Drug interaction and chronic obstructive respiratory disorders

Abstract

Chronic obstructive respiratory disorders uncontrolled by monotherapy should be given combinations of drugs that act by distinct mechanisms of action. The rationale for combining different classes of drugs should be to elicit a synergistic interaction, lower the dose of the single components in the combinations and, thus, reduce the risk of adverse events. The aim of this systematic review was to investigate the combined effect of drugs acting on human airways, by including studies that used a validated method for assessing the nature of drug interaction. Current evidence indicates that drug combinations modulating the bronchial contractility induce a synergistic relaxant effect when the individual components are combined at isoeffective concentrations. There are several mechanisms of action underlying drug interactions. Pharmacological research has been directed to elucidate what causes the synergism between long-acting β 2 -adrenoceptor (β 2 -AR) agonists (LABAs), long-acting muscarinic antagonist (LAMAs), and inhaled corticosteroids (ICS) administered as dual or triple combination. Conversely, the mechanisms behind the additive interaction between phosphodiesterase 3 and 4 inhibitors and LAMAs, and the synergistic interaction between proliferator-activated receptor gamma ligands and β 2 agonists have been only hypothesized. Overall, the synergism elicited by combined drugs for the treatment of chronic respiratory disorders is an effect of class, rather than specific for drug combinations. Optimal synergy can be achieved only when the single agents are combined at isoeffective concentrations, and when monocomponents are given concurrently to reach together the same levels of the bronchial tree.

Use of human airway smooth muscle in vitro and ex vivo to investigate drugs for the treatment of chronic obstructive respiratory disorders

“…An unknown factor in the sensitising serum related to IgE, but not IgE itself, has also been shown to contribute to non-specific AHR observed in isolated airways (Schmidt & Rabe, 2000). Although the precise underlying mechanisms leading to the AHR induced by passive sensitisation are not yet fully understood (Mitchell et al, 1997;Rabe, 1998;Schmidt et al, 1999), it has been extensively demonstrated that this phenomenon is associated with reduced synthesis of cyclic adenosine monophosphate (cAMP) in ASM and increased release of endogenous non-neuronal ACh (Calzetta et al, 2020;Rogliani et al, 2016Rogliani et al, , 2020Rogliani, Ritondo, Zerillo, et al, 2021c).…”

“…T A B L E 1 Summary of in vitro and ex vivo models from human airways. Pharmacological pathways can be also evaluated (Calzetta et al, 2011, Calzetta, Pistocchini, et al, 2023b, Manson et al, 2020, Naline et al, 1989, Naline et al, 2018, Rogliani et al, 2015 Isolated (Calzetta et al, 2020;Calzetta, Matera, Facciolo, et al, 2018b;Matera et al, 2011;Mitchell et al, 1997;Rabe, 1998;Rogliani et al, 2016Rogliani et al, , 2020Rogliani, Ritondo, Zerillo, et al, 2021c;Schmidt et al, 1999;Schmidt & Rabe, 2000) Normal (Calzetta, Pistocchini, et al, 2023b;Johnson et al, 1990Johnson et al, , 1992Kroegel et al, 1994;Rabe et al, 1994;Schmidt et al, 2002) Normal In vitro model of asthma / Inflammatory profile, alarmins (TSLP, IL-33 and IL-25) release, and pharmacological pathways can be evaluated (Calzetta, Matera, Facciolo, et al, 2018b;Calzetta, Rogliani, et al, 2014b;Fulcher et al, 2005…”

Beyond Dual Bronchodilation – Triple Therapy, When and Why

“…Solid evidence shows that among the various combinations, the ICS/LABA/LAMA triple combination is the one that induces the strongest synergistic bronchorelaxant effect in both the middle bronchi and small airways. 19 However, a translational study suggested that the synergistic interaction observed in vitro when adding a LAMA to the ICS/LABA combination may lead to maximal small airway, but not medium-calibre airway, relaxation in vivo. 20 When salbutamol was administered on top of triple therapy (2 h after the last inhalation of the triple combination) in severe COPD patients after two weeks of treatment, no significant improvement in peripheral resistance, expressed by the difference between resistance at 5 Hz (R5) and resistance at 19 Hz (R19) was detected whereas forced expiratory volume in 1 s (FEV 1 ) increased significantly.…”

Ensifentrine: A First-in-class Bifunctional Drug for the Treatment of Chronic Obstructive Pulmonary Disease

“…31 Ensifentrine acts as a dual inhibitor of PDE3/4, downstream effector proteins of the sympathetic signalling pathway triggered by β2-adrenoceptors. 32 As a result, it raises cAMP levels. Ensifentrine and LAMAs, in contrast, work on different signal transduction pathways that ultimately combine to produce the ASM bronchorelaxant effect.…”