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• W1973148624 abstract "In a 1998 report in the JACI, Nelson et al1Nelson HS Bensch G Pleskow WW. DiSantostefano R DeGraw S Reasner DS et al.Improved bronchodilation with levalbuterol compare with racemic albuterol in patients with asthma.J Allergy Clin Immunol. 1998; 102: 943-952Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar concluded that levalbuterol (the generic name for R-albuterol administered as a single enantiomer) had a better therapeutic ratio than racemic albuterol (which contains both the R- and S-enantiomers of albuterol). The following year, Gawchik et al2Gawchik 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: 615-621Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar likewise concluded that levalbuterol had fewer β-agonist–mediated side effects than racemic albuterol when administered in doses that produce similar efficacy. Handley et al3Handley DA Tinkelman D Noonan M Rollins TE Snider ME Caron J Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.J Asthma. 2000; 37: 319-327Crossref PubMed Scopus (37) Google Scholar also reported that nebulized levalbuterol, in doses yielding comparable bronchodilation, had fewer β-agonist–mediated side effects than nebulized racemic albuterol (R,S-albuterol). All 3 reports implied that levalbuterol had a therapeutic advantage over racemic albuterol because less R-albuterol was required to produce the same degree of efficacy when administered as levalbuterol than when administered in a racemic formulation. Negative effects of the Senantiomer were proposed as the explanation for this. The lower dose of R-albuterol (levalbuterol), in turn, resulted in fewer systemic effects for the same degree of bronchodilator efficacy (ie, a better “therapeutic ratio”).However, in a report appearing in this month's issue of the Journal, Lötvall et al4Lötvall 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: 726-731Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar arrived at a different conclusion. They failed to find any difference between the therapeutic ratios for levalbuterol and the racemic formulation. Specifically, they found that all pharmacologic effects of racemic albuterol reside with levalbuterol (the R-enantiomer) and that the S-albuterol was clinically inactive. Why the difference, and which conclusion should guide therapeutic decision-making?Concerns about potential adverse effects of S-albuterol were first supported by results obtained from preclinical animal and in vitro models.5Mazzoni L Naef R Chapman ID Morley J. Hyperresponsiveness of the airways following exposure of guinea-pigs to racemic mixtures and distomers of β2 selective sympathomimetics.Pulm Pharmacol. 1994; 7: 367-376Crossref PubMed Scopus (79) Google Scholar, 6Leff RA 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: 97-104Crossref PubMed Scopus (42) Google Scholar, 7Handley DA McCullough JR Crowther SD Morley J Sympathomimetic enantiomers and asthma.Chirality. 1998; 10: 262-272Crossref PubMed Scopus (37) Google Scholar These studies, previously reviewed in the pages of this Journal,8Waldeck B. Enantiomers of bronchodilating β2-adrenoceptor agonists: is there a cause for concern?.J Allergy Clin Immunol. 1999; 103: 742-748Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 9Nelson HS Clinical experience with levalbuterol.J Allergy Clin Immunol. 1999; 104: S77-S84Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 10Handley D The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists.J Allergy Clin Immunol. 1999; 104: S69-S76Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar indicated that S-albuterol had proinflammatory effects, increased airway smooth muscle responsiveness to LTC4 and histamine, and acted in opposition to the airway protective effects of R-albuterol (levalbuterol) against antigen-induced bronchospasm.On the basis of these preclinical studies, clinically relevant adverse effects of S-albuterol in human beings were postulated.10Handley D The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists.J Allergy Clin Immunol. 1999; 104: S69-S76Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar These included the following: diminution of the efficacy of R,S-albuterol by working in opposition to the bronchodilator and bronchoprotective effects of R-albuterol; the development of tolerance to beneficial effects of R,S-albuterol with repeated use, based on the preferential accumulation of S-albuterol versus R-albuterol in the lung; increased airway responsiveness, possibly due to proinflammatory effects of S-albuterol; and the potential for producing paradoxical bronchospasm. The potential for these clinically important adverse effects from S-albuterol provided the rationale for clinical development of a nebulized formulation of relatively pure R-albuterol (levalbuterol) and its marketing under the trade name Xopenex.Because the conclusions of Lötvall et al4Lötvall 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: 726-731Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar in this issue of the Journal conflict with those in the other publications noted above,1Nelson HS Bensch G Pleskow WW. DiSantostefano R DeGraw S Reasner DS et al.Improved bronchodilation with levalbuterol compare with racemic albuterol in patients with asthma.J Allergy Clin Immunol. 1998; 102: 943-952Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 2Gawchik 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: 615-621Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 3Handley DA Tinkelman D Noonan M Rollins TE Snider ME Caron J Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.J Asthma. 2000; 37: 319-327Crossref PubMed Scopus (37) Google Scholar it is appropriate to reexamine the weight of evidence from all of the published clinical trials that have attempted to test the hypothesized adverse effects of S-albuterol and the associated potential benefits of using levalbuterol rather than racemic albuterol.Hypothesis: S-albuterol works in opposition to the bronchodilator and bronchoprotective effects of R-albuterolIf true in human beings, this adverse effect of S-albuterol would cause R-albuterol, administered as levalbuterol, to be significantly more potent than an equal amount of R-albuterol given in the racemic formulation. Let us first look in more detail at the studies whose conclusions supported this hypothesis. The study by Nelson et al evaluated the bronchodilator effects of the levalbuterol and racemic formulations in 362 adolescent and adult subjects treated with levalbuterol, racemic albuterol, or placebo 3 times daily for 4 weeks. Two doses of each formulation were given: 630 and 1250 μg of levalbuterol and 1250 and 2500 μg of the racimate. These doses were matched to deliver the same quantities of R-albuterol (ie, 630 and 1250 μg). The mean peak change in FEV1 from baseline that occurred with the active regimens ranged from approximately 35% to 42%. Given the mean baseline FEV1 of approximately 60% of predicted, this is consistent with postbronchodilator values that differed very little, averaging from approximately 81% to 85% of predicted for each of the active regimens. Although the mean differences between active regimens were small, a statistically significant difference was found between levalbuterol and the racemic preparation after the first dose, though not after 4 weeks of 3-times-a-day treatment.In a study of 43 children, Gawchik et al2Gawchik 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: 615-621Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar compared 4 single doses of levalbuterol, ranging from 160 to 1250 μg, with 1250- and 2500-μg doses of the racemic formulation. Although all regimens provided a significant bronchodilator effect in comparison with placebo, no significant difference in bronchodilator effect could be demonstrated between any of the active regimens.The report of Handley et al3Handley DA Tinkelman D Noonan M Rollins TE Snider ME Caron J Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.J Asthma. 2000; 37: 319-327Crossref PubMed Scopus (37) Google Scholar compared several doses of levalbuterol, ranging from 310 to 1250 μg, with a 2500-μg dose of the racemic formulation. No significant differences between active regimens were reported among the 20 adult subjects.Authors of all 3 of these studies1Nelson HS Bensch G Pleskow WW. DiSantostefano R DeGraw S Reasner DS et al.Improved bronchodilation with levalbuterol compare with racemic albuterol in patients with asthma.J Allergy Clin Immunol. 1998; 102: 943-952Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 2Gawchik 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: 615-621Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 3Handley DA Tinkelman D Noonan M Rollins TE Snider ME Caron J Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.J Asthma. 2000; 37: 319-327Crossref PubMed Scopus (37) Google Scholar found similar bronchodilatation for the 630-μg dose of levalbuterol and the 2500-μg dose of racemic albuterol. This has been taken to indicate that levalbuterol as the single enantiomer has a better therapeutic index by being more effective and having less potential for adverse effects in the absence of the S-enantiomer.However, none of these studies provides strong support for the hypothesis that R-albuterol is more potent when administered as levalbuterol than when administered in the racemic formulation. In fact, the results of each of these studies violate the basic validity criteria that apply to investigations intended to compare the potencies of formulations.12Ahrens RC On comparing beta adrenergic agonists.Ann Allergy. 1991; 67: 296-298PubMed Google Scholar, 13Finney DJ. Statistical methods in biological assay.in: 3rd ed. : Charles Griffin & Co, London1978: 105-147Google Scholar Such violation occurs in more than one way, but the most important is this: none of these studies was able to demonstrate a significant dose-response relationship. Stated another way: If these studies cannot detect differences between different doses of the same formulation, then they clearly are inadequate to evaluate and quantitate differences between different formulations.Rigorous methods for comparing and estimating differences in potency of inhaled β-agonist formulations have been published.12Ahrens RC On comparing beta adrenergic agonists.Ann Allergy. 