Inhaled glycopyrrolate for the treatment of chronic obstructive pulmonary disease.

Long-acting muscarinic antagonists (LAMAs), along with long-acting ß2-agonists (LABAs), are the mainstay for treatment of patients with COPD. Glycopyrrolate, or glycopyrronium bromide, like other LAMAs, inhibits parasympathetic nerve impulses by selectively blocking the binding of acetylcholine to muscarinic receptors. Glycopyrrolate is unusual in that it preferentially binds to M3 over M2 muscarinic receptors, thereby specifically targeting the primary muscarinic receptor responsible for bronchoconstriction occurring in COPD. Inhaled glycopyrrolate is slowly absorbed from the lungs and rapidly eliminated from the bloodstream, most likely by renal excretion in its unmetabolized form, limiting the potential for systemic adverse events. Inhaled glycopyrrolate is a fast-acting, efficacious treatment option for patients with moderate-severe COPD. It improves lung function, reduces the risk of exacerbations, and alleviates the symptoms of breathlessness, which in turn may explain the improvement seen in patients' quality of life. Inhaled formulations containing glycopyrrolate are well tolerated, and despite being an anticholinergic, few cardiovascular-related events have been reported. Inhaled glycopyrrolate is thus of value as both monotherapy and in combination with other classes of medication for maintenance treatment of COPD. This review covers the mechanism of action of inhaled glycopyrrolate, including its pharmacokinetic, pharmacodynamic, and safety profiles, and effects on mucus secretion. It also discusses the use of inhaled glycopyrrolate in the treatment of COPD, as monotherapy and in fixed-dose combinations with LABAs and inhaled corticosteroid-LABAs, including a triple therapy recently approved in Europe.

Rising Costs of COPD and the Potential for Maintenance Therapy to Slow the Trend.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects an estimated 14% of adults in the United States between the ages of 40 and 79 years. This progressive disease is characterized by persistent airflow limitation. The management of patients with COPD is focused on reducing risk factors, relieving symptoms, and preventing exacerbations. OBJECTIVE: To examine the peer-reviewed literature on the impact of maintenance therapy on the direct treatment costs of patients with COPD in the United States. METHODS: PubMed was searched for articles written in English that were published between 2000 and 2013, using the search terms "COPD," "economics," "exacerbation," "maintenance," and related terms. Articles reporting the results of longitudinal studies of the costs associated with the management of patients with COPD, the costs associated with hospitalizations for acute exacerbations of COPD, and randomized clinical trials evaluating the effects of maintenance therapy on the incidence of COPD exacerbations were included in this review. RESULTS: The search identified a total of 277 articles, and 11 of these articles were deemed appropriate for inclusion in this review. The direct healthcare costs for patients with COPD increased by 38% between 1987 and 2007, and continued to increase by approximately 5% annually between 2006 and 2009. The costs associated with hospital admissions for patients with COPD accounted for the largest absolute increase ($2289 per admission in constant 2007 US dollars). Recent estimates suggest that the aggregate costs associated with the treatment of acute exacerbations are between $3.2 billion and $3.8 billion, and that annual healthcare costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations. The results of 2 large clinical trials of maintenance therapy, including a long-acting cholinergic antagonist or a long-acting beta-2 agonist, showed a 16% to 17% reduction in the incidence of exacerbations compared with placebo. Nevertheless, maintenance therapy remains underutilized, with only 30% to 35% of patients with COPD in private and public health insurance plans receiving prescriptions for maintenance therapy. CONCLUSIONS: The treatment of acute exacerbations of COPD remains the major driver of increasing healthcare costs associated with this condition. The appropriate use of maintenance therapy has been shown to reduce the incidence of exacerbations and has the potential to reduce overall costs associated with the management of patients with COPD.

Safety and tolerability of inhalational anticholinergics in COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. With the significant toll of the disease, more resources have been invested in developing new treatment modalities. Among these medications, inhalational anticholinergics are widely used for the management of stable COPD. The newer agents, with longer half-lives and better safety profiles, have emerged and helped to improve management of COPD patients. The available data from randomized clinical trials support use of these agents. Multiple randomized clinical trials show safety and efficacy of the newer long-acting inhaled anticholinergics, including tiotropium and aclidinium. A recent meta-analysis of tiotropium delivered with Respimat(®) raised some safety concerns. A large trial, comparing different doses and delivery methods of inhaled tiotropium, is ongoing to determine the effect on mortality. As clinical trials may not comprehensively represent the entire COPD population, caution should be exercised when these agents are used in higher-risk populations, like individuals with cardiac arrhythmias or urinary obstruction. In this publication, we review the safety of inhalational anticholinergics.

Novel antiinflammatory therapies for COPD.

The biologic nature of COPD inflammation is not well understood and agents that inhibit inflammation in COPD are a major unmet need. However, a variety of agents that have the potential to be inhibitors of COPD inflammation are in various stages of development. Agents that have been approved for a non-COPD indication but that have potential for inhibiting COPD inflammation include the statins, some phosphodiesterase inhibitors, some long-acting ß agonists, tiotropium bromide, the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, and various monoclonal antibodies. New molecular entities that are being developed specifically as antiinflammatory agents for COPD include a variety of chemokine receptor antagonists, inhibitors of matrix metalloproteinases, inhibitors of p38 mitogen-activated protein kinases, and stem cells. Some other novel agents that are in preclinical or early clinical stages are mentioned.

Efficacy and safety of once-daily aclidinium in chronic obstructive pulmonary disease.

BACKGROUND: The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD). METHODS: In two double-blind, 52-week studies, ACCLAIM/COPD I (n=843) and II (n=804), patients were randomised to inhaled aclidinium 200 µg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1<80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation. RESULTS: At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p<0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p<0.001). More patients had a SGRQ improvement≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p=0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p=0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p=0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p=0.9). Adverse events were minor in both studies. CONCLUSION: Aclidinium is effective and well tolerated in patients with moderate to severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Nebulized formoterol: a review of clinical efficacy and safety in COPD.

A nebulized formulation of formoterol, Perforomist, 20 microg/2 ml, has been available since 2007 for the maintenance treatment of chronic obstructive pulmonary disease (COPD). We review the safety and efficacy data obtained during its development. In a dose-finding study, formoterol inhalation solution (FFIS) was similar to the formoterol originator, Foradil 12 microg DPI (FA) in patients with COPD. In a 12-week efficacy study, FFIS manifested a rapid onset of action and FEV(1) peak, AUC(0-12), and trough levels similar to FA. No loss of efficacy, tachyphylaxis, was observed over 12 weeks of regular administration. In placebo-controlled studies in COPD patients receiving maintenance tiotropium, the addition of FFIS significantly augmented bronchodilation over the 6-week treatment duration, signifying that nebulized formoterol can further improve lung function in patients who are receiving tiotropium without an observed increase in adverse reactions. The safety profile of FFIS during 12-week and 1-year studies revealed adverse events that were similar to those of placebo and FA. Cardiac rhythm studies, including frequent ECGs and Holter monitoring, did not indicate any increase in rate or rhythm disturbances greater than placebo or FA. We conclude that maintenance use of Perforomist is appropriate for patients with COPD who require or prefer a nebulizer for management of their disease.