help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Barnes, P. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barnes, P. J.
American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 969-972, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.2606003

Pro/Con Editorials

Treatment with (R)-Albuterol Has No Advantage over Racemic Albuterol

Peter J. Barnes, D.M., D.Sc.

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

Inhaled beta2-adrenergic agonists are among the most widely used drugs in the world and are used by most patients with asthma for symptom relief. These drugs are the most effective bronchodilators known for the treatment of asthma, inhibiting the effects of all known bronchoconstrictor stimuli (1).

Most beta2-agonists have a chiral center so that different enantiomers exist. Epinephrine synthesis in the adrenal medulla by the enzyme dopamine beta-hydroxylase involves the stereoselective introduction of a hydroxyl group. Endogenous epinephrine is levorotatory and has the (R)-configuration (also known as L-isomer as it deviates polarized light to the left). Chemical synthesis of all beta2-selective agonists (including long-acting beta2-agonists), however, results in a 50:50 mixture of the (R)- and the (S)-enantiomer (also called the D-isomer, because it is dextrorotatory). The (R)-enantiomer is active, whereas the (S)-enantiomer has little or no activity at the beta2-receptor. However, it is now claimed that the (S)-enantiomer, rather than being inert, has detrimental effects in asthma, accounting for adverse effects of beta2-agonists. Novel methods of manufacture are now able to produce large amounts of the purified (R)-enantiomer of the most widely used beta2-agonist, albuterol (known outside the United States as salbutamol). It is argued that (R)-albuterol (often known as levalbuterol) is more effective than the racemic (R,S)-albuterol mixture, as a result of counteracting actions and a more prolonged effect of the (S)-enantiomer. However, as discussed below, there is little convincing evidence to support this assertion in clinical studies and no convincing case for substituting the expensive (R)-albuterol for racemic albuterol in the clinical management of asthma.

DETRIMENTAL EFFECTS OF B2-AGONISTS

Although inhaled beta2-agonists are highly effective bronchodilators, there is controversy surrounding their long-term safety in the treatment of asthma, and they have been implicated in the increase in mortality from asthma in the 1960s and in worsening control of asthma. This is a complex area, because interpretation is often confounded by the fact that beta2-agonists are used as rescue therapy, and they therefore may be linked to asthma severity and death from an asthma attack. There is some evidence that the nonselective isoproterenol and the more beta1 selective agonist fenoterol may be associated with increased mortality, but this has not been clearly seen with more beta2 selective agonists, such as albuterol (2, 3). The association between asthma mortality and increased use of rescue beta2-agonists appears to reflect increased severity of asthma (4) and underuse of inhaled corticosteroids (5). The original suggestion that regular fenoterol therapy worsens control of asthma (6) has not been confirmed in studies of regular albuterol (7, 8). Regular administration of beta2-agonists leads to down-regulation of beta2-receptors, but this does not affect bronchodilator responses because of the large reserve of beta2-receptors on airway smooth muscle cells. However, tolerance to nonbronchodilator effects of beta2-agonists has been demonstrated in vitro in inflammatory cells, such as mast cells, neutrophils, and monocytes, which is consistent with the relatively low beta2-receptor density expressed by these cells (9, 10). This is reflected in clinical studies that show that protection against indirect bronchoconstrictor challenges, such as adenosine, allergen, and exercise, produces rapid development of tolerance, which is likely to reflect down-regulation of beta2-receptors on airway mast cells (11–14). This may account for the increase in reactivity to these challenges and explain why some studies have demonstrated enhanced bronchoconstriction in patients with asthma after regular beta2-agonist therapy.

