The severity of ketoconazole-induced hepatotoxicity was closely related to the exposure level (AUC) of the drug.
Gamma Knife surgery offers a high rate of tumor control and a reasonable rate of endocrine remission in patients with Cushing's disease. The cessation of cortisol-lowering medications around the time of GKS appears to result in a more rapid rate of remission. Delayed hypopituitarism and endocrine recurrence develop in a minority of patients and underscore the need for long-term multidisciplinary follow-up.
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In a randomized trial we compared ketoconazole (400 mg once daily, 27 patients) and nystatin (3 X 10(6) units four times daily, 29 patients) for prevention of fungal infection in neutropenic patients undergoing marrow transplantation in a protective environment. Fewer weekly surveillance cultures contained Candida species in ketoconazole recipients than in nystatin recipients (70 [26%] of 274 vs. 151 [47%] of 322; P less than .001). When all fungi were considered, the difference in colonization was less but was still significant (117 [43%] of 274 vs. 173 [54%] of 322; P = .01), primarily due to increased colonization of the rectum with Torulopsis glabrata among ketoconazole recipients (P less than .001). No difference in the incidence of local mucosal infection was seen. Two disseminated fungal infections occurred, both in nystatin recipients. Compliance with ketoconazole was significantly better than was compliance with nystatin (96% vs. 68%; P less than .001), but similar effects on colonization were found in an analysis adjusting for compliance. Ketoconazole was better tolerated and more effective than nystatin in reducing colonization due to Candida species but was also associated with significantly increased rates of colonization with T. glabrata.
Ketoconazole was administered in a case of hirsutismus over a period of 4 months with high doses of 800 mg/day, and bilateral papilledema developed. After cessation of the drug the condition disappeared. As far as we know this is the first reported papilledema complication due to Ketoconazole.
Patients with solid tumor, head-neck cancer or hematological malignancy were recruited into the study. Demographic data on age, gender, type of cancer, preceding treatment with antibiotics, anti-fungal agents, chemotherapy, radiation or surgery and presence of dentures were recorded on admission. Oral examination and microbial swabs were obtained and yeast culture, identification and antifungal susceptibility performed.
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The in vitro activities of amphotericin B, miconazole, ketoconazole, 5-fluorocytosine, and potassium iodide (KI) were studied on human and wild-type isolates of Basidiobolus and Conidiobolus species. Of the antifungal agents tested, the imidazole derivatives, especially ketoconazole, were the most active against the agents of entomophthoromycosis. Transmission electron microscopy showed severe morphological alteration of Basidiobolus sp. exposed to 0.78 micrograms of ketoconazole per ml. The MIC and minimal fungicidal concentration of ketoconazole was often lowered in the presence of 10% fetal calf serum or antibiotic medium no. 3. Half of the Basidiobolus isolates and all Conidiobolus isolates were inhibited by amphotericin B at 0.39 micrograms/ml. None of the strains tested were inhibited or killed at maximum concentrations of 5-fluorocytosine and KI. The in vitro resistance of these fungi to KI at high concentrations suggests that the reported favorable treatment with KI may not be due to its direct effect on these fungi but rather to other, undefined factors in combination with KI. These data suggest that ketoconazole may be of use in the treatment of entomophthoromycosis, particularly in cases which are not responsive to KI.
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The aromatase inhibitory properties of the antifungal ketoconazole were compared with those of aminoglutethimide. In rat granulosa cells ketoconazole and aminoglutethimide showed IC50 values for aromatase inhibition of 2 X 10(-6) and 6 X 10(-7) M respectively. In the rat, in vivo, ketoconazole was 5 times less potent than aminoglutethimide. In young women, 400 mg of ketoconazole only marginally lowered plasma levels of estradiol-17 beta. It is concluded that ketoconazole is not a compound of choice for clinical use as an aromatase inhibitor.
A total of 20 new phenylenedithiourea derivatives was synthesized by reaction of phenylenediisothiocyanates with aromatic amines as aminobenzoic, aminosalicylic acid and their derivatives. Their chemical structures were confirmed by elemental analysis, IR spectrometry and 1H NMR. The compounds were screened for in vitro antifungal, antibacterial activities and some of them have strong antifungal activities comparable to the activity observed for ketoconazole.
