RESUMEN
BACKGROUND: Exercise-induced bronchospasm (EIB) affects up to 90% of all patients with asthma. Objective. This study evaluated the ability of levalbuterol hydrofluoroalkane (HFA) 90 mug (two actuations of 45 microg) administered via metered dose inhaler (MDI) to protect against EIB in mild-to-moderate asthmatics. METHODS: This was a randomized, double-blind, placebo-controlled, two-way cross-over study. Patients with asthma (n = 15) were > or =18 years, had a > or =6-month history of EIB, > or = 70% baseline predicted forced expiratory volume in 1 second (FEV1), and a 20% to 50% decrease in FEV(1) after treadmill exercise challenge using single-blind placebo MDI. Levalbuterol or placebo was self-administered 30 minutes before exercise. Treatment sequences were separated by a 3-to 7-day washout period. Spirometry was performed predose, 20 minutes postdose/pre-exercise, and 5, 10, 15, 30, and 60 minutes post-exercise. The primary endpoint was the maximum percent decrease in FEV1 from baseline (postdose/pre-exercise). The percentage of protected (< or = 20% decrease in post-exercise FEV1) patients was also assessed. RESULTS: Levalbuterol had significantly smaller maximum percent post-exercise decrease in FEV1 compared with placebo (LS mean +/- SE; -4.8% +/- 2.8% versus -22.5% +/- 2.8%, respectively). For levalbuterol, 14/15 (93.3%) patients had < 20% decrease in post-exercise FEV1 compared with 8/15 (53.3%) for placebo (p = 0.0143). Treatment was well tolerated. CONCLUSION: Levalbuterol HFA MDI (90 microg) administered 30 minutes before exercise was significantly more effective than placebo in protecting against EIB after a single exercise challenge and was well tolerated. CLINICAL IMPLICATIONS: Levalbuterol HFA MDI when administered before exercise was effective in protecting adults with asthma from EIB.
Asunto(s)
Agonistas Adrenérgicos beta/uso terapéutico , Albuterol/uso terapéutico , Asma Inducida por Ejercicio/prevención & control , Administración por Inhalación , Agonistas Adrenérgicos beta/administración & dosificación , Agonistas Adrenérgicos beta/efectos adversos , Adulto , Albuterol/administración & dosificación , Albuterol/efectos adversos , Asma Inducida por Ejercicio/fisiopatología , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico , Estudios Cruzados , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Inhaladores de Dosis Medida , EspirometríaRESUMEN
Precise thermodynamic integration free energy simulations have been applied to a congeneric series of 16 inhibitors to the p38 MAP kinase protein for which the experimental binding data (IC(50)) is known. The relative free energy of binding for each compound has been determined. For comparison, the same series of compounds have also scored using the best rapid scoring functions used in database screening. From the results of these calculations, we find (1) that precise free energy simulations allow predictions that are reliable and in good agreement with experiment; (2) that predictions of lower reliability, but still in good qualitative agreement with experiment, can be obtained using the OWFEG free energy grid method, at a much lower computational cost; (3) and that other methods, not based on free energy simulations yield results in much poorer agreement with experiment. A new predictive index, which measures the reliability of a prediction method in the context of normal use, is defined and calculated for each scoring method. Predictive indices of 0.84, 0.56, 0.04, -0.05, and 0.25 are calculated for thermodynamic integration, OWFEG, ChemScore, PLPScore, and Dock Energy Score, respectively, where +1.0 is perfect correct prediction, -1.0 is perfect incorrect prediction, and 0.0 is random.
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Inhibidores Enzimáticos/química , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas Activadas por Mitógenos/química , Derivados del Benceno/química , Derivados del Benceno/metabolismo , Sitios de Unión , Inhibidores Enzimáticos/metabolismo , Ligandos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Unión Proteica , Piridazinas/química , Piridazinas/metabolismo , Reproducibilidad de los Resultados , Sulfuros/química , Sulfuros/metabolismo , Termodinámica , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
BACKGROUND: The incidence of pediatric asthma has increased dramatically over the past few decades, with approximately 5% of American children affected by the disease. OBJECTIVES: To compare the efficacy and safety of once-daily budesonide Turbuhaler with placebo in asthmatic children previously treated with orally inhaled corticosteroids. METHODS: This randomized, double-blind, placebo-controlled, multicenter (17 centers) study included 274 male and female children (aged 6 to 17 years) with a history of asthma for at least the previous 6 months. Patients received placebo or budesonide Turbuhaler (200 microg or 400 microg) once daily for 12 weeks. Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second (FEV1), AM and PM peak expiratory flow rates (PEFRs), nighttime and daytime asthma symptom severity scores, patient discontinuations, use of beta2-agonists as breakthrough medication, forced vital capacity (FVC), and midexpiratory flow rate between 25% and 75% of FVC (FEF25%-75%). Safety was evaluated by adverse events, physical examinations, vital signs, and laboratory tests. RESULTS: Baseline characteristics were comparable among treatment groups. Percentage of predicted FEV1 at baseline was 76.6 +/- 6.9 for placebo, 77.5 +/- 7.1, and 77.0 +/- 7.8 for the budesonide Turbuhaler 200 microg and 400 microg groups, respectively. Significantly (P < or = 0.024) more placebo patients (24%) discontinued treatment because of disease deterioration or no improvement than budesonide Turbuhaler 200 microg (11%) or 400 microg patients (10%). Patients receiving budesonide Turbuhaler experienced significant improvements in FEV1 compared with patients receiving placebo (P < or = 0.015). Significant (P < or = 0.041) improvements over placebo also were observed in AM and PM PEFRs, FVC, FEF25%-75%, nighttime and daytime asthma symptoms, and amount of beta2-agonist used in both budesonide Turbuhaler groups. Adverse events were generally mild or moderate in intensity and similar among treatment groups. CONCLUSIONS: Once-daily budesonide Turbuhaler is effective and safe in children with persistent asthma previously maintained on at least twice-daily dosing regimens of inhaled corticosteroids.
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Antiinflamatorios/administración & dosificación , Antiinflamatorios/uso terapéutico , Budesonida/administración & dosificación , Budesonida/uso terapéutico , Administración por Inhalación , Adolescente , Adulto , Anciano , Esquema de Medicación , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Ápice del Flujo EspiratorioRESUMEN
A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques currently in wide use. The OWFEG free energy grid is generated from a one-window free energy perturbation MD simulation (Pearlman, D. A. J. Med. Chem. 1999, 42, 4313-4324). The OWFEG approach is applied to three protein systems: IMPDH, MAP kinase p38, and HIV-1 aspartyl protease. OWFEG scores are compared to experimental K(i) and IC50 data in each case. Empirical scoring functions applied to the same systems for comparison include ChemScore, Piecewise Linear Potential (PLP), and Dock energy score.
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Diseño de Fármacos , Ligandos , Proteínas/química , Bases de Datos Factuales , Modelos Moleculares , TermodinámicaRESUMEN
BACKGROUND: Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. OBJECTIVE: To determine the efficacy and safety of dry powder FP administered once or twice daily (200 microg per day) to children with persistent asthma. METHODS: Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 microg each morning, dry powder FP 100 microg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits. RESULTS: Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P < or = .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P < or = .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. CONCLUSIONS: Once daily dosing of dry powder FP 200 microg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.
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Androstadienos/farmacocinética , Androstadienos/uso terapéutico , Antiasmáticos/farmacocinética , Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Niño , Preescolar , Método Doble Ciego , Femenino , Fluticasona , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Polvos , Equivalencia TerapéuticaAsunto(s)
Mujeres Maltratadas/legislación & jurisprudencia , Atención a la Salud , Prevención Primaria/organización & administración , Violencia/legislación & jurisprudencia , Violencia/prevención & control , Mujeres Maltratadas/estadística & datos numéricos , Femenino , Política de Salud , Humanos , Responsabilidad Legal , Masculino , Medicina Preventiva/métodos , Estados UnidosRESUMEN
BACKGROUND: Intimate partner violence (IPV) is a significant public health problem in the United States. Estimates of incidence and prevalence vary widely, depending on the data source used. Combining information from different sources can enhance our understanding of IPV. METHODS: In this paper, we used 1998 data from the Rhode Island (RI) Department of Health Violence Against Women Public Health Surveillance System to describe the prevalence of IPV reported to police, the demographic characteristics and help-seeking efforts of women reporting IPV, and characteristics of IPV incidents. We used data from the 1998 RI Department of Health Behavioral Risk Factor Surveillance System survey to examine associations between health care use and health outcomes of victims and nonvictims of IPV, and to explore the correlates of IPV. We also discuss the use of both narrow and broad definitions of IPV. RESULTS: Our findings show that the definition of IPV and the source used to identify IPV victims can produce a markedly different picture of IPV victims, and that combining information from different data sources can enhance our understanding of IPV. An important finding for health care providers is that IPV victims do not appear to be significantly different from nonvictims in their access to and utilization of routine health care, and that more than 60% of victims at highest risk for injury reported seeing a health care provider because of IPV. CONCLUSIONS: Our findings underscore the importance of health care providers addressing IPV and its consequences among their patients.
