Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Bioorg Med Chem ; 9(2): 537-54, 2001 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11249145

RESUMEN

RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.


Asunto(s)
Antirreumáticos/síntesis química , Antirreumáticos/farmacocinética , Imidazoles/farmacología , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Administración Oral , Animales , Antirreumáticos/farmacología , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Artritis/prevención & control , Disponibilidad Biológica , Citocromo P-450 CYP1A1/efectos de los fármacos , Citocromo P-450 CYP1A1/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Imidazoles/síntesis química , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Ratones , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos
2.
Mutagenesis ; 9(3): 199-204, 1994 May.
Artículo en Inglés | MEDLINE | ID: mdl-7934960

RESUMEN

In order to validate the in vivo micronucleus test in mouse splenocytes using the cytokinesis block method, 14 compounds with various mechanisms of action were tested: three direct alkylating agents (mitomycin C, ethylnitrosourea, beta-propiolactone), seven indirect alkylating agents (cyclophosphamide, benzo[a]pyrene, diethylnitrosamine, dimethylnitrosamine, 4-aminophenol, 4-aminobiphenyl, 1,1-dimethylhydrazine), two intercalating agents (acridine orange, ethidium bromide) and two spindle poisons (vincristine, colchicine). Male mice were dosed once with the compound, and spleen samples were taken 2 or 14 days after treatment. A significant increase in the binucleated micronucleated splenocyte rate was observed with all the alkylating and intercalating agents at at least one sampling time. In contrast, no increase in the binucleated micronucleated splenocyte rate was observed with the spindle poisons. In conclusion, under these experimental conditions, this in vivo test seems appropriate for the detection of clastogenic compounds including compounds that cannot be detected in the bone marrow micronucleus test. The limit of this test, as expected, is the lack of detection of aneugenic compounds.


Asunto(s)
Pruebas de Micronúcleos/métodos , Alquilantes/toxicidad , Animales , Sustancias Intercalantes/toxicidad , Masculino , Ratones , Micronúcleos con Defecto Cromosómico/efectos de los fármacos , Pruebas de Micronúcleos/estadística & datos numéricos , Mutágenos/toxicidad , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Huso Acromático/efectos de los fármacos , Bazo/citología , Bazo/efectos de los fármacos , Factores de Tiempo
3.
Mutat Res ; 280(2): 137-42, 1992 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-1378538

RESUMEN

A micronucleus detection test using mouse splenocytes has been adapted from a method previously carried out using human lymphocytes. An ex vivo protocol was chosen: male C57B16 mice were treated with various compounds. Splenocytes were then isolated and placed in culture for 48 h and stimulated with concanavalin A and conditioned medium. The cytokinesis-block method reported by Fenech and Morley was used to detect and score micronuclei in the proliferating lymphocytes (3 micrograms/ml of cytochalasin B for 16 h). Three mutagenic clastogens, mitomycin C (MMC), a direct alkylating agent (0.4, 0.8 and 1.6 mg/kg), cyclophosphamide (CP), an indirect alkylating agent (25, 50 and 100 mg/kg) and diethylnitrosamine (DEN), an indirect alkylating agent with labile metabolites (25, 50 and 100 mg/kg), were tested at four sampling times (2, 4, 8 and 15 days). All three compounds were detected from 48 h after treatment. This method was indeed able to detect clastogenic compounds normally detected by the mouse bone marrow micronucleus test (MMC, CP) as well as a compound with labile metabolites which is not usually detected by this test (DEN). Maximum micronucleus induction was observed after 4 days for MMC, 2 days for CP and 15 days for DEN. This method thus appears to offer a potentially useful toxicological test for assessing in vivo clastogenicity.


Asunto(s)
Ciclofosfamida/toxicidad , Dietilnitrosamina/toxicidad , Mitomicina/toxicidad , Animales , Células Cultivadas , Cinética , Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Pruebas de Micronúcleos , Bazo/citología , Bazo/efectos de los fármacos
4.
J Histochem Cytochem ; 39(1): 15-21, 1991 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-1701186

RESUMEN

Erythroblast proliferation and maturation in bone marrow are the processes leading to the formation of polychromatic erythrocytes (PE) and normochromatic erythrocytes (NE), respectively. PE contain RNA but no DNA, and can therefore be distinguished both from NE (which lack both RNA and DNA) and from nucleated cells (which contain both DNA and RNA). Cytotoxic agents that induce impairment of the maturation process change the PE:NE ratio. We have developed a simple and rapid method of determining the PE:NE ratio, based on flow cytometric analysis of formaldehyde-fixed, acridine orange (AO)-stained cells. The effects of cyclophosphamide (CP), mitomycin C (MMC), and vincristine (VC) were tested and the PE:NE ratio was evaluated over 7 days of treatment. In this study we monitored the kinetics of these compounds and were able to demonstrate both a time- and a dose-dependent effect. We detected a difference between the effects of the alkylating agents tested and those induced by the spindle inhibitor tested. Flow cytometry of fixed bone marrow samples stained with AO provides more information, better and more rapid statistical analysis, than conventional microscopic methods for counting the PE:NE ratio.


Asunto(s)
Células de la Médula Ósea , Ciclofosfamida/farmacología , Eritropoyesis/efectos de los fármacos , Citometría de Flujo , Mitomicinas/farmacología , Vincristina/farmacología , Naranja de Acridina , Animales , Separación Celular , Supervivencia Celular/efectos de los fármacos , ADN/metabolismo , Formaldehído , Cinética , Ratones , Mitomicina , ARN/metabolismo , Coloración y Etiquetado
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...