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PubMed1994

Risk factors for hepatosplenic abscesses in patients with acute leukemia receiving empiric azole treatment.

The authors retrospectively evaluated 63 febrile neutropenic episodes in 33 consecutive patients with leukemia who received empiric azole treatment for refractory or relapsing fever that occurred despite broad-spectrum antibiotics. In 8 patients (24%), hepatosplenic abscesses (HSA) developed. To identify the risk factors for the development of HSA, the authors compared various characteristics of febrile episodes in those with and without HSA. The risk factors included relapsed status of leukemia (P = 0.04) and Candida colonization of surveillance cultures from the throat (P = 0.03) and stool (P = 0.03). However, the duration of neutropenia, gastrointestinal symptoms, types of chemotherapy, and leukemia subtypes were not correlated with the development of HSA. Based on these results, the authors identified the high risk group for the development for HSA as patients with relapsed leukemia with fungal colonization of gastrointestinal tract during neutropenia despite empiric antifungal treatment with azoles.

Abscess↗
PubMed1989

Toxicological profile and safety evaluation of antifungal azole derivatives.

For the development of new systemically acting, oral antifungal azoles, it is of key importance to compare them with ketoconazole, the first available drug in this therapeutic class. Ketoconazole is a major breakthrough although hepatic side-effects as well as interactions with mammalian steroids might rarely occur during prolonged treatment. The prediction of these side-effects is difficult but the potential to interact with mammalian cytochrome P-450 enzymes is considered to be important. Therefore, for the selection of itraconazole a multidisciplinary approach was applied to study this potential. The present paper deals with the toxicological profile of itraconazole and its safety evaluation. In addition, a further comparison with ketoconazole and also with fluconazole is provided, in so far sufficient information is available. For the liver as a potential target organ, the available data indicate that itraconazole is not a predictable hepatotoxic drug in man. The major endocrine targets for overdosing with antifungal azoles are the adrenal cortex and the gonads. Endocrine studies show that itraconazole is not bearing a potential to interfere with steroid hormones in patients, which is a major improvement when compared to ketoconazole. In rats, elevation of serum cholesterol is observed especially after chronic exposure to itraconazole. This species-specific phenomenon leads at toxic dose levels to secondary events, especially in the long-term toxicity studies. In man, including those with existing hypercholesterolemia, serum cholesterol is not adversely affected by itraconazole. In pregnant rats, ketoconazole was shown to be teratogenic at high, toxic doses. The same observation has been made for itraconazole and this also might be true for fluconazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1997

Reduced intracellular accumulation of azole antifungal results in resistance in Candida albicans isolate NCPF 3363.

Candida albicans strain NCPF 3363 was isolated from a British patient with chronic mucocutaneous candidiasis (CMC) and confirmed to be resistant to azole antifungal compounds. In this study we investigate the molecular basis of resistance and show that azole tolerance in NCPF 3363 was associated with reduced intracellular accumulation of drug and not reduced affinity for the target site, as previously indicated. Relative impermeability or the presence of transporters related to those responsible for multidrug resistance are implicated in the mechanism of resistance.

Antifungal Agents↗
PubMed2000

Phospholipid and sterol analysis of plasma membranes of azole-resistant Candida albicans strains.

The phospholipid and sterol composition of the plasma membranes of five fluconazole-resistant clinical Candida albicans isolates was compared to that of three fluconazole-sensitive ones. The three azole-sensitive strains tested and four of the five resistant strains did not exhibit any major difference in their phospholipid and sterol composition. The remaining strain (R5) showed a decreased amount of ergosterol and a lower phosphatidylcholine:phosphatidylethanolamine ratio in the plasma membrane. These changes in the plasma membrane lipid and sterol composition may be responsible for an altered uptake of drugs and thus for a reduced intracellular accumulation of fluconazole thereby providing a mechanism for azole resistance.

AIDS-Related Opportunistic Infections↗
PubMed1984

In vitro activities of two new antifungal azoles.

