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Alterations induced by the antifungal compounds ketoconazole and terbinafine in Leishmania.

Vannier-Santos MA, Urbina JA, Martiny A, Neves A, de Souza W.

Programa de Parasitologia e Biologia Celular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brasil.

The antiproliferative effects and ultrastructural alterations induced in vitro by two antifungal compounds, the azole ketoconazole and the allylamine terbinafine on Leishmania amazonensis are reported. Promastigotes treatment with ketoconazole and terbinafine induced growth arrest and cell lysis in 72 hours. Combination of the two agents produced additive effects on promastigote axenic growth and synergistic effects on intracellular amastigote proliferation. The amastigotes, either axenically grown or infecting murine macrophages, were about 100-fold more sensitive to the drugs. These compounds induced the appearance of large multivesicular bodies, especially after ketoconazole treatment, increased amount of lipid inclusions as well as numerous, polymorphic volutin granules, particularly in terbinafine-treated cells. Multivesicular bodies were observed in close apposition with organelles such as mitochondria, which also showed alterations in the distribution and appearance of cristae, and the formation of paracrystalline arrays within the matrix. Some cells presented large portions of cytoplasm wrapped by endoplasmic reticulum and many parasites also presented myelin-like endoplasmic reticulum profiles. Such alterations together with the strong acid phosphatase activity observed in the multivesicular bodies and volutin granules may indicate the existence of an unusual autophagic process in cells treated with ergosterol biosynthesis inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7620457&dopt=Abstract ketoconazole Nizoral



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Human liver cytochrome P4503A biotransformation of the cyclosporin derivative SDZ IMM 125.

Vickers AE, Meyer E, Dannecker R, Keller B, Tynes RE, Maurer G.

Sandoz Pharma Ltd., Drug Safety, Basel, Switzerland.

In humans, cytochrome P4503A (CYP3A) is the major cytochrome P450 gene family that metabolizes SDZ IMM 125 (IMM) to its primary metabolites. Human liver microsomes could be used for this study, because the metabolite profile matched that found in human blood. The apparent affinity (KM) of IMM for the cytochrome P450 proteins (5.1 +/- 1.8 microM) is similar to that of cyclosporin A (CSA). CSA competitively inhibited the metabolism of IMM, increasing the KM 2- and 4.6-fold in the presence of 4 and 10 microM CSA, respectively (Ki 3.8 +/- 1.1 microM). Ketoconazole exhibited competitive inhibition kinetics toward IMM biotransformation, increasing the KM of IMM 1.8-fold at 0.5 microM ketoconazole and 3.5-fold at 1 microM ketoconazole, with no effect on Vmax (Ki of 0.5 +/- 0.4 microM). These results indicate that both CSA and ketoconazole would cause drug interactions, interfering with the biotransformation of IMM. The metabolism of IMM was also greatly inhibited (approximately 80%) by the CYP3A suicide substrate triacetyloleandomycin and a CYP3A inhibitory antibody, indicating the involvement of CYP3A proteins in the biotransformation of IMM. Confirmation of CYP3A4 involvement in the formation of the three primary IMM metabolites was demonstrated with recombinant cells expressing human CYP3A4. Therefore, compounds interacting with CYP3A proteins are expected to cause drug-drug interactions (i.e. the antimycotics ketoconazole and clotrimazole, the steroids ethinylestradiol and testosterone, the ergots, the calcium channel blocker nifedipine, and the immunosuppressants FK-506 and rapamycin).(ABSTRACT TRUNCATED AT 250 WORDS)

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Inhibition of heme crystal growth by antimalarials and other compounds: implications for drug discovery.

Chong CR, Sullivan DJ Jr.

Department of Pharmacology, Medical Scientist Training Program, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

During intraerythrocytic infection, Plasmodium falciparum parasites crystallize toxic heme released during hemoglobin catabolism. The proposed mechanism of quinoline inhibition of crystal growth is either by a surface binding or a substrate sequestration mechanism. The kinetics of heme crystal growth was examined in this work using a new high-throughput crystal growth determination assay based on the differential solubility of free vs. crystalline FP in basic solutions. Chloroquine (IC(50)=4.3 microM) and quinidine (IC(50)=1.5 microM) showed a previously not recognized reversible inhibition of FP crystal growth. This inhibition decreased by increasing amounts of heme crystal seed, but not by greater amounts of FP substrate. Crystal growth decreases as pH rises from 4.0 to 6.0, except for a partial local maxima reversal from pH 5.0 to 5.5 that coincides with increased FP solubility. The new crystal growth determination assay enabled a partial screen of existing clinical drugs. Nitrogen heterocycle cytochrome P450 inhibitors also reversibly blocked FP crystal growth, including the azole antifungal drugs clotrimazole (IC(50)=12.9 microM), econazole (IC(50)=19.7 microM), ketoconazole (IC(50)=6.5 microM), and miconazole (IC(50)=21.4 microM). Fluconazole did not inhibit. Both subcellular fractionation of parasites treated with subinhibitory concentrations of ketoconazole and in vitro hemozoin growth assays demonstrated copurification of hemozoin and ketoconazole. The chemical diversity of existing CYP inhibitor libraries that bind FP presents new opportunities for the discovery of antimalarial drugs that block FP crystal growth by a surface binding mechanism and possibly interfere with other FP-sensitive Plasmodium pathways.

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[Cyclosporin A and ketoconazole, drug interaction or therapeutical combination?]

[Article in French]

Tillement JP, Albengres E.

Service Hospitalo-Universitaire de Pharmacologie de l'Universite de Paris XII, Faculte de Medecine, Creteil, France.

