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Long-acting β2-agonists in asthma: enantioselective safety studies are needed


Jacobson, GA and Raidal, S and Hostrup, M and Calzetta, L and Wood-Baker, R and Farber, MO and Page, CP and Walters, EH, Long-acting β2-agonists in asthma: enantioselective safety studies are needed, Drug Safety, 41, (5) pp. 441-449. ISSN 0114-5916 (2018) [Refereed Article]

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Copyright 2018 Springer International Publishing AG, part of Springer Nature

DOI: doi:10.1007/s40264-017-0631-1


Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without ICS. LABAs clearly demonstrate effective bronchodilatation and steroid-sparing activity, but long-term treatment can lead to tolerance of their bronchodilator effects. There are also concerns with regard to the effects of LABAs on bronchial hyperresponsiveness (BHR), where long-term use is associated with increased BHR and loss of bronchoprotection. A complicating factor is that formoterol and salmeterol are both chiral compounds, usually administered as 50:50 racemic (rac-) mixtures of two enantiomers. The chiral nature of these compounds has been largely forgotten in the debate regarding LABA safety and effects on BHR, particularly that (S)-enantiomers of β2-agonists may be deleterious to asthma control. LABAs display enantioselective pharmacokinetics and pharmacodynamics. Biological plausibility of the deleterious effects of β2-agonists (S)-enantiomers is provided by in vitro and in vivo studies from the short-acting β2-agonist (SABA) salbutamol. Supportive clinical findings include the fact that patients in emergency departments who demonstrate a blunted response to salbutamol are more likely to benefit from (R)-salbutamol than rac-salbutamol, and resistance to salbutamol appears to be a contributory mechanism in rapid asthma deaths. More effort should therefore be applied to investigating potential enantiospecific effects of LABAs on safety, specifically bronchoprotection. Safety studies directly assessing the effects of LABA (S)-enantiomers on BHR are long overdue.

Item Details

Item Type:Refereed Article
Keywords:LABA, safety, enantiomer, asthma, chiral
Research Division:Biomedical and Clinical Sciences
Research Group:Pharmacology and pharmaceutical sciences
Research Field:Pharmaceutical sciences
Objective Division:Health
Objective Group:Other health
Objective Field:Other health not elsewhere classified
UTAS Author:Jacobson, GA (Professor Glenn Jacobson)
UTAS Author:Wood-Baker, R (Professor Richard Wood-Baker)
UTAS Author:Walters, EH (Professor Haydn Walters)
ID Code:124802
Year Published:2018
Web of Science® Times Cited:8
Deposited By:Pharmacy
Deposited On:2018-03-09
Last Modified:2018-12-12

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