RESUMO
BACKGROUND: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids. METHODS: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV1) of ≥ 12% and ≥ 200 mL 10-30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21-24, and rescue medication use (puffs/day) over Weeks 1-24. Analyses were conducted across the full range of reversibility (-850-896 mL); however, results are presented for the range -100-400 mL because there were few participants with values outside this range. RESULTS: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV1, SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range. CONCLUSIONS: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/efeitos adversos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The relationship between inhaled corticosteroids and bone mineral density (BMD) remains uncertain despite extensive research. METHODS: This was an international, multicenter, randomized, double-blind, parallel-group, 3-year noninferiority study. Patients with chronic obstructive pulmonary disease (COPD) (⩾40 years of age; smoking history ⩾10 pack years) and at least one native hip evaluable for BMD were enrolled and randomized 1:1, stratified by sex, to treatment with vilanterol (VI) 25 µg or fluticasone furoate/vilanterol (FF/VI) 100 µg/25 µg. BMD measurements were taken via dual-energy X-ray absorptiometry every 6 months. The primary endpoint was assessment of the noninferiority of change from baseline in total hip BMD per year at the -1% noninferiority level. Change from baseline in BMD at the lumbar spine and BMD measurements by sex were secondary endpoints. Incidences of COPD exacerbations and bone fractures throughout the study were also recorded. RESULTS: Of 283 randomized patients, 170 (60%) completed the study. Noninferiority was demonstrated for FF/VI versus VI with regards to change from baseline in total hip BMD per year, with changes of -0.27% and 0.18%, respectively, and a treatment difference of -0.46% per year [95% confidence interval (CI) -0.97 to 0.06]. The treatment difference for FF/VI versus VI regarding lumbar spine BMD was -0.51% per year (95% CI -1.11 to 0.10). COPD exacerbations and bone fracture rates were similar between treatment groups. CONCLUSION: FF/VI showed noninferiority to VI for change from baseline in total hip BMD per year, when assessed at the -1% noninferiority margin in a combined sample of men and women with COPD.The reviews of this paper are available via the supplemental material section.
Assuntos
Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Clorobenzenos/administração & dosagem , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Androstadienos/efeitos adversos , Álcoois Benzílicos/efeitos adversos , Canadá , Clorobenzenos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Europa (Continente) , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
Purpose: To evaluate the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) vs twice-daily budesonide/formoterol (BUD/FOR) in patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations, from the Spanish National Healthcare System perspective. Patients and Methods: The validated GALAXY-COPD model was used to simulate disease progression and predict healthcare costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) over a 3-year time horizon for a Spanish population. Patient characteristics from published literature were supplemented by data from FULFIL (NCT02345161), which compared FF/UMEC/VI vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations. Treatment effects, extrapolated to 3 years, were based on Week 24 results in the FULFIL intent-to-treat population, including change in forced expiratory volume in 1 second, St. George's Respiratory Questionnaire score, and exacerbation rates. Treatment, exacerbations, and COPD management costs (2019) were informed by Spanish public sources and published literature. A 3% discount rate for costs and benefits was applied. One-way sensitivity and scenario analyses, and probabilistic sensitivity analysis (PSA), were performed. Results: FF/UMEC/VI treatment led to fewer moderate and severe exacerbations (2.126 and 0.306, respectively) vs BUD/FOR (2.608 and 0.515, respectively), with a mean incremental cost of 69 and gain of 0.107 QALYs, which resulted in an ICER of 642 per QALY gained. In sensitivity analyses, the ICER was most sensitive to treatment effect variations in exacerbations and healthcare resource utilization/event costs. Overall, 95% of 1000 PSA simulations resulted in an ICER less than 11,000 per QALY gained for FF/UMEC/VI vs BUD/FOR, confirming robustness of the results. The probability of FF/UMEC/VI being cost-effective vs BUD/FOR was 100% at a willingness-to-pay threshold of 30,000 per QALY gained. Conclusion: At the accepted Spanish ICER threshold of 30,000, FF/UMEC/VI represents a cost-effective treatment option vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Androstadienos/uso terapêutico , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Análise Custo-Benefício , Combinação de Medicamentos , Humanos , Nebulizadores e Vaporizadores , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
INTRODUCTION: Assessing clinically important measures of disease progression is essential for evaluating therapeutic effects on disease stability in chronic obstructive pulmonary disease (COPD). This analysis assessed whether providing additional bronchodilation with the long-acting muscarinic antagonist umeclidinium (UMEC) to patients treated with inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy would improve disease stability compared with ICS/LABA therapy alone. METHODS: This integrated post hoc analysis of four 12-week, randomized, double-blind trials (NCT01772134, NCT01772147, NCT01957163, NCT02119286) compared UMEC 62.5 µg with placebo added to open-label ICS/LABA in symptomatic patients with COPD (modified Medical Research Council dyspnea scale score ≥ 2). A clinically important deterioration (CID) was defined as: a decrease from baseline of ≥ 100 mL in trough forced expiratory volume in 1 s (FEV1), an increase from baseline of ≥ 4 units in St George's Respiratory Questionnaire (SGRQ) total score, or a moderate/severe exacerbation. Risk of a first CID was evaluated in the intent-to-treat (ITT) population and in patients stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) classification, exacerbation history and type of ICS/LABA therapy. Adverse events (AEs) were also assessed. RESULTS: Overall, 1637 patients included in the ITT population received UMEC + ICS/LABA (n = 819) or placebo + ICS/LABA (n = 818). Additional bronchodilation with UMEC reduced the risk of a first CID by 45-58% in the ITT population and all subgroups analyzed compared with placebo (all p < 0.001). Improvements were observed in reducing FEV1 (69% risk reduction; p < 0.001) and exacerbation (47% risk reduction; p = 0.004) events in the ITT population. No significant reduction in risk of a SGRQ CID was observed. AE incidence was similar between treatment groups. CONCLUSION: Symptomatic patients with COPD receiving ICS/LABA experience frequent deteriorations. Additional bronchodilation with UMEC significantly reduced the risk of CID and provided greater short-term stability versus continued ICS/LABA therapy in these patients. FUNDING: GlaxoSmithKline (study number: 202067). Plain language summary available for this article.
Assuntos
Álcoois Benzílicos , Clorobenzenos , Combinação Fluticasona-Salmeterol , Volume Expiratório Forçado/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica , Quinuclidinas , Idoso , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Progressão da Doença , Método Duplo-Cego , Feminino , Combinação Fluticasona-Salmeterol/administração & dosagem , Combinação Fluticasona-Salmeterol/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicamentos para o Sistema Respiratório/administração & dosagem , Medicamentos para o Sistema Respiratório/efeitos adversos , Prevenção Secundária/métodos , Avaliação de Sintomas/métodos , Resultado do TratamentoRESUMO
PURPOSE: To compare the efficacy and safety of two long-acting dual bronchodilator combinations: indacaterol/glycopyrrolate (IND/GLY) versus umeclidinium/vilanterol (UMEC/VI). METHODS: Studies A2349 and A2350 were replicate, randomized, double-blind, double-dummy, active-controlled, cross-over studies in patients with moderate-to-severe COPD. Patients were randomized to sequential 12-week treatments of twice-daily IND/GLY 27.5/15.6 µg and once-daily UMEC/VI 62.5/25 µg, each separated by a 3-week washout. The primary objective was to demonstrate non-inferiority of IND/GLY compared with UMEC/VI in terms of the 24-h forced expiratory volume in 1 s profile at week 12 (FEV1 AUC0-24). Rescue medication use, symptom control, and safety were assessed throughout. RESULTS: Both treatments delivered substantial bronchodilation over 12 weeks, with improvements in FEV1 AUC0-24h at week 12 of 232 and 185 mL for IND/GLY, and 244 and 203 mL with UMEC/VI in Studies A2349 and A2350, respectively. The primary efficacy objective of non-inferiority of IND/GLY relative to UMEC/VI was not met as the lower bound of the confidence interval for the LS treatment comparison was below the pre-specified non-inferiority margin of -20 mL in both studies: -26.9 and -34.2 mL, respectively (LS mean between-treatment differences: -11.5 and -18.2 mL). Both drugs were well tolerated, with AE profiles consistent with their respective prescribing information. CONCLUSIONS: IND/GLY and UMEC/VI provided clinically meaningful and comparable bronchodilation. Non-inferiority of IND/GLY to UMEC/VI could not be declared although between-treatment differences were not clinically relevant. The data support the use of IND/GLY as an efficacious and well tolerated treatment option in patients with COPD. (ClinicalTrials.gov NCT02487446 and NCT02487498).
