Diflucan
The effects of hepatic impairment on the pharmacokinetics of fosfluconazole and fluconazole following a single intravenous bolus injection of fosfluconazole.

Sobue S, Tan K, Haug-Pihale G.

Clinical Pharmacology, Pfizer Global R&D, Tokyo Laboratories, Pfizer Japan Inc., Tokyo, Japan. satoshi.sobue japan.pfizer.com

AIMS: Fosfluconazole is a phosphate pro-drug of fluconazole (FLCZ). This study was conducted to determine the pharmacokinetics of fosfluconazole and FLCZ following a single intravenous injection of fosfluconazole in subjects with hepatic impairment and to compare them with healthy subjects. METHODS: Twenty-four subjects (12 with normal hepatic function and 12 with chronic stable mild to moderate impaired hepatic function) received a single 1000-mg bolus intravenous injection of fosfluconazole. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 192 h and 48 h postdose, respectively. RESULTS: The total clearance of fosfluconazole was higher and the t(1/2,Z) and mean residence time were shorter in hepatically impaired subjects than in normal subjects. This may reflect more rapid conversion to FLCZ. The degree of protein binding of fosfluconazole (> 90%) and the amount of fosfluconazole excreted in the urine were similar in both groups. Slightly higher mean plasma concentrations of FLCZ were observed in the impaired group than in the normal group; however, hepatic impairment had no statistically significant effect on the FLCZ pharmacokinetic parameters apart from t(max). The t(max) values were 4.8 h and 3.1 h in the normal and impaired subjects, respectively. The shorter t(max) for FLCZ is also consistent with the more rapid conversion in the impaired subjects. The ratios (95% confidence intervals) for C(max) and AUC of FLCZ (impaired/normal) were 106.0% (92.8, 121.2) and 115.6% (86.4, 154.7), respectively. There were no serious adverse events, and no discontinuations due to adverse events or laboratory test abnormalities. The adverse events reported were mostly mild in severity and no trend could be discerned between the groups. CONCLUSIONS: Fosfluconazole was more rapidly converted to FLCZ in the hepatically impaired subjects but the FLCZ pharmacokinetic parameters (except t(max)) were not statistically significantly affected by hepatic impairment. Fosfluconazole was well tolerated by both groups. These results suggest that there is no requirement to adjust the dose of fosfluconazole when administered to subjects with mild to moderate hepatic impairment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15676037&dopt=Abstract fluconazole Diflucan



Diflucan
Reassessment of the in vitro synergistic effect of fluconazole with the non-steroidal anti-inflammatory agent ibuprofen against Candida albicans.

Arai R, Sugita T, Nishikawa A.

Department of Microbiology, Meiji Pharmaceutical University, Tokyo, Japan.

We reassessed the in vitro synergistic effect of fluconazole with the non-steroidal anti-inflammatory agent ibuprofen against the pathogenic yeast Candida albicans. No synergistic effect of fluconazole combined with ibuprofen was seen against fluconazole-susceptible strains, but a remarkable effect was seen against fluconazole-resistant strains (FIX index: 0.02-0.03). Furthermore, vigorous growth of the microorganism, the so-called 'Eagle effect', was observed at concentrations higher than the minimal inhibitory concentrations of ibuprofen and fluconazole. Our results suggest that the combination of ibuprofen and fluconazole should prove useful for treating infection caused by fluconazole-resistant C. albicans.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15679664&dopt=Abstract fluconazole Diflucan



Diflucan
Antifungal activity of posaconazole compared with fluconazole and amphotericin B against yeasts from oropharyngeal candidiasis and other infections.

Carrillo-Munoz AJ, Quindos G, Ruesga M, Alonso R, Del Valle O, Hernandez-Molina JM, McNicholas P, Loebenberg D, Santos P.

Departamento de Microbiologia, ACIA, PO Box 10178, E-08080 Barcelona.

