High plasma levels of fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] were associated with improved outcome in a phase II clinical trial. Low bioavailability of 4-HPR has been limiting its therapeutic applications. This study characterized metabolism of 4-HPR in humans and mice, and to explore the effects of ketoconazole, an inhibitor of CYP3A4, as a modulator to increase 4-HPR plasma levels in mice and to increase the low bioavailability of 4-HPR.
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Fungi were isolated and identified by classical methods and the antifungal susceptibility test was performed using the method of broth microdilution, according to a protocol recommended by the Clinical Laboratory Standards Institute (CLSI), through M38-A document.
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Multiple phaeohyphomycotic brain abscesses caused by Cladosporium species occurred in a 55 year old woman. No immunological abnormality could be detected. The disease ran a protracted course for a total of 20 months before she died from sudden rupture of an abscess loculus into the ventricular system. Course was characterised by spontaneous remissions and relapses totally independent of adequate doses and prolonged regimes of all the three available anti-fungal chemotherapeutic agents, namely amphotericin B, flucytosine and ketoconazole. Three surgical procedures were carried out; and surgical intervention appeared to be the only modality of treatment capable of prolonging the life or altering the course of the disease. An interesting transitory pulmonary phase of phaeohyphomycosis resembling miliary tuberculosis was noticed. This may help to explain the portal of entry and mole of spread of the fungus to the brain. A dematiaceous fungus was isolated from these abscesses. Mycologic features and histology of brain lesions are described.
The influence of topical corticosteroid on the efficacy of five topical antifungal agents was evaluated in a standardized rabbit model of Candida keratitis using a quantitative mycologic technique. Topical 1% prednisolone acetate worsened the disease when given alone and adversely influenced the efficacy of 5% natamycin, 1% flucytosine, and 1% miconazole when given in combination. The efficacy of amphotericin B appeared unaffected when the antifungal agent was administered in concentrations of 0.5% and 0.15%. The adverse effect of the topical corticosteroid appeared to be inversely related to the efficacy of the antifungal agent in vivo.
Caco-2 cells were incubated with TcdA and treated with rifaximin (0.1-10 μM) with or without ketoconazole (10 μM). The transepithelial electrical resistance (TEER) and viability of the treated cells was determined. Also, the expression of zona occludens-1 (ZO-1), toll-like receptor 4 (TLR4), Bcl-2-associated X protein (Bax), transforming growth factor-β-activated kinase-1 (TAK1), myeloid differentiation factor 88 (MyD88), and nuclear factor-kappaB (NF-κB) was determined.
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At 5 days after the initial session of LPT, the patient was able to eat gelatin, and on the following day, the number and severity of his intraoral lesions and his labial crusting and swelling had diminished. By 6 days after his initial session of LPT, most of the patient's intraoral lesions had disappeared, and the few that remained were painless; the patient was able to eat solid food by himself and was removed from the ICU. Ten sessions of LPT were conducted in the hospital. The patient underwent three further and consecutive sessions at the School of Dentistry, when complete healing of his oral lesions was observed.
The composite data suggests a potential beneficial effect of oral itraconazole and ketoconazole in patients with CRS and its subtypes. However, majority of the studies are uncontrolled case series, confounded by non-validated outcome variables. Randomized controlled trials are required to better elucidate their role in CRS.
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We used a species-specific approach to treat 10 patients with cutaneous leishmaniasis diagnosed using polymerase chain reaction. Non-antimony treatments (oral miltefosine, ketoconazole, and liposomal amphotericin B) were chosen as an alternative to pentavalent antimony drugs based on likely or proven drug efficacy against the infecting species. Leishmania Viannia panamensis was diagnosed in three patients and treated successfully with oral ketoconazole. Miltefosine treatment cured two patients with L. infantum chagasi. A wide variety of Leishmania responded to liposomal amphotericin B administered for 5-7 days. Three patients with L. V. braziliensis, one patient with L. tropica, and two patients with L. infantum chagasi were treated successfully. One person with L. V. braziliensis healed slowly because of a resistant bacterial superinfection, and a second patient with L. infantum chagasi relapsed and was retreated with miltefosine. These drugs were reasonably well-tolerated. In this limited case series, alternative non-antimony-based regimens were convenient, safe, and effective.
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Fathead minnows (Pimephales promelas) are a widely-used small fish model for regulatory ecotoxicology testing and research related to endocrine disrupting chemicals (EDCs). Quantitative real-time PCR assays for measuring fathead minnow gonadotropin (GtH) beta subunit transcripts were developed and "baseline" transcript levels in pituitary tissue were examined over a range of age classes and spawning states. Among females, GtHbeta transcripts did not vary significantly with gonadal-somatic index or gonad stage. However, in males, follicle-stimulating hormone beta subunit transcripts decreased significantly with increasing gonad stage, while mean luteinizing hormone beta subunit expression trended in the opposite direction. GtHbeta transcript levels measured in pituitaries from fish that had spawned within the preceding 24 h were not significantly different from those from fish that were 2-3 days post-spawn. Exposure to the fungicide ketoconazole, a known steroidogenesis inhibitor, for 21 days significantly affected the abundance of GtHbeta transcripts in pituitary tissue in males, but not females. This study provides critical data needed to design and interpret effective experiments for studying direct and indirect effects of EDCs on GtH subunit mRNA expression. Results of such experiments should facilitate a greater understanding of integrated system-wide responses of the fathead minnow brain-pituitary-gonadal axis to stressors including EDCs.
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Both groups were markedly hypermetabolic and catabolic throughout the acute hospital stay. Normalization of hypercortisolemia with ketoconazole therapy had no effect on whole-body catabolism or the post-burn inflammatory or hypermetabolic response, suggesting that hypercortisolemia does not play a central role in the post-burn hypermetabolic catabolic response.
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1. In humans, ambroxol is metabolized to dibromoanthranilic acid (DBAA) and 6,8-dibromo-3-(trans-4-hydroxycyclohexyl)-1,2,3,4-tetrahydroquinazoli ne (DHTQ). The formation of DHTQ proceeds non-enzymatically, whereas that of DBAA requires NADPH. Studies have been performed to identify the CYP isozyme(s) involved in the formation of DBAA using human liver microsomes and microsomes expressing recombinant human CYP isozymes (1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 and 4A11). 2. The apparent Vmax and Km for the formation of DBAA were 472+/-192 pmol/ min/mg protein and 248+/-40.6 microM respectively (mean +/- S.D., n = 3). 3. Of the recombinant CYP examined, only CYP3A4 metabolized ambroxol to DBAA. The apparent Vmax and Km were 1.42 pmol/min/pmol P450 and 287 microM respectively. 4. Among the CYP inhibitors examined (furafylline, sulphaphenazole, quinidine, diethyldithiocarbamic acid, ketoconazole), only ketoconazole inhibited the production of DBAA (> 80%) at 1 microM and anti-CYP3A antiserum almost completely inhibited the formation of DBAA. 5. These results suggest that CYP3A4 is predominantly involved in the metabolism of ambroxol to DBAA in humans.
