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M Schaferkorting - One of the best experts on this subject based on the ideXlab platform.
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skin blister fluid levels of Ketoconazole during repetitive administration in healthy man
Mycoses, 2009Co-Authors: H C Korting, A Lukacs, M Schaferkorting, J Heykants, H BehrendtAbstract:Summary: Ketoconazole administered orally is used in the treatment of superficial and deep mycoses. To evaluate its active concentrations in skin tissue, serum, suction blister fluid (SBF), and can-tharides blister fluid (CBF) levels of total and non-protein bound Ketoconazole were determined. In general, only the free drug is considered to be the active one. Six healthy subjects received 200 mg once daily for 5 days. Total Ketoconazole concentrations were determined by HPLC., The unbound fractions of Ketoconazole in SBF (2.3%) and CBF (1.2%) were, calculated from plasma protein binding (99.0%). Before the ultimate dose, levels of un bound Ketoconazole in SBF and CBF were 0.64 ± 0.16 and 0.70 ± 0.25 ng/ml and were thus in accordance with, free kelocoi nazole serum levels (0.52 ± 0.24 ng/ml; p > 0.05). Furthermore, following the ul timate dose, the areas under the blister fluid level-time curves of unbound ketoco nazole did not differ from the respective areas under the serum level time curves, thus distribution equilibrium between serum and skin blister fluid was obtained. Peak concentrations of free Ketoconazole were (SBF) 8.6 ± 2.9 ng/ml and (CBF) 8.9 ± 2.3 ng/ml. Free concentrations in SBF and CBF, were far below the MIC values for dermatophytes and Candida ssp. reported in the literature, leaving the concentration-effect relationship of Ketoconazole still open for discussion. Zusammentassung: Ketoconazol hat sich bei der oralen Behandlung von oberflach-lichen und tiefen Mykosen bewahrt. Zur Bestimmung der wirksamen Ketoconazol-Konzentrationen in der Haut wurden der Cesamtgehalt sowie die Konzentrationen an nicht Protein-gebundenem Wirkstoff in Serum, Saugblasenflussigkeit (SBF) und Kantharidinblasenflussigkeit (CBF) vergleichend untersucht. Ein pharmakolo-gischet Effekt wird in der Regel nur durch die freie Substanz bewirkt. Sechs gesunde Probanden nahmen einmal taglich 200 mg Ketoconazol uber 5 Tage ein. Die Cesamtkonzentrationen (freier plus ge-bundener Wirkstoff) wurden mittels HPLC bestimmt. Der freie Anteil in SBF (2,3 %) und CBF (1,2 %) wurde anhand der Plssmaproteinbindung (99,0%) berechnet. Unmittelbar vor der letzten Tablettenein-nahme unterschieden sich die Konzentrationen an freiem Ketoconazol in SBF (0.64 ± 0.16 ng/ml) und CBF (0.70 ± 0.25 ng/ml) nicht von den entsprechen-den Serumspiegeln (0.52 ± 0.24 ng/ml; p < 0,05). Ebenso stimmten die Flachen unter den Blasenflussigkeitsspiegel-Zeit-Kurven der freien Substanz mit der Flache unter der Serumspiegel-Zeit-Kurve uber-ein. Somit war das Verteilungsgleichge-wicht zwischen Serum und Hautblasen-flussigkeit erreicht. Da die Konzentratio-nen an ungebundenem Ketoconazol in SBF und CBF nach der letzten Einnahme maximal 8,6 ± 2,9 und 8,9 ± 2,3 ng/ml betrugen, lagen sie wesentlich niedriger als die publizierten MHK-Werte fur Der-matophyten und Candida-Arten. Die Kon-zentrations-Wirkungsbeziehung von Ketoconazol erscheint daher noch immer nicht abschliesend geklart.
