Short-acting Muscarinic Antagonists Research Articles

Changing face of β2-adrenergic and muscarinic receptor therapies in asthma.

Despite current available treatment options, a significant proportion of patients with asthma remain uncontrolled and asthma pharmacotherapy continues to evolve. β2-Adrenergic receptor agonists play a major role as bronchodilators in asthma therapy, although new perspectives reflect the potential for bias G-protein coupled receptor signaling pathways. Due to the success of muscarinic antagonists in chronic obstructive pulmonary disease, and the elucidation that muscarinic receptors play a role in airway remodeling, muscarinic receptors represent an attractive therapeutic target in asthma. Although short-acting muscarinic antagonists are currently limited to their use in acute asthma and as alternative bronchodilators in individuals who experience side effects with β2-agonists, recent clinical trials indicate that the long-acting muscarinic antagonist, tiotropium, deserves consideration as a potential therapeutic agent for select populations. The continued evolution of anticholinergic therapy in asthma will require appropriately designed studies to assess mechanisms, efficacy and safety in asthma.

Roflumilast and dyspnea in patients with moderate to very severe chronic obstructive pulmonary disease: a pooled analysis of four clinical trials.

PurposeBreathlessness is a predominant symptom of chronic obstructive pulmonary disease (COPD), making it a valuable outcome in addition to lung function to assess treatment benefit. The phosphodiesterase-4 inhibitor roflumilast has been shown to provide small but significant improvements in dyspnea, as measured by the transition dyspnea index (TDI), in two 1-year studies in patients with severe to very severe COPD.Patients and methodsTo provide a more comprehensive assessment of the impact of roflumilast on dyspnea, post hoc analyses of four 1-year roflumilast studies (M2-111, M2-112, M2-124, and M2-125) in patients with moderate to very severe COPD were conducted.ResultsIn this pooled analysis (N=5,595), roflumilast significantly improved TDI focal scores versus placebo at week 52 (treatment difference, 0.327; P<0.0001). Roflumilast was associated with significantly greater TDI responders and significantly fewer TDI deteriorators (≥1-unit increase or decrease from baseline, respectively) versus placebo at week 52 (P<0.01, both); these significant differences were apparent by week 8 and maintained until study end (P<0.05, all). At study end, the postbronchodilator forced expiratory volume in 1 second improvement in TDI responders was significantly greater with roflumilast versus placebo (P<0.05). Similar to the overall population, improvements in TDI focal scores at week 52 were small but consistently significant over placebo in patients with chronic bronchitis, regardless of exacerbation history, concomitant treatment with short-acting muscarinic antagonists or long-acting β2-agonists, or pretreatment with inhaled corticosteroids.ConclusionThis analysis shows that patients treated with roflumilast to reduce exacerbation risk may also experience small but significant improvements in dyspnea, with accompanying improvements in lung function.

Pharmacotherapies for COPD.

This review article summarizes the main treatments for chronic obstructive pulmonary disease, their mechanisms, and the key evidence from trials supporting their use. Drug classes covered were short acting beta agonists (SABA), short acting muscarinic antagonists (SAMA), long acting beta agonists (LABA), long acting antimuscarinics (LAMA), inhaled corticosteroids (ICS), LABA/ICS combinations, specific phosphodiesterase (PDE4) inhibitors, non-specific PDE inhibitors, mucolytics, and oxygen. Non-specific therapies, such as opiates for relief of dyspnoea and therapies for smoking cessation, are also covered briefly. For each class of drug, mechanisms of action are described, key clinical trial results are reported, and available agents compared. Finally, the place of each drug in therapy is compared between current worldwide guidelines.

Preclinical efficacy of THRX-200495, a dual pharmacology muscarinic receptor antagonist and β2-adrenoceptor agonist (MABA)

Combinations of a muscarinic receptor antagonist (MA) and a β2-adrenoceptor agonist (BA) improve bronchodilation in COPD patients to a greater extent than drugs with either mechanism alone. Here, using an in vivo model of bronchoprotection in guinea pigs, we characterize a single agent with dual-acting MA and BA activity, THRX-200495 (MABA). THRX-200495 was compared to a fixed-dose combination of a short-acting muscarinic receptor antagonist (SAMA) and a β2-adrenoceptor agonist (SABA). The SAMA/SABA combination consisted of a 1:5.7 ratio of ipratropium and albuterol (the components of Combivent®). Conscious guinea pigs received aqueous nebulized solutions of vehicle or test compound by aerosol exposure. Bronchoprotective potency was estimated in anesthetized, tracheotomized and ventilated guinea pigs at predetermined time points after aerosol exposure by measuring changes in ventilation pressure. The individual (MA, BA) and composite (MABA) pharmacologies were assessed by determining protection against bronchoconstrictor responses induced by methacholine in the presence of propranolol (for MA activity), histamine (for BA activity) or methacholine (MABA activity). Bronchoprotection was calculated as percent inhibition of methacholine or histamine response relative to the vehicle group. THRX-200495 exhibited matched MA (ID50 = 11.4 μg/mL) and BA (ID50 = 11.2 μg/mL) potency and potent dual pharmacology (MABA ID50 = 3.5 μg/mL) that persisted for over 24 h. The combination of ipratropium/albuterol exhibited bronchoprotective activity that was 2.6-fold more potent as a BA (ID50 = 5.7 μg/mL) than as an MA (ID50 = 14.6 μg/mL) at 0.5 h post-dose and 37-fold more potent as an MA (ID50 = 4.3 μg/mL) than a BA (ID50 = 159 μg/mL) at 1.5 h post aerosol exposure. Under MABA pharmacological conditions, ipratropium/albuterol produced potent bronchoprotective activity (ID50 = 2.0/11.4 μg/mL) and an apparent additive effect of the two pharmacologies. In conclusion, a dual-acting prototypical MABA, THRX-200495, demonstrated potent, balanced and long-lasting bronchodilation in a guinea pig model of bronchoprotection that was greater than either the MA or BA mechanisms alone.

Roflumilast with long-acting 2-agonists for COPD: influence of exacerbation history

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting β(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 μg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease.

Phosphodiesterase 4 (PDE4) is a member of the PDE enzyme superfamily that inactivates cyclic adenosine monophosphate and cyclic guanosine monophosphate, and is the main PDE isoenzyme occurring in cells involved in inflammatory airway disease such as chronic obstructive pulmonary disease (COPD). COPD is a preventable and treatable disease and is characterized by airflow obstruction that is not fully reversible. Chronic progressive symptoms, particularly dyspnoea, chronic bronchitis and impaired overall health are worse in those who have frequent, acute episodes of symptom exacerbation. Although several experimental PDE4 inhibitors are in clinical development, roflumilast, a highly selective PDE4 inhibitor, is the first in its class to be licensed, and has recently been approved in several countries for oral, once-daily treatment of severe COPD. Clinical trials have demonstrated that roflumilast improves lung function and reduces exacerbation frequency in COPD. Furthermore, its unique mode of action may offer the potential to target the inflammatory processes underlying COPD. Roflumilast is effective when used concomitantly with all forms of bronchodilator and even in patients treated with inhaled corticosteroids. Roflumilast thus represents an important addition to current therapeutic options for COPD patients with chronic bronchitis, including those who remain symptomatic despite treatment. This article reviews the current status of PDE4 inhibitors, focusing on the pharmacokinetics, efficacy and safety of roflumilast. In particular, it provides an overview of the effects of roflumilast on lung function and exacerbations, glucose homoeostasis and weight loss, and the concomitant use of long-acting beta(2)-adrenergic receptor agonists and short-acting muscarinic receptor antagonists.