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

Bases de datos
Tipo de estudio
Tipo del documento
País de afiliación
Intervalo de año de publicación
1.
J Biol Chem ; 287(29): 24228-38, 2012 Jul 13.
Artículo en Inglés | MEDLINE | ID: mdl-22637476

RESUMEN

One of the mitogen-activated protein kinases, p38, has been found to play a crucial role in various inflammatory responses. In this study, we analyzed the roles of p38α in multiple sclerosis, using an animal model, experimental autoimmune encephalomyelitis (EAE). p38α(+/-) mice (p38α(-/-) showed embryonic lethality) showed less severe neurological signs than WT mice. Adoptive transfer of lymph node cells (LNC) from sensitized WT mice with MOG(35-55) to naive WT-induced EAE was much more severe compared with the case using LNC from sensitized p38α(+/-) mice. Comprehensive analysis of cytokines from MOG(35-55)-challenged LNC by Western blot array revealed that production of IL-17 was significantly reduced by a single copy disruption of the p38α gene or a p38 inhibitor. Likewise, by a luciferase reporter assay, an electrophoresis mobility shift assay, and characterization of the relationship between p38 activity and IL-17 mRNA expression, we confirmed that p38 positively regulates transcription of the Il17 gene. Furthermore, oral administration of a highly specific p38α inhibitor (UR-5269) to WT mice at the onset of EAE markedly suppressed the progression of EAE compared with a vehicle group. These results suggest that p38α participates in the pathogenesis of EAE through IL-17 induction.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Animales , Ensayo de Cambio de Movilidad Electroforética , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/genética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Interleucina-17/genética , Interleucina-17/metabolismo , Masculino , Ratones , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 14 Activada por Mitógenos/genética , Regiones Promotoras Genéticas , Estabilidad del ARN/genética
2.
Biol Pharm Bull ; 32(12): 2010-7, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19952420

RESUMEN

In the present study, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) on the intragastric acidity of cynomolgus monkeys. The study was performed in a crossover manner with five male animals. CS-526 was administered orally or intravenously at doses of 3.0, 10 and 30 mg/kg, or 0.3, 1.0 and 3.0 mg/kg, respectively. The time period in which the intragastric pH was 4.0 or more (Time(pH > or = 4.0)) and the median pH were calculated for 24 h after the administration. The intragastric pH was elevated after CS-526 treatment. The Time(pH > or = 4.0) was increased in a dose-dependent manner (p = 0.0292) in the oral administration, and the median pH was also increased in a dose-dependent fashion (p = 0.0491) in the intravenous administration. The plasma concentration of CS-526 and its metabolite R-130185 was increased after oral and intravenous administration of CS-526, except for one animal which did not show any detectable amount of R-130185 after intravenous administration at the lowest dose. The area under the time-concentration curve of the active component was increased in the dose proportional manner after oral and intravenous administration. The absolute bioavailability of the active component was estimated to be approximately 1%. Correlation between the pharmacodynamic parameters and the pharmacokinetic parameters was observed in oral (p = 0.0029-0.0745), but not in intravenous administration (p = 0.0558-0.2789). In conclusion, oral and intravenous administration of CS-526 showed inhibition on gastric acidity in cynomolgus monkeys using intragastric pH-metry and some pharmacokinetic and pharmacodynamic parameters were well correlated.


Asunto(s)
Ácido Gástrico/metabolismo , Piridazinas/farmacología , Piridazinas/farmacocinética , Pirroles/farmacología , Pirroles/farmacocinética , Estómago/efectos de los fármacos , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Determinación de la Acidez Gástrica , Mucosa Gástrica/metabolismo , Concentración de Iones de Hidrógeno , Inyecciones Intravenosas , Macaca fascicularis , Masculino , Piridazinas/administración & dosificación , Pirroles/administración & dosificación , Factores de Tiempo
3.
J Pharmacol Exp Ther ; 326(1): 163-70, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18411413