OBJECTIVES: The in vitro antifungal activity of posaconazole was compared with that of fluconazole and amphotericin B. Materials and methods: A microdilution method (M27-A2) was used with 331 clinical yeast isolates. RESULTS: The geometric mean MICs of posaconazole, fluconazole and amphotericin B were 0.16, 0.91 and 0.15 mg/L, respectively. Posaconazole was markedly more active than fluconazole and was active against 9/11 fluconazole-resistant Candida albicans, and five Candida glabrata had an MIC of posaconazole of 16 mg/L. CONCLUSIONS: These data indicate that posaconazole is a potentially effective antifungal agent for the treatment of mycoses caused by yeasts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15705637&dopt=Abstract fluconazole Diflucan



Diflucan
[Prophylaxis of fungal infection in patients with hematologic neoplasms and severe neutropenia after high-dose chemotherapy]

[Article in Russian]

[No authors listed]

Infection is one of the main causes of death in patients with hemoblastoses. Within the last years there was observed an increase in the ratio of fungal infections in the structure of mortality among hematologic patients with neutropenia. The present study was aimed at comparative estimation of the efficacy of the prophylactic use of various azole antifungal agents in patients with hematologic neoplasms and severe neutropenia. The trial enrolled 88 patients comparable by the diagnosis and chemotherapy characteristics, in whom severe neutropenia developed after intensive therapy. Antifungal drugs were used prophylactically when the neutrophil count lowered below 1.0 x 10(9)/l until its increasing above 1.0 x 10(9)/l or when the signs of fungal infection were evident. Itraconazole was used in cyclodextrin solution in 30 patients in a dose of 0.2 g orally twice a day and fluconazole was used in capsules in 24 patients in a dose of 0.2 g orally once a day. The results were compared with those of the ketoconazole use in a dose of 0.2 g orally twice a day (n = 34). The frequency of fungal infection proved by the clinical documentation was 20.5% in the ketoconazole group (k) (7 out of 34 patients), 8.3% in the fluconazole group (f) (2 out of 24 patients) and 6.6% in the itraconazole group (i) (2 out of 30 patients), p (k-f) = 0.21, p (k-i) = 0.11 and p (f-i) = 0.74. The frequency of fungal infection proved by the microbiological documentation was statistically much higher in the ketoconazole group (38.2%) vs. the fluconazole group (8.3%) (p = 0.013) and the itraconazole group (6.6%) (p = 0.004). The prophylactic use of itraconazole and fluconazole was efficient in preventing development of invasive mycoses in the patients with hemoblastoses and severe neutropenia. Their efficacy was much higher than that of ketoconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15727147&dopt=Abstract fluconazole Diflucan



Diflucan
Efficacy of micafungin against deep-seated candidiasis in cyclophosphamide-induced immunosuppressed mice.

Ninomiya M, Mikamo H, Tanaka K, Watanabe K, Tamaya T.

Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.

OBJECTIVES: We investigated the effects of fluconazole and micafungin for the therapy of deep-seated candidiasis in a cyclophosphamide-induced immunosuppressed mouse model. METHODS: We used the experimental model of intraperitoneal fungal abscess caused by Candida albicans, as described previously. RESULTS AND CONCLUSIONS: Micafungin efficacy was equal to that of fluconazole in one-tenth dosage even in peritonitis. We also assessed the short-term (24 h) and long-term (8 days) therapeutic effects after the end of therapy. Although the therapeutic effect of fluconazole was similar to that of micafungin at 24 h after the end of therapy, the effect of micafungin was superior to that of fluconazole at 8 days after the end of therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15728144&dopt=Abstract fluconazole Diflucan



Diflucan
Fluconazole distribution in rat dermis following intravenous and topical application: A microdialysis study.

Mathy FX, Ntivunwa D, Verbeeck RK, Preat V.

Unite de Pharmacie Galenique, Universite catholique de Louvain, Av. E. Mounier 73, UCL 73.20, 1200 Brussels Belgium.

