Diflucan
Comparison of ketoconazole and fluconazole as cytochrome P450 inhibitors. Use of steady-state infusion approach to achieve plasma concentration-response relationships.

Ervine CM, Matthew DE, Brennan B, Houston JB.

Department of Pharmacy, University of Manchester, UK.

The ability of two azole antifungal agents, ketoconazole and fluconazole, to inhibit hepatic cytochrome P450 activity in vivo in the rat has been determined. To make a valid comparison, differences in pharmacokinetic properties between the azoles were accounted for by using an infusion approach to maintain steady-state plasma concentrations over a range of 1-48 mg/liter. Both compounds showed a maximum inhibitory effect, assessed by a reduction in antipyrine clearance, of approximately 75%. The relationship between steady-state plasma concentration and the degree of inhibition of antipyrine clearance was nonlinear for both azoles. However, the inhibitory effect resulted at lower concentrations for ketoconazole than for fluconazole. Analysis of these data provided Ki values of 3 and 10 microM, for ketoconazole and fluconazole, respectively, based on plasma concentration of azole. This difference in activity is 2 orders of magnitude greater when Ki values are expressed in terms of unbound concentration in the blood, which may be more representative of hepatic tissue concentrations. Ki values based on unbound drug concentration are 0.07 and 8.7 microM for ketoconazole and fluconazole, respectively. These data confirm the conclusions based on in vitro findings that ketoconazole is a more inhibitory of mammalian cytochrome P450 isoenzymes than fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8742233&dopt=Abstract fluconazole Diflucan



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Study of the role of iron in the anticryptococcal activity of human serum and fluconazole.

Grover DD, Brummer E, Stevens DA.

Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA.

Anticryptococcal activity of human serum and apotransferrin in RPMI 1640 was studied in vitro. The effects of varying concentrations of FeCl3 on this activity was investigated. Possible synergy of serum and apotransferrin with fluconazole was also measured. The fungistatic activity of human serum, whether lyophilized, stored at 4 degrees C, fresh frozen or purchased from commercial sources vs. Cryptococcus neoformans was comparable. There was no significant loss of fungistatic activity after freezing and thawing the serum up to 10 times. The fungistatic activity of human serum was similar when tested in different tissue culture media with the exception of Medium 199. The addition of apotransferrin (2.0 or 0.2 mg/ml) to RPMI 1640 had an inhibitory effect on cryptococcal growth. This effect was reversed by 20 microM, of FeCl3 at both apotransferrin concentrations. By contrast, addition of FeCl3 to human serum and RPMI 1640 did not reverse inhibition of growth. Fluconazole synergized with the human serum preparations described, but not with pooled commercial serum, for fungicidal activity. Synergistic activity of fluconazole and human serum was not affected by the addition of FeCl3. Apotransferrin did not show any synergistic fungicidal activity with fluconazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8751825&dopt=Abstract fluconazole Diflucan



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[Oropharyngeal candidiasis resistant to fluconazole in patients infected by HIV]

[Article in French]

Drobacheff C, Manteaux A, Millon L, Reboux G, Barale T, Laurent R.

Service de Dermatologie II, CHRU, Besancot.

PURPOSE: To study the susceptibility to fluconazole of Candida albicans strains in oral candidiasis of HIV positive patients. PATIENTS AND METHODS: Eleven HIV positive patients with confirmed oral candidiasis were included in a 4 to 10 months prospective study. In addition, 23 HIV positive patients were evaluated in a restrospective study (14 with oral candidiasis and 9 control subjects). The MICs to fluconazole of C. albicans were characterized by genotyping (electrophoretic karyotype). RESULTS: Thirty patients were evaluable. Oral candidiasis was found in 21 patients; 7/21 patients (33,3 p. 100) developed resistant C. albicans strain (MIC > 32 mg/ml) after a mean fluconazole cumulative dose of 18 g. In this study, the electrophoretic karyotype confirmed the persistence of the same C. albicans strain in each patient. In addition increased colonization by C. krusei or C. glabrata was found in 6/21 patients (28.5 p. 100). DISCUSSION: Our data demonstrate that prolonged treatment with fluconazole dose higher than 13 g induces the emergence of resistant C. albicans with persistence of the same C. albicans strain. Fluconazole has to be reserved to oral candidiasis after failure of a local treatment or to severe cases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8761757&dopt=Abstract fluconazole Diflucan



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[A new pharmaceutical concept for the therapy of oropharyngeal and esophageal candidiasis with fluconazole]

[Article in German]

Wildfeuer A, Laufen H, Yeates RA, Zimmermann T.