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antimicrobial effects of in vitro simulated Ketoconazole cantharidin blister fluid levels on candida albicans
Mycoses, 2009Co-Authors: H C Korting, Ulrike Schlafmaier, M SchaferkortingAbstract:Zusammenfassung: Candida albicans (Isolat Nr. 5125/85) wurde zum einen in Sabouraud-Glukose-Bouillon, zum anderen in einem flussigen synthetischen Aminosauremedium gegenuber standig schwankenden Konzentrationen von Ketoconazol exponiert. Zugrundegelegt wurden die Profile der freien wie die der Gesamtkonzentrationen, die beim Menschen nach einmaliger oraler Gabe von 200 mg in kutaner Kantharidinblasenflussigkeit gefunden wurden. Parallel zu jedem Versuchsansatz mit Ketoconazol wurde jeweils ein Ansatz ohne Wirkstoff mitgefuhrt. Bei Verwendung des ersteren, die Hefeform begunstigenden Mediums fand sich nur eine relativ geringe Wachstumshemmung. In dem die Pseudomyzelform begunstigenden synthetischen Medium war demgegenuber — konzentrationsabhangig — ein deutlicher antimikrobieller Effekt zu erkennen (Keimdichtenzunahme in Gegenwart der Gesamtkonzentration auf das 2, lfache, im Kontrollversuch auf das 15, 3fache). Die grosere Wirksamkeit von Ketoconazol auf die Pseudomyzelform von Candida albicans wird wiederum bestatigt, zugleich wird die geringere Sicherheitsmarge bei der systemischen Behandlung mit Azolen gegenuber der antimikrobiellen Chemotherapie mit Antibiotika deutlich. Untersuchungen vom vorliegenden Typ — wie sie in der klinischen Bakteriologie schon ofter durchgefuhrt wurden — konnten auch bei der Untersuchung neuer Antimykotika zunehmend an Bedeutung gewinnen. Summary: Candida albicans was exposed to continously changing concentrations of Ketoconazole in, on the one hand, Sabouraud Dextrose Broth and, on the other hand, a liquid synthetic amino-acid medium. The profiles of the free and total concentrations found in cutaneous cantha-ridin blister-fluid in humans after a single oral dose of 200 mg were used as basic information. For every experiment with Ketoconazole, an identical experiment without addition of an antimycotic was carried out Using the first, yeast-promoting medium, only a relatively small growth-inhibition was evident. Using the synthetic amino-acid medium, which promotes the pseudomycelial form, however, a marked, concentration-dependent, antimicrobial effect was observed. (The colonial density of Candida albicans increased 2.1 times in the presence of the total Ketoconazole concentrations, compared with 153 times in the control experiment.) The greater effectiveness of Ketoconazole against the pseudomycelial form of Candida albicans is again confirmed. At the same time, the smaller safety margin associated with systemic treatment with azoles as compared with anti-microbial therapy with antibiotics, is apparent. Investigations of the present type, which have often been carried out in clinical bacteriology, may also gain significance in the investigation of new antimycotics.
Jerold S Harmatz - One of the best experts on this subject based on the ideXlab platform.
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ritonavir is the best alternative to Ketoconazole as an index inhibitor of cytochrome p450 3a in drug drug interaction studies
British Journal of Clinical Pharmacology, 2015Co-Authors: Jerold S HarmatzAbstract:Aims The regulatory prohibition of Ketoconazole as a CYP3A index inhibitor in drug–drug interaction (DDI) studies has compelled consideration of alternative inhibitors. Methods The biomedical literature was searched to identify DDI studies in which oral midazolam (MDZ) was the victim, and the inhibitory perpetrator was either Ketoconazole, itraconazole, clarithromycin, or ritonavir. The ratios (RAUC) of total area under the curve (AUC) for MDZ with inhibitor divided by MDZ AUC in the control condition were aggregated across individual studies for each inhibitor. Results Mean (± SE) RAUC values were: Ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). RAUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre-exposure prior to administration of MDZ. Conclusions Ritonavir produces CYP3A inhibition equivalent to or greater than Ketoconazole, and is the best index CYP3A inhibitor alternative to Ketoconazole. Cobicistat closely resembles ritonavir in structure and function, and can also be considered. Itraconazole and clarithromycin are not suitable alternatives since they do not produce inhibition comparable with Ketoconazole or ritonavir, and have other significant disadvantages as well.
