New millennium bronchodilators for asthma: single-isomer beta agonists.
Racemic beta2 agonists are composed of a 50:50 mixture of R and S isomers. The R isomer exhibits virtually all the bronchodilation, whereas the S isomers are generally considered inert. However, (S)-albuterol was shown to enhance bronchial reactivity to methacholine, eosinophil activation, and histamine-induced influx of fluid, proteins, and neutrophils into the airspaces. Actions such as these may compress the potency and foreshorten the duration of (R)-albuterol. Accordingly, pure (R)-albuterol provides bronchodilation at lower doses than racemate, allowing for fewer beta-adrenergic-mediated side effects. In addition, differential metabolism may allow for the progressive accumulation of (S)-albuterol. This logic is applicable to long-acting beta2 agonists: the therapeutically active (R,R)-formoterol is currently being developed in the United States, and preliminary results suggest rapid improvements in FEV1 with up to 24-hour duration of action. These combined observations with the R isomers of beta2 agonists suggest that potential improvements in therapeutic indices can be achieved with isomerically pure versions of existing racemic drugs.
Handley
D A
DA
Scientific Affairs, Sepracor Inc., Marlborough, MA 01752, USA.
Anderson
A J
AJ
Koester
J
J
Snider
M E
ME
D000318:Adrenergic beta-Agonists / Q000737:chemistry* / Q000494:pharmacology; D000420:Albuterol / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy; D001980:Bronchi / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000737:chemistry* / Q000494:pharmacology; D004804:Eosinophils / Q000502:physiology; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology; D005122:Exudates and Transudates / Q000187:drug effects; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D016210:Methacholine Chloride / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects; D011506:Proteins / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004983:Ethanolamines; D011506:Proteins; D016210:Methacholine Chloride; D000420:Albuterol; D000068759:Formoterol Fumarate