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Neoscytalidium dimidiatum is an opportunistic fungus causing cutaneous infections mostly, which are difficult to treat due to antifungal resistance. In Malaysia, N. dimidiatum is associated with skin and nail infections, especially in the elderly. These infections may be mistaken for dermatophyte infections due to similar clinical appearance. In this study, Neoscytalidium isolates from cutaneous specimens, identified using morphological and molecular methods (28 Neoscytalidium dimidiatum and 1 Neoscytalidium sp.), were evaluated for susceptibility towards antifungal agents using the CLSI broth microdilution (M38-A2) and Etest methods. Amphotericin B, voriconazole, miconazole and clotrimazole showed high in vitro activity against all isolates with MIC ranging from 0.0313 to 1 µg/mL. Susceptibility towards fluconazole and itraconazole was noted in up to 10% of isolates, while ketoconazole was inactive against all isolates. Clinical breakpoints for antifungal drugs are not yet available for most filamentous fungi, including Neoscytalidium species. However, the results indicate that clinical isolates of N. dimidiatum in Malaysia were sensitive towards miconazole, clotrimazole, voriconazole and amphotericin B, in vitro.
Fluconazole and itraconazole are two investigational triazole antifungal agents that are currently undergoing clinical trials in the United States. Both are active orally, have favorable pharmacokinetics (i.e., good bioavailability, long half-life, low plasma protein binding), and possess activity against several systemic fungal pathogens. In addition, preliminary information suggests that these agents are substantially less toxic than currently available azole compounds. Fluconazole and, to a lesser degree, itraconazole have been shown to be highly effective for the treatment of cryptococcal meningitis. The potential for drug interactions is much lower with these agents compared to drugs such as ketoconazole.
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Five patients with African histoplasmosis were treated with ketoconazole. Three of these were children with disseminated disease and 2 were adults with localized cutaneous disease. Both patients with cutaneous disease responded to treatment, although one was lost to follow-up. Of the 3 children with disseminated disease, one was apparently cured, one responded well but subsequently relapsed, and one failed to respond in spite of having blood levels of ketoconazole within the therapeutic range. Further studies are needed to determine the optimum dosage and duration of treatment with ketoconazole for this condition.
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Metabolism of a new antitumor agent, CAI (NSC 609974), was investigated in human liver tissue in vitro and in plasma and urine of patients receiving CAI. Metabolites identified by HPLC following C-labeled CAI incubation with human liver microsomes and reported as percentage of total metabolites formed were M1 (0-3.4%), M2 (4. 5-33%), M3 (60-79%), and M4 (7.2-19%). Ketoconazole, an inhibitor of cytochrome P450 3A4, prevented formation of M1, M3, and M4 (concentration of drug that inhibited metabolite formation by 50% when compared to maximum uninhibited activity, 3.0 &mgr;M), but only weakly inhibited formation of M2 (concentration of drug that inhibited metabolite formation by 50% when compared to maximum uninhibited activity, >50&mgr;M). CAI incubated with recombinant human P450 3A4 microsomes produced metabolites M3 and M4. Conjugation of M3, most likely a glucuronide, was observed after incubation of C-labeled CAI and UDP-glucuronic acid with human liver 13,000 x g supernatant. Plasma samples from patients receiving CAI contained CAI (3.1-5.0 &mgr;g/ml), M1 (0.9-2.6 &mgr;g/ml), and M2 (1. 0-2.2 &mgr;g/ml). CAI and M3 but not M4 were observed in the urine samples. After incubation of the urine samples withbeta-glucuronidase, CAI concentrations increased 67%, M3 increased up to 9-fold, and M4 was detected. CAI is metabolized in vitro and in vivo by both Phase I and Phase II enzymes and is metabolized to M3 and M4 by P450 3A4. These studies suggest that elevated levels of CAI may result from P450 3A4 inhibition by ketoconazole if these two drugs are coadministered. Correlation between CAI metabolism in vitro and results obtained in patients demonstrates the usefulness of liver metabolism studies in vitro in the early stages of drug development.