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mechanism of cytochrome p450 3a inhibition by Ketoconazole
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Yanli Zhao, Sarah J Parent, Su X. Duan, Michael H Court, Jerold S Harmatz, Karthik Venkatakrishnan, Lisa L Von MoltkeAbstract:Objectives Ketoconazole is extensively used as an index inhibitor of cytochrome P450-3A (CYP3A) activity in vitro and in vivo, but the mechanism of Ketoconazole inhibition of CYP3A still is not clearly established. Methods Inhibition of metabolite formation by Ketoconazole (seven concentrations from 0.01 to 1.0 µm) was studied in human liver microsomes (n = 4) at six to seven substrate concentrations for triazolam, midazolam, and testosterone, and at two substrate concentrations for nifedipine. Key findings Analysis of multiple data points per liver sample based on a mixed competitive–noncompetitive model yielded mean inhibition constant Ki values in the range of 0.011 to 0.045 µm. Ketoconazole IC50 increased at higher substrate concentrations, thereby excluding pure noncompetitive inhibition. For triazolam, testosterone, and midazolam α-hydroxylation, mean values of α (indicating the ‘mix’ of competitive and noncompetitive inhibition) ranged from 2.1 to 6.3. However, inhibition of midazolam 4-hydroxylation was consistent with a competitive process. Determination of Ki and α based on the relation between 50% inhibitory concentration values and substrate concentration yielded similar values. Pre-incubation of Ketoconazole with microsomes before addition of substrate did not enhance inhibition, whereas inhibition by troleandomycin was significantly enhanced by pre-incubation. Conclusions Ketoconazole inhibition of triazolam α- and 4-hydroxylation, midazolam α-hydroxylation, testosterone 6β-hydroxylation, and nifedipine oxidation appeared to be a mixed competitive–noncompetitive process, with the noncompetitive component being dominant but not exclusive. Quantitative estimates of Ki were in the low nanomolar range for all four substrates.
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Ketoconazole inhibition of triazolam and alprazolam clearance differential kinetic and dynamic consequences
Clinical Pharmacology & Therapeutics, 1998Co-Authors: David J. Greenblatt, Lisa L Von Moltke, Jerold S Harmatz, Eugene C Wright, Bruce L Ehrenberg, L Harrel, Kate Corbett, Molly Counihan, Sara Tobias, Richard I ShaderAbstract:Background Kinetic and dynamic consequences of metabolic inhibition were evaluated in a study of the interaction of Ketoconazole, a P4503A inhibitor, with alprazolam and triazolam, two 3A substrate drugs with different kinetic profiles. Methods In a double-blind, 5-way crossover study, healthy volunteers received (A) Ketoconazole placebo plus 1.0 mg alprazolam orally, (B) 200 mg Ketoconazole twice a day plus 1.0 mg alprazolam, (C)Ketoconazole placebo plus 0.25 mg triazolam orally, (D) 200 mg Ketoconazole twice a day plus 0.25 mg triazolam, and (E) 200 mg Ketoconazole twice a day plus benzodiazepine placebo. Plasma concentrations and pharmacodynamic parameters were measured after each dose. Results For trial B versus trial A, alprazolam clearance was reduced (27 versus 86 mL/min; P < .002) and apparent elimination half-life (t½ prolonged (59 versus 15 hours; P < .03), whereas peak plasma concentration (Cmax) was only slightly increased (16.1 versus 14.7 ng/mL). The 8-hour pharmacodynamic effect areas for electroencephalographic (EEG) beta activity were increased by a factor of 1.35, and those for digit-symbol substitution test (DSST) decrement were increased by 2.29 for trial B versus trial A. For trial D versus trial C, triazolam clearance was reduced (40 versus 444 mL/min; P < .002), t½ was prolonged (18.3 versus 3.0 hours; P < .01), and Cmax was increased (2.6 versus 5.4 ng/mL; P < .001). The 8-hour effect area for EEG was increased by a factor of 2.51, and that for DSST decrement was increased by 4.33. Observed in vivo clearance decrements due to Ketoconazole were consistent with those anticipated on the basis of an in vitro model, together with in vivo plasma concentrations of Ketoconazole. Conclusion For triazolam, an intermediate-extraction compound, impaired clearance by Ketoconazole has more profound clinical consequences than those for alprazolam, a low extraction compound. Clinical Pharmacology & Therapeutics (1998) 64, 237–247; doi:
H C Korting - One of the best experts on this subject based on the ideXlab platform.
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skin blister fluid levels of Ketoconazole during repetitive administration in healthy man
Mycoses, 2009Co-Authors: H C Korting, A Lukacs, M Schaferkorting, J Heykants, H BehrendtAbstract:Summary: Ketoconazole administered orally is used in the treatment of superficial and deep mycoses. To evaluate its active concentrations in skin tissue, serum, suction blister fluid (SBF), and can-tharides blister fluid (CBF) levels of total and non-protein bound Ketoconazole were determined. In general, only the free drug is considered to be the active one. Six healthy subjects received 200 mg once daily for 5 days. Total Ketoconazole concentrations were determined by HPLC., The unbound fractions of Ketoconazole in SBF (2.3%) and CBF (1.2%) were, calculated from plasma protein binding (99.0%). Before the ultimate dose, levels of un bound Ketoconazole in SBF and CBF were 0.64 ± 0.16 and 0.70 ± 0.25 ng/ml and were thus in accordance with, free kelocoi nazole serum levels (0.52 ± 0.24 ng/ml; p > 0.05). Furthermore, following the ul timate dose, the areas under the blister fluid level-time curves of unbound ketoco nazole did not differ from the respective areas under the serum level time curves, thus distribution equilibrium between serum and skin blister fluid was obtained. Peak concentrations of free Ketoconazole were (SBF) 8.6 ± 2.9 ng/ml and (CBF) 8.9 ± 2.3 ng/ml. Free concentrations in SBF and CBF, were far below the MIC values for dermatophytes and Candida ssp. reported in the literature, leaving the concentration-effect relationship of Ketoconazole still open for discussion. Zusammentassung: Ketoconazol hat sich bei der oralen Behandlung von oberflach-lichen und tiefen Mykosen bewahrt. Zur Bestimmung der wirksamen Ketoconazol-Konzentrationen in der Haut wurden der Cesamtgehalt sowie die Konzentrationen an nicht Protein-gebundenem Wirkstoff in Serum, Saugblasenflussigkeit (SBF) und Kantharidinblasenflussigkeit (CBF) vergleichend untersucht. Ein pharmakolo-gischet Effekt wird in der Regel nur durch die freie Substanz bewirkt. Sechs gesunde Probanden nahmen einmal taglich 200 mg Ketoconazol uber 5 Tage ein. Die Cesamtkonzentrationen (freier plus ge-bundener Wirkstoff) wurden mittels HPLC bestimmt. Der freie Anteil in SBF (2,3 %) und CBF (1,2 %) wurde anhand der Plssmaproteinbindung (99,0%) berechnet. Unmittelbar vor der letzten Tablettenein-nahme unterschieden sich die Konzentrationen an freiem Ketoconazol in SBF (0.64 ± 0.16 ng/ml) und CBF (0.70 ± 0.25 ng/ml) nicht von den entsprechen-den Serumspiegeln (0.52 ± 0.24 ng/ml; p < 0,05). Ebenso stimmten die Flachen unter den Blasenflussigkeitsspiegel-Zeit-Kurven der freien Substanz mit der Flache unter der Serumspiegel-Zeit-Kurve uber-ein. Somit war das Verteilungsgleichge-wicht zwischen Serum und Hautblasen-flussigkeit erreicht. Da die Konzentratio-nen an ungebundenem Ketoconazol in SBF und CBF nach der letzten Einnahme maximal 8,6 ± 2,9 und 8,9 ± 2,3 ng/ml betrugen, lagen sie wesentlich niedriger als die publizierten MHK-Werte fur Der-matophyten und Candida-Arten. Die Kon-zentrations-Wirkungsbeziehung von Ketoconazol erscheint daher noch immer nicht abschliesend geklart.