Assuntos
Álcoois Benzílicos/uso terapêutico , Broncodilatadores/uso terapêutico , Clorobenzenos/uso terapêutico , Glicopirrolato/uso terapêutico , Indanos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Quinuclidinas/uso terapêutico , Idoso , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Glicopirrolato/efeitos adversos , Humanos , Indanos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinolonas/efeitos adversos , Quinuclidinas/efeitos adversos , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The contribution of fluticasone furoate (FF) on lung function in the FF/vilanterol (VI) 100/25 µg combination has been demonstrated numerically, but not statistically. METHODS: This multicentre, randomised, double-blind, controlled trial (GlaxoSmithKline study number 200820; clinicaltrials.gov NCT02105974) enrolled ≥40-year-old patients with chronic obstructive pulmonary disease (COPD), a ≥10-pack-year smoking history, a post-bronchodilator forced expiratory volume in 1 s (FEV1) 30-70% of the predicted value, a FEV1/forced vital capacity ratio of ≤0.70, ≥1 COPD exacerbation in the previous 12 months requiring corticosteroids, antibiotics and/or hospitalisation, and current COPD symptoms. Participants received FF/VI 100/25 µg or VI 25 µg once daily. The primary endpoint was the change from baseline in trough FEV1 at day 84. FINDINGS: 1620 patients were randomised and received at least one dose of FF/VI 100/25 µg (n = 806) or VI 25 µg (n = 814). At day 84, the FF/VI 100/25 µg group showed an adjusted mean treatment difference of 34 mL over VI 25 µg in change from baseline trough FEV1 (95% confidence interval [CI] 14-55; p = 0.001). There was no significant difference between the groups in the percentage of rescue medication-free 24-h periods. The FF/VI 100/25 µg group demonstrated a 42% risk reduction compared with the VI 25 µg group in time to first moderate/severe COPD exacerbation (95% CI 22-57; nominal p < 0.001). The incidence of on-treatment adverse events was similar between the groups. INTERPRETATION: The contribution of FF in the FF/VI 100/25 µg combination on lung function in COPD was statistically significant. FUNDING: GlaxoSmithKline.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Clorobenzenos/uso terapêutico , Glucocorticoides/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Idoso , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de VidaRESUMO
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular morbidity and mortality. Elevated arterial stiffness, measured by aortic pulse wave velocity (aPWV), is a cardiovascular risk surrogate and is potentially modifiable by inhaled corticosteroid/long-acting beta2-agonist combinations in patients with COPD. MATERIALS AND METHODS: The effects of once-daily inhaled fluticasone furoate/vilanterol (FF/VI) 100/25 µg, VI 25 µg, versus placebo on arterial stiffness in patients with COPD and baseline aPWV ≥11.0 m/s were investigated in a 24-week, multicenter, double-blind, randomized, stratified (by COPD exacerbation history), parallel-group, placebo-controlled trial. Eligible patients were ≥40 years old, with ≥10 pack-year smoking history, forced expiratory volume in 1 s (FEV1)/forced vital capacity ≤0.70, and post-bronchodilator FEV1 ≤70% of predicted. Patients with a major cardiovascular event in the previous 6 months/current severe heart failure/uncontrolled hypertension were excluded. Primary endpoint is change from baseline in aPWV after 24 weeks of treatment. Safety analyses included adverse events (AEs). RESULTS: The intent-to-treat population included 430 patients: FF/VI (n=135), VI (n=154), and placebo (n=141). Patients were predominantly male (79%) and Asian or White (each 48%), with a mean age of 68.5 years (standard deviation [SD] =7.9), percentage predicted post-bronchodilator FEV1 50.1% (SD =13.3), and aPWV 13.26 m/s (SD =2.22) at screening. At 24 weeks, mean (standard error [SE]) changes from baseline in aPWV were -1.75 m/s (SE =0.26, FF/VI), -1.95 m/s (SE =0.24, VI), and -1.97 m/s (SE =0.28, placebo). AEs occurred in 57% (FF/VI), 51% (VI), and 41% (placebo) of patients. CONCLUSION: No differences were observed in aPWV-adjusted mean change from baseline for FF/VI 100/25 µg, compared with placebo.
Assuntos
Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos , Administração por Inalação , Idoso , Androstadienos/efeitos adversos , Ásia , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Europa (Continente) , Feminino , Volume Expiratório Forçado , Humanos , Análise de Intenção de Tratamento , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Análise de Onda de Pulso , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Capacidade VitalRESUMO
COPD is characterized by persistent airflow obstruction caused by exposure to irritants including cigarette smoke, dust, and fumes. According to the latest GOLD (Global Initiative for Chronic Obstructive Lung Disease) guidelines, a combination of inhaled corticosteroids, long-acting ß2 agonists, and long-acting muscarinic receptor antagonists can be used for group D COPD patients who are at high risk for exacerbations. Umeclidinium/fluticasone furoate/vilanterol is one such triple-combination therapy currently under development with some completed and several ongoing clinical trials. This review paper summarizes the pharmacologic profiles of these medications and highlights findings from clinical trials, including safety and efficacy data, while speculating on the role of this therapy in current treatment for COPD.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Glucocorticoides/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Androstadienos/efeitos adversos , Animais , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Ensaios Clínicos como Assunto/métodos , Combinação de Medicamentos , Glucocorticoides/efeitos adversos , Humanos , Pulmão/fisiopatologia , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/efeitos adversos , Recuperação de Função Fisiológica , Projetos de Pesquisa , Resultado do TratamentoRESUMO
BACKGROUND: Current guidelines recommend the use of inhaled corticosteroids/long-acting beta2-agonists as first-line therapy for COPD patients at risk for acute exacerbations and/or severe airflow limitation. This systematic review assesses available evidence on the efficacy and safety of fluticasone furoate/vilanterol (FF/VI) combination versus each alone, for the treatment of patients with severe to very severe stable COPD. METHODS: Randomized, placebo-controlled trials of >8 weeks of duration were included. Primary end points were pulmonary function, COPD exacerbations and serious adverse events. FF/VI was compared with its mono-components. RESULTS: Five reports with six trials (n = 15,515 patients) met the entry criteria. FF/VI was associated with significant increases in trough FEV1 compared with vilanterol (VI) and fluticasone furoate (FF) (45 mL and 90 mL respectively). FF/VI significantly reduced the number of subjects with at least one moderate to severe exacerbation compared with VI (number needed to treat for benefit [NNTB] = 21) and with FF (NNTB = 26). There were no statistical differences in the rates of serious adverse events, cardiac events and all-cause mortality. On the contrary, FF/VI showed a significant 52% increase in the rate of pneumonia compared with VI monotherapy (5.3% vs. 3.5%). However, there was no difference in the rate of pneumonia when FF/VI was compared with FF alone. CONCLUSIONS: FF/VI combination was associated with a decrease of the rate of COPD exacerbations, without affecting mortality or cardiovascular outcomes in patients with moderate to severe stable COPD. Also, the use of FF was associated with an increased risk of pneumonia.
