RESUMEN
Apple leather is made by dehydration of cooked fruit into leathery sheets. Mould growth and patulin production can occur in damaged apples or when fallen fruit is collected for apple leather processing. A survey was conducted to determine levels and dietary intake of patulin from apple leather marketed in Iran. Patulin was detected in all samples at concentrations ranging from <10 to 2559 µg/kg. Mean patulin concentration was 620 µg/kg and 91.4% of the samples had levels higher than 50 µg/kg. Estimated daily intake (EDI) of patulin for adults and children considering the mean concentration of patulin obtained in this study (620 µg/kg) were higher than the provisional maximum tolerable daily intake (PMTDI) of 0.4 µg/kg bw/day for patulin that has been established by the Joint FAO/WHO Expert Committee on Food Additives. This indicated the need for stricter control and improvement in processing techniques to reduce the incidence of patulin in apple leather.
Asunto(s)
Dieta , Contaminación de Alimentos/análisis , Frutas , Hongos , Malus , Patulina/análisis , Adulto , Niño , Recolección de Datos , Microbiología de Alimentos , Frutas/microbiología , Humanos , Irán , Malus/microbiologíaRESUMEN
The in vitro and in vivo activities of four azole compounds belonging to a new series of 2(2,4-difluorophenyl)-3-(4-substituted piperazin-1-yl)-1-(1,2,4-triazol-1-yl) butanol antifungal agents is described. The compounds were selected from a library of azole compounds synthesized by our group. The in vitro activities of Syn2869, Syn2836, Syn2903, and Syn2921 against a panel of over 240 recently collected clinical isolates of yeast and molds were determined, and the results were compared with those obtained with fluconazole (FLC), itraconazole (ITC), and amphotericin B (AMB). The MICs at which 90% of the isolates were inhibited (MIC(90)s) for the four test compounds for strains of Candida spp. ranged from <0.048 to 0.78 microg/ml. All compounds were also active against FLC-resistant Candida albicans and other Candida sp. strains. Moreover, MIC(90)s for strains of Cryptococcus neoformans, Aspergillus spp., Trichophyton spp., and Microsporum spp. were also low and ranged from <0.048 to 0.39 microg/ml. The test compounds produced a fungistatic pattern during the time-kill kinetic studies. In vivo studies indicated that all four test compounds have good efficacies against C. albicans in a murine systemic infection model and significantly improved the survival rates of the infected mice. The results for Syn2903 were similar to those for FLC, while the other compounds were slightly less effective but had ranges of activities similar to the range of activity of ITC. The compounds were also evaluated against an Aspergillus fumigatus systemic infection. Syn2903 was also superior to ITC, whereas the efficacy data for the other compounds were similar to those for ITC. It was concluded from the data generated for this new series of azole compounds in the studies described above that further pharmacokinetic and toxicologic evaluations are warranted prior to selection of a candidate compound for preclinical testing.
Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Animales , Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones , Pruebas de Sensibilidad Microbiana , Piperazinas/farmacología , Piperazinas/uso terapéutico , Resultado del Tratamiento , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
A simple and rugged reversed-phase high-performance liquid chromatographic method with ultraviolet absorbance detection at 263 nm was developed and validated for the analysis of novel triazole antifungal agents SYN-2869 and its derivatives in tissues. The method involved homogenization with 0.01 M phosphate buffer (pH 7.8) for lung, brain and spleen tissues. The liver and kidneys were homogenized with acetonitrile:acetone (1:1). The plasma proteins were precipitated with ice-cold acetonitrile and supernatent was evaporated to dryness. The reconstituted samples were injected onto an HPLC system. SYN-2869 was separated from the matrix components on a symmetry C(18) column using a aqueous mobile phase of acetonitrile and water with a flow rate of 1 mL/min. A step gradient of 40-80% acetonitrile eluted SYN-2869 and the internal standard (SYN-2506). The linear range was 0.5-10 microgram/g (r(2) > 0.99). The limit of quantitation was 0.5 microgram/g. The inter-day precision and accuracy for SYN 2869 standard concentration were from 2.6 to 7.4% and from -1.56 to +3.29%, respectively. The method was applied to tissue samples collected from single intravenous administration to mice to evaluate the distribution of these novel antifungal agents to different tissues.