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antimicrobial effects of in vitro simulated Ketoconazole cantharidin blister fluid levels on candida albicans
Mycoses, 2009Co-Authors: H C Korting, Ulrike Schlafmaier, M SchaferkortingAbstract:Zusammenfassung: Candida albicans (Isolat Nr. 5125/85) wurde zum einen in Sabouraud-Glukose-Bouillon, zum anderen in einem flussigen synthetischen Aminosauremedium gegenuber standig schwankenden Konzentrationen von Ketoconazol exponiert. Zugrundegelegt wurden die Profile der freien wie die der Gesamtkonzentrationen, die beim Menschen nach einmaliger oraler Gabe von 200 mg in kutaner Kantharidinblasenflussigkeit gefunden wurden. Parallel zu jedem Versuchsansatz mit Ketoconazol wurde jeweils ein Ansatz ohne Wirkstoff mitgefuhrt. Bei Verwendung des ersteren, die Hefeform begunstigenden Mediums fand sich nur eine relativ geringe Wachstumshemmung. In dem die Pseudomyzelform begunstigenden synthetischen Medium war demgegenuber — konzentrationsabhangig — ein deutlicher antimikrobieller Effekt zu erkennen (Keimdichtenzunahme in Gegenwart der Gesamtkonzentration auf das 2, lfache, im Kontrollversuch auf das 15, 3fache). Die grosere Wirksamkeit von Ketoconazol auf die Pseudomyzelform von Candida albicans wird wiederum bestatigt, zugleich wird die geringere Sicherheitsmarge bei der systemischen Behandlung mit Azolen gegenuber der antimikrobiellen Chemotherapie mit Antibiotika deutlich. Untersuchungen vom vorliegenden Typ — wie sie in der klinischen Bakteriologie schon ofter durchgefuhrt wurden — konnten auch bei der Untersuchung neuer Antimykotika zunehmend an Bedeutung gewinnen. Summary: Candida albicans was exposed to continously changing concentrations of Ketoconazole in, on the one hand, Sabouraud Dextrose Broth and, on the other hand, a liquid synthetic amino-acid medium. The profiles of the free and total concentrations found in cutaneous cantha-ridin blister-fluid in humans after a single oral dose of 200 mg were used as basic information. For every experiment with Ketoconazole, an identical experiment without addition of an antimycotic was carried out Using the first, yeast-promoting medium, only a relatively small growth-inhibition was evident. Using the synthetic amino-acid medium, which promotes the pseudomycelial form, however, a marked, concentration-dependent, antimicrobial effect was observed. (The colonial density of Candida albicans increased 2.1 times in the presence of the total Ketoconazole concentrations, compared with 153 times in the control experiment.) The greater effectiveness of Ketoconazole against the pseudomycelial form of Candida albicans is again confirmed. At the same time, the smaller safety margin associated with systemic treatment with azoles as compared with anti-microbial therapy with antibiotics, is apparent. Investigations of the present type, which have often been carried out in clinical bacteriology, may also gain significance in the investigation of new antimycotics.
Wendy W. J. Van De Sande - One of the best experts on this subject based on the ideXlab platform.
