RESUMEN
PURPOSE: Due to the burden of COPD in Japan, new pharmacologic treatments are needed to meet patient requirements. This study assessed the efficacy and safety of glycopyrronium (GP) delivered via metered dose inhaler (MDI) in Japanese patients with moderate-to-severe COPD. METHODS: This Phase IIb, multicenter, randomized, double-blind, 7-day, crossover study compared GP MDI 28.8, 14.4, and 7.2 µg with placebo MDI (all administered as two inhalations, twice daily). The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary endpoints included FEV1 area under the curve from 0 to 2 hours (AUC0-2) and peak change from baseline in FEV1 on Days 1 and 8 and forced vital capacity AUC0-2 on Day 8. Safety was also assessed. ClinicalTrials.gov Identifier: NCT03256552; http://www.ClinicalTrials.gov. RESULTS: Sixty-six patients were randomized and 62 were included in the modified intent-to-treat population (mean age 67.5 years). All three GP MDI doses significantly improved change from baseline in morning pre-dose trough FEV1 on Day 8 compared with placebo MDI (least squares mean differences 108-131 mL; all p<0.0001). Significant improvements in secondary efficacy endpoints were also observed for all three GP MDI doses compared with placebo MDI (all p<0.0001). Dose-response plateaued at GP MDI 14.4 µg. No significant safety findings were observed with any GP MDI dose or placebo MDI. CONCLUSIONS: The results of this study suggest that GP MDI 14.4 µg (7.2 µg per inhalation) is the most appropriate dose for use in Phase III studies in Japanese patients with moderate-to-severe COPD.
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Broncodilatadores/administración & dosificación , Sistemas de Liberación de Medicamentos/instrumentación , Glicopirrolato/administración & dosificación , Pulmón/efectos de los fármacos , Inhaladores de Dosis Medida , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Adulto , Anciano , Anciano de 80 o más Años , Broncodilatadores/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Glicopirrolato/efectos adversos , Humanos , Análisis de Intención de Tratar , Japón , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: We examined the association of outdoor air pollution and meteorological parameters with primary care visits (PCVs) at night due to asthma attack. SETTING: A case-crossover study was conducted in a primary care clinic in Himeji City, Japan. PARTICIPANTS: Participants were 1447 children aged 0-14â years who visited the clinic with an asthma attack from April 2010 until March 2013. EXPOSURE: Daily concentrations of air pollutants and meteorological parameters were measured. PRIMARY OUTCOME: PCVs at night due to asthma attack. A conditional logistic regression model was used to estimate ORs of PCVs per unit increment of air pollutants or meteorological parameters (the per-unit increments of particulate matter with an aerodynamic diameter ≤2.5â µm (PM2.5) and ozone were 10â µg/m(3) and 10â ppb, respectively). Analyses took into consideration the effects of seasonality. RESULTS: We noted an association between PCVs and daily ozone levels on the day before a PCV (OR=1.17; 95% CI 1.01 to 1.35; p=0.04), as well as between PCVs and 3-day mean ozone levels before a PCV (OR=1.29; 95% CI 1.00 to 1.46; p=0.04), from April until June. We also observed an association between PCVs and daily PM2.5 levels on the day before a PCV from December until March (OR=1.16; 95% CI 1.01 to 1.33; p=0.05). Meteorological parameters, such as hours of sunshine from September until November, atmospheric pressure from April until June, and temperature from April until August, were also found to be associated with PCVs. CONCLUSIONS: The findings in the present study supported an association between ozone and PCVs and suggest that certain meteorological items may be associated with PCVs.
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Atención Posterior/estadística & datos numéricos , Contaminación del Aire/efectos adversos , Asma/etiología , Exposición a Riesgos Ambientales/efectos adversos , Atención Primaria de Salud/estadística & datos numéricos , Tiempo (Meteorología) , Adolescente , Contaminación del Aire/análisis , Asma/epidemiología , Presión Atmosférica , Niño , Preescolar , Estudios Cruzados , Exposición a Riesgos Ambientales/análisis , Femenino , Humanos , Lactante , Japón/epidemiología , Modelos Logísticos , Masculino , Ozono/efectos adversos , Ozono/análisis , Material Particulado/efectos adversos , Material Particulado/análisisRESUMEN
AIM: In January 2013, extremely high concentrations of fine particles (PM2.5) were observed around Beijing, China. In Japan, the health effects of transboundary air pollution have been a matter of concern. We examined the association between the levels of outdoor PM2.5 and other air pollutants with primary care visits (PCVs) at night due to asthma attack in Himeji City, western Japan. METHODS: A case-crossover study was conducted in a primary care clinic in Himeji City, Japan, involving 112 subjects aged 0-80 years who visited the clinic due to an asthma attack between 9 p.m. and 6 a.m. during the period January-March, 2013. Daily concentrations of particulate matter, ozone, nitrogen dioxide, and some meteorological elements were measured, and a conditional logistic regression model was used to estimate the odds ratios (OR) of PCVs per unit increment in air pollutants or meteorological elements. RESULTS: Of the 112 subjects, 76 (68 %) were aged <15 years. We did not note any association between daily PM2.5 levels and PCVs due to asthma attack at night. A positive relation between ozone and PCVs due to asthma attack was detected. The OR per 10 ppb increment in daily mean ozone the day before the visit was 2.31 (95 % confidence interval 1.16-4.61). CONCLUSION: These findings do not support an association between daily mean concentration of PM2.5 and PCVs at night. However, we did find evidence suggesting that ozone is associated with PCVs.
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Contaminantes Atmosféricos/análisis , Asma/epidemiología , Exposición a Riesgos Ambientales , Material Particulado/análisis , Adolescente , Adulto , Anciano , Asma/inducido químicamente , Niño , Preescolar , China , Estudios Cruzados , Femenino , Humanos , Lactante , Japón/epidemiología , Masculino , Persona de Mediana Edad , Dióxido de Nitrógeno/análisis , Oportunidad Relativa , Ozono/análisis , Tamaño de la Partícula , Tiempo (Meteorología) , Adulto JovenRESUMEN
AIM: The association of outdoor air pollution and meteorological elements with primary care visits at night due to asthma attack was studied. METHODS: A case-crossover study was conducted in a primary care clinic in Himeji City, Japan. The subjects were 956 children aged 0-14 years who visited the clinic with an asthma attack between the hours of 9 p.m. and 6 a.m. Daily concentrations of particulate matter, ozone, nitrogen dioxide, and a number of meteorological elements were measured, and a conditional logistic regression model was used to estimate odds ratios (ORs) of primary care visits per unit increment of air pollutants or meteorological elements. The analyses took into consideration the effects of seasonality. RESULTS: Of the 956 children, 73 (7.6 %) were aged <2 years and 417 (43.6 %) were aged 2-5 years. No association between daily ozone levels and primary care visits due to asthma attack at night in the spring or summer was found. An inverse relation between suspended particulate matter and primary care visits due to asthma attack was detected in the winter. ORs in the summer per degree increment in daily mean temperature was 1.31 [95 % confidential interval (CI) 1.09-1.56], and ORs in the autumn per hourly increment in daily hours of sunshine was 0.94 (95 % CI 0.90-0.99). CONCLUSION: The findings of our study fail to support any association between daily mean concentration of air pollutant and primary care visits at night. However, we did find evidence indicating that certain meteorological elements may be associated with primary care visits.
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Contaminantes Atmosféricos/análisis , Asma/epidemiología , Exposición a Riesgos Ambientales , Adolescente , Asma/inducido químicamente , Niño , Preescolar , Estudios Cruzados , Monitoreo del Ambiente , Femenino , Humanos , Lactante , Masculino , Dióxido de Nitrógeno/análisis , Ozono/análisis , Tamaño de la Partícula , Material Particulado/análisis , Tiempo (Meteorología)RESUMEN
A series of optically active, helically twisted [1 + 1]macrocycles connected via o-, m-, and p-linkages (o-, m-, and p-) was prepared from the corresponding linear duplexes stabilized by complementary amidinium-carboxylate salt bridges bearing two arms with terminal vinyl groups at both ends through the ring-closing metathesis reaction in the good yields of 67, 92, and 96%, respectively. The chiroptical properties of the macrocycles were dependent on the linker geometries and could be controlled by acid-base interactions and zinc coordination, the changes in which were detected by their CD and absorption spectral changes and fluorescence colors.
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Amidinas/química , Ácidos Carboxílicos/química , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Fenómenos Ópticos , Sales (Química)/químicaRESUMEN
BACKGROUND: The aim of this study was to clarify whether some environmental and genetic factors (food allergy, older siblings, early day-care attendance and parents' allergy history) are related to the development of allergic symptoms (wheezing in the previous 12 months [WP], eczema symptoms in the previous 12 months [EP], and rhinoconjunctivitis symptoms in the previous 12 months [RP]) in Japanese children. METHODS: Using the modified version of the International Study on Asthma and Allergies in Childhood (ISSAC) questionnaire, we studied the prevalence of WP, EP and RP among six-year-old children attending 72 primary schools throughout Himeji City, Japan, during the two years from 2005 to 2006. RESULTS: Food allergy and parents' history of allergy showed a significant relationship with the prevalence of WP, EP and RP. Day-care attendance in the first two years of life and presence of older siblings showed a significant inverse relationship with the prevalence of RP. However, neither day-care attendance nor presence of older siblings was related to the development of W and ER. CONCLUSIONS: Among Japanese children, food allergy and parents' history of allergy are risk factors for WP, ES or RS. However, early day-care attendance and presence of older siblings might be protective factors against RS. Infections in early life may affect the prevalence of rhinoconjunctivitis in six-year-old children.
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Conjuntivitis Alérgica/epidemiología , Eccema/epidemiología , Hipersensibilidad/epidemiología , Ruidos Respiratorios , Rinitis/epidemiología , Niño , Guarderías Infantiles , Conjuntivitis Alérgica/etiología , Eccema/etiología , Femenino , Hipersensibilidad a los Alimentos , Humanos , Hipersensibilidad/etiología , Japón/epidemiología , Masculino , Prevalencia , Ruidos Respiratorios/etiología , Rinitis/etiología , Factores de Riesgo , Hermanos , Encuestas y CuestionariosRESUMEN
The conversion of ketones to esters has been achieved through the use of Cu catalyst and tetrabutylammonium nitrite. This reaction involves the activation of the less activated C-C bond, and the alkyl group is removed as a leaving group. Various isopropyl ketones are found to be good substrates for this reaction.
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Cobre/química , Ésteres/síntesis química , Cetonas/química , Catálisis , Ésteres/química , Estructura Molecular , EstereoisomerismoRESUMEN
The aim of the study was to clarify the relationship between current pet ownership, passive smoking, and allergic diseases among the Japanese children. From 1995 to 2001, we distributed the Japanese edition of the questionnaire of the American Thoracic Society and the Division of Lung Diseases (ATS-DLD) to survey allergic diseases among 35,552 6-yr-old children at primary school in the city of Himeji, Japan. We analyzed the data by multiple logistic regression and calculated adjusted odds ratios for environmental factors, including passive smoking and pet (dog and/or cat) ownership. There were no significant relationships between the prevalence of asthma and current pet ownership and passive smoking. However, current cat ownership was related to a significantly lower prevalence of atopic dermatitis [adjusted odds ratio (aOR) 0.79, 95% confidence interval (CI) 0.67-0.93], allergic rhinitis (aOR: 0.71, 95% CI 0.57-0.89) and Japanese cedar pollinosis (aOR 0.57, 95% CI 0.44-0.75). Strikingly, passive smoking was also related to a significantly lower prevalence of allergic rhinitis (aOR 0.83, 95% CI 0.77-0.89) and Japanese cedar pollinosis (aOR 0.81, 95% CI 0.74-0.88). Current cat ownership was associated with a lower prevalence of atopic dermatitis, allergic rhinitis, and Japanese cedar pollinosis. In addition, passive smoking was also associated with a lower prevalence of allergic rhinitis and Japanese cedar pollinosis.