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Cytochrome P-450 (CYP) 3A4 is an inordinately important CYP enzyme that catalyzes the metabolism of a vast array of clinically used drugs. Microsomal proteins of Spodoptera frugiperda (Sf21) insect cells infected with recombinant baculoviruses encoding CYP3A4 cDNA were used to immunize mice and to develop a monoclonal antibody (mAb(3A4a)) specific to CYP3A4 through the use of hybridoma technology. The mAb is both a potent inhibitor and a strong binder of CYP3A4. One and 5 microl (0.5 and 2.5 microM IgG(2a)) of the mAb mouse ascites in 1-ml incubation containing 20 pmol of CYP3A4 strongly inhibited the testosterone 6beta-hydroxylation by 95 and 99%, respectively, and, to a lesser extent, cross-inhibited CYP3A5 and CYP3A7 activity. mAb(3A4a) exhibited no cross-reactivity with any of the other recombinant human CYP isoforms (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) in the course of CYP reaction phenotyping and Western immunoblot analyses. The potency of mAb-induced inhibition is insensitive to substrate concentration in human liver microsomes. Therefore, mAb(3A4a) was used to assess the quantitative role of CYP3A4/5 to the metabolism of testosterone and diazepam in five human liver microsomes. The results showed that CYP3A4 and CYP3A5 contribute >95% to both testosterone 6beta-hydroxylation and diazepam 3-hydroxylation and 52 to 73% to diazepam N-demethylation, respectively. In addition, mAb(3A4a) significantly inhibited testosterone 6beta-hydroxylase activity in rhesus monkey liver microsomes to a degree equal to that observed with CYP3A4 in human liver microsomes. By comparison, no inhibition of testosterone 6beta-hydroxylase activity was observed in the presence of dog, rat, and mouse liver microsomes. The selectivity of ketoconazole, a chemical inhibitor of CYP3A4, was probed with mAb(3A4a) and was shown to be highly concentration dependent in the diazepam N-demethylation by human liver microsomes. The results demonstrate that inhibitory and immunoblotting mAb(3A4a) can offer a precise and useful tool for quantitative identification of CYP3A4/5 in the metabolism of drugs in clinical use and drugs in development.
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A moderate, but statistically significant interaction between emedastine and ketoconazole was observed. Pharmacodynamic data indicate no increase in the QTc interval during concomitant therapy. This result is consistent with the multiple emedastine metabolic pathways shown in man which supplement the metabolism by different enzymatic isoforms of CYP450. Concomitant treatment with emedastine and ketoconazole in subjects with normal QT intervals can therefore, be undertaken without special precautions.
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Some intermediaries of cortisol synthesis, especially the sulfated ester of dehydroepiandrosterone (DHEAS), are picrotoxin-like antagonists of the gamma-aminobutyric acid A (GABA-A) receptor and exert potent anxiogenic effects. We report 5 men and 7 women with refractory anxiety disorders, who had late-onset congenital adrenal hyperplasia (CAH), and in whom interactions between neuroactive steroids and anomalous brain substrates may have participated in the pathophysiology and treatment of anxiety.
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Inhibition of CYP3A by concomitant high-dose ketoconazole administration does not result in a uniform reduction of docetaxel clearance and does not reduce the inter-individual variability in docetaxel AUC or clearance. This approach is unsuitable as method to achieve a uniform docetaxel PK profile.
Skin scrapings from the toe clefts, soles and nail plates of 138 HIV-infected patients at various stages were examined for the presence of dermatophytes using both microscopy and culture. Dermatophytes, in particular Trichophyton rubrum, could be grown in 58 cases (42%). Although cultures were more often positive in late stages of disease, there was no close correlation with the clinical stage or the T4/T8 ratio. Susceptibility to itraconazole, but not to other antimycotics, was correlated with the immune status (P < 0.05). Pedal dermatophyte infection does not seem to be a major problem in HIV infection.
