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Evaluation of the bioequivalence of capsules containing 150 mg of fluconazole.

Porta V, Chang KH, Storpirtis S.

Faculdade de Ciencias Farmaceuticas, Universidade de Sao Paulo, Av. Prof. Lineu Prestes, 580, Sao Paulo, SP 05508-900, Brazil. vporta usp.br

Fluconazole is an antifungal agent. The purpose of this study was to evaluate bioequivalence of two commercial 150 mg capsule formulations of fluconazole available in the Brazilian market. The study was an open, randomized, two-period, two-group crossover trial with a 2-week washout interval. Blood samples were collected throughout a 96-h period after administration of reference product (R) and test product (T) to 28 fasting volunteers. A simple, accurate, precise and sensitive high-performance liquid chromatographic (HPLC) method with ultraviolet detection was developed and validated for quantification of fluconazole in plasma samples after liquid-liquid extraction. Bioequivalence between the products was determined by calculating 90% confidence intervals (90% C.I.) for the ratio of C(max), AUC(0-t) and AUC(0-infinity) values for the test and reference products, using logarithmic transformed data. The 90% confidence intervals for the ratio of C(max) (101.06-105.45%), AUC(0-t) (97.11-104.69%) and AUC(0-infinity) (97.96-103.36%) values for the test and reference products are within the 80-125% interval, proposed by FDA and EMEA. It was concluded that the two fluconazole formulations are bioequivalent in their rate and extent of absorption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15607260&dopt=Abstract fluconazole Diflucan



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In vitro antifungal activity of sertaconazole compared with nine other drugs against 250 clinical isolates of dermatophytes and Scopulariopsis brevicaulis.

Carrillo-Munoz AJ, Guglietta A, Palacin C, Casals J, del Valle O, Guardia C, Rodriguez V, Quindos G.

Departamento de Microbiologia, Asesoria, Cientifica y de la Investigacion Aplicada, Hospital Vall d'Hebron, Barcelona, Espana. acarrillo ya.com

We have tested 250 strains belonging to 15 species of clinically important dermatophytes and Scopulariopsis against ten antifungal drugs using an agar diffusion method (NeoSensitabstrade mark, Rosco, Taastrup, Denmark). Some of the experimental factors were adapted to dermatophyte development, such as temperature (28 vs. 35 degrees C) and time of incubation (2-5 days vs. 21-74 h). The antifungals used are itraconazole, ketoconazole, miconazole, clotrimazole, sertaconazole, terbinafine, tioconazole, fluconazole, isoconazole and econazole. Except for fluconazole, all the drugs tested have shown to be highly effective, especially sertaconazole and terbinafine. Percentages of susceptibility ranged between 94% for terbinafine, 87.6% for sertaconazole and 86.4% clotrimazole; 81.6% econazole; 42.8% fluconazole; 57.2% isoconazole; 78.4% itraconazole; 74.4% ketoconazole; 73.3% miconazole, and 85.2% for tioconazole. Percentages of resistance were similar between sertaconazole and terbinafine (4%) but in contrast to the 48% obtained for fluconazole. 2004 S. Karger AG, Basel.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15608448&dopt=Abstract fluconazole Diflucan



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Characterization of mechanisms of fluconazole resistance in a Candida albicans isolate from a Japanese patient with chronic mucocutaneous candidiasis.

Kamai Y, Maebashi K, Kudoh M, Makimura K, Naka W, Uchida K, Yamaguchi H.

Teikyo University Institute of Medical Mycology, Hachioji, 192-0395, Japan. ykamai sankyo.co.jp

We examined the mechanisms of fluconazole resistance in a fluconazole-resistant Candida albicans isolate from a Japanese patient with chronic mucocutaneous candidiasis. It was demonstrated that the highly resistant phenotype of this strain was associated with combined mechanisms of the energy-dependent reduced intracellular accumulation of fluconazole, presumably due to the increased expression of the ATP-binding cassette efflux pump CDR gene(s), and the reduced affinity of the target enzyme, Erg11p, to fluconazole. In particular, the reduced affinity of Erg11p was considered to contribute largely to the fluconazole resistance in the TIMM3209 strain. Biochemical studies indicated that the Erg11p from the TIMM3209 strain showed reduced susceptibility both to fluconazole and itraconazole of cell-free ergosterol biosynthesis, and cytochrome P-450 also showed reduced affinity to fluconazole in the carbon monoxidecytochrome P-450 complex formation assay. We identified two amino acid substitutions, Y132H and G448V, in Erg11p from the TIMM3209 strain. We found that the cytochrome P-450 from the TIMM3209 strain decayed during incubation at 37 C without fluconazole although it is unknown whether or not the phenomenon is linked to the resistant phenotype. These mutations are thought to confer the above-mentioned characteristics to Erg11p.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15611610&dopt=Abstract fluconazole Diflucan



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Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice.

Kamai Y, Kakuta M, Shibayama T, Fukuoka T, Kuwahara S.

Biological Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. ykamai sankyo.co.jp

The activities of R-135853, a novel sordarin derivative that possesses a 1,4-oxazepane ring moiety, were evaluated in vitro and in vivo. R-135853 exhibited potent in vitro activities against Candida albicans (fluconazole-susceptible strains), Candida glabrata, Candida tropicalis, and Cryptococcus neoformans, with MICs at which 90% of isolates were inhibited of 0.03, 1, 0.5, and 0.5 microg/ml, respectively. R-135853 also exhibited potent activities against fluconazole-susceptible dose-dependent and fluconazole-resistant strains of C. albicans, with MICs ranging from 0.03 to 0.06 mug/ml. However, R-135853 exhibited weak or no activity against Candida parapsilosis, Candida krusei, and Aspergillus spp. R-135853 exhibited dose-dependent efficacy against experimental murine hematogenous candidiasis induced by C. albicans when it was administered by both the subcutaneous and the oral routes and reduced viable cell counts in the kidneys significantly when it was administered at 50 mg/kg of body weight/dose (administration three times a day). In this model, R-135853 also exhibited dose-dependent efficacy by single oral administration. Subcutaneous administration of R-135853 exhibited dose-dependent efficacy against experimental murine esophageal candidiasis induced by fluconazole-resistant C. albicans, against which fluconazole at 50 mg/kg/dose was ineffective, and reduced viable cell counts in the esophagus significantly when it was administered at 10 and 50 mg/kg/dose. R-135853 eradicated C. albicans from the esophagi of one and four of five mice when it was administered at 10 and 50 mg/kg/dose, respectively. These results suggest that R-135853 is promising for the treatment of disseminated or mucosal candidiasis, including fluconazole-refractory infections.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15616275&dopt=Abstract fluconazole Diflucan



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Combination therapy of once-weekly fuloconazole (100, 150, or 300 mg) with topical application of ketoconazole cream in the treatment of onychomycosis.

Chen X, Hiruma M, Shiraki Y, Ogawa H.

Department of Dermatology, Juntendo University School of Medicine, Tokyo 113-8421, Japan.

In order to assess the safety and efficacy of once-weekly fluconazole orally (100, 150, or 300 mg) with once-a-day topical application of 1% ketoconazole cream in the treatment of onychomycosis in Japan, 121 patients were assigned to one of three fluconazole dosages (100, 150, or 300 mg) and took fluconazole orally, once weekly, for 12 months or until a complete cure was achieved. In addition, once-a-day topical ketoconazole cream was applied. At each weekly visit, adverse events were investigated and the length of the diseased nails was measured. Treatment efficacy was assessed 12 months after discontinuation of fluconazole using the following scale: cured, markedly improved, improved, slightly improved, no change. Mycological cure was assessed using KOH wet mount and fungus culture. The results showed that the numbers of patients achieving marked improvement or better were 38/68 (55%), 13/22 (60%), and 21/31 (67%) for the 100 mg, 150 mg, and 300 mg groups, respectively. There was no significant difference between any two groups. The duration of fluconazole therapy was the longest for patients in the 100 mg group. None of the patients reported adverse effects. These findings led to the conclusion that once-weekly fluconazole with once-a-day application of topical ketoconazole cream appears safe and effective for treating onychomycosis. The dosage of 150 mg once weekly for 6 months was recommended, considering both effectiveness and economy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15623951&dopt=Abstract fluconazole Diflucan



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Hepatotoxicity induced by antifungal drugs itraconazole and fluconazole in rats: a comparative in vivo study.

Somchit N, Norshahida AR, Hasiah AH, Zuraini A, Sulaiman MR, Noordin MM.

Pharmacology and Toxicology Unit, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia. nhareet medic.upm.edu.my

Itraconazole and fluconazole are oral antifungal drugs, which have a wide spectrum antifungal activity and better efficacy than the older drugs. However, both drugs have been associated with hepatotoxicity in susceptible patients. The mechanism of antifungal drug-induced hepatotoxicity is largely unknown. Therefore, the aim of this present study was to investigate and compare the hepatotoxicity induced by these drugs in vivo. Rats were treated intraperitoneally with itraconazole or fluconazole either single (0, 10, 100 and 200 mg/kg) or subchronic (0, 10, 50 and 100 mg/kg per day for 14 days) doses. Plasma and liver samples were taken at the end of the study. A statistically significant and dose dependent increase of plasma alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities were detected in the subchronic itraconazole-treated group. In addition, dose-dependent hepatocellular necrosis, degeneration of periacinar and mizonal hepatocytes, bile duct hyperplasia and biliary cirrhosis and giant cell granuloma were observed histologically in the same group. Interestingly, fluconazole treated rats had no significant increase in transaminases for both single and subchronic groups. In the subchronic fluconazole treated rats, only mild degenerative changes of centrilobular hepatocytes were observed. These results demonstrated that itraconazole was a more potent hepatotoxicant than fluconazole in vivo in rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15625777&dopt=Abstract fluconazole Diflucan



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Evaluation of Mycograb, amphotericin B, caspofungin, and fluconazole in combination against Cryptococcus neoformans by checkerboard and time-kill methodologies.

