RESUMEN
We evaluated the effects of NT-702 (parogrelil hydrochloride, NM-702, 4-bromo-6-[3-(4-chlorophenyl) propoxy]-5-[(pyridine-3-ylmethyl) amino] pyridazin-3(2H)-one hydrochloride), a selective phosphodiesterase 3 inhibitor, on the asthmatic response in guinea pigs. NT-702 at a concentration of 1 x 10(-7)M elevated the cyclic adenosine monophosphate content in prostaglandin E(2)-treated guinea pig tracheal smooth muscle cells. Leukotriene (LT) D(4)- and histamine-induced contraction of isolated guinea pig tracheal strips was inhibited by NT-702, with EC(50) values of 3.2 x 10(-7) and 2.5 x 10(-7)M, respectively. In an in vivo study, NT-702 suppressed LTD(4)-induced bronchoconstriction and the ovalbumin-induced immediate asthmatic response in guinea pigs through its bronchodilating effect. Furthermore, NT-702 also suppressed the ovalbumin-induced late asthmatic response, airway hyperresponsiveness, and the accumulation of inflammatory cells in the bronchoalveolar lavage fluid. These results suggest that NT-702 has an anti-inflammatory effect as well as a bronchodilating effect and might be useful as a novel potent therapeutic agent for the treatment of bronchial asthma, a new type of agent with both a bronchodilating and an anti-inflammatory effect.
Asunto(s)
Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Broncodilatadores/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Fosfodiesterasa 3 , Piridazinas/farmacología , Animales , Antiinflamatorios/uso terapéutico , Antígenos/inmunología , Asma/metabolismo , Asma/patología , Asma/fisiopatología , Broncoconstricción/efectos de los fármacos , Broncoconstricción/inmunología , Broncodilatadores/uso terapéutico , Movimiento Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Dinoprostona/farmacología , Inhibidores Enzimáticos/uso terapéutico , Cobayas , Histamina/farmacología , Técnicas In Vitro , Leucotrieno D4/farmacología , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiopatología , Piridazinas/uso terapéutico , Tráquea/efectos de los fármacosRESUMEN
We started a disease management model, Carna, that includes two programs: one for primary prevention of lifestyle diseases and one for secondary/tertiary prevention of diabetes mellitus. These programs support the family doctor system and education for participants to allow the concept of disease management to take root in Japan. We developed a critical pathway system that can optimize health care of individual participants by matching individual status. This is the core technology of the project. Under the primary prevention program, we can perform the health check-up/ instruction tasks in the 'Tokutei Kenshin', which will start for all Japanese citizens aged 40-74 years in April 2008. In the diabetic program, Carna matches doctors and new patients, prevents patient dropout, supports detection of early-stage complications by distributing questionnaires periodically, and facilitates medical specialists' cooperation with family doctors. Carna promotes periodic medical examinations and quickly provides the result of blood tests to patients. We are conducting a study to assess the medical outcomes and business model. The study will continue until the end of 2007.
Asunto(s)
Vías Clínicas , Diabetes Mellitus/terapia , Manejo de la Enfermedad , Algoritmos , Humanos , Japón , Modelos Teóricos , Factores de RiesgoRESUMEN
When wild-type BALB/c mice were transferred with OVA-specific Th2 cells followed by OVA inhalation, a severe eosinophilia, mucus hypersecretion and airway hyper-responsiveness (AHR) was induced in parallel with a marked elevation of IL-4, IL-5 and IL-13 levels in bronchoalveolar lavage fluid (BALF). However, neither eosinophilia, AHR nor mucus hypersecretion was induced in Th2 cell-transferred STAT6-/- mice. The failure of eosinophilia was not due to the defect of Th2 cytokine production in BALF of STAT6-/- mice transferred with Th2 cells, but because of the defect of STAT6-dependent eotaxin production. Indeed, intranasal administration of eotaxin reconstituted pulmonary eosinophilia but not AHR and mucus hypersecretion in OVA-inhalated STAT6-/- mice. These results initially provided direct evidence that STAT6-dependent eotaxin production is essential for pulmonary eosinophilia. We also dissociated the role of STAT6 for eosinophilia from that for AHR and mucus hypersecretion. Thus, STAT6 also plays a critical role at late phase of Th2-dependent allergy induction.
Asunto(s)
Asma/inmunología , Hiperreactividad Bronquial/inmunología , Eosinofilia/inmunología , Hipersensibilidad/inmunología , Células Th2/inmunología , Transactivadores/deficiencia , Administración Intranasal , Animales , Asma/etiología , Asma/fisiopatología , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Diferenciación Celular , Quimiocina CCL11 , Quimiocinas CC/administración & dosificación , Quimiocinas CC/inmunología , Eosinofilia/etiología , Eosinofilia/fisiopatología , Pulmón/inmunología , Pulmón/patología , Ratones , Moco/metabolismo , Ovalbúmina/efectos adversos , Ovalbúmina/inmunología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Factor de Transcripción STAT6 , Transactivadores/inmunologíaRESUMEN
Bronchial asthma is characterized by massive infiltration of eosinophils and airway hyperreactivity (AHR), which are caused by overproduction of Th2 cytokines (IL-4, IL-5, and IL-13) by allergen-specific T cells. We recently demonstrated a critical contribution of OX40 ligand (OX40L) to the development of Th2-mediated experimental leishmaniasis. In this study, we have examined the role of OX40L in the development of Th2-mediated pulmonary inflammation by utilizing OX40L-deficient mice and a neutralizing anti-OX40L mAb in a murine model of asthma. Sensitization and airway challenge with ovalbumin in wild-type BALB/c mice induced a typical allergic asthma characterized by AHR, accumulation of eosinophils, increased mucus production, and high levels of Th2 cytokines in the lung. All these asthmatic responses were not induced in OX40L-deficient BALB/c mice. Administration of neutralizing anti-OX40L mAb in wild-type BALB/c mice during the sensitization period also abolished the induction of asthmatic responses. In contrast, administration of anti-OX40L mAb during the challenge period did not inhibit the asthmatic responses. These results indicate a critical role for OX40L in the induction phase, which leads to the development of pathogenic Th2 cells, but not in the effector phase, which includes migration and activation of pathogenic Th2 cells in the lung.