M$, respectively) in response to frog pituitary homogenates (FPH). However, fluconazole (FCZ), miconazole (MCZ) and econazole (ECZ) were not effective in the suppression of $P_5$ production. Not all the azoles examined suppressed the conversion of exogenous $P_5$ to progesterone ($P_4$) (by $3{\beta}$- HSD) or $P_4$ to $17{\alpha}$-hydroxyprogesterone ($17{\alpha}$-OHP) (by $17{\alpha}$-hydroxylase), or androstenedione (AD) to testosterone (T) (by $17{\beta}$-HSD). In contrast, CTZ, MCZ and ECZ in medium partially suppressed the conversion of $17{\alpha}$-OHP to AD (by C17-20 lyase) ($ED_{50};\;0.25{\mu} M,\;4.5{\mu}M,\;and\;0.7{mu}M$, respectively) and CTZ, KCZ, ECZ and MCZ strongly suppressed the conversion of exogenous T to estradiol ($E_2$) (by aromatase) ($ED_{50};\;0.02{\mu}M,\;8{\mu}M,\;0.07{\mu}M,\;0.8{\mu}M$, respectively). These results demonstrated that some azole agents strongly suppress amphibian follicular steroidogenesis and particularly, P450scc and aromatase are more sensitive to azoles than other steroidogenic enzymes.

• YAKHAK HOEJI
• /
• v.35 no.4
• /
• pp.308-313
• /
• 1991

The synthesis of 1-[(2-phenyl-1, 3-benzodioxol-2-yl)methyl]-1H-imidazole derivatives is described starting with 2-bromoacetophenones and catechols. 1-[(2-Phenyl-1, 3-benzodioxol-2-yl)methyl]-1H-imidazole (9-$_{12}$) showed potent broad-spectrum activity, not only against Candida species but also Cr. neofortnans, S. cerevisiae and T. mentagrophytes.

• Journal of the Korean Chemical Society
• /
• v.57 no.6
• /
• pp.744-754
• /
• 2013

Quantitative structure-activity relationship (QSAR) analysis for recently synthesized imidazole-(benz)azole and imidazole - piperazine derivatives was studied for their anticancer activities against breast (MCF-7) cell lines. The statistically significant 2D-QSAR models ($r^2=0.8901$; $q^2=0.8130$; F test = 36.4635; $r^2$ se = 0.1696; $q^2$ se = 0.12212; pred_$r^2=0.4229$; pred_$r^2$ se = 0.4606 and $r^2=0.8763$; $q^2=0.7617$; F test = 31.8737; $r^2$ se = 0.1951; $q^2$ se = 0.2708; pred_$r^2=0.4386$; pred_$r^2$ se = 0.3950) were developed using molecular design suite (VLifeMDS 4.2). The study was performed with 18 compounds (data set) using random selection and manual selection methods used for the division of the data set into training and test set. Multiple linear regression (MLR) methodology with stepwise (SW) forward-backward variable selection method was used for building the QSAR models. The results of the 2D-QSAR models were further compared with 3D-QSAR models generated by kNN-MFA, (k-Nearest Neighbor Molecular Field Analysis) investigating the substitutional requirements for the favorable anticancer activity. The results derived may be useful in further designing novel imidazole-(benz)azole and imidazole-piperazine derivatives against breast (MCF-7) cell lines prior to synthesis.

• KSBB Journal
• /
• v.18 no.1
• /
• pp.1-7
• /
• 2003

Screening of a strain was carried out to produce an enantioselective lipase toward the precursor of ltraconazole as azole-containg compounds, which are well known as antifungal drug agents. An Acinetobacter sp. SY-01 strain which can selectively hydrolyze the racemic substrates was isolated and the racemic substrate was resolved to the S-ester in 95.6% enantiomeric excess after 74.8% hydrolysis. The optimum temperature and pH for the conversion were $50^{\circ}C$, pH 7.0. However, the temperature and pH had no effect on the enantiomeric excess. Addition of solvents decreased the conversion and slightly increased the enantiomeric excess. However, the kind of solvents had no effect on enantiomeric excess. The substrate concentration decrease enantiomeric excess and this is confirmed by the products generated from hydrolysis, and also enantiomeric excess could be increased by the removal of reaction products.

