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The possible mechanism of action of ciclopirox olamine in the yeast Saccharomyces cerevisiae.

Leem SH, Park JE, Kim IS, Chae JY, Sugino A, Sunwoo Y.

Department of Biology, Dong-A University, Busan 604-714, Korea. shleem daunet.donga.ac.kr

Ciclopirox olamine is a synthetic antifungal agent with a high affinity for trivalent metal cations. Ciclopirox olamine can be used to synchronize mammalian cells, but its mechanism of action is not understood well. In this study, we investigated the effect of ciclopirox olamine in yeast cells and used a genetic approach to identify potential ciclopirox olamine targets in yeast. Wild type strains of the yeast Saccharomyces cerevisiae were weakly sensitive to ciclopirox olamine, but high concentrations of the drug arrested their growth at many different stages. MMS-mutagenized yeast clones were screened for increased sensitivity to ciclopirox olamine. Fourteen mutants, cos101-cos114, were identified and characterized. The targets of ciclopirox olamine in S. cerevisiae appear to include multiple proteins that participate in various components of cellular metabolism, including DNA replication, DNA repair, and cellular transport. Three genes were cloned: a Fe/Cu reductase (FRE1/COS107), an oxidative stress response gene (YAP1/COS110), and a gene involved in signal transduction (YBR203W/COS111). These results suggest that CPO inhibits multiple aspects of cell growth and metabolism, possibly via multiple targets.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12661761&dopt=Abstract ciclopirox Penlac



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Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors.

Niewerth M, Kunze D, Seibold M, Schaller M, Korting HC, Hube B.

Robert Koch-Institut, 13353 Berlin, Germany.

The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concentration (0.6 micro g/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl(3) to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12760852&dopt=Abstract ciclopirox Penlac



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Anodic polarographic determination of ciclopirox olamine in pure and certain pharmaceutical preparations.

Ibrahim F, el-Enany N.

Department of Analytical Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. fibrahim mum.mans.eun.eg

The anodic polarographic behavior of ciclopirox have been studied in Britton Robinson buffer (BRb) over the pH range 6-11. In BRb of pH 7 a well defined anodic wave was produced with diffusion current constant (Id) of 4.86+/-0.048 (n=6) using DC(t) mode. Adopting both of direct current (DC(t)) and differential pulse polarographic (DPP) modes, the current-concentration relationship was found to be rectilinear over the range 4 to 24 and 2 to 12 microg ml(-1) respectively, with minimum detectability (S/N=2) of 0.2 microg ml(-1) (1 x 10(-6) M) using the DPP mode. The average percent recovery was favourably compared to a reference method, with a satisfactory standard deviation, the proposed method was further applied to the determination of ciclopirox olamine in certain pharmaceutical preparations including lotion and cream. The average percentage recoveries for lotion were 100.06+/-0.94 and 100.06+/-1.08 using DC(t) and DPP modes respectively, and for cream were 100.17+/-0.64 and 100.34+/-1.28 using DC(t) and DPP modes, respectively. A pathway for the electrode reaction was postulated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12763546&dopt=Abstract ciclopirox Penlac



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In vitro evaluation of three topical antimycotics against ring-worm fungi singly and in combination.

Rai MK, Upadhyay SK, Agrawal SC.

Department of Botany, Danielson College, Chhinwara.

Three antimycotic drugs, viz., Miconazole nitrate, Econazole nitrate and ciclopirox olamine were tested singly and in combination of miconazole nitrate and Econazole nitrate, Miconazole nitrate and Ciclopirox olamine, and Econazole nitrate and Ciclopirox olamine to evaluate in vitro efficacy against Trichophyton mentagrophytes and Macrosporum nanum. The best efficacy was shown by Ciclopirox olamine (MIC 0.78 microgram/ml) and a combination of Miconazole nitrate and Econazole nitrate (MIC 0.78 microgram/ml).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1289296&dopt=Abstract ciclopirox Penlac



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In vitro susceptibility testing of ciclopirox, terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungal activity.

Gupta AK, Kohli Y.

