• Paola Rogliani, Beatrice L Ritondo, Francesco Cavalli, Federica M Giorgino, Andrea Girolami, Gloria Pane, Gabriella Pezzuto, Bartolomeo Zerillo, Ermanno Puxeddu, and Josuel Ora.
• Unit of Respiratory Medicine, Department of Experimental Medicine, Tor Vergata University, Rome, Italy - paola.rogliani@uniroma2.it.
• Minerva Med. 2022 Feb 1; 113 (1): 17-30.

IntroductionInhaled corticosteroids are the cornerstone for the treatment of stable asthma, however, when disease severity increases, escalating therapy to combinations of drugs acting on distinct signalling pathways is required. It is advantageous to providing evidence of a synergistic interaction across drug combinations, as it allows optimizing bronchodilation while lowering the dose of single agents. In the respiratory pharmacology field, two statistical models are accepted as gold standard to characterize drug interactions, namely the Bliss Independence criterion and the Unified Theory. In this review, pharmacological interactions across drugs approved for the treatment of asthma have been systematically assessed.Evidence AcquisitionA comprehensive literature search was performed in MEDLINE for studies that used a validated pharmacological method for assessing drug interaction. The results were extracted and reported via qualitative synthesis.Evidence SynthesisOverall, 45 studies were identified from literature search and 5 met the inclusion criteria. Current evidence coming from ex-vivo models of asthma indicates that drug combinations modulating bronchial contractility induce a synergistic bronchorelaxant effect. In murine models of lung inflammation, the combination between inhaled corticosteroids and β2-adrenoceptor agonists synergistically improve lung function and the inflammatory profile.ConclusionsThere is still limited knowledge regarding the mechanistic basis underlying pharmacological interactions across drugs approved for asthma. The synergism elicited by combined agents is an effect of class. Specifically designed clinical trials are needed to confirm the results coming from preclinical evidence, but also to establish the minimal dose for combined agents to induce a synergistic interaction and maximize bronchodilation.

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