RESUMO
BACKGROUND: Currently, data on the possible synergy of adding a LAMA to ICS/LABA combination are missing and no studies assessed whether triple therapy may induce ceiling bronchodilator effect. A translational study was performed to investigate the interaction between glycopyrronium bromide (GB) and beclomethasone dipropionate (BDP)/formoterol fumarate (FF) combination in human isolated airways and the effect on FEV1 and small airway resistance of BDP/FF/GB in COPD. METHODS: The interaction of adding GB to BDP/FF combination was tested in vitro in medium and small airways via Bliss, Loewe, and Highest Single Agent models. The peak and trough effect on FEV1 and R5-R19 of salbutamol on top of BDP/FF/GB 100/6/12.5 µg FDC via extrafine formulation was investigated in severe COPD patients after two weeks of treatment. RESULTS: GB plus BDP/FF elicited significant synergistic bronchorelaxation in medium and small isolated airways (overall maximal effect: +32% vs. additive effect). No significant (P > 0.05) improvement in R5-R19 was detected when salbutamol was administered on top of BDP/FF/GB 100/6/12.5 µg FDC (peak -0.12 ± 0.22 cmH2O/L/s, trough -0.23 ± 0.25 cmH2O/L/s). Salbutamol significantly (P < 0.01) increased FEV1 when administered on top of triple FDC (peak +145 ± 119 ml, trough +221 ± 111 ml). CONCLUSION: The synergistic interaction detected in vitro when adding GB to BDP/FF combination may lead to ceiling bronchorelaxation of small airways in vivo, an effect that may improve hyperinflation in subjects with small airway disease and, thus, explain the substantial clinical benefits of triple combination therapy administered via extrafine formulation in severe COPD patients. STUDY REGISTRATION: ISRCTN94089001.
Assuntos
Beclometasona , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Beclometasona/uso terapêutico , Broncodilatadores/uso terapêutico , Combinação de Medicamentos , Fumarato de Formoterol/uso terapêutico , Glicopirrolato/uso terapêutico , Humanos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Resultado do TratamentoAssuntos
Líquido da Lavagem Broncoalveolar/química , Broncoscopia/métodos , Infecções por Coronavirus/diagnóstico , Pulmão/diagnóstico por imagem , Nasofaringe/virologia , Pneumonia Viral/diagnóstico , RNA Viral/análise , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , COVID-19 , Teste para COVID-19 , Técnicas de Laboratório Clínico , Proteínas do Envelope de Coronavírus , Proteínas do Nucleocapsídeo de Coronavírus , RNA-Polimerase RNA-Dependente de Coronavírus , Diagnóstico Diferencial , Feminino , Humanos , Pneumopatias Fúngicas/diagnóstico , Masculino , Pessoa de Meia-Idade , Nasofaringe/química , Proteínas do Nucleocapsídeo/genética , Pandemias , Fosfoproteínas , Pneumonia Bacteriana/diagnóstico , Pneumonia Pneumocócica/diagnóstico , RNA Polimerase Dependente de RNA/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SARS-CoV-2 , Sensibilidade e Especificidade , Infecções Estafilocócicas/diagnóstico , Tomografia Computadorizada por Raios X , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genéticaRESUMO
INTRODUCTION: Inhaled corticosteroids are the cornerstone for the treatment of stable asthma, however, when disease severity increases, escalating therapy to combinations of drugs acting on distinct signalling pathways is required. It is advantageous to providing evidence of a synergistic interaction across drug combinations, as it allows optimizing bronchodilation while lowering the dose of single agents. In the respiratory pharmacology field, two statistical models are accepted as gold standard to characterize drug interactions, namely the Bliss Independence criterion and the Unified Theory. In this review, pharmacological interactions across drugs approved for the treatment of asthma have been systematically assessed. EVIDENCE ACQUISITION: A comprehensive literature search was performed in MEDLINE for studies that used a validated pharmacological method for assessing drug interaction. The results were extracted and reported via qualitative synthesis. EVIDENCE SYNTHESIS: Overall, 45 studies were identified from literature search and 5 met the inclusion criteria. Current evidence coming from ex-vivo models of asthma indicates that drug combinations modulating bronchial contractility induce a synergistic bronchorelaxant effect. In murine models of lung inflammation, the combination between inhaled corticosteroids and ß
Assuntos
Corticosteroides , Agonistas de Receptores Adrenérgicos beta 2 , Asma , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Animais , Asma/tratamento farmacológico , Brônquios , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , CamundongosRESUMO
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) therapy includes a multi-dimensional approach, taking into account both symptoms of the patient and the number of acute exacerbations of COPD (AECOPDs). There are three main pharmaceutical classes currently available including long-acting muscarinic antagonists (LAMA), long-acting ß2-agonists (LABA) and inhaled corticosteroids (ICS). COPD is a major risk factor for most cardiovascular diseases, and cardiac comorbidities are very common in COPD patients. Both LAMA and LABA have a considerable impact on cardiac function by stimulating cardiac ß2-adrenergic receptors or inhibiting the heart M2 muscarinic receptors. ICS alone or in combination has never been associated with a real cardiovascular risk. AREAS COVERED: This review explores the data published on the safety of COPD therapy and the implications for current pharmacotherapy. EXPERT OPINION: Several studies have confirmed the good safety profile of bronchodilators available both in monotherapy and in association with other bronchodilators of different classes or with ICS despite the device used. Cardiovascular events in clinical trials are generally low and balanced between groups. The actual cardiovascular risk of fixed-dose combinations (FDCs) in an unselected COPD population will need to be investigated through post-marketing surveillance studies and observational studies.