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Research ArticleInflammation, Immunopharmacology, and Asthma

Bronchoprotection by Olodaterol Is Synergistically Enhanced by Tiotropium in a Guinea Pig Model of Allergic Asthma

Marieke Smit, Annet B. Zuidhof, Sophie I. T. Bos, Harm Maarsingh, Reinoud Gosens, Johan Zaagsma and Herman Meurs
Journal of Pharmacology and Experimental Therapeutics February 2014, 348 (2) 303-310; DOI: https://doi.org/10.1124/jpet.113.208439
Marieke Smit
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Annet B. Zuidhof
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Sophie I. T. Bos
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Harm Maarsingh
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Reinoud Gosens
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Johan Zaagsma
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Herman Meurs
Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, and Groningen Research for Asthma and COPD, University of Groningen, Groningen, The Netherlands
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Abstract

The novel once-daily β2-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β2-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

Footnotes

    • Received August 5, 2013.
    • Accepted December 2, 2013.
  • This study was financially supported by Boehringer Ingelheim Pharma GmbH & Co.

  • dx.doi.org/10.1124/jpet.113.208439.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 348 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 348, Issue 2
1 Feb 2014
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Research ArticleInflammation, Immunopharmacology, and Asthma

Synergism between Olodaterol and Tiotropium

Marieke Smit, Annet B. Zuidhof, Sophie I. T. Bos, Harm Maarsingh, Reinoud Gosens, Johan Zaagsma and Herman Meurs
Journal of Pharmacology and Experimental Therapeutics February 1, 2014, 348 (2) 303-310; DOI: https://doi.org/10.1124/jpet.113.208439

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Research ArticleInflammation, Immunopharmacology, and Asthma

Synergism between Olodaterol and Tiotropium

Marieke Smit, Annet B. Zuidhof, Sophie I. T. Bos, Harm Maarsingh, Reinoud Gosens, Johan Zaagsma and Herman Meurs
Journal of Pharmacology and Experimental Therapeutics February 1, 2014, 348 (2) 303-310; DOI: https://doi.org/10.1124/jpet.113.208439
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