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Mujeres Maltratadas/estadística & datos numéricos , Vigilancia de la Población/métodos , Adolescente , Adulto , Distribución por Edad , Intervalos de Confianza , Femenino , Humanos , Modelos Logísticos , Masculino , Notificación Obligatoria , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Rhode Island/epidemiología , Medición de Riesgo , Sensibilidad y EspecificidadRESUMEN
This multicenter, double-masked, randomized, parallel-group study compared the efficacy and safety of ketorolac tromethamine 0.5% ophthalmic solution with levocabastine 0.05% and ketorolac tromethamine vehicle in patients with seasonal allergic conjunctivitis. One drop of ketorolac, levocabastine, or vehicle was instilled in each eye four times daily for 6 weeks. In the majority of efficacy variables, ketorolac produced the greatest improvements, followed by levocabastine and vehicle. Ketorolac was significantly more effective (P < .05) than vehicle in reducing mean itching scores, palpebral hyperemia, bulbar hyperemia, and edema. Patients treated with ketorolac reported significant improvements (P < .05) in their ability to sleep and to concentrate on work, compared with those who received vehicle. No significant differences were noted among the treatment groups in safety or tolerability. Ketorolac tromethamine 0.5% ophthalmic solution instilled four times daily is effective and safe in reducing the signs and symptoms of seasonal allergic conjunctivitis.
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Antiinflamatorios no Esteroideos/uso terapéutico , Conjuntivitis Alérgica/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Ketorolaco Trometamina/uso terapéutico , Piperidinas/uso terapéutico , Adolescente , Adulto , Anciano , Análisis de Varianza , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: This study was undertaken to examine the dose-response relationship of zafirlukast (5 to 40 mg BID) and to assess the efficacy and tolerability of the 10-mg BID dose in school-aged children with mild to moderate asthma. BACKGROUND: The efficacy and tolerability of zafirlukast, an oral leukotriene-receptor antagonist, has been demonstrated in adolescents and adults aged > or = 12 years. METHODS: Data from 2 placebo-controlled, parallel-group, multicenter trials (trial 1, 4-week double-blind; trial 2, 6-week double-blind) were integrated. Children aged 5 to 11 years were randomly assigned to receive zafirlukast 5 mg BID (n = 99), 10 mg BID (n = 205), 20 mg BID (n = 105), 40 mg BID (n = 99), or placebo (n = 206). The primary outcome was change from baseline in forced expiratory volume in 1 second (FEV1) expressed as percent of predicted normal. Secondary outcomes were FEV1 (L), morning and evening peak expiratory flow, peak flow variability, short-acting beta2-agonist use, asthma episode score, and nights awakened by asthma. RESULTS: Mean baseline FEV1 was 76.5% of predicted. The greatest improvements were generally seen with zafirlukast 5 mg BID or 10 mg BID, with no additional clinically significant benefits seen at higher doses. The pooled data analysis showed that 10 mg BID compared with placebo significantly improved (P < 0.045) all efficacy outcomes except asthma-episode score and nights awakened with asthma. However, in the subset of children who had > or = 1 night awakened per week at baseline (zafirlukast 10 mg BID = 78; placebo = 86), 10 mg BID significantly reduced nights awakened (P = 0.009) (mean difference from placebo at end point = -0.81 night/wk). All zafirlukast doses were well tolerated and had tolerability profiles that were clinically indistinguishable from placebo. CONCLUSION: These results support the effectiveness and tolerability of the 10-mg BID dose of zafirlukast for the prophylaxis and chronic treatment of mild to moderate asthma in children.
Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Compuestos de Tosilo/uso terapéutico , Adolescente , Antiasmáticos/efectos adversos , Niño , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Humanos , Indoles , Fenilcarbamatos , Placebos , Sulfonamidas , Compuestos de Tosilo/efectos adversosRESUMEN
BACKGROUND: Although inhaled glucocorticoids are recommended for all stages of persistent asthma, compliance with long-term therapy is often poor, leading to significant morbidity and mortality. A simplified, once-daily dosing regimen may foster improved compliance. OBJECTIVE: To compare the efficacy and safety of once-daily (AM) administration of mometasone furoate dry powder inhaler (MF DPI) 200 microg and 400 microg with placebo in patients with asthma previously maintained only on short-acting inhaled beta-adrenergic receptor agonists. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel group study. The mean change from baseline to endpoint (last treatment visit) for FEV1 was the primary efficacy variable. RESULTS: At endpoint, both doses of MF DPI were significantly more effective than placebo (P < or = .05) in improving FEV1. Based on morning peak expiratory flow rate, once-daily MF DPI 400 microg was more effective than placebo (P < or = .001) at endpoint. Both active treatments also demonstrated improvement at endpoint in asthma symptom scores, physician-evaluated response to therapy and use of rescue medication. Although both MF DPI dosages were efficacious, MF DPI 400 microg provided additional improvement in some measures of pulmonary function (eg, morning PEFR) when these agents were administered once daily in the morning. Both doses of MF DPI were well tolerated and treatment-related adverse events occurred at a similar incidence among the three treatment groups. CONCLUSIONS: The results of this study indicate that once-daily (AM) MF DPI provides a convenient and effective treatment option for patients with mild or moderate persistent asthma.
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Antiasmáticos/uso terapéutico , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Pregnadienodioles/uso terapéutico , Adolescente , Adulto , Anciano , Antiasmáticos/administración & dosificación , Antiinflamatorios/administración & dosificación , Niño , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Furoato de Mometasona , Pregnadienodioles/administración & dosificación , Calidad de Vida , Pruebas de Función Respiratoria , Resultado del TratamientoRESUMEN
OBJECTIVE: Intranasal corticosteroids are used widely for the treatment of allergic rhinitis because they are effective and well tolerated. However, their potential to suppress growth of pediatric subjects with allergic rhinitis continues to be a concern, particularly in light of reports of growth suppression after treatment with intranasal beclomethasone dipropionate or intranasal budesonide (see the article by Skoner et al in this month's issue). A 1-year study of prepubertal patients between 3 and 9 years of age with perennial allergic rhinitis was conducted to assess the effects on growth of mometasone furoate aqueous nasal spray (MFNS), a new once-daily (QD) intranasal corticosteroid with negligible bioavailability. METHODS: This was a randomized, placebo-controlled, double-blind, multicenter study. Ninety-eight subjects were randomized to treatment with either MFNS 100 microg QD or placebo for 1 year. Each subject's height was required to be between the 5th and 95th percentile at baseline, and skeletal age at screening was required to be within 2 years of chronological age, as determined by left wrist x-rays. Washout periods for medications that affect either childhood growth or allergic rhinitis symptoms were established based on estimated period of effect, and these medications were prohibited during the study. However, short courses of either oral prednisone lasting no longer than 7 days or low-potency topical dermatologic corticosteroids lasting no longer than 10 days were permitted if necessary. Height was measured with a calibrated stadiometer at baseline and at 4, 8, 12, 26, 39, and 52 weeks, and the primary safety variable was the change in standing height. The rate of growth was also calculated for each subject as the slope (linear regression) of the change in height from baseline using data from all visits of subjects who had at least 2 visits. Hypothalamic-pituitary-adrenocortical- (HPA)-axis function was assessed via cosyntropin stimulation testing at baseline and at 26 and 52 weeks. All analyses were based on all randomized subjects (intent-to-treat principle). The change from baseline in standing height was analyzed by a 2-way analysis of variance that extracted sources of variation attributable to treatment, center, and treatment-by-center interaction. RESULTS: Demographic characteristics were similar at baseline. Eighty-two subjects completed the study (42 in the MFNS group and 40 in the placebo group), and 93% of subjects achieved at least 80% compliance with therapy. After 1 year of treatment, no suppression of growth was seen in subjects treated with MFNS, and mean standing heights were similar for both treatment groups at all time points. For the primary safety variable (change in height from baseline), both treatment groups were similar at all time points except for weeks 8 and 52. Subjects treated with MFNS had a slightly greater mean increase in height than subjects treated with placebo at these time points: the change in height was 6.95 cm versus 6.35 cm at the 1-year time point. However, the rate of growth (.018 cm/day) averaged for all time points over the course of the study was similar for both treatment groups. Additional analyses found that MFNS did not retard growth in any sex or age subgroup of subjects. The use of exogenous corticosteroids other than the study drug was also similar among the 2 treatment groups. Results from cosyntropin stimulation testing confirmed the absence of systemic effects of MFNS. The change from baseline in the difference between prestimulation and poststimulation levels was similar for both treatment groups after 1 year of treatment, with no evidence of HPA-axis suppression in MFNS-treated subjects at any time point. Incidences of treatment-related adverse events were similar for both treatment groups, with 16% of MFNS-treated subjects reporting adverse events, compared with 22% of placebo-treated subjects. CONCLUSIONS: (ABSTRACT TRUNCATED)
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Antiinflamatorios/uso terapéutico , Crecimiento/efectos de los fármacos , Pregnadienodioles/uso terapéutico , Rinitis Alérgica Perenne/tratamiento farmacológico , Administración Intranasal , Antiinflamatorios/efectos adversos , Niño , Método Doble Ciego , Femenino , Glucocorticoides , Trastornos del Crecimiento/inducido químicamente , Humanos , Masculino , Furoato de Mometasona , Pregnadienodioles/efectos adversosRESUMEN
BACKGROUND: Montelukast, an oral, once-daily leukotriene receptor antagonist, provides protection against exercise-induced bronchoconstriction. OBJECTIVE: To evaluate the effect of 8 weeks of therapy with salmeterol aerosol or montelukast on exercise-induced bronchoconstriction in adults with asthma. DESIGN: 8-week multicenter, randomized, double-blind study. SETTING: 17 asthma treatment centers in the United States. PATIENTS: 191 adults with asthma who had documented exercise-induced bronchoconstriction. INTERVENTION: Qualified patients were randomly assigned to double-blind treatment with montelukast (10 mg once in the evening) or salmeterol (50 microg [2 puffs] twice daily). MEASUREMENTS: Changes in pre-exercise and postexercise challenge values; percentage inhibition in the maximal percentage decrease in FEV1; the area above the FEV1-time curve; and time to recovery of FEV1 at days 1 to 3, week 4, and week 8 of treatment. RESULTS: By day 3, similar and statistically significant reductions in maximal percentage decrease in FEV1 were seen with both therapies. Sustained improvement occurred in the montelukast group at weeks 4 and 8; at these time points, the bronchoprotective effect of salmeterol decreased significantly. At week 8, the percentage inhibition in the maximal percentage decrease in FEV1 was 57.2% in the montelukast group and 33.0% in the salmeterol group (P = 0.002). By week 8, 67% of patients receiving montelukast and 46% of patients receiving salmeterol had a maximal percentage decrease in FEV1 of less than 20%. CONCLUSIONS: The bronchoprotective effect of montelukast was maintained throughout 8 weeks of study. In contrast, significant loss of bronchoprotection at weeks 4 and 8 was seen with salmeterol. Long-term administration of montelukast provided consistent inhibition of exercise-induced bronchoconstriction at the end of the 8-week dosing interval without tolerance.
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Acetatos/administración & dosificación , Albuterol/análogos & derivados , Asma Inducida por Ejercicio/prevención & control , Broncoconstricción/efectos de los fármacos , Broncodilatadores/administración & dosificación , Antagonistas de Leucotrieno/administración & dosificación , Quinolinas/administración & dosificación , Acetatos/efectos adversos , Acetatos/farmacocinética , Administración Oral , Adolescente , Adulto , Albuterol/administración & dosificación , Albuterol/efectos adversos , Albuterol/farmacocinética , Área Bajo la Curva , Asma Inducida por Ejercicio/fisiopatología , Broncodilatadores/efectos adversos , Broncodilatadores/farmacocinética , Ciclopropanos , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Antagonistas de Leucotrieno/efectos adversos , Antagonistas de Leucotrieno/farmacocinética , Masculino , Persona de Mediana Edad , Quinolinas/efectos adversos , Quinolinas/farmacocinética , Xinafoato de Salmeterol , SulfurosRESUMEN
BACKGROUND: Long-acting beta(2)-sympathomimetic agonists such as salmeterol have been proved safe and effective for the treatment of asthma. However, controversy still exists as to the appropriateness of scheduled long-term therapy with these agents. OBJECTIVE: This study assessed the degree of bronchodilation provided by treatment with salmeterol for a period of 52 weeks and evaluated bronchial hyperresponsiveness to methacholine during and after the treatment period. METHODS: Three hundred fifty-two patients with mild to moderate asthma were assessed by 12-hour serial spirometry and serial methacholine challenge tests. RESULTS: The mean area under the FEV(1) curve above baseline over 12 hours after drug at day 1 was significantly greater with salmeterol powder compared with placebo (5.06 liter hours vs 0.77 L/h) and did not change significantly over 1 year. The mean increase in the log(2) of the provocative cumulative methacholine dose producing a 20% decrease in FEV(1) (PD(20)FEV(1)) during treatment was significantly higher in the salmeterol-treated patients than in the placebo group (1.02 doubling doses vs 0.43 doubling doses at week 4, 1.06 doubling doses vs 0.41 doubling doses at week 24). At week 52 the increase from baseline in log(2)PD(20)FEV(1) was not significantly different between salmeterol and placebo (1.08 vs 0.69 doubling doses). Seven days after treatment the log(2)PD(20)FEV(1) was -0.60 doubling doses lower than baseline for salmeterol compared with 0.10 doubling doses for placebo (P =.031). Long-term salmeterol use was not associated with a deleterious effect on asthma control during and after treatment. CONCLUSION: This study demonstrates that the bronchodilator properties of salmeterol are sustained over 52 weeks and that bronchial hyperresponsiveness to methacholine is decreased to a modest degree during treatment. Clinically significant increases in hyperresponsiveness did not develop after discontinuation of salmeterol treatment.
Asunto(s)
Agonistas Adrenérgicos beta/administración & dosificación , Albuterol/análogos & derivados , Broncodilatadores/administración & dosificación , Adolescente , Adulto , Anciano , Albuterol/administración & dosificación , Asma/diagnóstico , Asma/fisiopatología , Pruebas de Provocación Bronquial , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ápice del Flujo Espiratorio/efectos de los fármacos , Pruebas de Función Respiratoria , Xinafoato de SalmeterolRESUMEN
Traditional window-based free energy calculations can precisely determine the free energy corresponding to a molecular change of interest. However, calculations performed in this fashion are typically slow and resource-intensive, which renders them less than ideal for drug design. To circumvent this drawback, a new approximate free energy method, OWFEG, has been developed and tested. OWFEG replaces the exact free energy calculation for a single change with a set of approximate calculations for a grid of possible changes surrounding a molecule. One of the key features of OWFEG is that a floating independent reference frame (FIRF) is used, so that each grid point moves with the region of the molecule to which it is closest. In this way, this approach has been made applicable to flexible molecules. OWFEG is applied to two model systems and then to the FKBP-12.FK506 protein-ligand complex. On the basis of the results of these tests, this approximate method shows promise as a predictive tool for drug design.
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Diseño de Fármacos , Ligandos , Modelos Moleculares , Relación Estructura-Actividad , Tacrolimus/químicaRESUMEN
A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.
Asunto(s)
Antialérgicos/administración & dosificación , Antiinflamatorios/administración & dosificación , Asma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antialérgicos/efectos adversos , Antiinflamatorios/efectos adversos , Niño , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Flujo Espiratorio Medio Máximo/efectos de los fármacos , Persona de Mediana Edad , Furoato de Mometasona , Ápice del Flujo Espiratorio/efectos de los fármacos , Pregnadienodioles , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacosRESUMEN
Airway allergic reactions enlist diverse cells and a multitude of chemical mediators that are responsible for the clinical symptoms of allergic rhinitis and asthma. Experiments in vitro and in animal models, as well as increasingly numerous studies in atopic human subjects, are revealing that an orchestrated continuum of cellular activities leading to airway allergic inflammation is set in motion in genetically predisposed individuals at the first exposure to a novel antigen. This sensitization step likely depends on differentiation of and cytokine release by T(H)2 lymphocytes. Among T(H)2-derived cytokines, IL-4 potently enhances B-lymphocyte generation of immunoglobulin E antibodies. The attachment of these antibodies to specific receptors on airway mast cells sets the stage for an acute inflammatory response on subsequent antigen exposure because IgE cross-linking by a bound antigen activates mast cells to release numerous inflammatory mediators. These mast cell-derived mediators collectively produce acute-phase clinical symptoms by enhancing vascular leak, bronchospasm, and activation of nociceptive neurons linked to parasympathetic reflexes. Simultaneously, some mast cell mediators up-regulate expression on endothelial cells of adhesion molecules for leukocytes (eosinophils, but also basophils and lymphocytes), which are key elements in the late-phase allergic response. Chemoattractant molecules released during the acute phase draw these leukocytes to airways during a relatively symptom-free recruitment phase, where they later release a plethora of cytokines and tissue-damaging proteases that herald a second wave of airway inflammatory trauma (late-phase response). The repetition of these processes, with the possible establishment in airway mucosa of memory T lymphocytes and eosinophils that are maintained by paracrine and autocrine cytokine stimulation, may account for airway hypersensitivity and chronic airway symptoms.
Asunto(s)
Asma/etiología , Hipersensibilidad/etiología , Rinitis/etiología , Reacción de Fase Aguda/etiología , Reacción de Fase Aguda/inmunología , Asma/inmunología , Linfocitos B/inmunología , Humanos , Hipersensibilidad/inmunología , Mediadores de Inflamación , Mastocitos , Modelos Inmunológicos , Neuronas , Rinitis/inmunología , Células Th2/inmunologíaRESUMEN
BACKGROUND: A powder formulation of salmeterol has been shown to prevent exercise-induced bronchospasm (EIB) in asthmatic children and adults; however, the delivery device (Diskhaler; Glaxo Wellcome Inc, Research Triangle Park, NC) must be reloaded after 4 doses. A new multidose powder inhaler (Diskus) provides 60 doses of salmeterol in a blister pack presentation with a dose counter. OBJECTIVE: To evaluate the safety and efficacy of 50-microg salmeterol powder via two different delivery systems (Diskhaler and Diskus) in preventing EIB in asthmatic children. STUDY DESIGN: A randomized, double-blind, double-dummy, single-dose, placebo-controlled, three-way crossover study was conducted in 24 children 4 to 11 years of age demonstrating EIB and mild to moderate asthma. Serial forced expiratory volume in 1 second (FEV(1)) was measured before and after treadmill exercise challenges conducted at 1, 6, and 12 hours after study drug administration. Adverse events were also assessed. RESULTS: During all exercise challenges, EIB-mediated reductions in FEV(1) were minimized or prevented in patients receiving single doses of salmeterol powder compared with placebo. Single doses of salmeterol powder delivered via either system were equally effective in preventing EIB. There were no drug-related adverse events, cardiovascular, or other clinically relevant safety concerns. CONCLUSIONS: Single doses of salmeterol powder delivered by either delivery system are safe and effective in preventing EIB for >/=12 hours in asthmatic children.
Asunto(s)
Agonistas Adrenérgicos beta/administración & dosificación , Albuterol/análogos & derivados , Asma Inducida por Ejercicio/tratamiento farmacológico , Espasmo Bronquial/prevención & control , Nebulizadores y Vaporizadores , Administración por Inhalación , Agonistas Adrenérgicos beta/uso terapéutico , Albuterol/administración & dosificación , Albuterol/uso terapéutico , Asma Inducida por Ejercicio/fisiopatología , Niño , Preescolar , Estudios Cruzados , Método Doble Ciego , Prueba de Esfuerzo , Femenino , Humanos , Masculino , Polvos , Xinafoato de Salmeterol , Factores de TiempoRESUMEN
INTRODUCTION: This study examines the association between recent screening for breast and cervical cancers, knowledge of cancer risk factors, and perceptions of surviving cancer. METHODS: Data were from the Cancer Control Supplement to the 1992 National Health Interview Survey (NHIS-CCS). The dependent variable combined breast and cervical cancer screening practices into a single composite index. Two independent variables combined women's knowledge about breast and cervical cancers into single indicators--one representing risk factor knowledge, the other representing perceived likelihood of surviving breast and cervical cancers following early detection. RESULTS: Multivariate analysis showed that recency of screening for both breast and cervical cancers was associated with knowledge of cancer risk factors and perceptions of surviving cancer. Education, household income, and smoking status also were correlates of comprehensive screening. Significant interactions between income and perceived survivability, and between education and perceived survivability suggested that the effects of income and education on comprehensive screening varied with perceptions about surviving cancer. CONCLUSION: The study suggests that knowledge and attitudinal questions can be combined for two diseases to enhance understanding of who is most likely to be screened comprehensively for breast and cervical cancers. Although national trends show that large percentages of women over age 50 are having mammograms and Pap tests, this progress is not likely to be sustained unless existing barriers are eliminated. Limited knowledge about breast and cervical cancer risk factors and misperceptions about survival from cancer represent two of these barriers.
