Pharmacology of novel treatments for COPD: are fixed dose combination LABA/LAMA synergistic?

Abstract

Bronchodilators are mainstay for the symptomatic treatment of chronic obstructive pulmonary disease (COPD) and the introduction of long-acting bronchodilators has led to an improvement in the maintenance treatment of this disease. Various clinical trials have evaluated the effects of fixed dose long-acting β2-agonists (LABA)/long-acting anti-muscarinics (LAMA) combinations and documented greater improvements in spirometry but such improvements do not always translate to greater improvements in symptom scores or reduction in the rates of exacerbation compared with a single component drug. An analysis of whether this significantly greater change in spirometry with combination therapy is additive or synergistic was undertaken and is the subject of this review. Bronchodilators are not disease modifiers and whilst glucocorticosteroids have been shown to reduce rates of exacerbation in moderate to severe COPD, the increase risk of pneumonia and bone fractures is a motivation enough to warrant developing novel anti-inflammatory and disease-modifying drugs and with the expectation of positive outcomes.

Searching for the synergistic effect between aclidinium and formoterol: From bench to bedside

“…Although the synergism was detected also at the plateau, its intensity was less relevant compared with that observed in the first minutes after the inhalation of medications. This peculiar trend can be well explained by several mathematical models that attempted to describe the pharmacological interaction between drugs, such as the easy and effective BI theory, the elegant median-effect equation proposed by Chou, and the Loewe additively model that employs complex isobolographic techniques to compare the dose equivalent effect of drugs when used alone and in combination [25,26]. Thus, the clinical findings of this study enable to further confirm the theoretical concept that the synergistic interaction between LABAs and LAMAs is greatest when the fractional response of the drugs administered alone is less intense or, more pragmatically, by combining bronchorelaxant medications at low doses [4,18,24e26].…”

Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease

“…[26][27][28][29][30][31][32] Combining both drug classes may be expected to maximise overall benefits, with perhaps synergistic rather than additive effects under certain conditions. [33] One limitation of our analyses is that we are unable to examine whether FEV 1 is the strongest lung function predictor of improvement in patient reported outcomes. It is certainly M A N U S C R I P T…”

How Do Dual Long-Acting Bronchodilators Prevent Exacerbations of Chronic Obstructive Pulmonary Disease?

“…The importance of accurate exacerbation detection was highlighted in this study that used electronic diaries to detect and flag exacerbations; this resulted to higher rates of reported exacerbations vs most previous studies, but the authors emphasized that this was unlikely to bias treatment comparisons. This view is supported by the fact that results for mild exacerbations (those most likely to be increased with the reporting method used) were matched by those for moderate or severe exacerbations (29 LAMAs when they are administered together (33), and some preclinical studies provide some implications for potential synergistic effects (34,35). Inhibition of M2 receptors enhances the actions of norepinephrine at β 2 receptors by interacting with adenylyl cyclase to raise intracellular cyclic adenosine monophosphate (cAMP) levels in airway smooth muscle cells and thus relax airway smooth muscle (35).…”

“…This view is supported by the fact that results for mild exacerbations (those most likely to be increased with the reporting method used) were matched by those for moderate or severe exacerbations (29 LAMAs when they are administered together (33), and some preclinical studies provide some implications for potential synergistic effects (34,35). Inhibition of M2 receptors enhances the actions of norepinephrine at β 2 receptors by interacting with adenylyl cyclase to raise intracellular cyclic adenosine monophosphate (cAMP) levels in airway smooth muscle cells and thus relax airway smooth muscle (35). Interestingly, this interaction only lasts for a few hours, which has led to speculation about the potential improvements in efficacy when a LABA and LAMA are administered together (36).…”