RESUMEN
Allergic rhinitis is an inflammatory disease of the nasal mucosa, induced by histamine, leukotrienes, and other substances released from mast cells. Fexofenadine hydrochloride, the active metabolite of terfenadine, is a novel, nonsedating antiallergic drug having H1 receptor antagonistic activity. Fexofenadine is effective for the treatment of allergic rhinitis. However, its mechanism of action in attenuating nasal congestion has not yet been elucidated. Therefore, we first examined the effects of fexofenadine on a guinea pig model of antigen-induced rhinitis. We also evaluated the effects of mepyramine, zafirlukast and ramatroban in this model; these drugs are an H1 receptor antagonist, a selective leukotriene antagonist and a selective thromboxane antagonist, respectively. Rhinitis was induced by ovalbumin (OVA) instillation into the nasal cavity of animals that had been sensitized by two earlier OVA injections (s.c. and i.p.). The nasal airway resistance was measured for 45 min after the challenge. Fexofenadine hydrochloride (20 mg/kg) and terfenadine (20 mg/kg) administered orally 70 min prior to the challenge significantly inhibited (fexofenadine, p < 0.001, terfenadine, p < 0.05) the increase in nasal airway resistance. Ramatroban (30 mg/kg) administered orally 60 min prior to the challenge also significantly inhibited (p < 0.05) the increase in nasal airway resistance. In contrast, mepyramine (3 mg/kg i.v.) and zafirlukast (3 mg/kg p.o.) failed to reduce the increase in nasal airway resistance. These results suggest that thromboxane may be involved in the increase in the nasal airway resistance in this model. Accordingly, fexofenadine may reduce the increase in nasal airway resistance by inhibiting the release of chemical mediators, including thromboxane, that are involved in the increase in nasal airway resistance in this model.
Asunto(s)
Resistencia de las Vías Respiratorias/efectos de los fármacos , Antialérgicos/farmacología , Rinitis/tratamiento farmacológico , Terfenadina/análogos & derivados , Animales , Área Bajo la Curva , Carbazoles/farmacología , Modelos Animales de Enfermedad , Cobayas , Indoles , Leucotrienos/fisiología , Masculino , Ovalbúmina/inmunología , Fenilcarbamatos , Pirilamina/farmacología , Sulfonamidas/farmacología , Terfenadina/farmacología , Terfenadina/uso terapéutico , Tromboxanos/fisiología , Compuestos de Tosilo/farmacologíaRESUMEN
1. We have examined the effects of HR780, a novel 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on porcine endothelial cell (EC) injury induced by xanthine (X)/xanthine oxidase (XO), a source of superoxide anion. Furthermore, the effects of HR780 on platelet-derived growth factor (PDGF)-induced migration and fetal calf serum (FCS)-induced proliferation of rabbit smooth muscle cells (SMC) were investigated. 2. Probucol, at 10 micro mol/L, significantly (P < 0.001) and completely suppressed lactate dehydrogenase leakage induced by X/XO. At 10 micro mol/L, HR780 significantly (P = 0.010) inhibited X/XO-induced EC injury. 3. HR780 dose-dependently inhibited PDGF-induced SMC migration and FCS-induced SMC proliferation. The addition of mevalonate completely abolished the inhibitory effect of HR780 on SMC proliferation. Another HMG-CoA reductase inhibitor, simvastatin (0.1-100 micro mol/L), also inhibited the migration and proliferation responses as potently as HR780. In contrast, pravastatin (0.1-100 micro mol/L) did not show any effects. 4. This in vitro study provides the first evidence that HR780 protects the vascular endothelium from oxidant stress and inhibits the migration and proliferation of SMC.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Músculo Liso Vascular/efectos de los fármacos , Piridinas/farmacología , Animales , Aorta Torácica/citología , Aorta Torácica/enzimología , División Celular/efectos de los fármacos , División Celular/fisiología , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Células Endoteliales/patología , Sangre Fetal/fisiología , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ácido Mevalónico/farmacología , Músculo Liso Vascular/citología , Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Factor de Crecimiento Derivado de Plaquetas/farmacología , Pravastatina/farmacología , Probucol/administración & dosificación , Probucol/farmacocinética , Conejos , Simvastatina/farmacología , Porcinos , Xantina/efectos adversos , Xantina/antagonistas & inhibidores , Xantina/metabolismo , Xantina Oxidasa/efectos adversos , Xantina Oxidasa/antagonistas & inhibidores , Xantina Oxidasa/metabolismoRESUMEN
The aim of this study was to evaluate the effects of (+)-(E)-6S-(2-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)ethenyl)-4R-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (HR780), a novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on hypercholesterolemia in Watanabe heritable hyperlipidemic (WHHL) rabbits and rabbits fed a diet with 1% cholesterol, in comparison with the effects of simvastatin. Each drug was administered orally to WHHL rabbits for 24 weeks and to 1% cholesterol-fed rabbits for 10 weeks. In WHHL rabbits, HR780 at doses of 1, 2.5 and 5 mg/kg/day reduced the plasma total cholesterol level by 15, 24 and 20%, respectively. In contrast, simvastatin at 5 mg/kg/day lowered the level by 23%. In 1% cholesterol-fed rabbits, HR780 (1 and 2.5 mg/kg/day) was found to inhibit the increases in the plasma total cholesterol and phospholipid levels and liver cholesterol contents in a dose-dependent manner. Simvastatin (5 mg/kg/day) also inhibited their increase. Neither HR780 nor simvastatin increased the contents of cholesterol and total bile acid in the gallbladder bile. In conclusion, long-term treatment with HR780 reduced the plasma cholesterol level in WHHL rabbits and 1% cholesterol-fed rabbits, and decreased the liver cholesterol contents in 1% cholesterol-fed rabbits.