Levalbuterol hydrochloride

Abstract

Racemic salbutamol (racemic albuterol) ameliorates symptoms of asthmaby activating b-adrenoceptors on nerve, smooth muscle and inflammatorycells within the airways. Racemic salbutamol comprises equal proportionsof 2 isomers: (S)-salbutamol and (R)-salbutamol, with the latter beingexclusively responsible for activation of b-adrenoceptors. Accordingly,within racemic salbutamol it is (R)-salbutamol that efficiently relievesobstruction of asthmatic airways and affords highly effective protectionfrom bronchoconstrictor stimuli, including allergens. During regular use ofracemic salbutamol, there is a progressive decline of protective efficacy anda corresponding intensification of airway responsiveness. This decline islargely absent during regular use of (R)-salbutamol. Consequently,bronchodilator responses to sub-maximal doses of (R)-salbutamol exceedresponses to the equivalent dose of (R)-salbutamol given as the racemate.For example, in asthmatics with baseline FEVs ≤ 60%, 1.25 mg of nebulised(R)-salbutamol achieved a maximal 52% change in FEV while 2.5 mg ofracemic salbutamol only achieved a 38% change in FEV. Since extrapulmonaryeffects (e.g., tremor, heart rate) of b agonists are related to dose andlimit the use of b agonist therapy, (R)-salbutamol at 0.63 mg providesuncompromised efficacy with marked reduction of side-effects. In additionto quantitative differences, the constituent isomers of salbutamol alsoexhibit qualitative differences. Thus, (R)-salbutamol inhibits activation ofhuman eosinophils in vitro whereas, under the same conditions andconcentrations, (S)-salbutamol augments activation of these cells. Thisproperty of (S)-salbutamol may explain why eosinophilia in inducedsputum from subjects with allergic asthma is increased by regular use ofracemic salbutamol. Similarly, the capacity of (R)-salbutamol to suppresshyperresponsiveness of the airways can be contrasted with the capacity of(S)-salbutamol to intensify hyperresponsiveness. This action of (S)-salbutamolwould explain why regular use of racemic salbutamol intensifies thebronchoconstrictor response to antigen in subjects with allergic asthma.Taken together, these findings imply that replacement of racemicsalbutamol by (R)-salbutamol will diminish, or even eliminate, theanomalous actions that have curtailed the efficacy of racemic salbutamol.Pharmacokinetically, (R)-salbutamol exhibits near absolute conformationalstability (i.e., no conversion to (S)-salbutamol). If in vitro anti-inflammatoryactions of (R)-salbutamol are also manifest in asthmatic airways, (R)-salbutamolcould provide a novel approach to asthma therapy which combinesbronchodilation and bronchoprotection with anti-inflammatory efficacy.