What have we learned from large drug treatment trials in COPD?

Calverley, Peter M.A.; Rennard, Stephen I.

doi:10.1016/s0140-6736(07)61381-6

Cited by 55 publications

(31 citation statements)

References 101 publications

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“…Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and with more severe exacerbations. A reduction in AECOPDs has been reported for LABAs, LAMAs, ICSs, and their combinations, as well as theophylline (3,(11)(12)(13)(14)(15)(16)81). We do not have a clear understanding of the mechanism by which any of these agents affects the frequency of AECOPDs.…”

Section: Discussionmentioning

confidence: 97%

“…Apart from that potential outcome, a reduction in AECOPDs is highly desirable in order to reduce the significant morbidity, mortality, and expense associated with these major events. The achievable reduction in exacerbations is limited with currently available COPD therapies: long-acting β 2 agonists ((LABA)s; [3,11,12]), long-acting muscarinic antagonists ((LAMA)s; [3,13]), ICSs (13)(14)(15)(16), and their combinations. A therapy that further reduces AECOPDs would be desirable.…”

Section: Introductionmentioning

confidence: 99%

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Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

Gross

Giembycz

Rennard

2010

COPD: Journal of Chronic Obstructive Pulmonary Disease

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Recent advances in chronic obstructive pulmonary disease (COPD) treatment offer symptom relief, but disease modification remains an unmet goal of pharmacotherapy. Reducing the frequency and severity of COPD exacerbations may help slow disease progression and reduce the morbidity, mortality, and costs associated with these major events. Other desirable characteristics for a COPD treatment include a once-daily dosing schedule, an oral formulation, and a low frequency of systemic side effects. Phosphodiesterase 4 inhibitors have been in clinical development for some years and roflumilast is currently the most advanced of these agents. In this review, the preclinical evidence, clinical safety, and efficacy of roflumilast available in published reports are considered. The data reviewed here suggest that the clinical efficacy of roflumilast occurs through a mechanism unrelated to bronchodilation and may be due to the suppression of lung inflammation. Lung function improved with roflumilast treatment and in some studies, the reduction in exacerbations was substantial and statistically significant. Notably, this effect appeared to be greatest in the subgroup of patients with more severe disease and more severe exacerbations. The evaluation of roflumilast safety largely centers on gastrointestinal adverse events, with diarrhea, nausea, and weight loss occurring more frequently with the drug than placebo. If approved for general use, we expect roflumilast to find its role initially as a substitute for inhaled corticosteroids in the maintenance treatment of severe and very severe disease, particularly in patients who have frequent acute exacerbations, and perhaps as a supplementary drug when symptoms are not adequately controlled by current conventional COPD therapy.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

Gross

Giembycz

Rennard

2010

COPD: Journal of Chronic Obstructive Pulmonary Disease

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“…These proteinases contribute to the degradation of extracellular matrix components and eventually to the development of emphysema. However, anti-inflammatory agents or antioxidants only reduce the symptoms, and they do not affect the decline in FEV1 [6] . Thus, further investigation is needed to understand the mechanisms underlying the pathogenesis of emphysema.…”

Section: Introductionmentioning

confidence: 98%

Interleukin-17A is involved in development of spontaneous pulmonary emphysema caused by Toll-like receptor 4 mutation

et al. 2011

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Aim: To explore the pathogenic role of Th17 cells and interleukin-17A (IL-17A)-associated signaling pathways in spontaneous pulmonary emphysema induced by a Toll-like receptor 4 mutant (TLR4 mut ). Methods: Lungs were obtained from wild-type (WT) or TLR4 mut mice that were treated with or without recombinant mouse IL-17A (1 μg·kg, ip) from the age of 3 weeks to 3 months. Pulmonary emphysema was determined using histology, immunochemistry, and biochemical analysis. T cell polarization was determined with flow cytometry, the levels of cytokines were measured using ELISA, and the levels of IL-17A-associated signaling molecules were detected using Western blot. Results: Compared to WT mice, 3 month-old TLR4 mut mice were characterized by significantly reduced infiltration of Th17 cells into lungs (2.49%±1.13% νs 5.26%±1.39%), and significantly reduced expression levels of IL-17A (3.66±0.99 pg/μg νs 10.67±1.65 pg/μg), IL-23 (12.43±1.28 pg/μg νs 28.71±2.57 pg/μg) and IL-6 (51.82±5.45 pg/μg νs 92.73±10.91 pg/μg) in bronchoalveolar lavage fluid. In addition, p38 MAPK phosphorylation and AP-1 expression were decreased to 27%±9% and 51%±8%, respectively, of that in WT mice. Treatment of TLR4 mut mice with IL-17A increased the infiltration of Th17 cells into lungs and expression levels of IL-17A, IL-6, and IL-23 in bronchoalveolar lavage fluid, attenuated MDA and apoptosis, and improved emphysema accompanied with increased phosphorylation of p38 MAPK and expression of AP-1. Conclusion: Th17 cells, in particular the cytokine IL-17A, play a crucial role in the pathogenesis of TLR4 mut -induced spontaneous pulmonary emphysema. Both of them are potential targets for therapeutic strategies for pulmonary emphysema.

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“…The conduct and outcomes of these large scale randomised controlled trials have been reviewed previously 2,3 and some general conclusions have been drawn about them. A recent series of review articles in the New England Journal of Medicine provides many insights into issues of trial design and conduct 4 , although the only large-scale respiratory trial to be mentioned is the Toward a Revolution in COPD Health (TORCH) study 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Chronic Obstructive Pulmonary Disease: Lessons from the Important Treatment Trials

Calverley¹,

Walker²

2017

BRN

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Since 1999, clinical trials have more precisely defined the impact of various treatments on important patient-centred outcomes, allowing the development of treatment guidelines and leading to personalised treatment. The use of larger populations, seen in the Toward a Revolution in COPD Health (TORCH), Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) and The Study to Understand Mortality and Morbidity (SUMMIT) trials, has allowed hypotheses to be answered clearly albeit not always positively. Notwithstanding, each study has provided important information, often through secondary outcomes, which have been prospectively tested in other trials. Nearly two decades on, we are clearer as to the role of lung volume reduction procedures, who should and shouldn't be prescribed inhaled steroids and long-acting bronchodilators and in what combinations, and who may benefit from roflumilast. Unexpected findings such as pneumonia risk from inhaled steroids and use of eosinophil count to direct their use have an important clinical impact now and in the future. (BRN Rev. 2017;3:286-98)

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What have we learned from large drug treatment trials in COPD?

Cited by 55 publications

References 101 publications

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

Treatment of Chronic Obstructive Pulmonary Disease with Roflumilast, a New Phosphodiesterase 4 Inhibitor

Interleukin-17A is involved in development of spontaneous pulmonary emphysema caused by Toll-like receptor 4 mutation

Chronic Obstructive Pulmonary Disease: Lessons from the Important Treatment Trials

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