• Journal of Veterinary Clinics
• /
• v.20 no.1
• /
• pp.86-90
• /
• 2003

Little is known to data about the in vitro activity of antimicrobial agents aganist Brucella cams (B cams) isolated from Korea. Our study aimed at determining the in vitro activities of 15 antimicrobial agents against 3 isolates and 52 isolates of B cams from dogs in 1994 and 2002, respectively. In minimal inhibitory concentration (MIC) study, minocycline and doxycycline showed the lowest MICs ( < 0.06-0.5 ug/ml). Gentamicin, streptomycin, ciprofloxacin, norfloxacin and rifampin showed MICs in the range of less than 1 ug/ml. Lincomycin and sulfisox azole showed the highest MICs ( > 32 ug/ml). Interestingly, MICs of macrolides (erythromycin, spiramycin, tylosin) against 52 isolates in 2002 were 16-64 times higher than that of 3 isolates in 1994. In minimal bactericidal concentration (MBC) study, gentamicin, streptomycin, ciprofloxacin and norfloxacin showed the lowest MBCs [0.12-1 ug/ml (1-2 times higher than MIC)], but minocycline and doxycycline showed the highest MBCs [8-32 ug/ml (128 times higher than MIC)]. Rifampin showed the MBCs in the range from 2 to 4 ug/ml (2-4 times higher than MIC).

• Archives of Pharmacal Research
• /
• v.27 no.3
• /
• pp.295-299
• /
• 2004

The antifungal activities of the essential oil from Agastache rugosa and its main component, estragole, combined with ketoconazole, one of the azole antibiotics commonly used to treat infections caused by Trichophyton species, were evaluated in this study. The combined effects were measured by the checkerboard microtiter and the disk diffusion tests, against T. erinacei, T. mentagrophytes, T. rubrum, T. schoenleinii and T. soudanense. Susceptibility of the five Trichophyton species to the oil alone, or ketoconazole alone, differed distinctly. The fractional inhibitory concentration indices (FICI) of ketoconazole combined with estragole or A. rugosa essential oil, against the tested Trichophyton species, were between 0.05 and 0.27, indicating synergistic effects. These drug combinations exhibited the most significant synergism against T. mentagrophytes, with FICIs of 0.05 and 0.09 for estragole and the essential oil fraction from A. rugosa, respectively. Isobolograms based on the data from checkerboard titer tests also indicated significant synergism between ketoconazole and the Agastache oil fraction or estragole, against the Trichophyton species evaluated. Trichophyton susceptibility to ketoconazole was significantly improved by combination with the Agastache rugosa oil fraction or its main component, estragole.

• Korean Journal of Microbiology
• /
• v.47 no.2
• /
• pp.163-166
• /
• 2011

For reduction of side effects by anti-fungal agents, a less toxic anti-fungal substance or a synergistic substance with a new mechanism is needed. The anti-yeast substance (AYS) originated from Rahnella aquatilis strain AY2000 is like to be a heterogeneous protein. The AYS inhibited the growth of Candida albicans in culture broth, and AYS-treated cells were arrested in each phase during cell cycle. Among AYS-treated cells, the population of the cells belonging to sub-G1 phase was not increased during cell cycle. Therefore, AYS has rather yeaststatic than yeastcidal effect to C. albicans. Moreover, with combination of itraconazole or fluconazole, AYS had a synergistic anti-yeast activity against Saccharomyces cerevisiae based on the analysis of fractional inhibitory concentration index.

• Pediatric Infection and Vaccine
• /
• v.12 no.1
• /
• pp.75-85
• /
• 2005

Purpose : Fungal infection is one of the important causes of morbidity and mortality in patients with hematologic malignancies. Amphotericin B(ABV) and itraconazole(ITZA) have been used as the standard empirical antifungal therapy in neutropenic patients with acute leukemia who have persistent fever that does not respond to antibiotic therapy. ABV is an antifungal drug associated with side effects such as fever and chills, symptoms which may be mediated by pro-inflammatory cytokines such as interleukin-$1{\beta}$(IL-$1{\beta}$) and tumor necrosis factor-${\alpha}$(TNF-${\alpha}$). We assessed modulation of these pro-inflammatory cytokines as well as the anti-inflammatory cytokines(IL-4, IL-1Ra) by ABV and ITZA. Methods : From March 2004 to February 2005, a total of 30 episodes from acute leukemia patients with febrile neutropenia were analyzed for this study. They were randomly allocated to receive intravenous ABV or ITZA for 14 days. Clinical responses were evaluated at the completion of therapy, and cytokine IL-$1{\beta}$, TNF-${\alpha}$, IL-4, and IL-1Ra were measured for determination to know the correlation between two antifungal agents and inflammatory cytokines. Results : Empirical antifungal agents were given to 37 patients(ABV 20, ITZA 17), and 30 patients(ABV 15, ITZA 15) were evaluable for efficacy. White blood cell and absolute neutrophil count in the group treated with ITZA increased early days of treatment, so the duration of neutropenia in ITZA group is shorter. Serum creatinine level is lower in ITZA group than in ABV group but this is not statistically significant. There was no significant difference in response rate between two groups. The IL-$1{\beta}$ was increased in ABV treatment group and the ratio of IL-1Ra/IL-$1{\beta}$ is markedly decreased in ABV treatment group while increased in ITZA group. Conclusion : ITZA and ABV have at least equivalent efficacy as empirical antifungal therapy in neutropenic children with acute leukemia. However ITZA is associated with significantly less toxicity in clinical and molecular aspects.