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Rebuttal by Dr. Barnes

National Heart & Lung Institute, Imperial College, London, United Kingdom

Although, as Drs. Ameredes and Calhoun point out, detrimental effects of (S)-albuterol and greater effects of (R)-albuterol compared with (R,S)-albuterol have been documented in various cells and in vivo animal models (rats and guinea pigs, which poorly reflect clinical asthma), these effects are not consistent and tend to be found at high concentrations of agonists that are unlikely to be of clinical relevance. The only studies that really count are clinical studies and, as I have pointed out, there is no convincing evidence for an important clinical advantage of (R)-albuterol over the normally used (R,S)-albuterol and no persuasive evidence that (S)-albuterol worsens asthma. Since the article was submitted, other clinical studies have been published. A very large multicenter trial comparing nebulized (R)-albuterol with racemic albuterol showed no clinically important differences in the recovery from an acute asthma exacerbation (1) and no clinically important differences in the control of asthma in young children after regular dosing (2). The recent availability of (R)-albuterol in a pressurized metered-dose inhaler (MDI) should make it easier to carry out long-term studies to compare (R)-albuterol with (R,S)-albuterol on asthma control and exacerbation frequency.

Several trials of racemic albuterol have shown that it does not increase asthma symptoms (3, 4). The increased odds ratio of mortality from asthma of 2.4 in the Saskatchewan study is almost certainly accounted for by underuse of inhaled corticosteroids rather than a detrimental effect of albuterol. Indeed, not a single patient on regular inhaled corticosteroids in that cohort died of asthma (5). The protective effect of inhaled corticosteroids against mortality applies to all ₂-agonists (including long-acting ₂-agonists), and therefore it is highly unlikely that any specific protection against the deleterious effects of (S)-albuterol could be relevant. The B16 Arg-Arg polymorphism of the ₂-receptor is associated with a poor response to ₂-agonists (6, 7), but this would certainly also apply to (R)-albuterol to the same extent, because this is dependent only on the specific binding of the active enantiomer to its receptor.

The issue of higher drug cost would not be a major consideration if the use of (R)-albuterol were clinically advantageous and if there were convincing evidence for detrimental effects of (S)-albuterol. I do not believe that clear evidence in favor of the more expensive (R)-albuterol is currently very convincing. What is now needed is an independent study of the long-term effects of (R)-albuterol as an MDI compared with (R,S)-albuterol, with a proper economic evaluation. Short-acting ₂-agonists, such as albuterol, are not recommended for regular use; they should be replaced by the more effective long-acting ₂-agonists salmeterol and formoterol, so that (R)-albuterol would only ever be used as a rescue therapy. Because the aim of asthma management is control of asthma so that the use of rescue medication is minimal, the amount of short-acting ₂-agonist used would normally be very small. Until clear evidence is available for a clinical advantage of (R)-albuterol, I do not recommend switching from regular racemic albuterol as a rescue therapy or substituting nebulized (R)-albuterol in the treatment of acute severe asthma.

REFERENCES

1. Nowak R, Emerman C, Hanrahan JP, Parsey MV, Hanania NA, Claus R, Schaefer K, Baumgartner RA. A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults. Am J Emerg Med 2006;24:259–267.[CrossRef][Medline]
2. Skoner DP, Greos LS, Kim KT, Roach JM, Parsey M, Baumgartner RA. Evaluation of the safety and efficacy of levalbuterol in 2–5-year-old patients with asthma. Pediatr Pulmonol 2005;40:477–486.[CrossRef][Medline]
3. Dennis SM, Sharp SJ, Vickers MJ, Frost CD, Crompton GK, Barnes PJ, Lee TH. The effects of regular inhaled salbutamol on asthma control. Lancet 1999;355:1675–1679.
4. Drazen JM, Israel E, Boushey HA, Chinchilli VM, Fahy JV, Fish JE, Lazarus SC, Lemanske RF, Martin RJ, Peters SP, et al. Comparison of regularly scheduled with as needed use of albuterol in mild asthma. N Engl J Med 1996;335:841–847.[Abstract/Free Full Text]
5. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000;343:332–336.[Abstract/Free Full Text]
6. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig TJ, Deykin A, Fagan JK, Fahy JV, Fish J, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004;364:1505–1512.[CrossRef][Medline]
7. Wechsler ME, Lehman E, Lazarus SC, Lemanske RF Jr, Boushey HA, Deykin A, Fahy JV, Sorkness CA, Chinchilli VM, Craig TJ, et al. -Adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006;173:519–526.[Abstract/Free Full Text]

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