EXPERIMENTAL STUDIES OF ALBUTEROL ENANTIOMERS

Airway Smooth Muscle
Several studies have demonstrated that (S)-albuterol either has no effect on airway smooth muscle in vitro or antagonizes the bronchodilator effects of (R)-albuterol (15). (S)-albuterol increases intracellular calcium ion concentrations in bovine airway smooth muscle cells and enhances cell shortening secondary to an increase in the intracellular messenger inositol (1, 4, 5) trisphosphate (16). Unexpectedly, this response is blocked by atropine but not by a beta2-adrenergic blocker, indicating that the effects of (S)-albuterol are mediated via muscarinic receptors. Similar data have been reported with (S)-albuterol in human airway smooth muscle cells, in which an increase in inhibitory G-protein is also reported (17). In these cells, there is also activation of phosphoinositide-3 kinase and nuclear factor-{kappa}B, suggesting that inflammatory pathways are activated by (S)-albuterol. (S)-albuterol has no effect on resting tone in human airways in vitro, but enhanced contractile responses are seen with histamine and leukotriene D4, but not with other spasmogens, including methacholine, electrical field stimulation, or bradykinin (18). The effects of (S)-albuterol on airway smooth muscle are therefore inconsistent, and confirmation of detrimental effects at therapeutically relevant concentrations is unclear.

In Vivo Animal Studies
Systemic administration of (R,S)-albuterol caused an initial protection against bronchoconstriction induced by inhaled allergen in ovalbumin-sensitized guinea pigs, but prolonged administration increased bronchoconstriction and bronchoconstrictor responses to spasmogens. These adverse events are mimicked by (S)-albuterol and blocked by sectioning of the vagus nerve, suggesting a cholinergic mechanism (19). Animals, particularly guinea pigs, have proved to poor predictors of drug effects in patients with asthma (20), and these interesting early observations have not been reported in any other experimental species.

Effects on Inflammation
beta2-Agonists have several nonbronchodilator actions that may contribute to their clinical efficacy (10). At therapeutic concentrations, beta2-agonists inhibit mast cell mediator release in vitro and in vivo, and this action may contribute to their efficacy in preventing bronchoconstriction induced by triggers, such as allergen and exercise. beta2-Agonists also have inhibitory effects on other inflammatory cells, including neutrophils, eosinophils, macrophages, and T lymphocytes, although these effects are usually transient due to rapid down-regulation of beta2-receptors. However, corticosteroid therapy may counteract this down-regulation by increasing the synthesis of beta2-receptors in these cells (21).

(S)-albuterol is reported to enhance the release of interleukin (IL)-4 from murine mast cells, with a minimal increase in histamine release after allergen exposure, but (R)-albuterol had no protective effect, so these results are difficult to interpret (22). Murine mast cells may not behave in the same way as human mucosal mast cells and no studies of human mast cells have been reported. (R)-albuterol and (R,S)-albuterol inhibit the release of eosinophil peroxidase from circulating eosinophils derived from atopic and nonatopic donors, whereas (S)-albuterol was without effect (23). Human T lymphocytes show reduced proliferation and lymphokine production in response to (R)-albuterol, whereas (S)-albuterol is ineffective and even blocks the response to (R)-albuterol (24). At high concentrations, (S)-albuterol increases the production of IL-2 and IL-13. Unexpectedly, the effects of both (R)- and (S)-albuterol were blocked by a beta-blocker (24).

There are few studies of the comparative effects of albuterol enantiomers on allergic inflammation in animals in vivo. A recent study demonstrated that (R)- and (R,S)-albuterol had equivalent protective effects against the response to inhaled allergen challenge in sensitized guinea pigs and the subsequent hyperresponsiveness to histamine, whereas (S)-albuterol was ineffective (25). Interestingly, (R)-, (R,S)-, or (S)-albuterol did not have any effect on the pulmonary inflammatory response to allergen.

Overall, some, but not all, studies suggest (S)-albuterol may increase inflammatory cell activation in vitro, although the studies are difficult to interpret. This does not translate into studies showing enhanced allergic inflammation in vivo. It is always difficult to interpret the clinical relevance of drug effects on inflammatory cells in vitro because the therapeutic concentrations of inhaled drugs are largely unknown. Most important are clinical studies which have compared therapeutic doses of inhaled (R)-, (S)-, and (R,S)-albuterol on airway function and in patients with asthma.

BRONCHOPROVOCATION STUDIES IN ASTHMA

An initial preliminary study that showed inhaled (R,S)- and (S)-albuterol provided less protection against inhaled methacholine challenge than (R)-albuterol (26) was not confirmed in subsequent more carefully controlled studies. Nebulized (R)-albuterol (1.25 mg) and (R,S)-albuterol (2.5 mg) had similar protective effects against methacholine challenge in patients with mild asthma, whereas (S)-albuterol (1.25 mg) had no effect. Furthermore, the bronchodilator response and side effects in response to single doses of (R)- and (R,S)-albuterol were identical, with no effect of (S)-albuterol (27). Another study confirmed these results against methacholine challenge but additionally showed equivalent protection of (R)- and (R,S)-albuterol against adenosine monophosphate challenge, which is mediated through mast cell activation and therefore tests their action on mast cell beta2-receptors (28). Again, (S)-albuterol had no effect and did not increase the response to AMP. In a careful crossover cumulative dose–response study in patients with asthma, (R)- and (R,S)-albuterol had comparable bronchodilator efficacy, with the expected potency ratio of 2:1, whereas (S)-albuterol had no effect (29). Furthermore, side effects, measured by heart rate and fall in plasma potassium, showed these same differences. Repeated dosing (three times daily for 6 days) gave similar results for bronchodilatation and protection against methacholine and isocapnic hyperventilation (30, 31). These carefully conducted and controlled studies demonstrate conclusively that inhaled (S)-albuterol is not detrimental in patients with asthma, even after repeated administration, and that (R,S)-albuterol is not inferior to (R)-albuterol.

PHARMACODYNAMICS

It is common for different enantiomers to be metabolized differentially. Nebulized (S)-albuterol is metabolized more slowly than (R)-albuterol, with plasma half-lives of approximately 3 and 5 hours, respectively (32). It is argued that this leads to a differential accumulation of the (S)-enantiomer after repeated dosing, but plasma concentrations after inhaled albuterol are low and the higher concentrations of the inert S-isomer are unlikely to have any functional effect. However, another study demonstrated that, after inhalation, there was a higher plasma concentration of (R)-albuterol compared with (S)-albuterol and this was interpreted as preferential retention in the lung of the (S)-enantiomer (33). An alternative explanation is that (S)-albuterol is metabolized within the lung to a greater extent than (R)-albuterol. A more detailed study comparing inhaled (R)- and (S)-albuterol using charcoal to prevent gut absorption demonstrated similar plasma concentrations after each enantiomer, indicating that there was no differential metabolism within the lungs (34).

CLINICAL TRIALS IN ASTHMA

It is argued that repeated administration of inhaled (R,S)-albuterol may lead to differential accumulation of (S)-albuterol in the circulation and deleterious effects. There is no convincing evidence for this in patients with asthma, however. In any case, it is now recommended in most asthma guidelines that short-acting beta2-agonists be used as reliever therapy and not as a regular treatment because long-acting beta2-agonists (LABAs), such as salmeterol or formoterol, are preferred. LABAs should only be given in patients who are already treated with inhaled corticosteroids, preferably as a fixed combination inhaler. The one clinical situation where high doses of short-acting beta2-agonists are given is in the immediate management of severe exacerbations of asthma, when nebulized albuterol is usually chosen. A small but significantly greater bronchodilator response to high doses of nebulized (R)-albuterol compared with (R,S)-albuterol was found with the first dose, but no significant differences were found after 4 weeks of administration (35). In children, there were no differences in bronchodilator responses after nebulized (R)-albuterol compared with (R,S)-albuterol (36, 37), although some small safety advantage for (R)-albuterol was claimed. These clinical trials in patients with stable asthma have thus identified no clear advantage for (R)-albuterol in efficacy or safety, a similar conclusion reached by others on reviewing these data in detail (38). In a study comparing (R)-albuterol with (R,S)-albuterol in acute severe asthma, there was a small but significant reduction in the number of children requiring hospital admission, although the length of hospitalization was the same (39). One reason for this difference is that more children in the (R)-albuterol group were treated with inhaled corticosteroids and cromolyn than in the (R,S)-albuterol group. However, two more recent studies of acute severe asthma in children showed no therapeutic advantage for (R)-albuterol compared with (R,S)-albuterol in improving lung function, hospitalization rate, or side effects (40, 41). It is noteworthy that the only favorable trials with (R)-albuterol have been sponsored by the sole pharmaceutical company marketing the product.

COSTS

The cost of medication is increasingly important as health resources become more and more pressurized. (R)-albuterol (Xopenex) has only been available in a nebulized form until recently. (R)-albuterol is approximately six times more expensive than nebulized (R,S)-albuterol, and (R,S)-albuterol delivered by metered-dose inhaler (MDI) with a large-volume spacer is even cheaper. It is possible that if hospital admissions or time of hospitalization were reduced by nebulized (R)-albuterol, this could offset its high cost, but this has not yet been shown. An MDI form of (R)-albuterol has now been licensed, but the costs compared with generic MDI (R,S)-albuterol are not yet known. Because there is no clear therapeutic advantage for (R)-albuterol in management of acute or chronic asthma, it is difficult to recommend a much more expensive equivalent therapy.

OTHER beta2-AGONIST ENANTIOMERS

All beta2-agonists have one or two chiral centers so that different enantiomers exist; the same arguments therefore have been applied to other beta2-agonists. Formoterol exists in four possible racemic forms. The active (R,R)-enantiomer has an equivalent bronchoprotective effect and side-effect profile to the racemic mixture in a primate, whereas (S,S)-formoterol was ineffective and did not block the action of (R,R)-formoterol (42). In patients with asthma, (R,R)-formoterol and racemic formoterol are similarly efficacious and have similar cardiovascular side effects, whereas (S,S)-formoterol is inactive (43). This indicates that there is unlikely to be any advantage of other (R)-enantiomers of beta2-agonists compared with the normal racemic forms of these drugs.

CONCLUSIONS

The activity of normally used racemic albuterol resides in the R-enantiomer, whereas the (S)-enantiomer is inactive. Some in vitro studies have demonstrated that the S-enantiomer may increase contractility of airway smooth muscle or mediator release, but this has not been confirmed in recent animal studies in vivo. More important, in patients with asthma, no consistent differences have been found with (R)-albuterol compared with (R,S)-albuterol in bronchodilatation, bronchoprotection, or side effects, whereas (S)-albuterol is inactive with no documented adverse effects. (R)-albuterol is only currently available as a nebulized form, but in view of its clinical equivalence and considerably higher costs compared with the normal (R,S)-albuterol, this treatment cannot be recommended in any patient groups. Similar considerations appear to apply to other beta2-agonists.

FOOTNOTES

Conflict of Interest Statement: P.J.B. has received research funding and lecture fees and has served on scientific advisory boards for GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Novartis, Altana, Pfizer and Scios.

REFERENCES

  1. Sears MR, Lotvall J. Past, present and future: beta2-adrenoceptor agonists in asthma management. Respir Med 2005;99:152–170.[CrossRef][Medline]
  2. Beasley R, Pearce N, Crane J, Burgess C. Beta-agonists: what is the evidence that their use increases the risk of asthma morbidity and mortality? J Allergy Clin Immunol 1999;104:S18–S30.[CrossRef][Medline]
  3. Sears MR. Adverse effects of beta-agonists. J Allergy Clin Immunol 2002;110:S322–S328.[CrossRef][Medline]
  4. Ernst P, Habbick B, Suissa S, Hemmelgarn B, Cockroft D, Buist AS, Horwitz RI, McMutt M, Spitzer WO. Is the association between inhaled beta-agonist use and life-threaening asthma because of confounding severity? Am Rev Respir Dis 1993;148:75–79.[Medline]
  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. Sears MR, Taylor DR, Print CG, Lake DG, Li Q, Flannery EM, Yates DM, Lucas MK, Herbison GP. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990;336:1391–1396.[CrossRef][Medline]
  7. 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]
  8. 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.
  9. Chong LK, Morice AH, Yeo WW, Schleimer RP, Peachell PT. Functional desensitization of beta agonist responses in human lung mast cells. Am J Respir Cell Mol Biol 1995;13:540–546.[Abstract]
  10. Barnes PJ. Effect of beta agonists on inflammatory cells. J Allergy Clin Immunol 1999;104:10–17.
  11. O'Connor BJ, Aikman SL, Barnes PJ. Tachyphylaxis to terbutaline in asthma: evidence for a greater effect on airway mast cells than in airway smooth muscle. Am Rev Respir Dis 1992;146:560–564.[Medline]
  12. O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the non-bronchodilator effects of inhaled beta2-agonists. N Engl J Med 1992;327:1204–1208.[Abstract]
  13. Cockroft D, McParrand CP, Britto SA, Swystun VA, Rutherford C. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993;342:833–837.[CrossRef][Medline]
  14. Hancox RJ, Subbarao P, Kamada D, Watson RM, Hargreave FE, Inman MD. beta2-Agonist tolerance and exercise-induced bronchospasm. Am J Respir Crit Care Med 2002;165:1068–1070.[Abstract/Free Full Text]
  15. Page CP, Morley J. Contrasting properties of albuterol stereoisomers. J Allergy Clin Immunol 1999;104:S31–S41.[CrossRef][Medline]
  16. Mitra S, Ugur M, Ugur O, Goodman HM, McCullough JR, Yamaguchi H. (S)-albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle. Mol Pharmacol 1998;53:347–354.[Abstract/Free Full Text]
  17. Agrawal DK, Ariyarathna K, Kelbe PW. (S)-albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells. J Allergy Clin Immunol 2004;113:503–510.[CrossRef][Medline]
  18. Templeton AG, Chapman ID, Chilvers ER, Morley J, Handley DA. Effects of S-salbutamol on human isolated bronchus. Pulm Pharmacol Ther 1998;11:1–6.[CrossRef][Medline]
  19. Mazzoni L, Naef R, Chapman ID, Morley J. Hyperresponsiveness of the airways following exposure of guinea-pigs to racemic mixtures and distomers of beta2-selective sympathomimetics. Pulm Pharmacol 1994;7: 367–376.[CrossRef][Medline]
  20. Canning BJ. Modeling asthma and COPD in animals: a pointless exercise? Curr Opin Pharmacol 2003;3:244–250.[CrossRef][Medline]
  21. Barnes PJ. Scientific rationale for combination inhalers with a long-acting beta2-agonists and corticosteroids. Eur Respir J 2002;19:182–191.[Abstract/Free Full Text]
  22. Cho SH, Hartleroad JY, Oh CK. (S)-albuterol increases the production of histamine and IL-4 in mast cells. Int Arch Allergy Immunol 2001;124: 478–484.[CrossRef][Medline]
  23. Leff AR, Herrnreiter A, Naclerio RM, Baroody FM, Handley DA, Munoz NM. Effect of enantiomeric forms of albuterol on stimulated secretion of granular protein from human eosinophils. Pulm Pharmacol Ther 1997;10:97–104.[CrossRef][Medline]
  24. Baramki D, Koester J, Anderson AJ, Borish L. Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer. J Allergy Clin Immunol 2002;109:449–454.[CrossRef][Medline]
  25. Westerhof FJ, Zuidhof AB, Kok L, Meurs H, Zaagsma J. Effects of salbutamol and enantiomers on allergen-induced asthmatic reactions and airway hyperreactivity. Eur Respir J 2005;25:864–872.[Abstract/Free Full Text]
