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PubMed2006

In vivo activity of terpinen-4-ol, the main bioactive component of Melaleuca alternifolia Cheel (tea tree) oil against azole-susceptible and -resistant human pathogenic Candida species.

BACKGROUND: Recent investigations on the antifungal properties of essential oil of Melaleuca alternifolia Cheel (Tea Tree Oil, TTO) have been performed with reference to the treatment of vaginal candidiasis. However, there is a lack of in vivo data supporting in vitro results, especially regarding the antifungal properties of TTO constituents. Thus, the aim of our study was to investigate the in vitro and the in vivo anti-Candida activity of two critical bioactive constituents of TTO, terpinen-4-ol and 1,8-cineole. METHODS: Oophorectomized, pseudoestrus rats under estrogen treatment were used for experimental vaginal infection with azole (fluconazole, itraconazole) -susceptible or -resistant strains of C. albicans. All these strains were preliminarily tested for in vitro susceptibility to TTO, terpinen-4-ol and 1,8-cineole for their antifungal properties, using a modification of the CLSI (formerly NCCLS) reference M27-A2 broth micro-dilution method. RESULTS: In vitro minimal inhibitory concentrations (MIC90) values were 0.06% (volume/volume) for terpinen-4-ol and 4% (volume/volume) for 1,8-cineole, regardless of susceptibility or resistance of the strains to fluconazole and itraconazole. Fungicidal concentrations of terpinen-4-ol were equivalent to the candidastatic activity. In the rat vaginal infection model, terpinen-4-ol was as active as TTO in accelerating clearance from the vagina of all Candida strains examined. CONCLUSION: Our data suggest that terpinen-4-ol is a likely mediator of the in vitro and in vivo activity of TTO. This is the first in vivo demonstration that terpinen-4-ol could control C. albicans vaginal infections. The purified compound holds promise for the treatment of vaginal candidiasis, and particularly the azole-resistant forms.

Animals↗
PubMed2005

Second-generation azole antifungal agents.

The development of the triazole antifungal agents in the 1980s and 1990s greatly enhanced physicians' ability to treat fungal infections due to the lower toxicity of these agents compared with previous antifungal therapies. Despite the addition of these agents, there continues to be limited therapeutic choices for a number of mycoses that cause significant disease in humans. Three new agents (voriconazole, posaconazole and ravuconazole) have been developed which appear to have expanded antifungal activity compared with prior azoles. This review discusses the pharmacology, in vitro and in vivo activity, clinical studies and toxicities of these second-generation azoles. Presently, only voriconazole is available clinically and is indicated for the treatment of esophageal candidiasis, invasive aspergillosis, and refractory infections with Scedosporium apiospermum and Fusarium spp. Posaconazole and ravuconazole are still in development for human use.

Animals↗
PubMed2005

Application of deoxyribonucleic acid microarray analysis to the study of azole antifungal resistance in Candida albicans.

The near completion of sequencing the Candida albicans genome has made it possible to employ genomic technologies, such as microarray analysis, to aid in identifying key genes involved in such clinical problems as the acquisition of high-level resistance to azole antifungal agents. Here, we outline in detail the methodologies utilized in our laboratory to culture clinical isolates of C. albicans, isolate ribonucleic acid from such cultures, synthesize labeled complimentary deoxyribonucleic acid probes from the ribonucleic acid samples, hybridize the probes to microarray chips, analyze the data from such hybridizations, and validate results using reverse transcriptase-polymerase chain reactions. Microarray analysis gives researchers the ability to identify genes involved in processes such as acquisition of azole resistance and to use the data in a way that may lead to clinical approaches to inactivate these genes and improve patient outcomes.

Antifungal Agents↗
PubMed2006

Factors influencing the magnitude and clinical significance of drug interactions between azole antifungals and select immunosuppressants.

