Andrea Segreti

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.

Novel bronchodilators in asthma

Purpose of review Because of the central role of bronchodilators in the treatment of asthma, in recent years there has been a renewed interest in the field and now once-daily bronchodilators are in development in an attempt to simplify their use. Recent findings A variety of β2-agonists with long half-lives, also called ultra long-acting β2-agonists (ultra-LABAs; indacaterol, carmoterol, milveterol, GSK-642444, BI-1744-CL, LAS-100977, and PF-00610355) are currently under development with the hopes of achieving once-daily dosing. Between them, indacaterol, GSK-642444, and carmoterol are at a more advanced stage of development. Also several novel inhaled long-acting antimuscarinic agents are currently being developed, but their role in the treatment of asthma is limited. As combination therapy with an inhaled corticosteroid (ICS) and a LABA is considered the first-line approach for treating patients suffering from asthma, some novel once-daily combinations of LABAs and ICSs are under development. Summary Bronchodilators are central in the symptomatic management of asthma. 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 in patients with asthma. In any case, as a LABA in combination with an ICS continues to be the most effective asthma treatment, once-daily combinations of ultra-LABAs and ICSs will be central in the treatment of asthmatic patients in the next years.

The prevalence of asthma and COPD in Italy: A practice-based study

We conducted a population-based cross-sectional epidemiologic survey of asthma and COPD in an adult representative national sample using information obtained from the Health Search Database owned by the Italian College of General Practitioners. General Practitioners who had a list of patient population of 909,638 individuals (429,962 men and 479,676 women; man/woman ratio [M/WR]: 0.89) ≥ 14 years old at the end of December 2009 were selected to be representatives of the whole Italian population. Cases of asthma and COPD were identified on the basis of the ICD-9 codes. The total sample included 55,500 (6.10% of the entire population; 5.49% of men and 6.64% of women; M/WR: 0.74) subjects suffering from asthma and 25,762 (2.83% of the entire population; 3.51% of men and 2.23% of women; M/WR: 1.41) subjects suffering from COPD. The asthma/COPD ratio in general population was 2.16. The odds ratio (OR) was chosen because asthma and COPD had a prevalence less than 10%. The OR of developing asthma decreased with age both in men and women, but in the first group of age (15-34 years) it was higher in men vs. women (1.69 vs. 1.00) although it became lower than 1 from 35 years old and up in men and from 75 years old and up in women. On the contrary, the OR of developing COPD became higher than 1 from 55 years old and up both in men and in women and progressively increased with age (in the group 75-84 years, it was 6.16 in men and 4.07 in women, respectively).

Change in asthma and COPD prescribing by Italian general practitioners between 2006 and 2008.

AIMS To explore the trend in prescribing of drugs classified within the R03 therapeutic pharmacological subgroup (drugs for obstructive airway diseases) of the Anatomical Therapeutic Chemical (ATC) classification. METHODS Comparison of GP-collected data on physician-patient contacts and drug prescriptions for asthma and COPD in 2006 and 2008. RESULTS Compared to 2006, in 2008 patients with COPD were prescribed more long-acting bronchodilators; use of tiotropium increased, whilst use of long-acting β2-agonists (LABAs) and short-acting antimuscarinic agents decreased. However, 55.9% of patients in 2006, and 47.8% in 2008, received an inhaled corticosteroid (ICS), mainly as a LABA/ICS fixed combination inhaler. Compared to 2006, in 2008 there were increased prescriptions of LABA/ICS fixed combination inhalers for asthma, but only 54.5% of all prescriptions included an ICS. This could explain the large use of short-acting β2-agonists, a marker of poor asthma control. Remarkably, LABA/ICS fixed combination inhalers were prescribed more frequently in COPD than in asthma. CONCLUSIONS Our data indicate that adherence to guidelines is still low. Patients with asthma and COPD are undertreated by Italian GPs, with a trend to a change in COPD prescribing likely driven by new scientific information.

An update on bronchodilators in Phase I and II clinical trials

Introduction: Inhaled bronchodilators are the mainstay of the current management of COPD at all stages of the disease, and are critical in the symptomatic management of asthma. Therefore, there is still considerable interest in finding novel classes of broncholytic drugs or, at least, in improving the existing classes of bronchodilator. Areas covered: This review paper mainly focuses on bronchodilators that are in Phase I and II clinical trials. Expert opinion: To date, finding new classes of bronchodilators has proved difficult. Consequently, many research groups have sought to improve the existing classes of bronchodytic drugs. The majority of programs in development for novel bronchodilators are focused on developing new ligands that interact with β2-adrenoceptors and/or muscarinic acetylcholine receptors in a manner that enhances their bronchodilator effectiveness and duration of action, which allows only one administration per day, although the twice-daily dosing of bronchodilators is still considered a useful approach to the symptomatic treatment of COPD, and improving their safety profiles. Moreover, the current opinion is that it is advantageous to develop inhalers containing combinations of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible. Another goal is to develop novel combinations of one or two classes of long-acting bronchodilators along with inhaled corticosteroids.

New developments in the combination treatment of COPD: focus on umeclidinium/vilanterol

An increasing body of evidence suggests that the long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination appears to play an important role in maximizing bronchodilation, with studies to date indicating that combining different classes of bronchodilators may result in significantly greater improvements in lung function compared to the use of a single drug, and that these combinations are well tolerated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). An inhaled, fixed-dose combination of two 24-hour bronchodilators, the LAMA umeclidinium and the LABA vilanterol, is under development as a once-daily treatment for COPD. The efficacy of both mono-components has already been demonstrated. The information currently available suggests that umeclidinium/vilanterol is an effective once-daily dual bronchodilator fixed-dose combination in the treatment of COPD. However, it remains to be seen if it compares favorably with current therapies. Moreover, the question remains whether umeclidinium/vilanterol fixed-dose combination, which significantly improves FEV1, is also associated with improvements in other outcome measures that are important to COPD patients.

Comorbidities of asthma: current knowledge and future research needs.

Purpose of review Asthma is often associated with different comorbidities, mainly gastro-oesophageal reflux disease and allergic rhinitis, but also obesity, depression, diabetes mellitus and cardiovascular disease, which may affect its clinical intensity and severity. The prevalence of these comorbidities varies tremendously between studies. Nevertheless, it imposes a significant reflection on the need to explore the phenomenon in depth. Recent findings Both clinical and basic studies have established that inflammation plays a vital role in the initiation and progression of several comorbidities. However, the role of systemic inflammation in asthma is still unclear. Understanding mechanism(s) that link(s) asthma and its comorbid diseases is essential to design an effective therapeutic approach. Summary In the future, researchers must identify the weight of any comorbidity in patients with asthma, find the true mechanism(s) that link(s) it to asthma and act on these mechanisms that probably create a vicious circle. Conversely, we do not think it reasonable that the generalization of treatment with a holistic approach might affect the link(s) between asthma and its comorbidities.

Comparative effectiveness of drugs for chronic obstructive pulmonary disease.

Current guidelines for the management of chronic obstructive pulmonary disease (COPD) recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids (ICSs) and their combinations for maintenance treatment of moderate to severe COPD. However, doctors still wonder if in patients with mild/moderate stable COPD it is best to start with a β-adrenoceptor agonist or an antimuscarinic agent. They also wonder if once- or twice-daily dosing is preferable, and if it is enough to develop a novel therapy that is dosed once daily rather than twice daily if the agents are both equally safe and effective. It also remains unclear whether and when a second bronchodilator with a different mechanism of action should be used in patients with stable COPD and when, in its place, an ICS must be added, and also whether long-acting antimuscarinic agent (LAMA)/long-acting β-adrenoceptor agonist (LABA) combination therapy is preferred over LAMA plus LABA/ICS. Moreover, there is no solid evidence of the best way to administer a triple combination product: should drugs be delivered concomitantly or sequentially? In any case, the growing evidence that COPD is a heterogeneous disease with characteristics that occur with different phenotypes suggests that a specific therapy may not be ultimately identified for every phenotype. Therefore, there is a clear need to move toward personalized treatment in COPD because phenotypic heterogeneity may affect treatment response and the clinical course of the disease. Unfortunately, however, there is not enough money or time to examine the impact of each treatment step or combination of treatments in each specific phenotype using randomized controlled trials. Consequently, doctors wonder if there is a role for comparative effectiveness research (CER), which can be considered a subset of patient-oriented research that examines available therapeutic options in particular patients to determine relevant health outcomes. There is a strong agreement that carefully designed CER studies, which explicitly address treatment and population heterogeneity, will provide exciting opportunities to develop an evidence base for guiding decisions about how best to tailor care for individual patients with COPD.

Emerging drugs for chronic obstructive pulmonary disease

Introduction: Chronic obstructive pulmonary disease (COPD) is a major public health problem with increasing morbidity and mortality. It is characterized by airflow obstruction that is usually progressive, not fully reversible and does not change markedly over several months. It is associated with an enhanced inflammatory response in the airways and the lung to noxious particles or gases. Therefore, bronchial relaxation and inflammatory response suppression represent a mechanistic approach to the treatment of COPD. Areas covered: This review article is focused on emerging treatment for COPD that is mainly based on new bronchodilators and anti-inflammatory drugs. We also mention new pharmacologic agents whose mechanisms of action target protease activity at the enzymatic level and the potential regenerative therapy for COPD. Expert opinion: New drugs for the treatment of COPD are greatly needed, but development of novel drugs for COPD has proved to be very difficult. Nevertheless, in these last years, several new potential targets have been identified and novel agents for these new targets, as well for known targets, have been developed. Rational therapy depends on elucidating the cellular and molecular mechanisms that are involved in bronchodilation and inflammation in COPD patients, and the structural changes and aberrant repair mechanisms that characterize the pathophysiology of COPD.

Pharmacological assessment of the onset of action of aclidinium and glycopyrronium versus tiotropium in COPD patients and human isolated bronchi

Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400µg, glycopyrronium 50μg and tiotropium 18µg and FEV1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10nM to 1µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5min) and glycopyrronium (17.9±10.4min) enhanced 15% FEV1 more rapidly than tiotropium (42.5±19.4min), with no significant difference (P>0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10nM: 8.2±1.3min, 100nM: 7.1±2.1min, 1μM: 3.4±0.4min) that was faster compared to that induced by aclidinium (1μM: 6.4±0.5min) and tiotropium (1μM: 8.4±1.1min) (P<0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients.