[Frontiers in Bioscience E2, 1081-1092, June 1, 2010]

Albuterol enantiomers: pre-clinical and clinical value?

Bill T. Ameredes, William J. Calhoun

Department of Internal Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1083


1. Abstract
2. Introduction
3. The beta-agonist controversy in asthma
4. Effect of beta-2-adrenergic receptor agonists in animal and human model systems
4.1. Overview of preclinical data
4.2. Key preclinical enantiomer data on airway contractile function
4.2.1. In vitro animal models of airway contractility
4.2.2. In vivo animal models of airway contractility
4.2.3. Human airway tissue contractility
4.3. Key preclinical enantiomer data on airway inflammation effects
4.3.1. In vitro leukocyte models of inflammation
4.3.2. In vitro airway cell models of inflammation
4.3.3. In vivo animal studies of airway inflammation
5. Bronchoprovocation studies of enantiomers in asthmatics
6. Clinical effects potentially associated with (S)-albuterol
7. Effects of albuterol in clinical trials
7.1. Randomized controlled efficacy clinical trials of albuterol in asthma
7.2. Controlled trials in acute asthma in adults and children
8. Summary
9. Acknowledgements
10. References


Albuterol has been used in the acute treatment of asthma exacerbations for over 25 years. Its cost is low, and delivery can be tailored to allow dose-effect titration. Like other beta-2-adrenergic receptor agonists, it can exist as a racemate of two enantiomers, one active ((R)-albuterol), and one traditionally considered inert ((S)-albuterol). Basic investigations in airway cells and models from animals and humans have shown that (R)-albuterol, in both racemic and single enantiomer formulations, produces changes consistent with both relaxation of airway smooth muscle cells, and the reduction of inflammation. In contrast, (S)-albuterol typically has produces effects opposite to those of (R)-albuterol, i.e., antagonistic to the beneficial desired effects. Coupled with the fact that (S)-albuterol can persist 12 times longer than (R)-albuterol within the human circulation, findings suggest that paradoxical effects, sometimes seen with chronic racemic albuterol use, are due to (S)-albuterol. A number of clinical studies, to date, have been generally consistent with these findings; however, overwhelming evidence for clinical superiority of the (R)-albuterol single enantiomer over that within racemic albuterol remains to be obtained.