RESUMEN

In the present report, we evaluated the effect of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) and 2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-1H-benzimidazole (lansoprazole) on rebound gastric acid secretion, using an intragastric dialysis membrane perfusion model and on the serum and antral gastrin level after a 14-day treatment in rats. The effect of CS-526 on gastric acid secretion was almost constant during the 14 days of treatment. After the 14-day treatment, gastric acid secretion had returned to pretreatment levels. However, CS-526 slightly increased and lansoprazole potently increased gastric acid secretion thereafter. In the posttreatment period, the influence on rebound gastric acid secretion by lansoprazole treatment was significant, but that by CS-526 was not. The serum gastrin concentration after the 14-day treatment with CS-526 did not increase significantly, even at 100 mg/kg/day. On the other hand, lansoprazole at 100 mg/kg/day significantly elevated the serum gastrin concentration. After the 14-day treatment with CS-526 at 100 mg/kg/day, the antral gastrin content significantly increased. Lansoprazole at the doses of 30 and 100 mg/kg/day also significantly increased the antral gastrin content after the 14-day treatment. The elevation of the serum gastrin level after the lansoprazole treatment was suppressed by the concomitant administration of CS-526. In conclusion, CS-526 has a potent antisecretory effect on gastric acid secretion without rebound gastric hypersecretion. Moreover, CS-526 had minimal effects on the serum and antral gastrin elevation. It is suggested that these effects on gastric acid secretion and serum gastrin after subchronic treatment with CS-526 would be beneficial in clinical use.


Asunto(s)
Ácido Gástrico/metabolismo , Gastrinas/sangre , Inhibidores de la Bomba de Protones , Bombas de Protones/sangre , Piridazinas/administración & dosificación , Pirroles/administración & dosificación , Animales , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Gastrinas/análisis , Masculino , Bombas de Protones/metabolismo , Ratas , Ratas Sprague-Dawley
4.
J Pharmacol Exp Ther ; 323(1): 308-17, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17630360

RESUMEN

The pharmacological profiles of the novel acid pump antagonist 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-{[(1S,2S)-2-methylcyclopropyl]methyl}-1H-pyrrolo[2,3-d]pyridazine (CS-526) were investigated in terms of hog gastric H+,K+-ATPase activity, gastric acid secretion, and acute gastroesophageal lesions in comparison with other proton pump inhibitors (PPIs). CS-526 inhibited H+,K+-ATPase activity in a concentration-dependent manner, with an IC50 value of 61 nM. The inhibitory effect of CS-526 on H+,K+-ATPase activity was more potent than that of any of the other PPIs examined. The inhibitory mechanism of CS-526 on H+,K+-ATPase was a competitive antagonism to the K+ binding site of H+,K+-ATPase, and it was also a reversible inhibition. In pylorus-ligated rats, intraduodenal or oral administration of CS-526 inhibited gastric acid secretion in a dose-dependent manner, and the ID50 values were 2.8 or 0.7 mg/kg, respectively. In Heidenhain pouch dogs, intrapouch administration of CS-526 inhibited histamine-stimulated gastric acid secretion in a dose- and retention time-dependent manner. In a reflux esophagitis model, intraduodenal and oral administration of CS-526 prevented esophageal lesions with ID50 values of 5.4 and 1.9 mg/kg, respectively. Lansoprazole prevented esophagitis only by intraduodenal administration (ID50 = 2.2 mg/kg). Furthermore, CS-526 inhibited acute gastric mucosal lesions. These data demonstrate that the novel acid pump antagonist CS-526 has potent antisecretory and antiulcer effects. These findings indicate that CS-526 would have a curative effect on gastroesophageal reflux disease via its potent antisecretory and antiulcer actions.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Ácido Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Fármacos Gastrointestinales/farmacología , Inhibidores de la Bomba de Protones , Piridazinas/farmacología , Pirroles/farmacología , Animales , Modelos Animales de Enfermedad , Perros , Inhibidores Enzimáticos/química , Esofagitis Péptica/tratamiento farmacológico , Esofagitis Péptica/metabolismo , Esofagitis Péptica/patología , Mucosa Gástrica/enzimología , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Fármacos Gastrointestinales/química , Riñón/efectos de los fármacos , Riñón/enzimología , Masculino , Estructura Molecular , Piridazinas/química , Pirroles/química , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Porcinos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA