Luigino Calzetta

Pharmacology and Therapeutics of Bronchodilators

Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, β2-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily β2-AR agonists or ultra-long-acting β2-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.

β2‐adrenoceptor agonists: current and future direction

Despite the passionate debate over the use of β2‐adrenoceptor agonists in the treatment of airway disorders, these agents are still central in the symptomatic management of asthma and COPD. A variety of β2‐adrenoceptor agonists with long half‐lives, also called ultra long‐acting β2‐adrenoceptor agonists (ultra‐LABAs; indacaterol, olodaterol, vilanterol, carmoterol, LAS100977 and PF‐610355) are currently under development with the hopes of achieving once‐daily dosing. It is likely that the once‐daily dosing of a bronchodilator would be a significant convenience and probably a compliance‐enhancing advantage, leading to improved overall clinical outcomes. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is important for treating patients suffering from asthma, and a combination with an inhaled long‐acting antimuscarinic agent (LAMA) is important for treating COPD patients whose conditions are not sufficiently controlled by monotherapy with a β2‐adrenoceptor agonist, some novel once‐daily combinations of LABAs and ICSs or LAMAs are under development.

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Tumor necrosis factor (TNF)-alpha, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lungs. Given that there is significant literature supporting the pathobiologic role of TNF-alpha in asthma, mainly in severe refractory asthma, and COPD, TNF-alpha inhibitors (infliximab, golimumab and etanercept) are now regarded as the potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-alpha inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-alpha inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-alpha, perhaps in a more carefully selected patient group. TNF-alpha treatment should, therefore, not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-alpha inhibitors.

Asthma and comorbid medical illness

Asthma is associated with several comorbidities but the magnitude of the association has not been clearly defined. We aimed to examine the relationship between asthma and comorbidities using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (Società Italiana Medici Generici, Florence, Italy). We conducted a population-based retrospective study using information obtained from the HSD. The software system used codes of all the diagnostic records using the 9th revision of the International Classification of Diseases. Asthma appeared to be weakly associated with cardiovascular and hypertensive diseases. Intriguingly, the odds ratio of acute or old myocardial infarction was 0.84 (95% CI 0.77–0.91). Asthma was also weakly associated with depression, diabetes mellitus, dyslipidaemia, osteoporosis and rhinosinusitis. In contrast, it was strongly associated with gastro-oesophageal reflux disease (GORD) and, particularly, allergic rhinitis. Age did not influence the association of asthma with comorbidities whereas sex had a different impact according to the specific comorbidity. Our results indicate that asthma is weakly associated with several comorbidities, whereas its association with allergic rhinitis or GORD is stronger.

Efficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials.

BACKGROUND Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug. METHODS Between February, 2009, and January, 2013, we undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned (1:1:1) to receive an inhaled dose of RPL554 (0·003 mg/kg or 0·009 mg/kg) or placebo by a computer-generated randomisation table. Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 (three received 0·009 mg/kg and three received 0·018 mg/kg) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 (0·018 mg/kg) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection. Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 (0·018 mg/kg) for 6 consecutive days in a single-blind (patients masked), placebo-controlled study in 12 men with clinically stable asthma. The safety and bronchodilator effect of RPL554 (0·018 mg/kg) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD. In study 4, a placebo-controlled crossover trial, the effect of RPL554 (0·018 mg/kg) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men. In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment. Analyses were by intention to treat. All trials were registered with EudraCT, numbers 2008-005048-17, 2011-001698-22, 2010-023573-18, and 2012-000742-34. FINDINGS Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups. Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s (FEV1) and provocative concentration of methacholine causing a 20% fall in FEV1 (PC20MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV1 increase at 1 h of 520 mL (95% CI 320-720; p<0·0001), which was a 14% increase from placebo, and increased the PC20MCh by 1·5 doubling doses (95% CI 0·63-2·28; p=0·004) compared with placebo. The primary endpoint of study 2 was maximum FEV1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV1 from placebo on day 1 (555 mL, 95% CI 442-668), day 3 (505 mL, 392-618), and day 6 (485 mL, 371-598; overall p<0·0001). A secondary endpoint of study 3 (patients with COPD) was the increase from baseline in FEV1. RPL554 produced bronchodilation with a mean maximum FEV1 increase of 17·2% (SE 5·2). In healthy individuals (study 4), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 (0·018 mg/kg) did not significantly reduce the percentage of neutrophils in sputum (80·3% in the RPL554 group vs 84·2% in the placebo group; difference -3·9%, 95% CI -9·4 to 1·6, p=0·15), since RPL554 significantly reduced neutrophils (p=0·002) and total cells (p=0·002) to a similar degree. INTERPRETATION In four exploratory studies, inhaled RPL554 is an effective and well tolerated bronchodilator, bronchoprotector, and anti-inflammatory drug and further studies will establish the full potential of this new drug for the treatment of patients with COPD or asthma. FUNDING Verona Pharma.

Pharmacological characterization of the interaction between aclidinium bromide and formoterol fumarate on human isolated bronchi

Long-acting muscarinic receptor antagonists (LAMAs) and long-acting β2-adrenoceptor agonists (LABAs) cause airway smooth muscle (ASM) relaxation via different signal transduction pathways, but there are limited data concerning the interaction between these two drug classes on human bronchi. The aim of this study was to investigate the potential synergistic interaction between aclidinium bromide and formoterol fumarate on the relaxation of human ASM. We evaluated the influence of aclidinium bromide and formoterol fumarate on the contractile response induced by acetylcholine or electrical field stimulation (EFS) on human isolated airways (segmental bronchi and bronchioles). We analyzed the potential synergistic interaction between the compounds when administered in combination by using Bliss independence (BI) theory. Both aclidinium bromide and formoterol fumarate completely relaxed segmental bronchi pre-contracted with acetylcholine (Emax: 97.5±2.6% and 96.4±1.1%; pEC50 8.5±0.1 and 8.8±0.1; respectively). Formoterol fumarate, but not aclidinium bromide, abolished the contraction induced by acetylcholine in bronchioles (Emax: 68.1±4.5% and 99.0±5.6%; pEC50 7.9±0.3 and 8.4±0.3; respectively). The BI analysis indicated synergistic interaction at low concentrations in segmental bronchi (+18.4±2.7%; P<0.05 versus expected effect) and from low to high concentrations in bronchioles (+19.7±0.9%; P<0.05 versus expected effect). Low concentrations of both drugs produced a synergistic relaxant interaction on isolated bronchi stimulated with EFS that was sustained for 6h post-treatment (+55.1±9.4%; P<0.05 versus expected effect). These results suggest that combining aclidinium bromide plus formoterol fumarate provides synergistic benefit on ASM relaxation of both medium and small human airways, which may have major implications for the use of this combination in the clinic.

Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis.

In order to clarify the possible role of N-acetylcysteine (NAC) in the treatment of patients with chronic bronchitis and chronic obstructive pulmonary disease (COPD), we have carried out a meta-analysis testing the available evidence that NAC treatment may be effective in preventing exacerbations of chronic bronchitis or COPD and evaluating whether there is a substantial difference between the responses induced by low (≤600 mg per day) and high (>600 mg per day) doses of NAC. The results of the present meta-analysis (13 studies, 4155 COPD patients, NAC n=1933; placebo or controls n=2222) showed that patients treated with NAC had significantly and consistently fewer exacerbations of chronic bronchitis or COPD (relative risk 0.75, 95% CI 0.66–0.84; p<0.01), although this protective effect was more apparent in patients without evidence of airway obstruction. However, high doses of NAC were also effective in patients suffering from COPD diagnosed using spirometric criteria (relative risk 0.75, 95% CI 0.68–0.82; p=0.04). NAC was well tolerated and the risk of adverse reactions was not dose-dependent (low doses relative risk 0.93, 95% CI 0.89–0.97; p=0.40; high doses relative risk 1.11, 95% CI 0.89–1.39; p=0.58). The strong signal that comes from this meta-analysis leads us to state that if a patient suffering from chronic bronchitis presents a documented airway obstruction, NAC should be administered at a dose of ≥1200 mg per day to prevent exacerbations, while if a patient suffers from chronic bronchitis, but is without airway obstruction, a regular treatment of 600 mg per day seems to be sufficient. Evidence that high doses of NAC protect against COPD exacerbations with a favourable risk-benefit ratio http://ow.ly/NeSbl

Pharmacological interaction between LABAs and LAMAs in the airways: optimizing synergy

Nowadays there is solid clinical information for combining β2-agonists and anti-muscarinic agents, although the nature (additive or synergistic) of the net clinical result obtained by co-administration of these two classes of bronchodilators is not completely elucidated from a pharmacological point of view. Recent preclinical studies demonstrated that combining a long-acting β2-agonist (LABA) with a long-acting anti-muscarinic agent (LAMA) provides synergistic benefit on airway smooth muscle relaxation, which may have major implications for the use of LABA/LAMA combinations in the treatment COPD. Indeed, the LABA/LAMA synergism has been proved also in patients with moderate-to-severe COPD. Nevertheless, there is still a strong medical need for dose-finding clinical trials designed to identify the most favourable doses of LABA/LAMA combinations able to induce a real synergism. We strongly believe that the Bliss Independence theory represents an effective model for investigating the cross-talk between β2-adrenoreceptor and the muscarinic pathways leading to the synergistic interaction between β2-agonists and anti-muscarinic agents. In any case, the possibility of eliciting a synergistic bronchodilator effect when combining a LABA and a LAMA suggests that the therapeutic approach proposed by GOLD recommendations to only use LABA/LAMA combination in more severe COPD patients who are not controlled by a single bronchodilator should be reconsidered. We support the possibility of an early intervention with low doses of LABA/LAMA combination to optimize bronchodilation and reduce the risk of adverse events that characterize both LABAs and LAMAs, especially when administered at the full doses currently approved for the treatment of COPD.

Cardiovascular disease in asthma and COPD: A population-based retrospective cross-sectional study

We conducted a large population-based retrospective cross-sectional study for determining the extent of clinically recognized chronic obstructive pulmonary disease (COPD) and asthma, and the prevalence of associated cardiovascular diseases (CVDs), using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (SIMG). Our study provides further evidence that patients with the diagnosis of COPD are at increased association with the diagnosis of most CVDs. It also documents that age clusters between 35 and 54 years are those at highest association of simultaneous presence of the diagnosis of CVD and that of COPD, with a progressive significant reduction in older age clusters. Moreover, it shows that the diagnosis of asthma is modestly associated with the diagnosis of different CV morbidities.

Translational Study Searching for Synergy between Glycopyrronium and Indacaterol

Abstract We aimed to explore whether the acute bronchodilation induced by indacaterol 150 μg and glycopyrronium bromide 50 μg is additive or synergistic with respect to monocomponents by testing the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients. Both indacaterol and glycopyrronium caused a concentration-dependent relaxation of human isolated bronchial tissues sub-maximally pre-contracted with acetylcholine; glycopyrronium was significantly more potent than indacaterol. The analysis of data using the Bliss Independence (BI) criterion indicated that glycopyrronium plus indacaterol produced an additive interaction at the isoeffective concentrations inducing EC20 and a significant synergistic relaxant effect at isoeffective concentrations inducing EC30. In COPD patients, the inhalation of indacaterol and glycopyrronium in combination significantly anticipated at 15 min post-administration the mean peak of bronchodilatory effect compared to the two drugs administered alone. The study of interaction between indacaterol and glycopyrronium by BI analysis evidenced an additive effect for FEV1 between 5 min and 180 min post-inhalation, with synergistic interaction at 15 min post-administration, compared to the bronchodilation induced by these drugs administered alone. This study suggests that the combination ensures a broncholytic effect that is greater than that induced by the single monocomponents.