Assuntos
Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Clorobenzenos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Broncodilatadores/uso terapêutico , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Combinação de Medicamentos , Humanos , Pneumonia/epidemiologia , Guias de Prática Clínica como Assunto , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de DoençaRESUMO
BACKGROUND: New treatments need to be evaluated in real-world clinical practice to account for co-morbidities, adherence and polypharmacy. METHODS: Patients with chronic obstructive pulmonary disease (COPD), ≥ 40 years old, with exacerbation in the previous 3 years are randomised 1:1 to once-daily fluticasone furoate 100 µg/vilanterol 25 µg in a novel dry-powder inhaler versus continuing their existing therapy. The primary endpoint is the mean annual rate of COPD exacerbations; an electronic medical record allows real-time collection and monitoring of endpoint and safety data. CONCLUSIONS: The Salford Lung Study is the world's first pragmatic randomised controlled trial of a pre-licensed medication in COPD. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01551758.
Assuntos
Androstadienos/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Glucocorticoides/administração & dosagem , Pulmão/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Adulto , Aerossóis , Androstadienos/efeitos adversos , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Protocolos Clínicos , Progressão da Doença , Esquema de Medicação , Combinação de Medicamentos , Inaladores de Pó Seco , Registros Eletrônicos de Saúde , Inglaterra , Feminino , Glucocorticoides/efeitos adversos , Humanos , Pulmão/fisiopatologia , Masculino , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Projetos de Pesquisa , Fatores de Tempo , Resultado do TratamentoRESUMO
An intake of C14 in the form of dichlorobenzene was followed up with 90 spot urine samples over a period of almost 2 weeks. This dataset has been fitted by a model consisting of three exponential terms. The intake and effective dose have been calculated. This case has been used to examine the effects of recent proposals by ICRP concerning the calculation of effective dose and the use of non-standard biokinetic models.
Assuntos
Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Administração por Inalação , Poluentes Ocupacionais do Ar/efeitos adversos , Poluentes Ocupacionais do Ar/urina , Poluentes Radioativos do Ar/efeitos adversos , Poluentes Radioativos do Ar/urina , Radioisótopos de Carbono/urina , Clorobenzenos/urina , Feminino , Humanos , Cinética , Modelos Biológicos , Exposição Ocupacional/efeitos adversos , Doses de Radiação , Monitoramento de RadiaçãoRESUMO
BACKGROUND: Fluticasone furoate (FF)/vilanterol (VI) is a novel once-daily inhaled corticosteroid/long-acting ß2-agonist combination therapy for COPD. We aimed to assess the efficacy and safety of two strengths of FF/VI (100/25 µg; 50/25 µg) vs. individual components (FF 100 µg, VI 25 µg) and placebo over 24 weeks. METHODS: Multicentre, randomised, placebo-controlled, double-blind, parallel-group study of patients (N = 1030) with moderate-to-severe COPD. All medication was administered once daily in the morning. Co-primary efficacy endpoints were: (1) weighted mean (wm) FEV1 (0-4 h post-dose on day 168) to assess acute lung function effects; and (2) trough FEV1 (23-24 h post-dose on day 169) to assess long-lasting effects. Symptom-related outcomes were analysed and adverse events (AEs) assessed. RESULTS: Main findings were: (1) the combination of FF/VI at a strength of 100/25 µg significantly (p < 0.001) improved wm FEV1 (173 ml) and trough FEV1 (115 ml) vs. placebo. Similar effects were observed with FF/VI 50/25 µg; (2) no significant difference was seen between FF/VI 100/25 µg and VI 25 µg for trough FEV1 (48 ml, p = 0.082), while an effect was observed between FF/VI 100/25 µg and FF 100 µg for wm FEV1 (120 ml, p < 0.001); (3) VI 25 µg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 (103 ml, p < 0.001) and trough FEV1 (67 ml, p = 0.017); and (4) no safety signal was observed. CONCLUSIONS: In subjects with moderate-to-severe COPD, FF/VI 100/25 µg provides rapid and significant sustained bronchodilation at 24 weeks. Lung function is improved to a similar extent with FF/VI 50/25 µg and to a somewhat lesser extent with VI 25 µg. All treatments were well tolerated. GSK study number: HZC112206. ClinicalTrials.gov: NCT01053988.