Cyclosporin A is potentiated by ketoconazole, mainly by inhibiting its P-450 dependent biotransformations. The other interest of ketoconazole is related to its antifungal effect, which is often used in immunodepressed patients. Thus for both pharmacodynamic and pharmacokinetic reasons, the combination of the two drugs is of interest. Another advantage is that whereas ketoconazole is a cheap drug, cyclosporin A is an expensive one, thus their combination may save a part of the cyclosporin A cost. Various questions remain to be solved: is it useful to combine in the same tablet selected amounts of the two drugs and if so in which ratio? Such a strategy supposes that intra and inter-individual variability of cyclosporin A metabolism in humans can be tightly monitored. Is it without risk to definitely inhibit some P-450 isoenzymes? Could not the expected simplification of drug dosages generate the need for more cyclosporin A blood level assays, thus leading to an additional cost?

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7667796&dopt=Abstract ketoconazole Nizoral



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Comparative and collaborative evaluation of standardization of antifungal susceptibility testing for filamentous fungi.

Espinel-Ingroff A, Dawson K, Pfaller M, Anaissie E, Breslin B, Dixon D, Fothergill A, Paetznick V, Peter J, Rinaldi M, et al.

Medical College of Virginia/Virginia Commonwealth University, Richmond, USA.

The purpose of the study was to evaluate the interlaboratory agreement of broth dilution susceptibility methods for five species of conidium-forming (size range, 2 to 7 microns) filamentous fungi. The methods used included both macro- and microdilution methods that were adaptations of the proposed reference method of the National Committee for Clinical Laboratory Standards for yeasts (m27-P). The MICs of amphotericin B, fluconazole, itraconazole, miconazole, and ketoconazole were determined in six centers by both macro- and microdilution tests for 25 isolates of Aspergillus flavus, Aspergillus fumigatus, Pseudallescheria boydii, Rhizopus arrhizus, and Sporothrix schenckii. All isolates produced clearly detectable growth within 1 to 4 days at 35 degrees C in the RPMI 1640 medium. Colony counts of 0.4 x 10(6) to 3.3 x 10(6) CFU/ml (mean, 1.4 x 10(6) CFU/ml) were demonstrated in 90% of the 148 inoculum preparations. Overall, good intralaboratory agreement was demonstrated with amphotericin B, fluconazole, and ketoconazole MICs (90 to 97%). The agreement was lower with itraconazole MICs (59 to 79% median). Interlaboratory reproducibility demonstrated similar results: 90 to 100% agreement with amphotericin B, fluconazole, miconazole, and ketoconazole MICs and 59 to 91% with itraconazole MICs. Among the species tested, the MICs for S. schenckii showed the highest variability. The results of the study imply that it may be possible to develop a reference method for antifungal susceptibility testing of filamentous fungi.

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In vitro prediction of the terfenadine-ketoconazole pharmacokinetic interaction.

von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111.

Biotransformation of the peripherally acting H-1 histamine antagonist, terfenadine, to its desalkyl and hydroxy metabolites was studied in vitro using microsomal preparations from six separate human livers. These metabolic reactions are mediated by the specific cytochrome P450-3A4. Addition of ketoconazole to the reaction mixtures reduced the rate of formation of both metabolites in a manner consistent with competitive inhibition. Ketoconazole inhibition constants (Ki) averaged 0.024 microM for the desalkyl terfenadine pathway, and 0.237 microM for the hydroxy terfenadine pathway. A mathematical model, based on the in vitro Ki values and the usual clinical range of plasma ketoconazole concentrations (1-5 micrograms/mL; 1.88-0.94 microM), predicted that plasma terfenadine levels during coadministration of ketoconazole would increase by a factor ranging from 13-fold to 59-fold relative to the same dose of terfenadine given without ketoconazole. Actual plasma terfenadine levels during terfenadine-ketoconazole coadministration in a clinical pharmacokinetic study were close to those predicted by the model. These plasma levels were associated with prolongation of the corrected QT interval, thereby explaining the potentially life-threatening ventricular arrhythmias reportedly associated with terfenadine-ketoconazole cotherapy. Thus, data from studies of drug metabolism in vitro can be used to predict and thereby possibly avoid clinically important drug interactions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7738219&dopt=Abstract ketoconazole Nizoral



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Cortisol synthesis inhibition: a new treatment strategy for the clinical and endocrine manifestations of depression.

Thakore JH, Dinan TG.

Dept. of Psychological Medicine, St. Batholomew's Hospital, West Smithfield, London, UK.

Evidence exists that oversecretion of cortisol may be responsible for the clinical manifestations and serotonergic abnormality in depressive illness. Using the cortisol synthesis inhibitor ketoconazole, we investigated the effects of directly lowering cortisol on the symptoms and the response of prolactin (PRL) to d-fenfluramine in eight patients suffering from major depression. Prolactin responses to d-fenfluramine were measured, and patients were treated with 400-600 mg of ketoconazole for 4 weeks, after which they were retested. Five patients treated with ketoconazole recovered from their depression, while the other three had decreases in their Hamilton Depression Rating Scale (HAMD) scores of < or = 50% and were deemed partial responders. Posttreatment prolactin responses to d-fenfluramine were higher than pretreatment values. Ketoconazole normalizes the blunted prolactin responses to d-fenfluramine and may be an effective method by which to treat depression. This implies that hypercortisolemia may be responsible for the clinical features and serotonergic subsensitivity observed in depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7772644&dopt=Abstract ketoconazole Nizoral