Asunto(s)
Antifúngicos/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Piperazinas/farmacocinética , Triazoles/farmacocinética , Animales , Ratones , Estándares de Referencia , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Distribución TisularRESUMEN
The pharmacokinetics and distribution in tissue of several novel triazole antifungal agents were studied in different animal species in order to select an appropriate lead compound. The purpose of the study was also to determine species differences in pharmacokinetics for SYN azoles to select the most appropriate species for secondary efficacy and toxicological evaluation of the selected compound. SYN-2836, SYN-2869, SYN-2903, and SYN-2921 were rapidly absorbed into the systemic circulation and reached maximum concentrations (C(max)s) of 7.31 +/- 2.53, 6.29 +/- 0.85, 6.16 +/- 0.39, and 3.41 +/- 0.34 microg/ml, respectively, in BALB/c mice after administration of an oral dose of 50 mg/kg of body weight, with bioavailability being greater than 45% in all mice. The areas under the concentration-time curve from time zero to infinity (AUC(0-infinity)s) after administration of a single intravenous dose of 20 mg/kg to mice varied between 25.0 and 63.6 microg. h/ml. The half-life was in the range of 4.5 to 6 h. In Sprague-Dawley rats there was no significant difference in AUC(0-infinity) after administration of a single intravenous dose of 20 mg/kg, but on oral administration, the bioavailability of SYN-2836 was extremely low, while that of SYN-2869 was only 14.7%. In New Zealand White rabbits the C(max) and the time to reach C(max) for SYN-2836 and SYN-2869 after administration of a single oral dose of 50 mg/kg were similar. There were significant differences in AUC(0-infinity) and half-life between SYN-2836 and SYN-2869. On the other hand, in beagle dogs the C(max) and AUC(0-infinity) of SYN-2836 after administration of a single oral dose of 30 mg/kg were 4.82 +/- 1.54 microg/ml and 41.8 +/- 15.7 microg. h/ml, respectively, which were threefold higher than those of SYN-2869. The concentrations of the SYN compounds in tissue indicated that the AUC(0-infinity)s of SYN-2836, SYN-2869, SYN-2903, and SYN-2921 in mouse lungs were significantly different from each other. The ratios of the concentrations of the SYN azoles in lungs to those in plasma were also significantly different from those for itraconazole. Among the SYN azoles the highest concentration in the lungs was found for SYN-2869. The higher level of distribution of SYN-2869 into lung tissue was considered to contribute to the potent efficacy in respiratory tract infection models compared with the potency of itraconazole. Significant differences in the pharmacokinetics of these compounds were observed in different animal species, and selection of an animal model for further evaluation was based on results obtained from these studies.
Asunto(s)
Antifúngicos/farmacocinética , Piperazinas/farmacocinética , Triazoles/farmacocinética , Administración Oral , Animales , Antifúngicos/sangre , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Perros , Semivida , Inyecciones Intravenosas , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Piperazinas/sangre , Conejos , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Triazoles/sangreRESUMEN
A simple reversed-phase high-performance liquid chromatography (HPLC) method with UV detection was developed and validated for the quantitation of SYN-2869, a novel triazole antifungal agent and its analogs in rat plasma. The method involved a simple precipitation of plasma protein with acetonitrile (1:10 ratio). The reconstituted sample after evaporation to dryness was injected onto a HPLC column. SYN-2869 and its analogs were separated from the matrix components on a symmetry C18 column using an aqueous mobile phase of acetonitrile and water with a flow rate of 1 ml min(-1). A step gradient of 40-80% acetonitrile eluted all four compounds. The run time was 30 min. The linear range was 0.5 10 microg ml(-1)(r2 > 0.999). The limit of quantitation was 0.5 microg ml(-1). The inter-day precision and accuracy for SYN-2869 standard concentration were from 1.9 to 8.5% and from 1.4 to +/- 4.40%, respectively. The precision and accuracy of intra-day quality control samples were from 4.6 to 5.2% and from 4.6 to 12%, respectively.
Asunto(s)
Antifúngicos/análisis , Piperazinas/análisis , Triazoles/análisis , Animales , Antifúngicos/sangre , Cromatografía Líquida de Alta Presión , Ratones , Estructura Molecular , Piperazinas/sangre , Piperazinas/farmacocinética , Ratas , Reproducibilidad de los Resultados , Triazoles/sangre , Triazoles/farmacocinéticaRESUMEN
Ethyl cellulose encapsulated aspirin particles, suitable for preparation of direct compression tablets were prepared by the solvent evaporation method. Ethyl acetate was used as a solvent for the polymer in combination with a saturated solution of aspirin as the dispersing medium to prevent partitioning and drug loss. This resulted in a high yield of free-flowing, non-aggregated particles. In vitro-in vivo evaluations of the experimental aspirin tablets (made by direct compression of ethyl cellulose encapsulated particles) and three different commercial aspirin products (a conventional tablet, a timed-release tablet, and a timed-release caplet) were undertaken. Comparison of the dissolution in acidic media at pH 1.2 showed different release profiles for these products. While the conventional tablet and the timed-release caplet showed the highest and the lowest rate of release, respectively; the timed-release tablet and the experimentally made tablet revealed an intermediate rate and very similar release profiles. The cumulative urinary excretion data collected in a complete crossover study, using five healthy subjects further indicated that the experimental tablet has an in vivo availability identical to that of the timed-release tablet.