The objective of this study was to investigate the skin distribution of fluconazole, a water-soluble antifungal agent, following intravenous (i.v.) and topical administration in the awake freely moving rat. Following i.v. bolus injection of fluconazole (10 mg/kg), a dual-site microdialysis sampling was performed in jugular vein and dermis in five rats. In addition, cutaneous absorption was studied by dermal microdialysis sampling following topical application of Diflucan(R) Gel 0.5% to 12 rats. Fluconazole microdialysate concentrations were measured by on-line HPLC. To calibrate in vivo the probes, a fluorinated analog (UK-54737) of fluconazole was used as retrodialysis marker after demonstrating that recoveries were no different. Following i.v. bolus injection, fluconazole rapidly penetrates into the dermis. Cutaneous microdialysis sampling provided dermal concentrations of fluconazole, which were very similar to the unbound plasma concentrations determined by vascular microdialysis. The distribution equilibrium was rapidly achieved with a dermis-to-plasma partition coefficient of 1.02 +/- 0.04 (n = 5). Following topical application of 0.5 g of Diflucan Gel(R) containing 0.5% of fluconazole, active unbound concentrations in dermis were measured by cutaneous microdialysis for 11 h after application. The area under the curve (AUC) of fluconazole in dermal dialysate was relatively constant to an implantation depth of approximately 350 mum. Below this depth, the AUC progressively decreased with increasing implantation depth of the probe. Finally, this study shows that cutaneous microdialysis is an effective and minimally invasive tool to evaluate the dermal pharmacokinetics of fluconazole following intravenous or topical administration. (c) 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:770-780, 2005.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15729707&dopt=Abstract fluconazole Diflucan



Diflucan
In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans.

Miller JL, Schell WA, Wills EA, Toffaletti DL, Boyce M, Benjamin DK Jr, Bartroli J, Perfect JR.

Department of Medicine, Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.

The activity of albaconazole (UR-9825; J. Uriach & Cia. S.A., Barcelona, Spain) was compared to that of fluconazole against 12 isolates of Cryptococcus neoformans in vitro and against 1 isolate in vivo in a rabbit model of cryptococcal meningitis. Albaconazole was 100-fold more potent in vitro than fluconazole on a per-weight basis and was fungicidal at potentially relevant concentrations for two isolates. MICs ranged from </=0.0012 to 1.25 micro g/ml, with the MICs for most isolates being between 0.039 and 0.156 micro g/ml. Isolates were from human immunodeficiency virus (HIV)-infected and non-HIV-infected patients and were of serotypes A, B, and C; and the fluconazole MICs for some of the isolates were elevated. Infected rabbits were treated with either fluconazole or albaconazole at dosages ranging from 5 to 80 mg/kg of body weight/day. The peak concentrations of albaconazole in serum and cerebrospinal fluid (CSF) averaged 4.14 and 0.62 micro g/ml, respectively, in animals receiving 80 mg/kg/day. Comparison of the concentrations in serum and CSF suggested a level of CSF penetration of approximately 15%. Despite limited penetration into the subarachnoid space, at all three doses tested albaconazole was as effective as fluconazole for the treatment of cryptococcal meningitis in rabbits.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14742184&dopt=Abstract fluconazole Diflucan



Diflucan
Clinical and mycological responses to fluconazole and fluconazole MIC in oropharyngeal candidiasis in HIV-infected patients.

Bussaratid V, Tansupasawasdikul S, Simpson A, Pitisuttithum P, Phonrat B, Howe P, White NJ.

Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

INTRODUCTION: OPC is a common opportunistic infection in HIV-infected patients. Although some patients are asymptomatic, progression of the disease may occur leading to esophageal candidiasis. Fluconazole resistant candidiasis has been reported in several international studies. OBJECTIVES: This study aimed to test the MICs (minimal inhibitory concentrations) to fluconazole of Candida species isolated from mouthwash specimens of 54 HIV positive patients with oral candidiasis. Clinical and mycological responses to fluconazole were also assessed in 16 patients. MATERIAL AND METHOD: This was a prospective study. Mouthwash specimens were cultured on sabouraud dextrose agar twice. Candida species identification was performed and MICs for fluconazole were obtained using NCCLS guidelines. Clinical and mycological responses were assessed on day 14 and 42 in 16 patients who received a 14-day course of fluconazole. RESULTS: 48/54 patients (88.89%) were found to carry pure C. albicans. The other 6 patients (11.11%) had mixed Candida species on cultures. Among these 6 patients, 5 patients had mixed C. albicans and C. glabrata, and 1 patient had C. albicans and C. krusei. Fluconazole MICs of C. albicans, C. glabrata, and C. krusei ranged from 0.125-32 (median=0.250), 4-64 (median=2), and 8 g/L respectively. This study showed that the MICs to fluconazole of oropharyngeal Candida was a good predictor of the therapeutic responses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12296406&dopt=Abstract fluconazole Diflucan