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Sterol 14-demethylase P450 (CYP51) is an essential enzyme for sterol biosynthesis by eukaryotes. We have cloned rat and human CYP51 cDNAs [Aoyama, Y., Noshiro, M., Gotoh, O., Imaoka, S., Funae, Y., Kurosawa, N., Horiuchi, T., and Yoshida, Y. (1996) J. Biochem. 119, 926-933]. The cloned rat CYP51 cDNA was expressed in Escherichia coli with modification of the N-terminal amino acid sequence, and the expressed protein (CYP51m) was purified to gel-electrophoretic homogenity. The spectrophotometrically determined specific content of CYP51m was 16 nmol/mg protein and the apparent molecular weight was estimated to be 53,000 on SDS-PAGE. Soret peaks of the oxidized and reduced CO-complex of CYP51m were observed at 417 and 447 nm, respectively. The purified CYP51m catalyzed the 14-demethylation of lanosterol and 24,25-dihydrolanosterol upon reconstitution with NADPH-P450 reductase purified from rat liver microsomes. The apparent K(m) and V(max) values for lanosterol were 10.5 microM and 13.9 nmol/min/nmol P450, respectively, and those for 24, 25-dihydrolanosterol were 20.0 microM and 20.0 nmol/min/nmol P450, respectively. The lanosterol demethylase activity of the reconstituted system of CYP51m was inhibited by ketoconazole, itraconazole and fluconazole with apparent IC(50) values of 0.2, 0.7, and 160 microM, respectively.
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The history of corticosteroid use in clinical medicine has been colorful, noisy, and always controversial. Therapeutic corticosteroid indications that initially seemed rational have frequently been refuted on closer, rigorous clinical trial inspection. Although it may be prudent to provide stress-dose steroids to children with septic shock who are clinically at risk for adrenal insufficiency (chronic or recent steroid use, purpura fulminans, etomidate or ketoconazole administration, hypothalamic, pituitary, adrenal disease), the safety and efficacy of stress-dose steroids as general adjunctive therapy for pediatric septic shock have not been established. Glucocorticoid administration does add potential risk to critically ill children. In particular, although adjunctive corticosteroids may hasten resolution of unstable hemodynamics in septic shock, this may occur at the metabolic cost of hyperglycemia. Clinical practice that fosters innovative therapy (off-label use) over research probably represents bad medical and social policy. Accordingly, pediatric critical care researchers have a responsibility to generate pediatric-specific evidence-based medicine for adjunctive corticosteroid therapy for severe sepsis in children.
A Trichophyton mentagrophytes infection of guinea pigs induced by an occlusive procedure is described. The method of evaluation permits comparison of efficacy of antifungal agents which are not tested simultaneously. Activity was demonstrated following topical application of clotrimazole, miconazole, tolnaftate or griseofulvin and oral administration of griseofulvin. Oral ketoconazole had little effect in this dermatophyte model.
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The in vitro antimycotic activity and the in vivo antimycotic activity (in a rabbit model) of itraconazole against P. orbiculare were compared to the corresponding activities of ketoconazole. Fluconazole's in vitro antimycotic activity and in vivo antimycotic activity against P. orbiculare were tested in the same models. The MIC values of itraconazole against P. orbiculare were 0.1-0.2 micrograms/ml compared to 0.02-0.05 micrograms/ml for ketoconazole. For fluconazole, the MIC values were 12.5-50.0 micrograms/ml against P. orbiculare. In a rabbit model, orally administered itraconazole (5 mg/kg) afforded protection against experimental pityriasis (tinea) versicolor in four out of five rabbits. Ketoconazole (1 mg/kg) was effective in all four animals. The in vivo results with fluconazole were in contrast to its low in vitro activity. Fluconazole (5 mg/kg) afforded protection against experimental pityriasis (tinea) versicolor in five out of six animals.
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Most active antidandruff shampoos exhibit a strong activity against the yeast Malassezia ovalis. The present study was undertaken to compare the prolonged antifungal effect of three proprietary shampoos containing either 2% ketoconazole, 1.5% zinc pyrithione or 2.5% selenium sulphide. Superficial squames were harvested from the scalp in the days following a 6-week antifungal shampoo treatment. Counts of yeasts highlighted by a fluorochrome were made using computerized image analysis. Data show the increased duration of yeast reduction for the ketoconazole shampoo over the two other formulations. The lingering effect of ketoconazole is explained by the combination of its antifungal and pharmacokinetic properties.
