Maria Gabriella Matera

Oxidative stress is recognized to be one of predisposing factor in the pathogenesis of COPD. The oxidant/antioxidant imbalance is significantly pronounced in patients with COPD exacerbation. N-acetylcysteine (NAC) seems to be able to reduce COPD exacerbations by modulating the oxidative stress in addition to its well-known mucolytic activity, but there are discordant findings on the actual anti-oxidant activity of NAC. The anti-oxidant effect of NAC and its impact on the inflammatory response have been pharmacologically characterized on a human ex vivo model of COPD exacerbation induced by lipopolysaccharide (LPS). NAC prevented the desensitization induced by LPS incubation on the contractile tone in linear concentration-response manner. Concentrations of NAC ≥1 μM reduced the pro-oxidant response (peroxidase activity, hydrogen peroxide, malondialdehyde, nitric oxide), and improved the anti-oxidant response (total anti-oxidant capacity, glutathione, superoxide dismutase) induced by LPS. Lower concentrations of NAC (<1 μM) did not modulate the bronchial oxidative imbalance. Concentrations of NAC ≥300 μM inhibited the inflammatory response (release of IL-1β, IL-8, and TNF-α) of human airways induced by the overnight stimulation with LPS, whereas lower concentrations of NAC (≥1 μM) were sufficient to reduce the release of IL-6 elicited by LPS. Both the anti-oxidant effect and the anti-inflammatory effect of NAC were inversely correlated with the release of NKA. The findings of this study suggest that NAC may have a role in modulating the detrimental effect induced by LPS in course of COPD exacerbation. It may elicit both anti-oxidant and anti-inflammatory effects when administered at high concentrations.

Introduction. The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting β₂-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.

Aclidinium is a twice-daily long-acting muscarinic receptor antagonist (LAMA) with an interesting pharmacological profile. Recent evidence indicates that this LAMA, in addition to causing a significant improvement in lung function and other important supportive outcomes, such as health related quality of life, dyspnea and nighttime/early morning symptoms in patients suffering from COPD, is also able to significantly reduce the rate of exacerbations of any severity, is extremely effective in controlling the COPD symptoms, is able to reduce lung hyperinflation, and has an excellent cardiovascular safety profile. Consequently, aclidinium should be considered a first-line approach at least for the symptomatic treatment of COPD although there are still few head-to-head studies comparing this LAMA with other bronchodilators. In any case, aclidinium can be taken into account in the treatment of different COPD phenotypes (emphysema, chronic bronchitis, exacerbators and patients with overlap COPD asthma).

Co-administration of a long-acting β₂-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β₂-agonist fixed-dose combination that has been studied for this therapeutic indication.

Background and Purpose: The ability of a chronic treatment with indacaterol, a new ultra‐long‐acting β₂‐adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β₁‐adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF).Experimental Approach: We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β‐adrenoceptor‐mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham‐operated rats; HF rats; HF + indacaterol 0.3 mg·kg⁻¹·day⁻¹; HF + metoprolol 100 mg·kg⁻¹·day⁻¹; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks.Key Results: Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β₁ adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group.Conclusion and Implications: The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD.

The need for a rapid onset of action and a long duration of the broncholytic effect is the likely reason for the development of new long-acting β2-agonists (LABAs) that are fast acting and have true 24 h duration of action. Indacaterol is the archetype of once-daily LABAs and already marketed as a maintenance therapy in patients with moderate to severe chronic obstructive pulmonary disease (COPD).