RESUMEN
(2R,4R)-Monatin salt [sodium/potassium 2R,4R-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate] was fed at 5000, 15,000, or 35,000 ppm to Crl:CD(SD) rats over two generations. Reduced body weights were observed at all dose levels. Sustained effect on body weight gain at 35,000 ppm in the F0 and F1 parental animals was associated with lower feed efficiency, soft stool, and slightly lower numbers of implantation sites. Lower numbers of pups born and live litter size at 35,000 ppm were considered secondary to slightly lower numbers of former implantation sites in the dams. Spermatogenic endpoints, estrous cyclicity, reproductive performance, mean gestation length, and parturition were unaffected in the F0 and F1 generations. There were no effects on F1 and F2 generation postnatal survival. Reduced pre-weaning pup body weights at 35,000 ppm resulted in lower F1 and F2 body weights at study termination. Slight delays in pubertal landmarks in the F1 offspring were considered secondary to the reduced pup body weights. The no-observed-adverse-effect level (NOAEL) was 15,000 ppm for systemic, reproductive, and neonatal effects based on test article-related effects on body weight and food efficiency, slight decrease in maternal implantation sites and corresponding reduction in live litter size, and reductions in pre-weaning pup body weights at 35,000 ppm.
Asunto(s)
Ácido Glutámico/análogos & derivados , Indoles/toxicidad , Reproducción/efectos de los fármacos , Animales , Conducta Alimentaria , Femenino , Ácido Glutámico/toxicidad , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
[14C]-Labeled arruva [sodium/potassium (2R,4R)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate] was administered as a single gavage dose (10 mg/kg bw) to male and female Beagle dogs and 1 bile duct-cannulated male. The mean peak arruva plasma concentration equivalent of 1.2 µg/g occurred at first sampling time point of 1 hour postdosing. The mean area under the concentration versus time curve from 0 hour postdosing to the last time point was approximately 20 µg·h/g and the mean terminal plasma elimination half-life ranged from 15 hours in females to 21 hours in males. Over 168 hours postdosing, 35% to 50% of the administered arruva was eliminated in the urine with 44% to 53% eliminated in feces; 1.3% of the administered dose was recovered in bile. Arruva and its derivatives were identified using tandem mass spectrometry, and the relative percentage of each substance was quantified via radio high-performance liquid chromatography. Over a 168-hour collection period, combined urine and feces extract data from the 6 noncannulated dogs showed that approximately 91% of the dose was excreted as unchanged parent arruva (41% in urine and 50% in feces). In the cannulated male, 95.3% was excreted as unchanged parent arruva; 50.2% in urine, 43.9% in feces, and 1.3% in bile. Lactone and lactam derivatives of arruva and 1 unidentified substance were detected in urine only during the first 24 hours postdosing with the greatest amounts detected during the first 6 hours of collection; up to 1% of lactone or lactam derivatives were detected in bile samples. Plasma pharmacokinetics data indicated rapid absorption of arruva with the majority of radioactivity located in the feces collected in the first 48 hours.
Asunto(s)
Ácido Glutámico/análogos & derivados , Indoles/metabolismo , Absorción Intestinal , Edulcorantes no Nutritivos/metabolismo , Animales , Animales Endogámicos , Bilis/química , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Perros , Heces/química , Femenino , Ácido Glutámico/sangre , Ácido Glutámico/química , Ácido Glutámico/metabolismo , Ácido Glutámico/orina , Semivida , Indoles/sangre , Indoles/química , Indoles/orina , Eliminación Intestinal , Cinética , Lactamas/sangre , Lactamas/química , Lactamas/metabolismo , Lactamas/orina , Lactonas/sangre , Lactonas/química , Lactonas/metabolismo , Lactonas/orina , Masculino , Estructura Molecular , Edulcorantes no Nutritivos/química , Eliminación Renal , Caracteres Sexuales , Espectrometría de Masas en TándemRESUMEN
Arruva, the R,R-isomer of monatin (sodium/potassium 2R,4R-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate), an intense sweetener originally identified in root bark of the South African shrub Schlerochitin ilicifolius, was examined for its mutagenic and genotoxic potential via bacterial reverse mutation, mouse lymphoma and in vivo mouse micronucleus assays, all accomplished in the presence and absence of S9 metabolic activation. In the bacterial reverse mutation assay, arruva was determined to not cause reverse mutations in four Salmonella typhimurium strains and one Escherichia coli strain at concentrations up-cells did not exhibit concentration-related increases in mutant frequency at test concentrations up to 3200µg/ml. In the in vivo micronucleus test, arruva was administered to male mice via single gavage doses at 500, 1000 or 2000mg/kg bw. At 24 or 48h post-dose, the mice were euthanized and femoral bone marrow cells were collected for evaluation of micronucleated polychromatic erythrocyte (MPCE) presence. No statistically significant increases of MPEs were observed relative to the respective vehicle control groups. Under the conditions of these studies, arruva was concluded to be negative in all three assays, thereby indicating the absence of its potential mutagenicity or genotoxicity under the conditions tested.
