Bronchodilators: Current and Future

Both communicable and non-communicable chronic respiratory conditions have accorded for suffering of millions of people of all ages and stated to be leading cause of death, morbidity, economic and social pressures, and disability-adjusted life-years (DALYs) worldwide. These illnesses impair patient's health and negatively impacts families and society, particularly in low and middle-income countries. Chronic respiratory diseases (CRDs) affect different organs of respiratory system, involving airways, parenchyma, and pulmonary vasculature. As the number of respiratory diseases are exponentially escalating but still the stakeholders are not paying attention towards its serious complications. Currently, the treatment being used primarily focusses only on alleviating symptoms of these illness rather delivering the therapeutic agent at target site for optimal care and/or prevention. Lately, extensive research is being conducted on airways and systemic inflammation, oxidative stress, airway, or parenchymal rehabilitation. From which macrophages, neutrophils, and T cells, as well as structural cells as fibroblasts, epithelial, endothelial, and smooth muscle cells have been found to be active participants that are involved in these chronic respiratory diseases. The pathogenesis of all these chronic respiratory diseases gets caused differently via mediators and proteins, including cytokines, chemokines, growth factors and oxidants. Presently, the target of prescription therapies is to reduce the inflammation of airways and relieve the airway contraction. In all studies, cytokines have been found to play an imperative role in fostering chronic airway inflammation and remodelling. Owing to the limitations of conventional treatments, the current review aims to summarize the current knowledge about the chronic respiratory disease and discuss further about the various conventional methods that can be used for treating this ailment. Additionally, it also highlights and discusses about the advanced drug delivery system that are being used for targeting the interleukins for the treatment of CRDs.

Bronchodilators are the mainstay of the current management of COPD and are critical in the symptomatic management of asthma. Three classes of bronchodilators (β₂-AR agonists, mAChR antagonists, and xanthines) are currently available. The combination of two or more drugs with dissimilar but complementary mechanisms of action, of which at least one is a bronchodilator, has become standard in the treatment of asthma and COPD. However, they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is a considerable amount of research being undertaken to improve the existing classes of bronchodilators with the development of novel β₂-AR agonists, mAChR antagonists, and xanthines. Research is also ongoing to develop new options for combination therapy such as, bifunctional bronchodilator drugs and bifunctional bronchodilator/anti-inflammatory drugs. However, the limits that characterize the existing classes of bronchodilators have maintained a lively interest in identifying new therapeutic options to induce bronchodilation that could help to overcome these limits. Although novel classes have proved difficult to develop, in recent years new targets have been identified. These new opportunities are mostly in a preclinical phase.

The purpose of this study was to screen a bronchodilator from old drugs and elucidate the underlying mechanism. Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug. It has been reported that it inhibits the generation of prostaglandin and histamine, which play roles in asthma. These findings led us to explore whether paracetamol could be a potential bronchodilator. Paracetamol inhibited high K⁺- and acetylcholine (ACH)-induced precontraction of mouse tracheal and bronchial smooth muscles. Moreover, the ACH-induced contraction was partially inhibited by nifedipine (selective blocker of LVDCCs), YM-58483 (selective inhibitor of store-operated Ca²⁺ entry (SOCE), canonical transient receptor potential 3 (TRPC3) and TRPC5 channels) and Y-27632 (selective blocker of ROCK, a linker of the Ca²⁺ sensitization pathway). In single airway smooth muscle cells, paracetamol blocked the currents sensitive to nifedipine and YM-58483, and inhibited intracellular Ca²⁺ increases. In addition, paracetamol inhibited ACH-induced phosphorylation of myosin phosphatase target subunit 1 (MYPT1, another linker of the Ca²⁺ sensitization pathway). Finally, in vivo paracetamol inhibited ACH-induced increases of mouse respirator system resistance. Collectively, we conclude that paracetamol inhibits ASM contraction through blocking LVDCCs, SOCE and/or TRPC3 and/or TRPC5 channels, and Ca²⁺ sensitization. These results suggest that paracetamol might be a new bronchodilator.

COPD is a chronic inflammatory disease characterized by partially reversible airflow limitation. Currently, phosphodiesterase4 inhibitors and inhaled corticosteroids are anti-inflammatory agents that can be used in patients with severe COPD, always added to at least one bronchodilator. In this prospective interventional pilot study, we investigated the effect of adding oral roflumilast 500 μg once-daily or inhaled ciclesonide 160 μg once-daily to glycopyrronium 44 μg once-daily on lung volumes and exercise tolerance in 16 patients with severe COPD, of which 8 received roflumilast and 8 ciclesonide for 8 weeks. Detailed pulmonary function and endurance shuttle tests were performed at time 0, after 2 weeks of glycopyrronium and after 8 weeks of add-on of either roflumilast or ciclesonide. Glycopyrronium increased significantly (p < .05) FEV₁, and IC at rest and at the peak of exercise and improved the walking distance. In particular, it induced a bronchodilation similar to that elicited by salbutamol 800 μg. After 8 weeks of combination therapy, both the trough and the post bronchodilator FEV₁ further improved but the increase was very small and not significant. Furthermore, adding either roflumilast or ciclesonide did not provide a further improvement in IC and walking distance. This study provides further evidence of the efficacy of glycopyrronium 44 μg once daily, confirming that improvements in airflow are associated with increases in IC and improvements in exercise tolerance. The addition of anti-inflammatory drugs, regardless of class used, does not seem to add benefits on lung function and exercise tolerance, likely because of the large effect induced by glycopyrronium.