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Actitud Frente a la Salud , Neoplasias de la Mama/diagnóstico , Conocimientos, Actitudes y Práctica en Salud , Neoplasias del Cuello Uterino/diagnóstico , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/psicología , Escolaridad , Femenino , Encuestas Epidemiológicas , Humanos , Renta , Modelos Logísticos , Mamografía/psicología , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Estados Unidos , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/psicología , Frotis Vaginal/psicologíaRESUMEN
BACKGROUND: Perennial rhinitis is a common condition that affects up to 10% to 20% of the population. Multiple agents are frequently administered since no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important especially for newly approved agents such as ipratropium bromide nasal spray 0.03%, a topical anticholinergic agent, approved specifically for the treatment of rhinorrhea in allergic and non-allergic perennial rhinitis. OBJECTIVE: To compare the efficacy and safety of the combined use of ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) and beclomethasone dipropionate nasal spray (84 microg per nostril bid) against that of either active agent alone for the treatment of rhinorrhea. DESIGN: Multicenter, 6-week, double-blind, randomized active- and placebo-controlled, parallel trial. SETTING: Allergist and general practitioner clinical practices. PATIENTS: Five hundred thirty-three patients with perennial rhinitis (279 allergic and 274 non-allergic), 8 to 75 years of age, who had at least a mild degree of severity of rhinorrhea for a minimum of 2 hours per day during the 1 week screening period as well as congestion or sneezing also of at least mild severity. INTERVENTION: Either (1) ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) plus beclomethasone dipropionate nasal spray (84 microg per nostril bid), (2) ipratropium bromide nasal spray 0.03% (42 microg per nostril tid) alone, (3) beclomethasone dipropionate nasal spray (84 microg per nostril bid) alone, or (4) vehicle [matching placebo nasal spray for the ipratropium bromide (2 sprays per nostril tid)] or beclomethasone dipropionate (2 sprays per nostril bid). MAIN OUTCOME MEASURE: Severity and duration of rhinorrhea, and patient and physician global assessment of control of rhinorrhea. RESULTS: Ipratropium bromide nasal spray plus beclomethasone nasal spray was more effective than either active agent alone or vehicle in reducing the average severity and duration of rhinorrhea during 4 weeks of treatment. The advantage of ipratropium bromide plus beclomethasone nasal spray was evident by the first day of combined treatment and continued throughout the 2-week treatment period. Ipratropium bromide nasal spray had a faster onset of action during the first week of treatment and reduced the duration of rhinorrhea more than beclomethasone. Beclomethasone nasal spray was more effective in reducing the severity of congestion and sneezing than ipratropium. In patients who had not responded well to a nasal steroid prior to participation in the study based on a questionnaire administered at screening, ipratropium bromide was as effective in the steroid non-responders as steroid responders, whereas beclomethasone was more effective in steroid responders. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide or beclomethasone nasal spray alone. CONCLUSIONS: The combined use of ipratropium bromide nasal spray with beclomethasone dipropionate nasal spray is more effective than either active agent for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions. Ipratropium bromide nasal spray 0.03% alone should be considered in patients for whom rhinorrhea is the primary symptom, and its use in combination with a nasal steroid should be considered in patients where rhinorrhea is one of the predominant symptoms, or in patients with rhinorrhea not fully responsive to other therapy.
Asunto(s)
Beclometasona/uso terapéutico , Ipratropio/uso terapéutico , Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis/tratamiento farmacológico , Administración por Inhalación , Adolescente , Adulto , Anciano , Antiasmáticos/administración & dosificación , Antiasmáticos/efectos adversos , Antiasmáticos/uso terapéutico , Beclometasona/administración & dosificación , Beclometasona/efectos adversos , Broncodilatadores/administración & dosificación , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico , Niño , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Ipratropio/administración & dosificación , Ipratropio/efectos adversos , Masculino , Persona de Mediana Edad , Calidad de VidaRESUMEN
BACKGROUND: The effectiveness of inhaled glucocorticoids in the treatment of asthma is well documented; however, times to onset and maximal treatment effects of these agents have been poorly described. OBJECTIVE: We sought to determine the time to onset of effect and the time to the best observed effect of inhaled fluticasone propionate (FP) in patients with asthma. METHODS: Data from 8 randomized, double-blind, placebo-controlled clinical trials of at least 8 weeks' duration were analyzed. Corticosteroid-naive patients (n = 1461) were treated with either FP (25 micrograms to 500 micrograms) or placebo twice daily. Efficacy evaluations included morning peak expiratory flow (PEF), asthma symptom scores, supplemental albuterol use, and FEV1. RESULTS: Statistically significant improvements in PEF, asthma symptom scores, and supplemental albuterol use were observed beginning on day 1 of treatment in the FP group versus the placebo group (P <.001); significant increases in FEV1 were observed at the first measurement at week 1 (P <.001). The best observed effect occurred within 3 weeks of the start of FP treatment for PEF (+36 L/min) and FEV1 (+0.52 L) and within 2 weeks for reduction in supplemental albuterol use and asthma symptom scores. Patients with the most severe airflow obstruction had the greatest change in PEF (+56 L/min) and fastest time to 50% of best observed effect (3 days) compared with patients with mild or moderate airflow obstruction; however, time to best observed effect was similar in the 3 groups (20 to 27 days). CONCLUSION: In patients with asthma, the onset of significant benefit of FP on PEF, symptoms, and rescue albuterol use occurred within 1 day of the start of therapy. FEV1 improved within 1 week of the start of therapy (the first measurement after randomization). There was no effect of sex, age, or dose of FP on the time to response. The best observed response in PEF varies with the degree of baseline airflow obstruction; however, the degree of airflow obstruction has no effect on the time to best observed response.