The antifungal antibiotic clotrimazole potently inhibits L-type calcium current in guinea-pig ventricular myocytes.
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The antimycotic agent clotrimazole (CLT) is a promising potential therapeutic agent for a variety of diseases including cancer. Although it is known that CLT alters calcium homeostasis in many cell types, its cardiac effects are virtually unknown. We investigated the effects of CLT on L-type calcium current (ICa,L) and action potentials in guinea-pig ventricular myocytes. CLT (5, 25 and 50 microM) inhibited basal ICa,L by 16, 59 and 93%, respectively. The inhibitory effect of CLT was rapid and the peak effect was attained within 3 min. At a concentration of 25 microM, the inhibitory effect of CLT was partially reversible whereas the response to 50 microM CLT persisted following drug withdrawal. CLT abbreviated action potential duration at 50 and 90% of repolarization and suppressed the plateau significantly. These results indicate that CLT may have important cardiac effects at concentrations used to induce the antiproliferative action of the drug. (+info)
PCR-restriction enzyme analysis for detection of Candida DNA in blood from febrile patients with hematological malignancies.
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Blood samples were drawn daily from 72 patients who had hematological malignancies, neutropenia, and fever and who had failed to respond to broad-spectrum antibiotics. Each sample was used for conventional fungal blood cultures and for detection and identification of Candida DNA by a PCR method with subsequent restriction enzyme analysis (REA) recently developed in our laboratory. The PCR method was able to detect five CFU of Candida spp. per ml of blood, and subsequent REA of the amplicons allowed the identification of the Candida species most commonly implicated in cases of candidiasis. Thirty-one patients were PCR-REA positive, and four of these patients were also culture positive. The ultimate diagnosis for 13 of these patients and 1 patient who was PCR-REA negative was disseminated candidiasis (confirmed by clinical data, multiple cultures, histology, autopsy, and/or ultrasonographic evidence of hepatosplenic candidiasis). The molecular method is significantly more sensitive than conventional fungal blood cultures and has a high negative predictive value (97.5%) for the development of disseminated candidiasis in neutropenic patients. (+info)
Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans.
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Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents. (+info)
Sensitivity distribution of phytopathogenic bacteria and fungi to antibiotics.
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The minimal inhibitory concentrations (MIC) of various antibiotics and fungicides for Erwinia carotovora, Pseudomonas coronafaciens var. atropurpurea, P. lachrymans, Alternaria mali, A. kikuchiana, Pyricularia oryzae, Botrytis sp. and Sclerotinia sp. isolated from diseased plants in various localities of Japan were examined to enable the isolates to be gruoped into sensitive and resistant strains. To minimize the effects of various variable conditions, MIC of isolates were pooled for either 2 or 3 years and were plotted in a single figure. The grouping values were determined on the basis of MIC values of the antibiotics and agricultural chemicals on phytopathogenic bacteria and fungi under investigations. The relationships between grouping values for isolates of bacteria and fungi and the control of disease on the plants correlated to each other were studied. (+info)
A critical comparison of the hemolytic and fungicidal activities of cationic antimicrobial peptides.
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The hemolytic and fungicidal activity of a number of cationic antimicrobial peptides was investigated. Histatins and magainins were inactive against human erythrocytes and Candida albicans cells in phosphate buffered saline, but displayed strong activity against both cell types when tested in 1 mM potassium phosphate buffer supplemented with 287 mM glucose. The HC50/IC50 ratio, indicative of the therapeutic index, was about 30 for all peptides tested. PGLa was most hemolytic (HC50 = 0.6 microM) and had the lowest therapeutic index (HC50/IC50 = 0.5). Susceptibility to hemolysis was shown to increase with storage duration of the erythrocytes and also significant differences were found between blood collected from different individuals. In this report, a sensitive assay is proposed for the testing of the hemolytic activities of cationic peptides. This assay detects subtle differences between peptides and allows the comparison between the hemolytic and fungicidal potency of cationic peptides. (+info)
How should managed care treat onychomycosis?
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This activity is designed for leaders and managers of managed care organizations and for primary care physicians and specialists involved in evaluating, treating, and caring for patients with onychomycosis. GOAL: To help health professionals care for patients with onychomycosis through a discussion of new treatment choices that exist due to recently approved oral antifungal agents for this chronic medical condition. OBJECTIVES: 1. Review the anatomy of the nail unit in relation to the pathogenesis, epidemiology, and clinical features of onychomycosis. 2. Stress the importance of confirming the diagnosis of onychomycosis using relatively simple and cost-effective laboratory procedures, since there are many other nonfungal conditions that can pathologically involve the nail unit. 3. Detail the ways in which onychomycosis can adversely affect a patient's quality of life. 4. Analyze the change in treatment patterns brought about by newer potentially curative oral antifungal therapy. 5. Identify potential problems with onychomycosis oral antifungal therapy, including dosing issues, possible adverse events, and drug-drug interactions. (+info)
Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial.
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We performed a prospective, randomized, multicenter trial to evaluate the effectiveness of prophylactic inhalations with aerosolized amphotericin B (aeroAmB) to reduce the incidence of invasive aspergillus (IA) infections in patients after chemotherapy or autologous bone marrow transplantation and an expected duration of neutropenia of at least 10 days. From March 1993 until April 1996, 382 patients with leukemias, relapsed high-grade non-Hodgkin lymphomas, or solid tumors were randomized with a 13:10 ratio to receive either prophylactic aeroAmB inhalations at a dose of 10 mg twice daily or no inhalation prophylaxis in an unblinded fashion. The incidence of proven, probable, or possible IA infections was 10 of 227 (4%) in patients who received prophylactic aeroAmB. This did not differ significantly from the 11 of 155 (7%) incidence in patients who received no inhalation prophylaxis (P =.37). Moreover, no differences in the overall mortality (13% v 10%; P =.37) or in the infection-related mortality (8% v 7%; P =.79) were found. In contrast to other nonrandomized trials, we observed no benefit from prophylactic aeroAmB inhalations, but the overall incidence of IA infections was low. (+info)
Failure of amphotericin B colloidal dispersion in the treatment of paracoccidioidomycosis.
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Although amphotericin B desoxycholate is considered the most effective treatment for disseminated Paracoccidioides brasiliensis infections, little is known about the efficacy of lipid-based formulations of amphotericin B in this infection. In this study, we treated four adults with the juvenile form of paracoccidioidomycosis with 3 mg/kg/day of amphotericin B colloidal dispersion for at least 28 days. Although all of the patients initially responded by clinical observation, all four patients relapsed within six months. The use of amphotericin B colloidal dispersion for the initial induction of paracoccidioidomycosis failed to cure this infection. Possible reasons for failure include dose, duration, or reduced efficacy of this lipid preparation. For many fungal infections, lipid-based preparations have been shown to have a therapeutic-toxic advantage, but our experience with Paracoccidioides infections suggests that more careful studies will need to be performed before they can be recommended for use in this mycosis. (+info)