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1. Recent guidance from the US Food and Drug Administration (USFDA) has advocated testing of time-dependent inhibition of cytochrome P450 (CYP), which can be addressed by performing IC(50) shift as well as K(I)/k(inact) determinations. 2. Direct (IC(50), K(i)) and time-dependent inhibition (IC(50) shift, K(I)/k(inact)) assays were validated in human liver microsomes with liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis for the following enzyme/substrate/inhibitor combinations: CYP1A2/phenacetin/alpha-naphthoflavone/furafylline, CYP2C8/amodiaquine/montelukast/gemfibrozil-1-O-beta-glucuronide, CYP2C9/diclofenac/sulfaphenazole/tienilic acid, CYP2C19/S-mephenytoin/S-benzylnirvanol/S-fluoxetine, CYP2D6/dextromethorphan/quinidine/paroxetine, and CYP3A4/midazolam/testosterone/ketoconazole/azamulin/verapamil/diltiazem. IC(50) shift assays were performed with two pre-incubation time points (10 and 30 min) to facilitate k(inact) assay design. 3. Data obtained show good agreement with literature values. For rapid acting inhibitors, such as azamulin/CYP3A4 and tienilic acid/CYP2C9, the IC(50) shifts were similar at both time points suggesting a short maximum pre-incubation time with closely spaced time points for the K(I)/k(inact) assay. Slow acting inhibitors (such as verapamil/CYP3A4 or S-fluoxetine/CYP2C19) showed an increase in IC(50) shift between 10 and 30 min suggesting a longer maximum pre-incubation time with wider spacing of time points for K(I)/k(inact). 4. The two-time point IC(50) shift experiment proved to be an excellent method for the selection of appropriate K(I)/k(inact) assay parameters and is suitable for the routine analysis of P450 inhibition by drug candidates.
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A metabolic interaction between stiripentol (STP), an anticonvulsant agent that inhibits the activity of several cytochromes P450 (P450s), and clobazam (CLB), a 1,5-benzodiazepine, used in association with STP in severe myoclonic epilepsy in infancy was observed in vivo. This interaction was characterized in vitro using cDNA-expressed CYP3A4 and CYP2C19 (main P450 involved in CLB metabolism) to calculate K(i) and IC(50) of stiripentol in comparison with ketoconazole (CYP3A4 inhibitor) and omeprazole (CYP2C19 inhibitor). STP inhibited N-demethylation of CLB to N-desmethylclobazam (NCLB) mediated by CYP3A4 (noncompetitively) and CYP2C19 (competitively) with K(i) = 1.59 +/- 0.07 and 0.516 +/- 0.065 microM and IC(50) = 1.58 microM [95% confidence interval (CI95%) = 1.20-2.08] and 3.29 microM (CI95% = 1.87-5.79), respectively. STP inhibited also more strongly the 4'-hydroxylation of NCLB to 4'-hydroxy-N-desmethylclobazam by CYP2C19 [competitive interaction with K(i) = 0.139 +/- 0.025 microM and IC(50) = 0.276 microM (CI95% = 0.206-0.371)]. The inhibitory effect of STP on CLB demethylation by CYP3A4 was much weaker than that of ketoconazole [IC(50) = 0.023 microM (CI95% = 0.016-0.033)], whereas its effect on NCLB hydroxylation by CYP2C19 was much higher than that of omeprazole [IC(50) = 2.99 microM (CI95% = 2.11-4.24)]. The major in vitro inhibitory effect of STP on CLB metabolism and mostly on NCLB biotransformation is consistent with the changes in vivo in CLB and NCLB plasma concentrations in children treated by the association CLB/STP.
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With mycelium, arthrospores and microconidia of trichophyton mentagrophytes as inocula, a variety of in-vitro tests were used to assess the antifungal activity of the imidazoles; miconazole, clotrimazole, ketoconazole, econazole and tioconazole. For mycelial sensitivity, an agar plus method, a microtitre method using fragmented mycelial suspension and a turbidometric method were employed to determine fungistatic effects while a mycelial plug method indicated fungicidal activity. Spore susceptibility was determined by broth dilution and agar dilution methods for fungistatic action, while fungicidal activity was determined by measurement of rate of kill. The results obtained were affected to varying degrees by the test procedure, temperature and time of incubation, medium, pH and solvent. The spore forms were not more resistant than mycelium to the fungistatic effects of the imidazoles. There was little to choose between the various imidazoles in respect to their performance in these tests, with the exception of ketoconazole, which consistently gave higher MICs.
A literature search was conducted to extract published studies on the pharmacodynamics and drug interactions involving NOACs. Available data from US FDA and European Medicine Agency were also included. As these agents are substrates of permeability glycoprotein (P-gp) efflux transporter and/or CYP3A4 enzymes, articles focusing on the co-administration of NOACs and drugs affecting these pathways are discussed. Concomitant use of NOACs with antiplatelet agents may potentially increase bleeding risk.
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A chromatographic method was developed for the determination of cyclosporin A in human whole blood using reversed-phase HPLC at room temperature. Most previous reports carried out this liquid chromatographic separation at temperatures above 70 degrees C. The present procedure greatly improves the detection limit by controlling peak broadening effects, as well as the lifetime of the column at room temperature. Under optimal conditions and using ketoconazole as an internal standard, the calibration graph was linear in the range of 16-1000 microg/L with a relative standard deviation of 3.72% at 150 microg/L and 2.45% at 300 microg/L (n = 11) of cyclosporin A. The detection limit was of 5.0 microg/L cyclosporin A. By this procedure, cyclosporin A pharmacokinetic parameters in healthy Chinese subjects were studied. The developed method could be applied to the quantification of cyclosporin A in human blood samples and allows the study of its pharmacokinetics in routine laboratories.
The objective of this project was to develop a cell based in vitro experimental procedure that can differentiate P-glycoprotein (P-gp) substrates from inhibitors in a single assay. Caco-2 cells grown to confluency on 12-well Transwell were used for this study. The efflux permeability (B to A) of P-gp specific probe (viz., digoxin) in the presence of test compounds (e.g. substrates, inhibitors and non-substrates of P-gp) was monitored, and the influx permeability (A to B) of test compounds was evaluated after complete P-gp blockade. Radiolabelled digoxin was added on the basolateral side with buffer on the apical side. The digoxin concentration appearing on the apical side represents digoxin efflux permeability during the control phase (0-1 h period). After 1 h, a test compound (10 microM) was added on the apical side. The reduced efflux permeability of digoxin suggests that the added test compound is an inhibitor. The influx permeability of test compound is also determined during the 1-2 h study period by measuring the concentration of the test compound in the basolateral side. At the end of 2 h, a potent P-gp inhibitor (GF120918) was added. The increased influx permeability of test compound during the 2-3 h incubation period indicates that the added test compound is a substrate. Samples were taken from both sides at the end of 1-3 h and the concentrations of the test compounds and digoxin were quantitated. Digoxin efflux permeability remained unchanged when incubated with P-gp substrates (e.g., etoposide, rhodamine123, taxol). However, when a P-gp inhibitor was added to the apical side, the digoxin efflux (B to A permeability) was significantly reduced (ketoconazole=51% reduction) as expected. The influx permeability of substrates increased significantly (rhodamine123=70%, taxol=220%, digoxin=290%) after the P-gp inhibitor (GF120918) was introduced, whereas the influx permeability of P-gp inhibitor and non-substrates was not affected by GF120918. Thus, this combined assay provides an efficient cell based in vitro screening tool to simultaneously distinguish compounds that are P-gp substrates from P-gp inhibitors.
The metabolic activities of aminopyrine N-demethylation and tolbutamide methylhydroxylation by the human hepatic cytochrome P450 (P450 or CYP) 2C subfamily were compared and the effects of azole antifungal agent on the drug-metabolizing activity of CYP2C8 were investigated.
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Growth inhibition of six Trichophyton spp. by herbal essential oils was accessed and the combined effects of P. graveolens oil and its main components citronellol and geraniol were evaluated using a checkerboard microtitre assay against T. schoenleinii, T. erinacei and T. soudanense. The essential oil fraction of P. graveolens and its main components, geraniol and citronellol, exhibited strong synergism with ketoconazole against T. schoenleinii and T. soudanense, with fractional inhibitory concentration (FIC) indices in the range of 0.18-0.38.
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CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.
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Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines.
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PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.