Division of Dermatology, Department of Medicine, Sunnybrook and Women's College Health Science Center, Sunnybrook site, and the University of Toronto, Toronto, ON, Canada. agupta execulonk.com

BACKGROUND: With the development of newer antifungal agents with activity against both yeasts and filamentous fungi, there is an increased need to develop and standardize in vitro assays that will evaluate the activity of antimycotics against filamentous fungi. In vitro analysis of antifungal activity of these agents would also allow for the comparison between different antimycotics, which in turn may clarify the reasons for lack of clinical response or serve as an effective therapy for patients with chronic infection. OBJECTIVES: To determine the in vitro susceptibility of fungal organisms to ciclopirox, terbinafine, ketoconazole and itraconazole and to evaluate the in vitro activity and mode of interaction of ciclopirox in combination with either terbinafine or itraconazole. MATERIALS AND METHODS: In the minimum inhibitory concentration (MIC) study 133 strains were evaluated, including dermatophytes (110 strains; 98 from Trichophyton spp.), Candida spp. (14 strains) and nondermatophyte moulds (nine strains). In vitro susceptibility testing was conducted in microbroth dilutions based on the National Committee for Clinical Laboratory Standards (NCCLS) M27-A proposed standard. The testing MIC ranges were 0.003-2 microg mL-1 for ciclopirox and terbinafine, and 0.06-32 microg mL-1 for itraconazole and ketoconazole. For inoculum preparation, dermatophytes were grown on Heinz oatmeal cereal agar slants. Inoculum suspensions of dermatophytes were diluted in RPMI 1640 (Sigma-Aldrich) with the desired final concentration being 2-5 x 103 c.f.u. mL-1. Once inoculated, the microdilution plates were set up according to the NCCLS M27-A method, incubated at 35 degrees C, and read visually following 7 days of incubation. For azole agents, the MIC was the lowest concentration showing 80% growth inhibition; for terbinafine and ciclopirox, the MIC was the lowest concentration showing 100% growth inhibition. In the synergy studies, 29 strains from nondermatophyte species were evaluated using a checkerboard microdilution method. The concentrations tested were: 0 and 0.06-32 microg mL-1 for itraconazole, and 0 and 0.003-4 microg mL-1 for both terbinafine and ciclopirox. Modes of interaction between drugs were classified as synergism, additivism, antagonism or indifference based on fractional inhibitory concentration index values (FIC index). Synergism was defined as an FIC index of < or = 0.50, additivity as an FIC index of < or = 1.0, and antagonism as an FIC index of > or = 2.0. The drug combination was interpreted as indifferent if neither of the drugs had any visible effect on the presence of the other drug. RESULTS: In the MIC study, the dermatophyte MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.04 +/- 0.02), terbinafine (0.04 +/- 0.23), itraconazole (2.28 +/- 7.42) and ketoconazole (0.83 +/- 1.99). The yeast MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (0.05 +/- 0.02), terbinafine (1.77 +/- 0.58), itraconazole (0.18 +/- 0.27) and ketoconazole (0.56 +/- 0.60). The non-dermatophyte fungi MIC values (microg mL-1) (mean +/- SEM) were: ciclopirox (1.04 +/- 2.62), terbinafine (1.04 +/- 0.95), itraconazole (17.87 +/- 16.75) and ketoconazole (10.69 +/- 13.09). In the synergy study, with ciclopirox in combination with terbinafine, mainly a synergistic or additive reaction was observed; there were no cases of antagonism. For ciclopirox in combination with itraconazole, there were some instances of additivism or synergism, with indifference in the majority of instances; there were no cases of antagonism. CONCLUSIONS: In vitro susceptibility testing indicates that ciclopirox may have a broad antimicrobial profile including dermatophytes, yeasts and other nondermatophytes. Terbinafine is extremely potent against dermatophytes. In vitro evaluation of activity of ciclopirox and terbinafine suggests many instances of synergy or additivism; for ciclopirox and itraconazole there may be indifference, synergy or additivism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12932235&dopt=Abstract ciclopirox Penlac