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the combination of amoxicillin clavulanic acid and Ketoconazole in the treatment of madurella mycetomatis eumycetoma and staphylococcus aureus co infection
PLOS Neglected Tropical Diseases, 2014Co-Authors: Najwa A Mhmoud, El Sheikh Mahgoub, Ahmed Hassan Fahal, Wendy W. J. Van De SandeAbstract:Eumycetoma is a chronic progressive disabling and destructive inflammatory disease which is commonly caused by the fungus Madurella mycetomatis. It is characterized by the formation of multiple discharging sinuses. It is usually treated by antifungal agents but it is assumed that the therapeutic efficiency of these agents is reduced by the co-existence of Staphylococcus aureus co-infection developing in these sinuses. This prospective study was conducted to investigate the safety, efficacy and clinical outcome of combined antibiotic and antifungal therapy in eumycetoma patients with superimposed Staphylococcus aureus infection. The study enrolled 337 patients with confirmed M. mycetomatis eumycetoma and S. aureus co-infection. Patients were allocated into three groups; 142 patients received amoxicillin-clavulanic acid and Ketoconazole, 93 patients received ciprofloxacin and Ketoconazole and 102 patients received Ketoconazole only. The study showed that, patients who received amoxicillin-clavulanic acid and Ketoconazole treatment had an overall better clinical outcome compared to those who had combined ciprofloxacin and Ketoconazole or to those who received Ketoconazole only. In this study, 60.6% of the combined amoxicillin-clavulanic acid/Ketoconazole group showed complete or partial clinical response to treatment compared to 30.1% in the ciprofloxacin/Ketoconazole group and 36.3% in the Ketoconazole only group. The study also showed that 64.5% of the patients in the ciprofloxacin/Ketoconazole group and 59.8% in the Ketoconazole only group had progressive disease and poor outcome. This study showed that the combination of amoxicillin-clavulanic acid and Ketoconazole treatment is safe and offers good clinical outcome and it is therefore recommended to treat eumycetoma patients with Staphylococcus aureus co-infection.
Cedric Duret - One of the best experts on this subject based on the ideXlab platform.
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Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor.
Molecular Pharmacology, 2006Co-Authors: Martine Daujat-chavanieu, Jean-marc Pascussi, Lydiane Pichard-garcia, Patrick Balaguer, Jean-michel Fabre, Marie-josé Vilarem, Patrick Maurel, Sabine Gerbal-chaloin, Cedric DuretAbstract:The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) play a major part in the control of drug metabolism and transport. We have previously shown that PXR and CAR expression is controlled by the glucocorticoid receptor (GR) and proposed the existence of a signal transmission cascade GR-(PXR/CAR)-drug metabolizing and transporter systems. In the current study, we investigated the effect of Ketoconazole and other azole-derived drugs, miconazole and fluconazole, on the transcriptional activity of the human GR (hGR) in HeLa and HepG2 cells, and in primary human hepatocytes. The data show that Ketoconazole inhibits GR transcriptional activity and competes with dexamethasone for hGR binding. In primary human hepatocytes, Ketoconazole inhibits the expression of 1) GR-responsive genes tyrosine aminotransferase and both PXR and CAR; 2) CAR and PXR target genes, including cytochromes P450 (P450) CYP2B6, CYP2C9, and CYP3A4; UDP-glucuronosyltransferase 1A1, glutathione S-transferases A1 and A2; and transporter proteins (phase III) solute carrier family 21 form A6 and multidrug resistance protein 2. In parallel experiments, Ketoconazole affected neither the expression of GR, the expression of glyceraldehyde-3-phosphate dehydrogenase, nor the inducible expression of CYP1A1 and 1A2. Miconazole behaved like Ketoconazole, whereas fluconazole had no effect. We conclude that, in addition to their well known inhibitory effect on P450 enzyme activities, Ketoconazole and miconazole are antagonists of hGR. These results provide a novel molecular mechanism by which these compounds may exert adverse and toxic effects on drug metabolism and other functions in human.