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Broncodilatadores/uso terapêutico , Clorobenzenos/uso terapêutico , Glucocorticoides/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Clorobenzenos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting ß(2) agonist is more protective than a once-daily longacting ß(2) agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone. METHODS: We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 µg vilanterol alone or 25 µg vilanterol combined with either 50 µg, 100 µg, or 200 µg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952). FINDINGS: 1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 µg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7-1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 µg and 100 µg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 µg group, 0·0244 for the 100 µg group, and 0·0004 for the 200 µg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 µg group, <0·0001 for the 100 µg group, and 0·0003 for the 200 µg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group. INTERPRETATION: Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk. FUNDING: GlaxoSmithKline.
Assuntos
Androstadienos , Álcoois Benzílicos , Clorobenzenos , Pneumonia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Sistema Respiratório/efeitos dos fármacos , Administração por Inalação , Idoso , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Monitoramento de Medicamentos , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/epidemiologia , Pneumonia/etiologia , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória/métodos , Sistema Respiratório/fisiopatologia , Medição de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Umeclidinium (UMEC; GSK573719) is a new long-acting muscarinic antagonist (LAMA) currently in development in combination with vilanterol (VI), an inhaled, long-acting beta2 agonist for the treatment of chronic obstructive pulmonary disease (COPD). The primary aim of this study was to evaluate the safety and tolerability of repeat dosing of UMEC and VI in combination once daily for 28 days in patients with COPD. METHODS: This was a multicenter, double-blind, placebo-controlled, parallel group study. Patients aged ≥40 years with post-bronchodilator FEV1 ≤80% of predicted normal values and FEV1/FVC ratio ≤0.70, and a smoking history of ≥10 pack-years, were randomized 4:1 to once-daily UMEC/VI (500/25 mcg; n = 42) or placebo (n = 9). RESULTS: UMEC/VI was non-inferior to placebo in weighted mean pulse rate over 0-6 h at Day 28 (primary endpoint: difference of -0.5 bpm, 95% CI: -5.5 to 4.5). There was no evidence of a difference between UMEC/VI compared with placebo in blood pressure, minimum and maximum pulse rate, or QTcF assessments. Adverse events (AEs) were reported by 11 (26%) patients in the UMEC/VI group and one (11%) patient in the placebo group. No serious AEs were reported. Both UMEC and VI showed rapid absorption (median t(max) â¼6 min for both drugs) with no evidence of accumulation for AUC or C(max) on Day 28 compared with Day 1 for UMEC or VI. There was no correlation between individual steady-state C(max) and pulse rate on Day 28. Change from baseline in trough FEV1 on Day 29 showed numerically greater improvements with UMEC/VI compared with placebo. CONCLUSION: Once-daily dosing with UMEC in combination with VI in patients with moderate-to-very-severe COPD was well tolerated over 28 days.
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Álcoois Benzílicos/uso terapêutico , Clorobenzenos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/uso terapêutico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Álcoois Benzílicos/administração & dosagem , Álcoois Benzílicos/efeitos adversos , Clorobenzenos/administração & dosagem , Clorobenzenos/efeitos adversos , Preparações de Ação Retardada , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The treatment of atrophic scars is difficult and dermal filler materials provide a simple alternative with immediate results. Esthélis® is an injectable non-animal crosslinked hyaluronic acid of Swiss origin characterized by a polydense cohesive matrix (CPM®) which produces a gel of uniform consistency with better biointegration to the tissues and a longer duration. OBJECTIVE: To evaluate Esthélis in the treatment of atrophic scars. PATIENTS AND METHODS: Twelve patients aged 18-56 years with facial atrophic scars caused by acne vulgaris, dog bite, piercing, basal cell carcinoma and leishmaniasis were treated with Esthélis. The injection technique was linear threading, serial puncture or a combination of both. Clinical efficacy was assessed independently by the authors and by patients immediately, one week and one month after the injection. Adverse events were registered. RESULTS: Authors described the results as moderate (27%), good (57%) and excellent (17%), immediately, one week and one month after the injection. Patients evaluated the cosmetic improvement as good (42%) or excellent (58%) one month after the treatment. Pain during the injection was described as slight or moderate. Only mild erythema was observed immediately after injection, which spontaneously resolved within few hours. CONCLUSION: Esthélis showed good or excellent results in most patients with atrophic scars, and these were perceived as even better when patients evaluated the cosmetic improvement. The best results were observed in patients with more deforming scars such as surgical scars or trauma.
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Carcinoma Basocelular/tratamento farmacológico , Clorobenzenos/uso terapêutico , Cicatriz/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Face , Ácido Hialurônico/uso terapêutico , Sulfetos/uso terapêutico , Acne Vulgar/complicações , Acne Vulgar/patologia , Adulto , Atrofia , Carcinoma Basocelular/complicações , Carcinoma Basocelular/patologia , Clorobenzenos/efeitos adversos , Cicatriz/patologia , Cicatriz/cirurgia , Técnicas Cosméticas/efeitos adversos , Excipientes , Humanos , Ácido Hialurônico/efeitos adversos , Injeções , Pessoa de Meia-Idade , Punções , Sulfetos/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
The relationship between exposure to p-dichlorobenzene (p-DCB) and urinary excretion of 2,5-dichlorophenol (2,5-DCP), the major metabolite of p-DCB, was examined to evaluate the usefulness of the metabolite as a biological index for low-level exposure of p-DCB in the general population. Personal exposure concentrations of p-DCB and concentrations of 2,5-DCP excreted in the urine of 119 adults living in Osaka were determined. Airborne p-DCB was collected for 24 h by passive gas sampling tubes packed with charcoal. The tubes were exchanged every 12 h. The sampling was started immediately after the subject woke up in the morning (7 A.M.). The collected p-DCB was desorbed with toluene and measured using a gas chromatograph with an electron capture detector (GC-ECD). On the other hand, the first morning urine samples were collected at the endpoint of airborne p-DCB sampling (7 A.M. the next morning). The urine samples were hydrolyzed with concentrated sulfuric acid. 2,5-DCP in the hydrolysates was extracted with n-hexane and measured by GC-ECD. Both p-DCB and 2,5-DCP were detected in more than 99% of the air and urine samples, respectively, from the participants. The median of p-DCB exposure concentrations for 24 h was 2.5 ppb, with a maximum concentration of 33.3 ppb. The median of urinary 2,5-DCP concentrations was 0.39 mg/g creatinine, with the maximum concentration of 3.32 mg/g creatinine. The regression line between the urinary 2,5-DCP concentration (y) and the p-DCB exposure concentration (x) was y = 0.080 x + 0.181, with the Pearson correlation coefficient of 0.81 (p < 0.001), demonstrating a strong association between these measurements. Consequently, urinary 2,5-DCP should be suitable as an index for monitoring low-level exposure of p-DCB in the general population.
Assuntos
Carcinógenos/análise , Clorobenzenos/análise , Clorofenóis/urina , Exposição Ambiental , Adulto , Biomarcadores/análise , Carcinógenos/efeitos adversos , Clorobenzenos/efeitos adversos , Clorobenzenos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Urinálise/métodosAssuntos
Carcinógenos/efeitos adversos , Clorobenzenos/efeitos adversos , Inseticidas/efeitos adversos , Animais , Exposição Ambiental , Estudos Epidemiológicos , Feminino , Humanos , Masculino , Camundongos , Neoplasias/induzido quimicamente , Neoplasias Experimentais/induzido quimicamente , Exposição Ocupacional , RatosRESUMO
o-Dichlorobenzene (o-DCB) is used as an organic solvent, as a chemical intermediate, and as a heat transfer medium. In humans, o-DCB is metabolized to 2,3- and 3,4-dichlorophenols, and 3,4- and 4,5-dichlorocatechols, and these metabolites are eliminated via the kidneys. In this study, we tried to determine the concentrations of urinary 2,3- and 3,4-dichlorophenols using a gas chromatograph (GC). When control urine specimens were spiked at concentrations of 10, 20 and 40 mg/l, the mean recovery rates of 2,3- and 3,4-dichlorophenols were 98.3 to 101.9% (CV = 4.0 to 4.8%) and 100.6 to 105.4% (CV = 2.5 to 7.0%), respectively. Next, urine samples collected from ten male workers exposed to o-DCB were analyzed. The concentrations of urinary 2,3- and 3,4-dichlorophenols determined by the GC method closely agreed with those by the HPLC method, which we had developed in a previous study, and these metabolite concentrations were linearly correlated to the 8-h TWA values of o-DCB in the range of 0.1 to 2.3 ppm. Consequently, the GC method can be used for biological monitoring of o-DCB, though it is necessary that the linear relation is confirmed in a higher range of exposure.
Assuntos
Clorobenzenos/metabolismo , Clorofenóis/urina , Exposição Ocupacional , Poluentes Ocupacionais do Ar , Clorobenzenos/efeitos adversos , Cromatografia Gasosa , Humanos , Masculino , Análise de RegressãoRESUMO
The acute toxicity of a number of chlorinated benzenes, ranging from monosubstituted to pentasubstituted benzenes, was studied in rats. Toxic effects on the liver, the kidneys, and the thyroid were monitored after a single ip administration of 1, 2, or 4 mmol/kg monochlorobenzene (MCB), 1,2-dichlorobenzene (1,2-DICB), 1,4-dichlorobenzene (1,4-DICB), 1,2,4-trichlorobenzene (1,2,4-TRCB), and pentachlorobenzene (PECB). Due to its low solubility, 1,2,4,5-tetrachlorobenzene (1,2,4,5-TECB) was tested at a highest dose of 0.8 mmol/kg. 1,2-DICB and 1,2,4-TRCB produced the most severe hepatotoxic effects when compared with an equimolar dose of the other chlorinated benzenes, as determined by plasma ALT profile and histopathological changes after 72 hr. MCB was considerably less hepatotoxic. Severe degenerative damage to the kidney was only observed in a few rats treated with 1,2,4-TRCB. However, protein droplets in the tubular epithelial cells were observed at 72 hr after administration of 1,4-DICB, 1,2,4-TRCB, 1,2,4,5-TECB, and PECB. In the latter two groups, these protein droplets were still observed 9 days after administration. All chlorinated benzenes tested excluding MCB induced a reduction in plasma thyroxine levels. The extent of decrease in plasma thyroxine was more severe in rats treated with 1,2,4-TRCB or PECB and correlated well with the relative binding affinities of the phenolic metabolites to the plasma transport protein for thyroxine, i.e., transthyretin. The present study indicates that the establishment of a structure-activity relationship with regard to toxicity depends on the sensitivity of the respective target organs. In the series of (poly)chlorinated benzenes studied, ranging from mono- to pentachlorobenzene, the most severe effects on liver, kidney, and thyroid were observed for 1,2,4-substitution.