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Candida albicans (48%) was the most frequently isolated species, followed by Candida kruzei (16.1%), Candida glabrata (13.5%), Candida kefyr (7.4%), Candida parapsilosis (4.8%), Candida tropicalis (1.7%) and other species (8.5%). Resistance varies depending on the species and the respective antifungal agents. Comparing the MIC90 for all the strains, the lower MIC90 was observed for caspofungin (0.5 µg/ml). The MIC90 for all Candida species were 64 µg/ml for fluconazole, 0.75 µg/ml for amphotericin B, 4 µg/ml for ketoconazole, 4 µg/ml for itraconazole, and 2 µg/ml for voriconazole.
This study reveals no significant effect of KCZ on the incidence of OHSS during ART cycles; however, also no significant negative effects of KCZ on the number and maturity of oocytes or on fertilization rate.
Adhesion of synchronised yeast-phase Candida albicans cells to tissue culture plastic, and the susceptibility of planktonic and adherent cells to antifungal agents, was investigated using a modified tetrazolium (XTT) assay. MIC data demonstrated that ketoconazole and amphotericin B were highly active against planktonic C. albicans yeast-phase cells. XTT tetrazolium assays permitted comparisons of MIC values with XTT formazan IC50 and IC80 (percentage inhibitory concentrations); IC50 and IC80 values for amphotericin B and ketoconazole were similar. Furthermore, IC50 and IC80 values for 24 h incubation with antifungal agent were typically higher than corresponding IC50 and IC80 values for 48 h incubation. Furthermore, in comparison to values for planktonic Candida cells, adherent cells were typically less susceptible to amphotericin B and ketoconazole. For example, with increasing incubation time following the initial adhesion period, cells became progressively less susceptible to amphotericin B and ketoconazole: 24 h (P < 0.05) and 48 h (P < 0.001). Furthermore, other azoles showed the same activities compared with ketoconazole against both planktonic and adherent cells. Overall, the data demonstrate the usefulness of the XTT tetrazolium assay in describing comparisons of the susceptibility profiles for both planktonic and adherent synchronous yeast phase C. albicans in vitro.
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Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f(m)) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.
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Ketoconazole is an imidazole derivative used to treat systemic and superficial mycoses by inhibiting sterol synthesis in fungi. The drug impairs steroid hormone synthesis by blocking mitochondrial P450-dependent enzyme systems. Because of its potent inhibitory effects on adrenal steroidogenesis, ketoconazole is valuable in controlling hypercortisolism. We investigated the effects of long-term treatment of this drug on three patients who had residual or recurrent Cushing's disease after surgical treatment. Ketoconazole was administered orally and adjusted according to individual response and 24-hour urinary free cortisol excretion levels. All three patients had good clinical and biochemical responses to ketoconazole therapy without adverse effects. The 24-hour urinary free cortisol levels were kept around 114.8+/-52.4 microg/24 h, 143.0+/-59.9 microg/24 h, and 122.9+/-79.9 microg/24 h, respectively (reference range, 35 to 120 microg/24 h). All three patients had follow-up magnetic resonance imaging or computed tomography of the pituitary gland, which revealed no significant changes in the sellar region. Daily ketoconazole doses ranged from 200 to 1200 mg per day. Follow-up periods were 65, 86, and 83 months, respectively. In conclusion, ketoconazole is valuable in the long-term treatment of residual or recurrent Cushing's disease when surgical treatment is contraindicated or unsuccessful.
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Eight healthy female subjects were each given (a) ketoconazole 400 mg orally, (b) ketoconazole 400 mg as a single vaginal pessary, (c) ketoconazole 800 mg as two vaginal pessaries, and (d) ketoconazole 1200 mg as three vaginal pessaries. The area under the plasma concentration time curve (AUC) after the oral dose was 51.41 +/- 10.99 mg l-1 h (mean +/- s.d.) and the half-life of ketoconazole was 2.98 +/- 1.41 h. The AUCs after vaginal administration were 0.27 +/- 0.14, 0.52 +/- 0.25, and 0.43 +/- 0.22 mg-1 l h following the 400, 800 and 1200 mg pessaries respectively. Systemic absorption of single doses of vaginally administered ketoconazole appears to be negligible in the absence of vaginal infection. There were no local or systemic side effects related to ketoconazole in these healthy volunteers.
To determine the human cytochromes mediating biotransformation of the imidazopyridine hypnotic, zolpidem, and the clinical correlates of the findings.
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Prospective, nonrandomized open trial.
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Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine.