Levalbuterol hydrochloride.
Racemic salbutamol (racemic albuterol) ameliorates symptoms of asthma by activating beta-adrenoceptors on nerve, smooth muscle and inflammatory cells within the airways. Racemic salbutamol comprises equal proportions of 2 isomers: (S)-salbutamol and (R)-salbutamol, with the latter being exclusively responsible for activation of beta-adrenoceptors. Accordingly, within racemic salbutamol it is (R)-salbutamol that efficiently relieves obstruction of asthmatic airways and affords highly effective protection from bronchoconstrictor stimuli, including allergens. During regular use of racemic salbutamol, there is a progressive decline of protective efficacy and a corresponding intensification of airway responsiveness. This decline is largely absent during regular use of (R)-salbutamol. Consequently, bronchodilator responses to sub-maximal doses of (R)-salbutamol exceed responses to the equivalent dose of (R)-salbutamol given as the racemate. For example, in asthmatics with baseline FEVs <or= 60%, 1.25 mg of nebulised (R)-salbutamol achieved a maximal 52% change in FEV while 2.5 mg of racemic salbutamol only achieved a 38% change in FEV. Since extrapulmonary effects (e.g., tremor, heart rate) of beta agonists are related to dose and limit the use of beta agonist therapy, (R)-salbutamol at 0.63 mg provides uncompromised efficacy with marked reduction of side-effects. In addition to quantitative differences, the constituent isomers of salbutamol also exhibit qualitative differences. Thus, (R)-salbutamol inhibits activation of human eosinophils in vitro whereas, under the same conditions and concentrations, (S)-salbutamol augments activation of these cells. This property of (S)-salbutamol may explain why eosinophilia in induced sputum from subjects with allergic asthma is increased by regular use of racemic salbutamol. Similarly, the capacity of (R)-salbutamol to suppress hyperresponsiveness of the airways can be contrasted with the capacity of (S)-salbutamol to intensify hyperresponsiveness. This action of (S)-salbutamol would explain why regular use of racemic salbutamol intensifies the bronchoconstrictor response to antigen in subjects with allergic asthma. Taken together, these findings imply that replacement of racemic salbutamol by (R)-salbutamol will diminish, or even eliminate, the anomalous actions that have curtailed the efficacy of racemic salbutamol. Pharmacokinetically, (R)-salbutamol exhibits near absolute conformational stability (i.e., no conversion to (S)-salbutamol). If in vitro anti-inflammatory actions of (R)-salbutamol are also manifest in asthmatic airways, (R)-salbutamol could provide a novel approach to asthma therapy which combines bronchodilation and bronchoprotection with anti-inflammatory efficacy.
Handley
D A
DA
Sepracor, Inc., 111 Locke Drive, Marlborough, MA 01752, USA.
Morley
J
J
Vaickus
L
L