Bifunctional drugs for the treatment of asthma and chronic obstructive pulmonary disease

Abstract

Over the last decade, there has been a steady increase in the use of fixed-dose combinations of drugs for the treatment of a range of diseases, including hypertension, cancer, AIDS, tuberculosis and other infectious diseases. It is now evident that patients with asthma or chronic obstructive pulmonary disease (COPD) can also benefit from the use of fixed-dose combinations, including combinations of a long-acting b 2 -agonist and an inhaled corticosteroid, and combinations of long-acting b 2 -agonists and long-acting muscarinic receptor antagonists. In fact, there are now a number of ''triple-inhaler'' fixed-dose combinations under development, with the first such triple combination having been approved in India. This use of combinations containing drugs with complementary pharmacological actions in the treatment of patients with asthma or COPD has also led to the discovery and development of drugs having two different primary pharmacological actions in the same molecule, which we have called ''bifunctional drugs''. In this review, we discuss the state of the art of these new bifunctional drugs as novel treatments for asthma and COPD that can be categorised as bifunctional bronchodilators, bifunctional bronchodilator/antiinflammatory drugs and bifunctional anti-inflammatory drugs. @ERSpublications Bifunctional drugs offer an exciting new approach to the treatment of asthma and COPD

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma

“…In addition to targeting phosphodiesterases to inhibit cAMP breakdown, many of the pipeline or existing drugs for asthma target activation of signaling pathways dependent on extracellular signal– regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase/Akt phosphorylation (26, 27). Therefore, we examined the effect of activation of the ASM CaSR on these pathways in human ASM cells.…”

“…Beyond contributions to AHR and airway remodeling (25), calcilytics prevent activation of intracellular pathways, which are currently being targeted by pipeline asthma drugs, specifically p38 MAPK and phosphodiesterase inhibitors (26). Indeed, both classes of inhibitors target various inflammatory cells, which release key mediators responsible for the remodeling and inflammation characteristic of these diseases.…”

Real-life use of long-acting antimuscarinic agents following their approval for COPD treatment

“…Many new treatments for COPD have been recently released or are about to be launched [11][12][13][14]. They include mostly new LABD, ICS and various combinations of these agents.…”

The future of bronchodilation: looking for new classes of bronchodilators

“…However, we understand that different PDE isozymes selectively regulate cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) signalling in different subcellular microdomains, and individual PDEs are likely involved in specific locations at certain time-points based on different stimulations/activations (figure 2) [8,9]. Furthermore, rather than involving a single PDE, we must consider the participation of multiple PDE variants in a complex signalling network involving central regulatory mechanisms [10,11]. It is also likely that compounds that inhibit PDE4 enzymes together with a second PDE family could provide a therapeutic benefit at a concentration that does not cause emesis [12].…”

“…These concepts have led to the investigation of the PDE family as an important target in the treatment of airways disorders and to explore the possibility of developing drugs with the ability not only to inhibit PDEs not fully evaluated in the past, such as PDE8 [13] and PDE9 that seem to regulate bovine tracheal smooth muscle relaxation [14], but also to interact simultaneously with different PDEs [10,11]. Dual PDE3/PDE4 inhibitors The recognition that the PDE4 isoenzyme is the principal isoenzyme in the majority of inflammatory cells of importance in the pathogenesis of asthma and COPD, and that PDE3 is the predominant PDE isoenzyme in ASM and its inhibition produces ASM relaxation as well as enhancement of relaxation evoked by β 2 -adrenoceptor stimulation [15], has led to the development of drugs having dual inhibitory activity for both PDE3 and PDE4 in order to obtain both bronchodilator and anti-inflammatory activity in the same molecule [10,11].…”