Asunto(s)
Daño del ADN/efectos de los fármacos , Ácido Glutámico/análogos & derivados , Indoles/toxicidad , Pruebas de Mutagenicidad/métodos , Mutágenos/toxicidad , Acanthaceae/química , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Escherichia coli/efectos de los fármacos , Ácido Glutámico/toxicidad , Linfoma/inducido químicamente , Masculino , Ratones , Pruebas de Micronúcleos/métodos , Extractos Vegetales/toxicidad , Raíces de Plantas/química , Salmonella typhimurium/efectos de los fármacos , Edulcorantes/toxicidadRESUMEN
The measurement of hydrogen in exhaled breath is widely accepted as a non-invasive yet efficient means to evaluate carbohydrate malabsorption. Hydrogen is not normally produced by mammalian cells and its appearance in breath indicates incomplete small intestinal carbohydrate absorption with subsequent breakdown of the carbohydrate by anaerobic bacteria in the colon. This study was undertaken to evaluate the absorption of a novel, slowly digestible carbohydrate sweetener, sucromalt. Two experiments occurred approximately 2 weeks apart with the participants randomly consuming one of two test foods on each visit. Following baseline breath hydrogen measurements, healthy 8-10 year-old children (n = 10) consumed a yogurt breakfast containing either 15 g of inulin (positive control) or 30 g of sucromalt. Every 15 min during the next 6 h, samples of exhaled breath were taken from each participant for hydrogen content analysis, thereby establishing 24 total data points. Participants' 6 h breath hydrogen responses were plotted against their baseline measurement and appropriate statistical evaluations were applied to the data. Following ingestion of inulin, breath hydrogen stayed near baseline for approximately 2 h but rose rapidly thereafter to a steady state of 20-30 ppm, which continued to the end of the study period. In contrast, exhaled hydrogen following sucromalt ingestion remained at or near baseline for the entire 6 h test period. A significantly higher level of hydrogen was exhaled with inulin ingestion compared to sucromalt (incremental area under the curve, p = 0.002). Results indicated complete absorption of sucromalt's saccharide constituents in children.
Asunto(s)
Carbohidratos de la Dieta/metabolismo , Digestión , Disacáridos/metabolismo , Fructosa/metabolismo , Hidrógeno/análisis , Absorción Intestinal , Síndromes de Malabsorción/metabolismo , Edulcorantes/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Pruebas Respiratorias , Niño , Femenino , Humanos , Hidrógeno/metabolismo , Síndromes de Malabsorción/diagnóstico , Síndromes de Malabsorción/fisiopatología , MasculinoRESUMEN
PURPOSE: Various ocular alkali burn classification schemes have been published and used to grade human chemical eye injuries for the purpose of identifying treatments and forecasting outcomes. The ILSI chemical eye injury classification scheme was developed for the additional purpose of collecting detailed human eye injury data to provide information on the mechanisms associated with chemical eye injuries. This information will have clinical application, as well as use in the development and validation of new methods to assess ocular toxicity. METHODS: A panel of ophthalmic researchers proposed the new classification scheme based upon current knowledge of the mechanisms of eye injury, and their collective clinical and research experience. Additional ophthalmologists and researchers were surveyed to critique the scheme. The draft scheme was revised, and the proposed scheme represents the best consensus from at least 23 physicians and scientists. RESULTS: The new scheme classifies chemical eye injury into five categories based on clinical signs, symptoms, and expected outcomes. Diagnostic classification is based primarily on two clinical endpoints: (1) the extent (area) of injury at the limbus, and (2) the degree of injury (area and depth) to the cornea. CONCLUSIONS: The new classification scheme provides a uniform system for scoring eye injury across chemical classes, and provides enough detail for the clinician to collect data that will be relevant to identifying the mechanisms of ocular injury.
Asunto(s)
Quemaduras Químicas/clasificación , Lesiones Oculares/clasificación , Irritantes/toxicidad , Índices de Gravedad del Trauma , Alternativas a las Pruebas en Animales , Clasificación/métodos , Árboles de Decisión , Lesiones Oculares/inducido químicamente , HumanosRESUMEN
Predictive skin irritation test methods, which do not require use of animals, are needed for the pre-market assessment of detergent formulations. The utility of a novel and ethical human acute skin irritation patch test method, originally developed for chemical skin irritation assessment, was evaluated. In this IRB-approved method, subjects were patched under occlusion for increasing periods of time up to 4h in duration. The total incidence of positive skin reactions for test products was compared to a positive control (20% aqueous sodium dodecyl sulfate [SDS]). Acutely irritating formulas were defined as those showing a significantly increased or equal incidence of positive responders compared with that of SDS. The time of exposure required for 50% of subjects to show a positive skin reaction (TR50 value) was calculated for each product and enabled test product comparisons within and between studies. Using this approach, 24 detergent formulations of various types were tested in seven individual studies. The skin irritation profiles were generally consistent within product types, which could be categorized as follows (by decreasing irritancy): mold/mildew removers (average TR50 = 0.37 h) > disinfectants/sanitizers (0.64 h) > fabric softener concentrate (1.09 h) = aluminum wash (1.20 h) > 20% SDS (1.81 h) > liquid laundry detergents (3.48 h) > liquid dish detergents (4.16 h) = liquid fabric softeners (4.56 h) = liquid hand soaps (4.58 h) = shampoos (5.40 h) = hard surface cleaners (6.34 h) > powder automatic dish detergents (>16 h) = powder laundry detergents (>16 h). In addition to formulation effects, some seasonal effects were noted; particularly greater winter-time reactivity to 20% SDS and the hard surface cleaner and liquid laundry formulations. These results demonstrate the utility of this patch test method for the comparative skin irritation assessment of these different product types.