Emmanuel Naline1, Stanislas Grassin Delyle2, Hélène Salvator3, Marion Brollo4, Christophe Faisy5, Tatiana Victoni6, Charlotte Abrial7, Philippe Devillier8. 1. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France; Department of Airway Diseases, Hôpital Foch, Suresnes, France. Electronic address: upresea220@orange.fr. 2. Department of Airway Diseases, Hôpital Foch, Suresnes, France; Mass Spectrometry Platform & INSERM UMR1173, UFR Sciences de la Santé Simone Veil, Université Versailles Saint Quentin en Yvelines, Université Paris Saclay, Montigny-le-Bretonneux, France. Electronic address: s.grassindelyle@hopital-foch.org. 3. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France; Department of Airway Diseases, Hôpital Foch, Suresnes, France. Electronic address: h.salvator@hopital-foch.org. 4. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France. Electronic address: m.brollo@hopital-foch.org. 5. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France. Electronic address: christophe.faisy@wanadoo.fr. 6. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France; Laboratory of Histocompatibility and Cryopresevation, Laboratory of Tissue Repair, Rio de Janeiro, Brazil. Electronic address: tatianavictoni@hotmail.com. 7. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France. Electronic address: abrial.charlotte@gmail.com. 8. Laboratory of Research in Respiratory Pharmacology-UPRES EA220, UFR Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Université Paris-Saclay, Suresnes, France; Department of Airway Diseases, Hôpital Foch, Suresnes, France. Electronic address: p.devillier@hopital-foch.org.
Abstract
BACKGROUND AND PURPOSE: Long-acting muscarinic antagonists (LAMAs) have been recommended for the treatment of chronic obstructive pulmonary disease and (more recently) asthma. However, the in vitro pharmacological profiles of the four LAMAs currently marketed (tiotropium, umeclidinium, aclidinium and glycopyrronium) have not yet been compared (relative to ipratropium) by using the same experimental approach. EXPERIMENTAL APPROACH: With a total of 560 human bronchial rings, we investigated the antagonists' potency, onset and duration of action for inhibition of the contractile response evoked by electrical field stimulation. We also evaluated the antagonists' potency for inhibiting cumulative concentration-contraction curves for acetylcholine and carbachol. KEY RESULTS: The onset and duration of action were concentration-dependent. At submaximal, equipotent concentrations, the antagonists' onsets of action were within the same order of magnitude. However, the durations of action differed markedly. After washout, ipratropium's inhibitory activity decreased rapidly (within 30-90 min) but those of tiotropium and umeclidinium remained stable (at above 70%) for at least 9 h. Aclidinium and glycopyrronium displayed less stable inhibitory effects, with a progressive loss of inhibition at submaximal concentrations. In contrast to ipratropium, all the LAMAs behaved as insurmountable antagonists by decreasing the maximum responses to both acetylcholine and carbachol. CONCLUSIONS AND IMPLICATIONS: The observed differences in the LAMAs' in vitro pharmacological profiles in the human bronchus provide a compelling pharmacological rationale for the differences in the drugs' respective recommended daily doses and frequencies of administration.
BACKGROUND AND PURPOSE: Long-acting muscarinic antagonists (LAMAs) have been recommended for the treatment of chronic obstructive pulmonary disease and (more recently) asthma. However, the in vitro pharmacological profiles of the four LAMAs currently marketed (tiotropium, umeclidinium, aclidinium and glycopyrronium) have not yet been compared (relative to ipratropium) by using the same experimental approach. EXPERIMENTAL APPROACH: With a total of 560 human bronchial rings, we investigated the antagonists' potency, onset and duration of action for inhibition of the contractile response evoked by electrical field stimulation. We also evaluated the antagonists' potency for inhibiting cumulative concentration-contraction curves for acetylcholine and carbachol. KEY RESULTS: The onset and duration of action were concentration-dependent. At submaximal, equipotent concentrations, the antagonists' onsets of action were within the same order of magnitude. However, the durations of action differed markedly. After washout, ipratropium's inhibitory activity decreased rapidly (within 30-90 min) but those of tiotropium and umeclidinium remained stable (at above 70%) for at least 9 h. Aclidinium and glycopyrronium displayed less stable inhibitory effects, with a progressive loss of inhibition at submaximal concentrations. In contrast to ipratropium, all the LAMAs behaved as insurmountable antagonists by decreasing the maximum responses to both acetylcholine and carbachol. CONCLUSIONS AND IMPLICATIONS: The observed differences in the LAMAs' in vitro pharmacological profiles in the human bronchus provide a compelling pharmacological rationale for the differences in the drugs' respective recommended daily doses and frequencies of administration.
Authors: Hélène Salvator; Aristine Cheng; Lindsey B Rosen; Peter R Williamson; John E Bennett; Anuj Kashyap; Li Ding; Kyung J Kwon-Chung; Ho Namkoong; Christa S Zerbe; Steven M Holland Journal: Respir Res Date: 2022-10-11