The magnitude of drug interactions between azole antifungals and immunosuppressants is drug and patient specific and depends on the potency of the azole inhibitor involved, the resulting plasma concentrations of each drug, the drug formulation, and interpatient variability. Many factors contribute to variability in the magnitude and clinical significance of drug interactions between an immunosuppressant such as cyclosporine, tacrolimus, or sirolimus and an antifungal agent such as ketoconazole, fluconazole, itraconazole, voriconazole, or posaconazole. By bringing similarities and differences among these agents and their potential interactions to clinicians' attention, they can appreciate and apply these findings in a individualized patient approach rather than follow only the one-size-fits-all dosing recommendations suggested in many tertiary references. Differences in metabolism and in the inhibitory potency of cytochrome P450 3A4 and P-glycoprotein influence the onset, magnitude, and resolution of drug interactions and their potential effect on clinical outcomes. Important issues are the route of administration and the decision to preemptively adjust dosages versus intensive monitoring with subsequent dosage adjustments. We provide recommendations for the concomitant use of these agents, including suggestions regarding contraindicated combinations, those best avoided, and those requiring close monitoring of drug dosages and plasma concentrations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Comparative toxicological assessment of a water-soluble azole administered both orally and by intravenous continuous infusion in cynomolgus monkeys.

The water-soluble azole, 4-[1-[(3-methylaminoacetoxymethyl-pyridin-2-yl)-methyl-carbamoyloxy]- ethyl]-1-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2- (2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride (hereinafter referred to as WSA), is a new water-soluble triazole anti-fungal compound. WSA is rapidly converted into its active metabolite after administration by either the intravenous or oral route. The clinical effects of WSA are expected to be consistent whether it is administered by injection (intravenous) or orally. To evaluate and compare the toxicities of WSA via oral and intravenous administration, repeated toxicity studies of WSA were conducted in cynomolgus monkeys (oral dosage levels: 0, 10, 30 and 90 mg/kg/day over a 4-week period; intravenous infusion dosage levels: 0, 10, 30 and 60 mg/kg/day over a 2-week period). In addition, a 2-week oral toxicity study of the active metabolite of WSA was conducted with similar dosages (0, 10, 30 and 90 mg/kg/day). From the results obtained from the evaluation, hepatotoxicity (liver) and endocrinological toxicity (adrenals) were the major toxicities, a finding which is comparable to other previously tested azole compounds. In the 4-week oral toxicity study, the lethal dose of WSA was determined to be 90 mg/kg. However, no animal mortality was observed during the 2-week intravenous continuous infusion study. The toxicokinetics (TK) profile of WSA at 10 and 30 mg/kg dosages illustrated a rapid, dose-dependent conversion of WSA to its active metabolite, and the plasma levels of Cmax and AUC were well correlated to their toxicities. However, at high dosages (60 and 90 mg/kg), WSA demonstrated high exposure beyond the dose-proportional manner. Overall, the results obtained indicate that maintaining an effective concentration and a non-toxic dosage level would be manageable by utilizing an initial intravenous continuous infusion followed by oral administration.

Administration, Oral↗
PubMed1985

The interaction of representative members from two classes of antimycotics--the azoles and the allylamines--with cytochromes P-450 in steroidogenic tissues and liver.

Spectrophotometric studies with ketoconazole, clotrimazole and miconazole show strong type-II interactions with several cytochromes P-450, particularly (Ks greater than 10(7)M-1; pH7.4; 25 degrees C) with the 11 beta-hydroxylase of adrenal mitochondria, with the 17 alpha/20 lyase of testis microsomes and with some forms of cytochromes P-450 of liver. A tight binding of the azoles also occurs to the reduced cytochromes, giving rise to an impeded CO binding to the haem iron. The binding of the azoles to 11 beta-hydroxylase and 17 alpha/20 lyase is much tighter than the binding of endogenous substrates, and consequently inhibition of steroidogenesis will occur at these sites. The metabolism of xenobiotic substrates by the cytochromes P-450 of liver will also be severely impeded. In contrast, the allylamines naftifine and SF 86-327 are type-I substrates for a small portion of cytochromes P-450 of liver microsomes only and there is no spectral evidence for binding to the cytochromes P-450 involved in steroid biosynthesis.

Adrenal Glands↗
PubMed1989

Uranyl-ion catalyzed oligonucleotide synthesis from adenosine-5'-phosphorazolide. The effect of azoles as nucleotide activating groups.

Polymerization of azole-activated nucleotides was conducted in an aqueous medium with uranyl ion as a catalyst. Imidazole, 2-methylimidazole, 4-methylimidazole, triazole, nitrotriazole, tetrazole and 2-methylbenzimidazole were used as an activation group for adenylic acid. Oligoadenylates up to the hexadecamer were obtained in high total yield under the optimum condition. The azole compounds had large effect on the rate of polymerization, the yield and the chain length of the resulting oligoadenylates.

Adenine Nucleotides↗
PubMedDate not supplied

[Quantitative "structure-antimicrobial activity" relations of the new azole derivatives].

New azole derivatives are synthesized and examined with the purpose of searching antimicrobic drugs and of determining the quantitative structure--activity relationships. Their antifungal and antibacterial activity is fixed. Certain regularities of the relationships between the chemical structure of compounds and their activity are determined by the Free-Wilson model. The influence of aryl and alkyl radicals in 1.2 and 5 positions of azoles on antimicrobial properties is discussed. Prospects for the further studies of this group of chemicals are shown.

Anti-Infective Agents↗
PubMed1997

[Azole antifungal agents in the prevention of fungal infections in neutropenic patients and bone marrow graft recipients].

Fungal infections are often encountered in neutropenic patients and bone marrow graft recipients. Several studies have demonstrated the efficacy of antifungal prophylaxis. Regimens including azole compounds are increasingly used due to facilitate administration. The efficacy of fluconazole to prevent systemic candidiasis was recently documented in multicentric studies in bone marrow recipients but is more controversial in neutropenic patients. The risk of selecting strains of Candida with lower sensitivity to azole compounds must also be taken into consideration. There has not been any large study evidencing a primary prophylactic affect of itraconazole against invasive aspergillosis, but the results of multicentric studies should be available soon. Recent trials have attempted to determine how these compounds can best be used in empirical treatment of persistent fever in neutropenic patients and in secondary prophylaxis for mycoses during later intensive treatment protocols.

Antifungal Agents↗
PubMed1998

Docking analysis of a series of cytochrome P-450(14) alpha DM inhibiting azole antifungals.

Binding modes of a series of structurally diverse azole antifungals belonging to triazole and imidazole classes have been studied using molecular modeling techniques. The predictive model was derived from docking experiments. The analysis of the resulting model indicated that the N3 of imidazole and N4 of triazole rings are in coordinate bond forming distances with heme iron. The aromatic ring has been found to interact with Phe87, Tyr96, Val295, Val396 and Ile395 at the hydrophobic site of the cytochrome P-450cam. In addition, the hydrogen bonding interaction between an etherial oxygen of compounds 2, 5, 8, 9 and 12 and Tyr96 OH seem to have a significant role. Solvent accessible surface area calculations suggested that the active site of the cytochrome P-450cam is highly hydrophobic. The results are in consistent with the biological activity of these compounds. The proposed active orientation model of azole antifungals could be useful for the rational design of more potent inhibitors.

Antifungal Agents↗
PubMed1999

Characteristics of the heterologously expressed human lanosterol 14alpha-demethylase (other names: P45014DM, CYP51, P45051) and inhibition of the purified human and Candida albicans CYP51 with azole antifungal agents.