Aminobenzolamide (5-sulfanilylamido-1,3,4-thiadiazole-2-sulfonamide) is a potent inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 184.108.40.206), being at the same time structurally similar to the antimicrobial sulfonamides. Here we report that the reaction of aminobenzolamide with arylsulfonyl isocyanates affords a series of new arylsulfonylureido derivatives which were subsequently used as ligands (in the form of conjugate bases, as sulfonamide anions) for the preparation of metal complexes containing Ag(I) and Zn(II). All the new compounds proved to be very potent inhibitors of CA (isozymes I, II and IV). The newly synthesized complexes, unlike the free ligands, also act as effective antifungal agents against several Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 1.8-5 microg/mL. The mechanism of antifungal action of these complexes seem to be unconnected with inhibition of lanosterol-14-alpha-demethylase, since the levels of sterols assessed in the fungi cultures were equal in the absence or in the presence of the tested compounds. Probably the new complexes act as inhibitors of phosphomannose isomerase, a key enzyme in the biosynthesis of yeast cell walls.
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Mycetomas are endemic to northwest Africa. Most frequently located in the foot, they are seldom seen in the orbit. The color of the grains provides a clue as to the etiology. Black-grain mycetomas are always fungal and are treated surgically--essentially like cancer--as the persistence of a single grain will cause a recurrence.
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Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R-138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2-week washout between periods. Ketoconazole decreased R-138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34-61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R-138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0-24 (area under the concentration-time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.
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A panel of 637 isolates of Candida albicans that had been typed by multilocus sequence typing (MLST) and tested for susceptibility to amphotericin B, caspofungin, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, terbinafine and voriconazole was the material for a statistical analysis of possible associations between antifungal susceptibility and other properties. For terbinafine and flucytosine, the greatest proportion of low-susceptibility isolates, judged by two resistance breakpoints, was found in MLST clade 1 and among isolates homozygous at the MAT locus, although only three isolates showed cross-resistance to the two agents. Most instances of low susceptibility to azoles, flucytosine and terbinafine were among oropharyngeal isolates from HIV-positive individuals. Statistically significant correlations were found between terbinafine and azole minimal inhibitory concentrations (MICs), while correlations between flucytosine MICs and azole MICs were less strong. It is concluded that a common regulatory mechanism may operate to generate resistance to the two classes of agent that inhibit ergosterol biosynthesis, terbinafine and the azoles, but that flucytosine resistance, although still commonly associated with MAT homozygosity, is differently regulated.
Infant exposure to ketoconazole in human milk was calculated to be 0.4% on average (maximum 1.4%) of those expected from therapeutic doses given directly to infants. Potential risk of adverse reactions from this low exposure level seem to be outweighed by the benefits of breast-feeding.
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In 1985, available drugs to cure deep mycosis are in fact limited to amphotericin B (Fungizone), 5-fluorocytosine (Ancotil) and ketoconazole (Nizoral). Potassium iodide is not much utilized. In diffuse aspergillosis and meningitic cryptococcosis, Fungizone by I.V. injection remains the high-grade antifungal drug--Ancotil is not actually used anymore in mono-therapy, but associated either with Fungizone in cryptococcosis and diffuse aspergillosis, or with Nizoral in systemic candidosis--Nizoral, which does not diffuse in C.S.F. and has a limited efficiency in immunosuppressive patients, is recommended in systemic candidosis and tropical deep mycosis, particularly histoplasmosis, blastomycosis, entomophtoromycosis, as well as in candidosis and diffuse aspergillosis prophylaxis in people at high risk. New antimycosis drugs are under studies: itraconazole efficient against aspergillus and fluconazole, which diffuses in C.S.F. and has a long time action.
Widespread and repeated use of fluconazole in the prophylaxis and therapy resulted in resistance among Candida strains. Investigation of the expression of efflux pump encoding genes was aimed in fluconazole-resistant and -susceptible C.albicans isolates in order to determine the role of this mechanism in fluconazole resistance. Five fluconazole-resistant, six -susceptible and four trailing effect showing susceptible C.albicans isolates were included in the study. The MIC values of fluconazole and other antifungal agents were determined by the microdilution method. The fluconazole MIC values of the fluconazole-resistant strains were also studied by E-test performed on yeast extract peptone dextrose agar with and without cyclosporin A. The expression levels of CDR1, CDR2 and MDR1 transcripts were determined by real-time PCR method. The expression of these genes was normalized with their ACT1 levels and compared with the fluconazole-susceptible C.albicans ATCC 14053 strain. It was detected that all strains were susceptible to amphotericin B and all except one strain were also susceptible to clotrimazole. Three out of five fluconazole-resistant strains and three out of four trailing effect showing susceptible strains were resistant to 5-flucytosine, and all except one susceptible strains were found as intermediate to 5-flucytosine. All except one fluconazole-resistant strains were determined as resistant to itraconazole and ketoconazole, and had miconazole MIC values of ≥ 64 µg/ml. All fluconazole-susceptible isolates were detected to be susceptible to ketoconazole and dose dependent susceptible to itraconazole. Fluconazole-resistant and -susceptible strains were determined as susceptible to voriconazole. Out of five fluconazole-resistant isolates, two strains overexpressed high levels and three strains overexpressed mild levels of CDR1/2; one strain overexpressed high levels and three strains overexpressed low levels of MDR1 in comparison to C.albicans ATCC 14053 control strain. It was observed that CDR1, CDR2 and MDR1 gene expression levels were mild in strains showing trailing effect except one which highly expressed MDR1, while susceptible isolates except three expressed efflux pump genes at low levels. It was determined that the expression levels of CDR1 and CDR2 genes for the same strain were in parallel for all isolates. It can be concluded that overexpression of efflux pump genes is an important mechanism of resistance in fluconazole-resistant C.albicans isolates.
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All patients received itraconazole for 3 months at a dose of 100 or 200 mg daily. Itraconazole levels of distal nail clippings were determined during a 6-month posttherapy period.
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Advanced prostate cancer remains dependent on androgens and signaling through the androgen receptor despite castrate levels of testosterone defined as testosterone levels <1.7 nmol/l. Ketoconazole, a nonspecific inhibitor of androgen synthesis, has been tested in clinical trials and showed clinical activity; however, high doses are needed which are associated with significant sides effects, mainly neurotoxicity, gastrointestinal intolerance, and liver toxicity. Abiraterone acetate is an irreversible inhibitor of two key enzymes of androgen synthesis, 17a-hydroxylase and 17,20-lyase, and has been tested in a randomized phase III study in patients with castration-resistant prostate cancer who progressed after chemotherapy. Abiraterone plus prednisone resulted in a significant overall survival benefit of 4.6 months compared to prednisone alone. Abiraterone was well tolerated, with mostly mild or moderate side effects consistent with secondary mineralocorticoid excess, namely fluid retention, hypokalemia, and hypertension. Abiraterone plus prednisone is considered a new standard therapy option for patients with castration-resistant prostate cancer who progressed after chemotherapy.
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Lenvatinib is an oral, multitargeted, tyrosine kinase inhibitor under clinical investigation in solid tumors. In vitro evidence indicates that lenvatinib metabolism may be modulated by ketoconazole, an inhibitor of CYP3A4 and p-glycoprotein.
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Cultured human epidermal keratinocytes were used as a model system for testing compounds with potential therapeutic effect against hyperproliferative skin disorders. We have investigated whether each test compound caused direct damage to the DNA or inhibited DNA repair and/or seminconservative replication of DNA, as well as its effect on the overall rate of protein synthesis and on expression of specific keratin genes. The following compounds were studied: (a) inhibitors of DNA polymerase alpha [aphidicolin and its derivative aphidicolin glycine], (b) inhibitors of topoisomerases [novobiocin, nalidixic acid, teniposide, etoposide, and 4'-(9-acridylamine) methanesulfon-m-anisidide], (c) modifiers of chromatin structure [sodium butyrate, 3-aminobenzamide, and nicotinamide], (d) inhibitors of calmodulin activation and protein kinase C [chlorpromazine and trifluoperazine]; and (e) drugs used in clinical dermatology [anthralin, fluocinolone acetonide, ketoconazole, and hydroxyurea]. The compounds were tested at concentrations at which they were known from the literature to be effective in their respective actions. Among the groups of compounds studied, the topoisomerase inhibitors were particularly interesting since they caused no detectable damage to DNA but exhibited maximal inhibitory effect on replication combined with minimal inhibition of DNA repair. In addition most of the topoisomerase inhibitors, particularly novobiocin, changed the pattern of gene expression by inhibiting the synthesis of certain keratins and inducing a Mr 67,000 protein in the prekeratin fraction. These properties combined with minimal systemic side effects may encourage the clinical exploration of some topoisomerase inhibitors for antiproliferative therapy of skin disorders.
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In docetaxel refractory mCRPC, the outcome of abiraterone treatment may be superior to ketoconazole.
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Fifty-one patients with nonmeningeal coccidioidomycosis were considered for treatment with intraconazole. Forty-nine patients who met study criteria were treated with itraconazole given orally in doses of 100 to 400 mg/day for periods up to 39 months. Of these patients, 12 had osteoarticular disease, 23 had chronic pulmonary disease, and 14 had skin or soft tissue disease. Clinical response was evaluated using a scoring system accounting for lesion number and size, symptoms, culture, and serologic titer. Remission was defined as reduction of the pretreatment score by 50% or more.
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An assessment was carried out in 59 women with proven vaginal candidosis to compare the efficacy and tolerance of itraconazole used in three different treatment regimens. Patients were allocated at random to receive a single oral dose of 200 mg itraconazole for 1, 2 or 3 days. They were reassessed 1 week and 4 weeks after treatment for remission of clinical signs and symptoms and repeat mycological investigations. All three regimens yielded successful clinical results, global evaluation at 4 weeks showing complete remission in 100% (5/5), 81.5% (25/27) and 92.3% (24/26) of patients, respectively. One patient (on 2-day treatment) required alternative treatment before the 4-week assessment. Minor gastric side-effects were reported by a few patients on the 2-day and 3-day treatment regimens; these resolved spontaneously.
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The in-vitro susceptibilities of 40 clinical isolates of Candida albicans to ketoconazole and fluconazole were determined and an attempt was made to correlate these data with the clinical responses of the patients from whom the strains were originally isolated to treatment with these agents. Of 40 patients with the acquired immunodeficiency syndrome (AIDS) with oropharyngeal and/or oesophageal candidosis, 21 received ketoconazole and 19 fluconazole. Susceptibility testing was performed by a microbroth dilution method with RPMI-2% glucose medium according to the recommendations of the National Committee for Clinical Laboratory Standards; growth inhibition was estimated spectrophotometrically and the MIC endpoint was defined in terms of the IC1/2. The MICs of 236 additional strains of C. albicans, which were also isolated from AIDS patients, were used to establish a susceptibility profile for this species. On the basis of the susceptibility test results and the clinical responses of the 40 patients, the following tentative breakpoints for ketoconazole and fluconazole are proposed: patients with infections caused by C. albicans strains with MICs of ketoconazole and fluconazole or < or = 0.001 and < or = 0.25 mg/L respectively would be expected to respond to treatment with these agents and isolates with MICs which meet these criteria are therefore classified as susceptible; patients with infections caused by strains with MICs of ketoconazole and fluconazole of > or = 0.06 and > or = 16.0 mg/L respectively would not be expected to respond to treatment with these agents and isolates with MICs which meet these criteria are therefore classified as resistant; the response of patients with infections caused by strains with MICs of ketoconazole and fluconazole of 0.003-0.03 and 0.5-8.0 mg/L respectively cannot be reliably predicted and isolates with MICs which fall within these ranges are therefore classified as being of indeterminate susceptibility. The present study demonstrates that the results of in-vitro susceptibility testing with RPMI-2% glucose broth correlate with the clinical response to therapy and can be used to facilitate optimal treatment in AIDS patients with oropharyngeal and/or oesophageal candidosis.
Methadone has become one of the most widely used drugs for opiate dependency treatment. This drug is extensively metabolized by the cytochrome P450 hepatic enzyme family in man, yielding an N-demethylated metabolite that cyclizes spontaneously into 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine. The specific forms of cytochrome P450 involved in this oxidative N-demethylation were examined in a panel of 20 human liver microsomal preparations previously characterized with respect to their P450 enzyme contents. Methadone was demethylated with an apparent Km of 545 +/- 258 microM (n = 3). The metabolic rates were 745 +/- 574 pmol/(min.mg of protein). This metabolic pathway was strongly correlated with estradiol 2-hydroxylation, testosterone 6 beta-hydroxylation, nifedipine oxidation, erythromycin N-demethylation, and toremifene N-demethylation, all of these monooxygenase activities being supported by P450 3A4. Furthermore, the total P450 3A content of liver microsomal samples, determined by immuno-quantification using a monoclonal anti-human P450 3A4 antibody, was correlated with methadone demethylation (r = 0.72; p < 0.003). Methadone metabolism was 60-72% inhibited either by three mechanism-based inhibitors of P450 3A4 (gestodene, TAO, and erythralosamine) or by four reversible inhibitors of P450 3A (ketoconazole, dihydroergotamine, quercetin, and diazepam with an apparent Ki of 50 microM) and by two nonspecific inhibitors (metyrapone and SKF-525A). Conversely, quinidine (inhibitor of P450 2D6), 7,8-benzoflavone (inhibitor of P450 1A), or sulfaphenazole (inhibitor of P450 2C) did not significantly inhibit, and may even have activated, methadone metabolism. Four heterologously expressed P450 proteins were able to catalyze the N-demethylation of methadone, namely, P450 2C8, P450 2C18, P450 2D6, and P450 3A4. However, referring to their relative liver content, it can be asserted that P450 3A4 is the major enzyme involved in the N-demethylation of methadone on average. Accordingly, caution should be advised in the clinical use of methadone when other drugs are also administered that induce or inhibit P450 3A4, such as rifampicin or diazepam, respectively.