Nooney L, Matthews RC, Burnie JP.

NeuTec Pharma plc, Manchester Royal Infirmary, Manchester M13 9WL, UK.

This article reported the identification of heat shock protein 90 (hsp90) homologues by immunoblot in Cryptococcus neoformans. Mycograb, a genetically recombinant antibody against hsp90, was evaluated against 8 clinical isolates and the National External Quality Assessment Service for Microbiology strain of C. neoformans alone and in combination with amphotericin B, caspofungin, and fluconazole by checkerboard assay. At the end point of an optically clear well, the minimum inhibitory concentration (MIC) 0's ranged from 256 to 1024 microg/mL for Mycograb, from 0.5 to 1 microg/mL for amphotericin B, and from 16 to 32 microg/mL for caspofungin. The combination of Mycograb and amphotericin B produced a fractional inhibitory concentration index from 0.27 to 0.56, indicating a mainly synergistic effect, whereas for caspofungin, it varied from 0.5 to 2. At an end point of > or =50% inhibition, the MIC-2s varied from 16 to 128 microg/mL for Mycograb and from 0.125 to 16 microg/mL for fluconazole. The fractional inhibitory concentration index classified the combination as indifferent for 5 isolates, additive for 3 more isolates, and synergistic in a single isolate. Time-kill analysis on 2 isolates (F/7844 and F/10156), which had synergistic and additive results with amphotericin B, respectively, on checkerboard was performed with 4-16 microg/mL of Mycograb, 2-8 microg/mL of fluconazole, and 0.0625-2 microg/mL of amphotericin B. This demonstrated an increasingly static effect with augmenting concentrations of fluconazole and an initial static effect with amphotericin B at lower concentrations, which became fungicidal as the level of drug increased. The addition of either 4 or 8 microg/mL of Mycograb to 0.5 microg/mL of amphotericin B with C. neoformans F/7844 changed a static effect to a fungicidal effect at 8 h with an increased killing of 1.2 logs at 48 h. With C. neoformans F/10156, the addition of 16 microg/mL of Mycograb to 0.25 microg/mL of amphotericin B produced a difference in killing from 1 logarithm after 4 h to 1.5 logarithms after 48 h. These data suggest that the combination of amphotericin B and Mycograb would be worth exploring in the treatment of infection due to C. neoformans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15629225&dopt=Abstract fluconazole Diflucan



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Toxic interactions between fluconazole and disopyramide in chick embryos.

Yoshiyama Y, Kanke M.

Division of Clinical Pharmacy, Kyoritsu University of Pharmacy, Tokyo, Japan. yoshiyama-yj kyoritsu-ph.ac.jp

The present study evaluated the effect of fluconazole on the heart, as well as and the toxic interactions between fluconazole and disopyramide in chick embryos. Chick embryos have been widely used in pharmacologic and toxicologic experiments for evaluating drug action. Fertilized eggs of White Leghorns were incubated and investigated. Fluconazole 0.4 mg/egg, 0.8 mg/egg, 1.2 mg/egg alone or disopyramide 0.3 mg/egg alone was injected into the air sac of each fertilized egg. And fluconazole 0.4 mg/egg with disopyramide 0.3 mg/egg was injected into the air sac of each fertilized egg. Electrocardiograms (ECGs) were recorded 0 to 60 min after the drug injection, and heart rate was determined from ECG wave cycles. Changes in heart rate were expressed as mean-percent changes of the drug-treated groups to the matched control. After the administration of fluconazole 0.4 mg/egg alone, the heart rate did not differ compared with that of the controls. However, the heart rate was significantly decreased with the administration of fluconazole 0.8 mg/egg and 1.2 mg/egg. The heart rate was also significantly decreased by the administration of fluconazole 0.4 mg/egg together with disopyramide 0.3 mg/egg. In addition, an arrhythmia was produced by fluconazole and disopyramide. These findings indicate that the interaction between fluconazole and disopyramide has a marked influence on the heart rate in chick embryos.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15635181&dopt=Abstract fluconazole Diflucan