Human and Candida albicans CYP51 were purified to homogeneity after GAL10-based heterologous expression in yeast in order to resolve the basis for the selective inhibition of the fungal enzyme over the human orthologue by the azole drugs ketoconazole and itraconazole, used in the treatment of systemic fungal infection. The purified proteins have similar spectral characteristics, both giving a maximum at 448 nm in reduced carbon monoxide difference spectra. Substrate affinity constants of 20.8 and 29.4 microM and Vmax of 0. 15 and 0.47 nmol/min/nmol were observed for C. albicans and human enzymes, respectively, in reconstituted enzymatic assays, using an intermediate of the demethylation reaction [32-3H]-3beta-hydroxylanost-7-en-32-ol as the substrate. Both enzymes gave similar type II spectra on titration with drugs, but a reduced affinity was observed for human CYP51 using the ability of carbon monoxide to displace the drug as a ligand and by calculation of IC50. However, although the results indicate higher affinity of the drugs for their target CYP51 in the major fungal pathogen C. albicans, when compared directly to CYP51 from humans, the difference was less than 10-fold. This difference is an order of magnitude lower than previously reported data based on measurements using unpurified human CYP51 enzyme preparations. Consequently, increased azole doses to combat resistant candidaemia may well inhibit endogenous human CYP51 and the potential consequences are discussed.

Antifungal Agents↗
PubMed1996

Inhibition of mitochondrial function in isolated rate liver mitochondria by azole antifungals.

Ketoconazole is an imidazole oral antifungal agent with a broad spectrum of activity. Ketoconazole has been reported to cause liver damage, but the mechanism is unknown. However, ketoconazole and a related rug, miconazole, have been shown to have inhibitory effects on oxidative phosphorylation in fungi. Fluconazole, another orally administered antifungal azole, has also been reported to cause liver damage despite its supposedly low toxicity profile. The primary objective of this study was to evaluate the metabolic integrity of adult rat liver mitochondria after exposure to ketoconazole, miconazole, fluconazole, and the deacetylated metabolite of ketoconazole by measuring ADP-dependent oxygen uptake polarographically and succinate dehydrogenase activity spectrophotometrically. Ketoconazole, N-deacetyl ketoconazole, and miconazole inhibited glutamate-malate oxidation in a dose-dependent manner such that the 50% inhibitory concentration (I50) was 32,300, and 110 microM, respectively. In addition, the effect of ketoconazole, miconazole, and fluconazole on phosphorylation coupled to the oxidation of pyruvate/malate, ornithine/malate, arginine/malate, and succinate was evaluated. The results demonstrated that ketoconazole and miconazole produced a dose-dependent inhibition of NADH oxidase in which ketoconazole was the most potent inhibitor. Fluconazole had minimal inhibitory effects on NADH oxidase and succinate dehydrogenase, whereas higher concentrations of ketoconazole were required to inhibit the activity of succinate dehydrogenase. N-deacetylated ketoconazole inhibited succinate dehydrogenase with an I50 of 350 microM. In addition, the reduction of ferricyanide by succinate catalyzed by succinate dehydrogenase demonstrated that ketoconazole caused a dose-dependent inhibition of succinate activity (I50 of 74 microM). In summary, ketoconazole appears to be the more potent mitochondrial inhibitor of the azoles studied; complex I of the respiratory chain is the apparent target of the drug's action.

Animals↗
PubMed2006

Mild copper-catalyzed vinylation reactions of azoles and phenols with vinyl bromides.

An efficient and straightforward copper-catalyzed method allowing vinylation of N- or O-nucleophiles with di- or trisubstituted vinyl bromides is reported. The procedure is applicable to a broad range of substrates since N-vinylation of mono-, di-, and triazoles as well as O-vinylation of phenol derivatives can be performed with catalytic amounts of copper iodide and inexpensive nitrogen ligands 3 or 8. In the case of more hindered vinyl bromides, the use of the original bidentate chelator 8 was shown to be more efficient to promote the coupling reactions than our key tetradentate ligand 3. The corresponding N-(1-alkenyl)azoles and alkenyl aryl ethers are obtained in high yields and selectivities under very mild temperature conditions (35-110 degrees C for N-vinylation reactions and 50-80 degrees C for O-vinylation reactions). Moreover, to our knowledge, this method is the first example of a copper-catalyzed vinylation of various azoles. Finally, this protocol, practical on a laboratory scale and easily adaptable to an industrial scale, is very competitive compared to the existing methods that allow the synthesis of such compounds.