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Leishmaniasis, which exists in both visceral and cutaneous forms, is currently treated with intramuscular antimony or intravenous amphotericin B. The primary unmet need is for oral therapy. Of the several drugs in clinical development, miltefosine is unique in being an oral agent with efficacy against both forms of the disease. Sitamaquine is an oral agent with substantial but not sufficient efficacy against visceral disease. Oral fluconazole has been shown to be more effective than placebo in one instance: for Leishmania major cutaneous disease from Saudi Arabia. Paromomycin is in widespread trial. Topical paromomycin formulations are being tested for cutaneous disease, and intramuscular paromomycin is in Phase III trial for Indian visceral disease. The most likely replacements for present therapy are oral miltefosine for many of the visceral and cutaneous syndromes, intramuscular paromomycin for visceral disease and topical paromomycin for some forms of cutaneous disease.
Randomised trials of amphotericin B, fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment in cancer patients with neutropenia.
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After cardiac transplantation, ketoconazole greatly reduced the need for cyclosporine, resulting in substantial cost savings. Ketoconazole also reduced the rates of rejection and infection, without persistent toxic effects. We now use ketoconazole routinely in cardiac-transplant recipients.
By principle both topical and systemic antifungals are available for oral candidosis. As therapeutic results have not yet reached an optimum these modalities deserve further consideration. This especially applies to bioavailability. As candidosis in general very often is a disease confined to other tissues than blood especially to cutaneous and mucosal surfaces, it is helpful to determine the drug level found at these sites. Both total and free drug levels should be looked at. The skin blistering techniques make this possible. In vitro simulation of the level profiles of various antifungals including in particular ketoconazole found in the skin can be simulated in vitro using Grasso's model. If this is done only a very limited candidacidal effect is to be seen. Taking this fact into account as well as a limited clinical efficacy of conventional treatment protocols it looks rewarding to use conventional antifungal drugs such as ketoconazole at comparatively high doses.
Combination therapy with ketoconazole and calcitriol or EB 1089 may enhance antitumor activities of vitamin D compounds for prostate cancer and alleviate side effects of vitamin D deficiency that are likely associated with ketoconazole therapy.
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The in vitro metabolism of ropinirole was investigated with the aim of identifying the cytochrome P450 enzymes responsible for its biotransformation. The pathways of metabolism after incubation of ropinirole with human liver microsomes were N-despropylation and hydroxylation. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to each pathway. A high affinity component with a K(M) of 5-87 microM and a low affinity component with a K(M) of approximately two orders of magnitude greater were evident. The high affinity component could be abolished by pre-incubation of the microsomes with furafylline. Additionally, incubation of ropinirole with microsomes derived from CYP1A2 transfected cells readily produced the N-despropyl and hydroxy metabolites. Some inhibition of ropinirole metabolism was also observed with ketoconazole, indicating a minor contribution by CYP3A. Multivariate correlation data were consistent with the involvement of the cytochrome P450 enzymes 1A2 and 3A in the metabolism of ropinirole. Thus, it could be concluded that the major P450 enzyme responsible for ropinirole metabolism at lower (clinically relevant) concentrations is CYP1A2 with a contribution from CYP3A, particularly at higher concentrations.
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Mycetoma is a variety of deep mycoses. The endemic centres are situated in the countries with tropic or subtropic climate. In diagnosis, the important place belongs to microbiological, histological and roentgenological investigations. Surgical treatment supposes the radical removal of a pathological focus in aiming at preservation of the weight-bearing surface of an extremity. In intact skin, the subcutaneous incision of the mycous infiltrate is performed. The extensive soft tissue defects, especially at the region of joints, require primary or secondary autodermoplasty. The medicamentous treatment of fungal mycetomas is ineffective. The positive effect of Ketocanazole (Nizoral) before the operation was noted.