The antifungal activities of equimolar quantities of three azole compounds, Bay n 7133 [1-(4-chlorophenoxy)-3,3-dimethyl-2-(1,2,4-triazole-1-yl)methylbutan-2-O1], Bay 1 19139 [1-(4-chlorophenoxy)-1-(1-imidazolyl)-3,3-dimethyl-2-butanol hydrochloride], and ketoconazole, were compared by testing the susceptibility in vitro of 10 clinical isolates each of Candida albicans, Candida parapsilosis, Torulopsis glabrata, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus, Rhizopus spp., Mucor spp., and Coccidioides immitis. Molecule for molecule, ketoconazole was consistently the most active drug. All three azoles were primarily fungistatic, although they were fungicidal at clinically relevant concentrations against some strains of A. niger.

Antifungal Agents↗
PubMed1997

Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus.

Resistance to antifungal drugs, specifically azoles such as fluconazole, in the opportunistic yeast Candida albicans has become an increasing problem in human immunodeficiency virus (HIV)-infected individuals. The molecular mechanisms responsible for this resistance have only recently become apparent and can include alterations in the target enzyme of the azole drugs (lanosterol 14alpha demethylase [14DM]), or in various efflux pumps from both the ABC transporter and major facilitator gene families. To determine which of these possible mechanisms was associated with the development of drug resistance in a particular case, mRNA levels have been studied in a series of 17 clinical isolates taken from a single HIV-infected patient over 2 years, during which time the levels of fluconazole resistance of the strain increased over 200-fold. Using Northern blot analysis of steady-state levels of total RNA from these isolates, we observed increased mRNA levels of ERG16 (the 14DM-encoding gene), CDR1 (an ABC transporter), and MDR1 (a major facilitator) in this series. The timing of the increase in mRNA levels of each of these genes correlated with increases in fluconazole resistance of the isolates. Increased mRNA levels were not observed for three other ABC transporters, two other genes in the ergosterol biosynthetic pathway, or the NADPH-cytochrome P-450 oxidoreductase gene that transfers electrons from NADPH to 14DM. Increases in mRNA levels of ERG16 and CDR1 correlated with increased cross-resistance to ketoconazole and itraconazole but not to amphotericin B. A compilation of the genetic alterations identified in this series suggests that resistance develops gradually and is the sum of several different changes, all of which contribute to the final resistant phenotype.

AIDS-Related Opportunistic Infections↗
PubMed1993

Management of persistent vulvo vaginal candidosis due to azole-resistant Candida glabrata.

CASE REPORT--SUBJECTS--Three cases are described of long-standing vaginal candidosis due to Candida glabrata. These had failed to respond to local and systemic antifungals. In each case the infecting strain appeared resistant to a range of azole drugs in vitro. CLINICAL COURSE--Case one--This patient recovered following prolonged treatment with oral itraconazole in combination with oral and vaginal nystatin. Case two. Yeasts were eradicated from this patient following cyclical treatment with oral dydrogesterone; prolonged vaginal treatment with nystatin may have helped. Case three. This patient did not respond to a prolonged course of oral itraconazole in combination with vaginal and oral nystatin, oral medroxyprogesterone or intravaginal boric acid. Eradication of C glabrata was finally achieved by local application of 1% gentian violet. Shortly after eradication of the C glabrata infection, both Case two and Case three developed infections with other Candida species responsive to azole antifungals.

Administration, Oral↗
PubMed2003

Modulatory effect of cAMP on fungal ergosterol level and inhibitory activity of azole drugs.

The functions and biosynthesis of sterols have been effective targets for fungal control in different areas, including pharmaceutical and agricultural applications. Fungi are among the organisms that synthesize sterols, principally ergosterol. In this paper, the effect of dibutyryl-cAMP (db-cAMP) on ergosterol level and the interaction of drugs that would change the concentration of cAMP with antifungal drugs have been investigated. Sterols were extracted from Candida albicans, and ergosterol was measured using the gas chromatography method. The interaction of different agents was measured by the broth dilution method. It was found that phosphodiesterase inhibitors reverse the inhibitory activity of azole antifungal drugs. Evaluating the ergosterol level of C. albicans incubated with db-cAMP revealed that it increased ergosterol level. Further experiments provided evidence attributing the observed interaction between azoles and phosphodiesterase inhibitors to the relationship between ergosterol and cAMP. The possible significance of this interaction includes potentiation of antifungal activity of drugs by manipulating the cAMP level.

Amphotericin B↗
PubMed1984

Reduction of the in vivo virulence of Candida albicans by pretreatment with subinhibitory azole concentrations in vitro.

Cells of Candida albicans exposed to subinhibitory concentrations of clotrimazole or bifonazole in shake cultures were found to have a reduced capacity to divide normally or produce germ tubes and mycelia under appropriate conditions, although treated cultures produced a cell mass equivalent to that of the untreated controls. The long-term morphological effects are considered to be due to azole-caused disturbances in ergosterol biosynthesis. When cells, pretreated with subinhibitory concentrations of the azole compounds, were injected intravenously in mice, the resultant infections were of reduced severity in comparison to controls, as measured by mortalities and colony forming units in kidneys.

Animals↗
PubMed1997

Studies on aromatase inhibitors. III. Synthesis and biological evaluation of [(4-bromobenzyl)(4-cyanophenyl)amino]azoles and their azine analogs.

A series of [(4-bromobenzyl)(4-cyanophenyl)amino]azoles and their azine analogs, which have the side chain of the selective aromatase inhibitor YM511, were synthesized and evaluated for aromatase-inhibitory activity (in vitro) and for pregnant mare serum gonadotropin (PMSG)-induced estrogen synthesis inhibitory activity (in vivo). Among these aza-heterocycles, the pyrimidin-5-yl derivative (6a) was the most potent aromatase inhibitor and its in vitro inhibitory activity was comparable to that of YM511. Compound 6a also showed weak inhibitory activity on aldosterone synthesis. These data indicated that the pyrimidin-5-yl moiety is useful as a new azole fragment in place of the 4H-1,2,4-triazol-4-yl moiety of the aromatase inhibitor YM511.

Aldosterone↗
PubMed2000

Azole antifungal agents related to naftifine and butenafine.

The methyl group of naftifine (1) and butenafine (2) was replaced by an azolic nucleus to obtain the new compounds 3-8 which exhibit the characteristics of both allylamine (or benzylamine) and azole antifungals. The title compounds were evaluated in vitro against several pathogenic fungi responsible for human disease. Among these, compounds 5, 6, and 8 were found to inhibit the growth of dermatophytes with a potency comparable to that of naftifine. The synthetic sequence includes the preparation of aminoazole Schiff bases, reduction, and alkylation of the corresponding secondary amines.

Allylamine↗
PubMedDate not supplied

Cyclosporine interactions with miconazole and other azole-antimycotics: a case report and review of the literature.

Several antimicrobial drugs have been shown to pharmacokinetically interact with cyclosporine. On two separate occasions, we observed increases in cyclosporine plasma concentrations during concomitant miconazole therapy in a heart transplant patient with an infection secondary to Pseudallescheria boydii. To our knowledge, no interaction between cyclosporine and miconazole has previously been reported. In addition, drug interactions were observed between cyclosporine and ketoconazole and possibly between cyclosporine and SCH 39304, an investigational azole-antifungal agent. No interaction was noted between cyclosporine and fluconazole. In general, clinicians should anticipate drug interactions between cyclosporine and azole-antimycotic agents.

Antifungal Agents↗
PubMed1997

[Molecular and genetic aspects of resistance to azoles in Candida albicans].

Fluconazole is one of the most useful drugs in the treatment of fungal systemic infections which frequently affect non immunocompetent individuals. However, the emergence of resistant strains in recent years may severely limit its usefulness in future. Although there are several described mechanisms involved in resistance to azoles, recent genetic studies demonstrate the role of specific genes in clinical resistance. Currently, the best characterized are the MDR1 and CDR1 genes, which code members of the MFS or ABC family of drug transporters, respectively. These proteins respond to the membrane potential (MFS) or hydrolyse ATP (ABC) thus promoting drug efflux and therefore reducing its intracellular accumulation. It has been shown that the mRNA from these genes is frequently increased in some Candida albicans resistant strains from patients receiving long term azole treatment. The development of molecular genetic tools in C. albicans is allowing characterization of their role in this and other important processes in the fungal cell.

English Abstract↗
PubMed1986

Azole resistance in Candida albicans.

An isolate of Candida albicans from a patient with chronic mucocutaneous candidosis who relapsed during ketoconazole treatment was compared with a number of other azole-sensitive and azole-resistant isolates by tests in vitro and in three animal models of vaginal or disseminated infection. In-vitro tests indicated that the isolate was cross-resistant to all imidazole and triazole antifungals tested. In the animal models, treatment with miconazole, ketoconazole, itraconazole or fluconazole failed to influence the infection.

Adult↗
PubMedDate not supplied

Terfenadine metabolism in human liver. In vitro inhibition by macrolide antibiotics and azole antifungals.

To determine whether the clinical adverse interactions of terfenadine with azole antifungals and macrolide antibiotics may be related to inhibition of terfenadine biotransformation, an in vitro system was developed to follow the metabolism of terfenadine by rat liver S9 or human liver microsomes. When test compounds were coincubated with terfenadine, the metabolites formed and unchanged terfenadine was quantitatively analyzed by HPLC. Five metabolites of terfenadine were formed by rat liver S9: predominantly alcohol metabolite (III), with four minor metabolites--azacyclonol (I), acid metabolite (II), an unidentified metabolite (IV), and a new ketone metabolite (V). By human liver microsomes, two major metabolites were formed: azacyclonol (I) and alcohol metabolite (III). Ketoconazole, fluconazole, itraconazole, erythromycin, clarithromycin, and troleandomycin potently inhibited terfenadine metabolism by human liver (IC50 = 4-10 microM), but inhibition by rat liver was weaker (IC50 = 87-218 microM) and 18% maximally for troleandomycin. Other CYP3A substrates (cyclosporin A, naringenin, and midazolam) also demonstrated potent inhibition of terfenadine biotransformation in human liver microsomes (IC50 = 17-24 microM). Substrates of other P450 families [sparteine (CYP2D6), caffeine (CYP1A), and diclofenac (CYP2C)] only very weakly inhibited terfenadine metabolism. Dixon plot analyses for human liver revealed competitive/reversible inhibition by the azole antifungals and macrolide antibiotics of azacyclonol and alcohol metabolite formations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Expression of the AZR1 gene (ORF YGR224w), encoding a plasma membrane transporter of the major facilitator superfamily, is required for adaptation to acetic acid and resistance to azoles in Saccharomyces cerevisiae.

In this work, we report results on the functional analysis of Saccharomyces cerevisiae ORF YGR224w, predicted to code for an integral membrane protein, with 14 potential transmembrane segments, belonging to the major facilitator superfamily (MFS) of transporters which are required for multiple-drug resistance (MDR). This MFS-MDR homologue is required for yeast adaptation to high stress imposed by low-chain organic acids, in particular by acetic acid, and for resistance to azoles, especially to ketoconazole and fluconazole; the encoding gene was thus named the AZR1 gene. These conclusions were based on the higher susceptibility to these compounds of an azr1Delta deletion mutant strain compared with the wild-type and on the increased resistance of both azr1Delta and wild-type strains upon increased expression of the AZR1 gene from a centromeric plasmid clone. AZR1 gene expression reduces the duration of acetic acid-induced latency, although the growth kinetics of adapted cells under acetic acid stress is apparently independent of AZR1 expression level. Fluorescence microscopy observation of the distribution of the Azr1-GFP fusion protein in yeast living cells indicated that Azr1 is a plasma membrane protein. Studies carried out to gain some understanding of how this plasma membrane putative transporter facilitates yeast adaptation to acetic acid did not implicate Azr1p in the alteration of acetic acid accumulation into the cell through the active efflux of acetate.

Acetic Acid↗
PubMed1990

Researches on antibacterial and antifungal agents, XII: Analogues of bifonazole with two imidazole moieties and related azoles.

Analogues of bifonazole bearing two imidazole rings and other related azoles have been synthesized and tested as antifungal agents against Candida albicans and Candida spp.. Only a slight part of the antifungal power of the parent drug is retained by some derivatives as evinced by the comparison of new compounds with bifonazole, miconazole, and ketoconazole.

Antifungal Agents↗