Journal Article↗
PubMed2001

Plant sterol 14 alpha-demethylase affinity for azole fungicides.

Azole fungicides were thought to have much greater affinity for the fungal cytochrome P450 enzyme, sterol 14 alpha-demthylase (CYP51) than the plant orthologue. Using purified CYP51 from the plant Sorghum bicolor L Moenech, a direct comparison of the sensitivity to the fungicides triadimenol and tebuconazole has been carried out. S. bicolor CYP51 was purified to homogenity as determined by SDS--PAGE and specific heme content. Addition of the azole fungicides triadimenol and tebuconazole induced type II spectral changes, with saturation occurring at equimolar azole/P450 concentrations. Inhibition of reconstituted activities revealed only a threefold insensitivity of the plant CYP51 compared to a fungal CYP51, from the phytopathogen Ustilago maydis, as judged by IC(50) values. The implications for fungicide mode of action and application are discussed.

Cytochrome P-450 Enzyme Inhibitors↗
PubMed1998

A study of solvent polarity and hydrogen bonding effects on the nitrogen NMR shielding of isomeric tetrazoles and ab initio calculation of the nitrogen shielding of azole systems

High-precision nitrogen NMR shieldings, bulk susceptibility corrected, are reported for the N-methyl derivatives of the two existing isomeric tetrazoles (I, II) in a variety of solvents which represent a wide range of solvent properties from the point of view of polarity as well as hydrogen bond donor and acceptor strength. The observed range of solvent-induced nitrogen shielding variations of I and II is significant for the pyrrole-type nitrogens (N-Me), up to 9 ppm, and even more so for pyridine-type nitrogen atoms, where it can attain a value of 20 ppm. There is a clear distinction between the two types of nitrogen atoms in that the former exhibit a deshielding effect with increasing polarity of the medium while the latter experience an increase in the magnetic shielding of their nuclei. The latter effect is significantly augmented by solvent-to-solute hydrogen-bond formation where the pyridine-type nitrogens are involved directly. It is also quite diversified throughout the pyridine-type nitrogen atoms and seems to constitute a measure of relative basicity with respect to hydrogen-bond formation of the nitrogens concerned. This basicity seems to parallel that with respect to a full transfer of a proton, as can be reckoned from ab initio calculations of the relevant protonation energies reported in the present study. The experimental data for the tetrazoles in cyclohexane solutions are combined with those obtained in our earlier extensive studies on azole, diazole, and triazole ring systems, for a comparison with ab initio calculations of the nitrogen shieldings concerned. The latter were carried out using the coupled Hartree-Fock/GIAO/6-31++G** approach and geometry optimizations employing the same basis set; they show a good linear correlation with the experimental data and reproduce not only major changes but also most of the subtle variations in the experimental nitrogen shieldings of the azole systems as a whole. Copyright 1998 Academic Press.

Journal Article↗
PubMed1987

In vitro sensitivity of environmental isolates of pathogenic dematiaceous fungi to azole compounds and a phenylpropyl-morpholine derivative.