Administration of fluconazole capsules is of proven worth in the treatment of candidosis of the mucous membranes, particularly in immunocompromised patients. An additional topical effect on the course of oropharyngeal and oesophageal candidosis can be expected when fluconazole is administered as a suspension. For this reason a crossover pharmacokinetic study with 12 healthy volunteers was carried out, in which the concentrations of the antimycotic were measured in saliva and plasma, after oral administration of 100 mg fluconazole as either a capsule or as a suspension. The time-courses of the concentration of fluconazole after the two formulations were very similar in plasma, but significantly different in saliva. The mean Cmax for fluconazole in saliva was 551 micrograms/ml 5 min after ingestion of the suspension and 3 micrograms/ml 4 h after taking the capsule. Over the observation time (0-96 h) the concentration of the antimycotic in saliva was more than 80% higher with the suspension than with the capsule.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8767284&dopt=Abstract fluconazole Diflucan



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Simple method for detecting fluconazole-resistant yeasts with chromogenic agar.

Patterson TF, Revankar SG, Kirkpatrick WR, Dib O, Fothergill AW, Redding SW, Sutton DA, Rinaldi MG.

Department of Medicine, University of Texas Health Science Center at San Antonio 78284, USA. PATTERSON UTHSCSA.EDU

A method for detecting fluconazole-resistant yeasts was developed that uses chromogenic agar containing fluconazole. Yeasts were plated on media with fluconazole at 0, 8, and 16 micrograms/ml. On media without fluconazole, normal growth of susceptible yeasts (defined as those having a fluconazole MIC of < 8 micrograms/ml) was detected, while fluconazole-containing media suppressed susceptible strains and normal colonies of resistant yeasts (fluconazole MICs of > or = 8 micrograms/ml) were detected. This method was used to screen for resistance in oropharyngeal candidiasis. Isolates having fluconazole MICs of > or = 8 micrograms/ml and < 8 micrograms/ml were correctly predicted in 43 of 45 cultures and 115 of 116 cultures, respectively. This screening method appears to be rapid and sensitive for detection of fluconazole-resistant yeasts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8784592&dopt=Abstract fluconazole Diflucan



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[Clinical efficacy of fluconazole against fungal infections in hematological diseases]

[Article in Japanese]

Morioka E, Asahara F, Nagano M, Kawasaki C, Yoshida T, Uchida T, Nakashima H, Suzumiya J, Kimura N, Hisano S, Okumura M.

First Department of Internal Medicine, School of Medicine, Fukuoka University.

Clinical efficacy of fluconazole was evaluated against fungal infections complicated with hematological diseases. Fluconazole 200 approximately 400 mg was administered intravenously to 20 suspected fungal infections occurring in patients with hematological diseases (acute leukemia 6, malignant lymphoma 11, adult T cell leukemia 2, chronic myelogenous leukemia blastic crisis 1). These mycoses included 8 cases of suspected pulmonary fungal infection, 10 cases suspected fungemia, and two cases of suspected hepatic fungal abscess. The clinical response rate was 60.0%. Side effects were observed in two cases, one with transient liver function test abnormality and the other with nausea. Fluconazole is considered to be a potent, safe antifungal agent for the treatment of suspected fungal infections associated with hematological diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8786630&dopt=Abstract fluconazole Diflucan



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Comparison of fluconazole and amphotericin B for treatment of experimental Candida albicans endocarditis in rabbits.

Chemlal K, Saint-Julien L, Joly V, Farinotti R, Seta N, Yeni P, Carbon C.

Unite 13, Institut National de la Sante et de la Recherche Medicale, Paris, France.

Amphotericin B (AmB) and fluconazole, administered intraperitoneally for 7 days, were compared in a rabbit model for Candida albicans endocarditis. When given early, AmB was more effective than fluconazole for reducing CFU counts in vegetations (P < 0.01) and kidneys. Forty-eight hours after the last dose, AmB was still detected in all vegetations whereas fluconazole was detected in only one case.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8787921&dopt=Abstract fluconazole Diflucan



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A comparison between solid phase extraction and supercritical fluid extraction for the determination of fluconazole from animal feed.

Khundker S, Dean JR, Jones P.

Department of Chemical and Life Sciences, University of Northumbria at Newcastle, Newcastle upon Tyne, UK.

The application of supercritical fluid extraction with carbon dioxide and modified carbon dioxide for the determination of fluconazole from an animal feed was studied. A fractional factorial design approach was used to examine the significant experimental variables for quantitative extraction of fluconazole. Gas chromatography with either flame ionisation or mass selective detection was used for quantitation of the extracts. The results indicated that modifier (methanol) had the greatest effect on the recovery of fluconazole from the animal feed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8788127&dopt=Abstract fluconazole Diflucan