  26. Perrin-Fayolle M, Blum PS, Morley J, Grosclaude M, Chambe MT. Differential responses of asthmatic airways to enantiomers of albuterol: implications for clinical treatment of asthma. Clin Rev Allergy Immunol 1996;14:139–147.[Medline]
  27. Cockcroft DW, Swystun VA. Effect of single doses of S-salbutamol, R-salbutamol, racemic salbutamol, and placebo on the airway response to methacholine. Thorax 1997;52:845–848.[Abstract]
  28. Ramsay CM, Cowan J, Flannery E, McLachlan C, Taylor DR. Bronchoprotective and bronchodilator effects of single doses of (S)-salbutamol, (R)-salbutamol and racemic salbutamol in patients with bronchial asthma. Eur J Clin Pharmacol 1999;55:353–359.[CrossRef][Medline]
  29. Lotvall J, Palmqvist M, Arvidsson P, Maloney A, Ventresca GP, Ward J. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol 2001; 108:726–731.[CrossRef][Medline]
  30. Cockcroft DW, Davis BE, Swystun VA, Marciniuk DD. Tolerance to the bronchoprotective effect of beta2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. J Allergy Clin Immunol 1999;103:1049–1053.[CrossRef][Medline]
  31. Sjosward KN, Hmani M, Davidsson A, Soderkvist P, Schmekel B. Single-isomer R-salbutamol is not superior to racemate regarding protection for bronchial hyperresponsiveness. Respir Med 2004;98:990–999.[CrossRef][Medline]
  32. Gumbhir-Shah K, Kellerman DJ, DeGraw S, Koch P, Jusko WJ. Pharmacokinetics and pharmacodynamics of cumulative single doses of inhaled salbutamol enantiomers in asthmatic subjects. Pulm Pharmacol Ther 1999;12:353–362.[CrossRef][Medline]
  33. Dhand R, Goode M, Reid R, Fink JB, Fahey PJ, Tobin MJ. Preferential pulmonary retention of (S)-albuterol after inhalation of racemic albuterol. Am J Respir Crit Care Med 1999;160:1136–1141.[Abstract/Free Full Text]
  34. Ward JK, Dow J, Dallow N, Eynott P, Milleri S, Ventresca GP. Enantiomeric disposition of inhaled, intravenous and oral racemic-salbutamol in man–no evidence of enantioselective lung metabolism. Br J Clin Pharmacol 2000;49:15–22.[Medline]
  35. Nelson HS, Bensch G, Pleskow WW, DiSantostefano R, DeGraw S, Reasner DS, Rollins TE, Rubin PD. Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. J Allergy Clin Immunol 1998;102:943–952.[CrossRef][Medline]
  36. Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS. The safety and efficacy of nebulized levalbuterol compared with racemic albuterol and placebo in the treatment of asthma in pediatric patients. J Allergy Clin Immunol 1999;103:615–621.[CrossRef][Medline]
  37. Milgrom H, Skoner DP, Bensch G, Kim KT, Claus R, Baumgartner RA. Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol 2001;108:938–945.[CrossRef][Medline]
  38. Ahrens R, Weinberger M. Levalbuterol and racemic albuterol: are there therapeutic differences? J Allergy Clin Immunol 2001;108:681–684.[CrossRef][Medline]
  39. Carl JC, Myers TR, Kirchner HL, Kercsmar CM. Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. J Pediatr 2003;143:731–736.[CrossRef][Medline]
  40. Hardasmalani MD, DeBari V, Bithoney WG, Gold N. Levalbuterol versus racemic albuterol in the treatment of acute exacerbation of asthma in children. Pediatr Emerg Care 2005;21:415–419.[CrossRef][Medline]
  41. Qureshi F, Zaritsky A, Welch C, Meadows T, Burke BL. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of acute pediatric asthma. Ann Emerg Med 2005;46:29–36.[CrossRef][Medline]
  42. Fozard JR, Buescher H. Comparison of the anti-bronchoconstrictor activities of inhaled formoterol, its (R,R)- and (S,S)-enantiomers and salmeterol in the rhesus monkey. Pulm Pharmacol Ther 2001;14:289–295.[CrossRef][Medline]
  43. Lotvall J, Palmqvist M, Ankerst J, Persson G, Rosenborg J, Bengtsson T, Rott Z, Poczi M, Devai A, Waldeck B. The effect of formoterol over 24 h in patients with asthma: the role of enantiomers. Pulm Pharmacol Ther 2005;18:109–113.[CrossRef][Medline]




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Barnes, P. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barnes, P. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2006 American Thoracic Society