The in vitro sensitivity (minimum inhibitory concentrations; MICs) of 42 environmental isolates of pathogenic dematiaceous fungi to 7 azole compounds, viz. thiabendazole, ketoconazole, miconazole, econazole bifonazole, Bay n 7133, Bay 1 9139 and phenylpropyl-morpholine derivative, Ro14-4767/002 was studied by an agar dilution method using Emmon's Sabouraud dextrose agar (ESDA) as the culture medium. The isolates of Fonsecaea pedrosoi, Cladosporium carrionii, Exophiala jeanselmei and Ramichloridium subulatum were most sensitive to bifonazole with mean MICs of 0.06 microgram/ml or less; Phialophora verrucosa had an MIC of 0.05 microgram/ml to ketoconazole and Ro14-4767/002, respectively. Ochroconis sp had an MIC of 0.025 microgram/ml to Ro14-4767/002 and Cladosporium tennuisimum 0.39 microgram/ml to ketoconazole. Econazole and thiabendazole also showed good antifungal activity. The fungi were relatively resistant to the more recently developed azoles, viz. Bay n 7133 and Bay 1 9139, the later failing to inhibit C. tennuisimum at a concentration of 100 micrograms/ml. The minimum fungicidal concentrations (MFC) of the drugs were mostly within 2 to 8 fold of the MICs.

Animals↗
PubMed2026

Evolution of Candidaemia and azole resistance in Italy: A multicentre retrospective study.

PURPOSE: Candidaemia is the most common healthcare-associated invasive fungal infection. The evolution of the epidemiology of candidaemia in Italy has not been assessed, except at the local level. The primary objective of this study is monitoring changes in the epidemiology of candidaemia and in the susceptibility profiles of Candida isolates between 2015 and 2023. METHODS: This retrospective multicentre study (2015-2023), involved 11 tertiary-care hospital microbiology laboratories across the Italian country. The confirmed candidaemia episodes were included and demographic data, hospital ward, species identification, and antifungal susceptibility profiles (Sensititre Yeast One) were collected. RESULTS: 6,927 candidaemia cases were identified; incidence increased from 1.1/1000 hospitalisations in 2017 to 2.3/1000 in 2020-2021, peaking during the COVID-19 pandemic, and declined in 2023 while remaining above prepandemic levels. Patients older than 65 years accounted for most infections. Medical wards represented the main setting of occurrence, followed by intensive care units, especially during pandemic years. C. albicans remained the most common species (45.4%), followed by C. parapsilosis (24.7%), C. glabrata (11.8%), and C. tropicalis (11.4%). Echinocandin resistance remained low (<&#x2009;2% for C. albicans and C. glabrata), whereas azole resistance increased markedly, particularly in C. parapsilosis, reaching fluconazole resistance rates of 25.6% in 2022. CONCLUSIONS: Candidaemia increased during the 9-year study period in Italy, particularly in the COVID-19 pandemic, in medical wards and ICU. Emerged a growing azole resistance, underscoring the need for enhanced surveillance and informed empirical treatment strategies.

Candida species etiology↗
PubMed1999

Effect of sequential combination of amphotericin B and azole antifungal agents against Aspergillus fumigatus.

Patients with aspergillosis have a poor prognosis because there are no effective antifungal agents except for amphotericin B. However, administration of amphotericin B is limited in immunocompromised patients due to its toxicity, which includes impairment of renal function. We attempted to evaluate the efficacy of a sequential combination of antifungal agents against Aspergillus fumigatus strain. The in vitro effects of sequential combinations of antifungal agents against five strains of Aspergillus fumigatus were determined by assessing changes in the wet weight of mycelial cells. The effect of a sequential combination was examined by pretreating mycelial cells with an antifungal agent, followed by the addition of a second antifungal agent. Pretreatment with amphotericin B (AMPH) followed by miconazole (MCZ) or fluconazole (FLCZ) resulted in better in vitro effects compared with the effect of simultaneous use of the agents. In contrast, pretreatment of mycelial cells with azole antifungal agents, other than MCZ, followed by AMPH, resulted in an increase in the wet weight compared with that recorded after simultaneous incubation with AMPH and azole antifungal agents. Our results showed that combined treatment, of AMPH followed by MCZ or FLCZ, inhibited the growth of A. fumigatus, suggesting that such a regimen may be effective against aspergillosis.

Journal Article↗