The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.

Single-inhaler triple therapy utilizing the once-daily combination of fluticasone furoate, umeclidinium and vilanterol in the management of COPD: the current evidence base and future prospects.

Maintenance pharmacological treatment for stable chronic obstructive pulmonary disease (COPD) is based on inhaled drugs, including long-acting muscarinic receptor antagonists (LAMA), long-acting ß2-adrenoceptor agonists (LABA) and inhaled corticosteroids (ICS). Inhaled pharmacological treatment can improve patients' daily symptoms and reduce decline of pulmonary function and acute exacerbation rate. Treatment with all three inhaled drug classes is reserved for selected, more severe, patients with COPD when symptoms are not sufficiently controlled by dual LABA/LAMA therapy and exacerbations are frequent. This review focuses on the role of single-inhaler triple therapy with once-daily fluticasone furoate/umeclidinium/vilanterol fixed-dose combination, which is in phase III clinical development for maintenance treatment of severe-to-very severe COPD. In this review, we summarize evidence providing the rationale for its use in COPD and discuss the gaps to be filled in this pharmacotherapeutic area.

Investigational beta-2 adrenergic agonists for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Long-acting bronchodilators are pivotal in the therapeutic management of COPD patients with moderate-to-severe airflow obstruction. New ultra-long-acting ß2-agnoists (ultra-LABAs) have been developed, some of which have been licensed for use as monotherapy and/or in combination with other bronchodilators or inhaled corticosteroids, for use in COPD patients with persistent symptoms and worsening airflow limitation. These new agents are faster in onset and have a prolonged duration of action, with a similar safety profile to the traditional twice-daily bronchodilators which may have an impact on patient concordance. Areas covered: A number of these ultra-LABAs are still under development and bi-functional hybrid molecules containing regions functioning as ß2-agonists, and as muscarinic agonists (MABAs) has been developed. This review summarizes these (excluding the licensed ultra-LABAs) with attention on phase II studies data available to-date on their pharmacological profiles, clinical efficacy and safety, and future perspectives. Expert opinion: Despite all the new agents' available, the challenges that persist include any differences in efficacy and safety between the various possible LAMA/LABA combinations, relative advantages of MABAs over fixed-dose LAMA/LABAs, and the impact of these new molecules in terms of long term safety, especially in certain populations in co-morbidities frequently associated with COPD.

Triple inhaled therapy for chronic obstructive pulmonary disease.

Combining individual drugs in a single inhaler is the most convenient way to deliver triple therapy. A long-acting muscarinic receptor antagonist (LAMA) added to an inhaled corticosteroid (ICS)/long-acting ß2-adrenoceptor agonist (LABA) fixed-dose combination (FDC) can improve efficacy of pharmacological treatment of patients with chronic obstructive pulmonary disease (COPD). New inhaled ICS/LABA/LAMA FDCs, including fluticasone furoate/vilanterol/umeclidinium, budesonide/formoterol/glycopyrronium and beclometasone/formoterol/glycopyrronium, are in Phase III of clinical development for COPD. Triple inhaled therapy might be particularly useful in patients with severe to very severe COPD, above all in those with peripheral blood or sputum eosinophilia, asthma-COPD overlap syndrome (ACOS) or frequent exacerbators. Future prospective studies should assess efficacy and safety of triple ICS/LABA/LAMA therapy in selected COPD phenotypes.

Vilanterol trifenatate for the treatment of COPD.

INTRODUCTION: Currently the treatment of chronic obstructive pulmonary disease (COPD) has limited effectiveness and there is a need to develop new drugs. International guidelines recommend the use of long-acting bronchodilators (ß2 agonists and anti-cholinergics/muscarinics), inhaled steroids and associations between these drugs in the maintenance treatment of moderate-to-severe COPD. AREA COVERED: Vilanterol trifenate is a new once-daily highly selective ß2-agonist available in USA and Europe in association with umeclidinium bromide (a long-acting anti-muscarnic agent) and fluticasone furoate (an inhaled corticosteroid) for the once-daily maintenance treatment of COPD. Vilanterol combined in fixed-dose treatments has been tested in numerous clinical trials involving thousands of patients. Expert commentary: These new once-daily formulations have the potential to improve compliance to long-term inhaled therapy. This paper will review the clinical and experimental data regarding vilanterol use in the regular treatment of COPD as well as provide a critical discussion of possible future treatment settings.

Rehabilitation and supportive therapy in elderly patients with Chronic Obstructive Pulmonary Disease.

Chronic Obstructive Pulmonary Disease (COPD) very often coexists with cardiovascular, musculoskeletal and metabolic comorbidities. This condition significantly impact on the general health, function, frailty and disability of such patients, and consequently on their prognosis. Indeed, complex and recurrent symptoms of general dysfunction are commonly present and burden on the health status. Symptomatic COPD patients, even with chronic and complex comorbidities or with different degree of severity, may benefit from rehabilitation including exercise and maintenance of physical activity, in order to reducing symptoms and restoring the highest possible level of independent function. This review will focus on the associated and relevant clinical problems of these patients at the onset of disability, methods of assessment and useful non-pharmacological treatments for caring and supporting them.

Biologic and pharmacologic therapies in clinical development for the inflammatory response in COPD.

Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating condition with declining lung function associated with airway inflammation, mucus hypersecretion and remodeling. Inflammatory cells contribute to the disease processes via the production of proteases, fibrotic or mitogenic growth factors, cytokines, chemokines and their receptors. Particularly newer agents that treat the underlying inflammation and remodeling. Here, we briefly review current understanding of the inflammatory mechanisms involved in the pathogenesis of COPD. This understanding has enabled the identification of several therapeutic targets that might have great potential for the development of novel anti-inflammatory and anti-remodeling biologic therapies with considerable clinical advantage for COPD. Some of these molecules have been assessed, and others are in the early stages of being assessed. This article gives an up-to-date summary of these novel therapies and their status of clinical development in targeting the various inflammatory pathways of COPD.

Folic acid in general medicine and dermatology.

Folic acid is a vitamin B essential for the integrity and function of DNA. Relative deficiency of folic acid may occur in conditions such as pregnancy and hyperproliferative or chronic inflammatory disorders. Folic acid supplementation has been proven to be beneficial in the prevention of neural tube defects and in limiting methotrexate side effects, and may reduce the risk of colorectal cancer. Folate is a critical vitamin in determining plasma homocysteine levels, which in turn is a major risk factor for cardiovascular diseases. The results of large clinical trials with dietary supplementation of folic acid, vitamin B12 and vitamin B6 have shown that this homocysteine-lowering therapy is effective in the secondary prevention of non-fatal strokes, but had no effect in the prevention of fatal cardiovascular diseases. Hyperhomocysteinemia has also been reported in age-related neurological conditions with cognitive impairment (e.g. dementia), and psychiatric disorders such as depression. Elevated homocysteine levels are frequent in patients with chronic immune-mediated disorders including rheumatoid arthritis, systemic lupus erythematosus, chronic plaque psoriasis and psoriatic arthritis, which have in common a tendency to an accelerated atherosclerosis leading to increased deaths from cardiovascular events. Folic acid supplementation appears as a reasonable therapeutic option in patients affected by chronic inflammatory skin diseases, such as moderate to severe psoriasis; in particular, those with concomitant hyperhomocysteinemia, low plasma folate and additional cardiovascular risk factors.