RESUMO
The oncogenic potential of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was assessed when it was administered in the diet of Charles River B6C3F1 mice for 78 weeks in dosages of 0, 30, 100 and 300 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Average food consumption, food efficiency and hematologic values also were apparently unaffected. Statistically significantly low body weights were observed in the 100 and 300 mg/kg/day mice. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed midzonal hepatocellular vacuolization compatible with lipid vacuoles in both sexes at the 300 mg/kg/day dose level. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in B6C3F1 mice when NS-21 was administered in the diet in concentrations to produce an intake of up to 300 mg/kg/day for 78 weeks.
Assuntos
Carcinógenos/toxicidade , Fenilacetatos/toxicidade , Transtornos Urinários/tratamento farmacológico , Administração Oral , Animais , Testes de Carcinogenicidade , Dieta , Feminino , Masculino , Camundongos , Estrutura Molecular , Fenilacetatos/administração & dosagem , Fenilacetatos/uso terapêutico , Fatores de Tempo , Incontinência Urinária/tratamento farmacológicoRESUMO
The oncogenic potential of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was assessed when it was administered in the diet of Charles River Fischer-344 rats for 2 years in dosages of 0, 10, 30 and 100 mg/kg/day. No drug-related effects occurred on survival, appearance or behavior, or occurrence, location or number of palpable masses. Food efficiency and hematologic values also were apparently unaffected. Statistically significantly low mean weekly body weights and average food consumption values were observed in the all dose groups. The plasma concentrations of NS-21 and its active metabolite, RCC-36, in the treated groups were increased in a dose-dependent manner. Histopathological examinations disclosed test article-related increases in the incidence of periportal hypertrophy and midzonal hepatocellular vacuolization in the livers of the 100 mg/kg/day animals. There were no test article-related effects on the incidence or type of neoplastic lesions. In conclusion, under the conditions of this study, no oncogenic effects were evident in Fischer-344 rats when NS-21 was administered in the diet in concentrations to produce an intake of up to 100 mg/kg/day for 2 years.
Assuntos
Carcinógenos/toxicidade , Fenilacetatos/toxicidade , Transtornos Urinários/tratamento farmacológico , Administração Oral , Animais , Testes de Carcinogenicidade , Dieta , Feminino , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Estrutura Molecular , Fenilacetatos/química , Fenilacetatos/uso terapêutico , Ratos , Ratos Endogâmicos F344 , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/patologia , Fatores de Tempo , Incontinência Urinária/tratamento farmacológicoRESUMO
Diatoms have co-evolved with the silicon cycle and are largely responsible for reducing surface concentrations of silicate in the ocean to their present levels. We quantify silicification in marine diatoms at a range of high silicate concentrations representative of environments found over their geological history. The species examined include Stephanopyxis turris, an ancient centric species found throughout the Cenozoic, Thalassiosira pseudonana and Thalassiosira weissflogii, two younger centric species, and two pennate ecotypes of Staurosirella pinnata isolated from different nutrient regimes. Frustule thickness and micromorphological structure are strongly affected by silicate concentration. All species become increasingly silicified with silicate concentrations at concentrations vastly in excess of surface ocean concentrations today. In contrast, the half-saturation constant for silicate uptake for most modern diatoms is below 2 µM. Based on the results, we hypothesize that silicate uptake is multiphasic in diatoms and that multiple silicate transport systems may have evolved in response to decreases in surface silicate concentration over geological time. The oldest species examined is more heavily silicified than the more modern species, presumably reflecting the conditions under which it originated. Yet diversification in silicification can be rapid, as illustrated by greater silicification in onshore versus the offshore ecotype of the same modern species. This work suggests that silicification of fossil frustules may eventually provide a paleoproxy for surface silicate concentrations over the Cenozoic, although development of species-specific calibrations will be necessary and the effects of a range of environmental conditions must be investigated.
Assuntos
Diatomáceas/classificação , Diatomáceas/fisiologia , Fósseis , Silício/análise , Adaptação Fisiológica , Animais , Diatomáceas/química , Diatomáceas/genética , Genótipo , Microscopia Eletrônica de Varredura , Oceanos e Mares , Paleontologia , Fenótipo , Especificidade da EspécieRESUMO
Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.