1991; 67: 296-298PubMed Google Scholar, 14Ahrens RC Hendeles L Clarke WR Dockhorn RJ Hill MR Vaughan LM et al.Therapeutic equivalence of Spiros DPI and Ventolin MDI: a bioassay using methacholine.Am J Respir Crit Care Med. 1999; 160: 1238-1243Crossref PubMed Scopus (28) Google Scholar, 15Parameswaran KN Inman MD Ekholm BP Morris MM Summers E O'Byrne PM et al.Protection against methacholine bronchoconstriction to assess relative potency of inhaled beta2-agonist.Am J Respir Crit Care Med. 1999; 160: 354-357Crossref PubMed Scopus (47) Google Scholar, 16Stewart BA Ahrens RC Carrier S Frosolono M Lux C Han S-H et al.Demonstration of in vivo bioequivalence of the Norton generic albuterol metered-dose inhaler to Ventolin.Chest. 2000; 117: 714-721Crossref PubMed Scopus (28) Google Scholar These methods use bioassay study design and statistical analyses to estimate differences in potency and are capable of making such estimates with a high degree of precision. The study by Lötvall et al,4Lötvall 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: 726-731Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar reported in this issue of the Journal, is the first to use statistical bioassay methodology to estimate the relative potency of levalbuterol and racemic albuterol. The authors examined the results of progressively increasing doses of R- or S-albuterol ranging from 625 to 3200 μg as the individual enantiomers and combined in the racemic formulation. The potency ratio that they calculated for R- versus R,S-albuterol was 1.9, indicating that each microgram of levalbuterol was equivalent to 1.9 μg of racemic albuterol. The 95% CI encompassed a relative potency of 2, as would be expected if all pharmacologic effects of racemic albuterol were entirely from the R-enantiomer. In other words, the pharmacologic activity of the Renantiomer was the same when the single enantiomer (levalbuterol) was used as when the S-enantiomer was also present, as in the racemic formulation. Although this study can be criticized for using a cumulative-dose design, which confounds the effects of time and dosing,17Asmus MJ, Ahrens RC, Clarke WR, Hendeles L. Therapeutic ratio of inhaled corticosteroids: fact or fiction [letter to the editor]? Am J Respir Crit Care Med. In press.Google Scholar the authors' approach nonetheless provides the most reliable estimates of differences in potency between levalbuterol and racemic albuterol available to date.Several other studies that have tested this hypothesis using albuterol-induced protection against methacholine challenge. Perrin-Fayolle,18Perrin-Fayolle M Salbutamol in the treatment of asthma [letter].Lancet. 1995; 346: 1101Abstract Full Text PDF PubMed Scopus (50) Google Scholar in a brief report published as a letter in The Lancet , described enhanced protection against methacholine challenge when levalbuterol (identified as D-salbutamol in the report) was administered as the single enantiomer in comparison with racemic albuterol and reported that S-salbutamol (identified as L-salbutamol in the report) increased airway sensitivity to methacholine. However, the differences observed between levalbuterol and the racemic formulation were not statistically significant, and others have failed to find any evidence of a difference in bronchoprotective or bronchodilator effect between R-albuterol given alone and R-albuterol given at the equivalent dose in the racemic formulation.19Cockcroft 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: 845-848Crossref PubMed Scopus (70) Google Scholar, 20Ramsay 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: 353-359Crossref PubMed Scopus (49) Google ScholarThe weight of evidence thus supports neither the concept that S-albuterol works in opposition to the bronchodilator and bronchoprotective effects of R-albuterol nor the concept that there is any difference in R-albuterol potency when it is administered as a single enantiomer rather than in a racemic formulation.Hypothesis: S-albuterol is responsible for development of tolerance to the beneficial effects of R,S-albuterolIf true in human beings, this would cause the tolerance after repeated administration of levalbuterol to be absent or at least smaller in magnitude than that associated with racemic albuterol. Only a study by Cockcroft et al21Cockcroft DW Davis BE Swystun VA Marciniuk DD. Tolerance to the bronchoprotective effect of β2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo.J Allergy Clin Immunol. 1999; 103: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar addresses this hypothesis. They administered R-albuterol alone, S-albuterol alone, racemic albuterol (all enantiomers in equimolar doses), or placebo for 6 days. On days 0 and 7, they evaluated the protective effect of the R-albuterol on methacholine responsiveness. They found a significant and equivalent degree of tolerance after R-albuterol and racemic albuterol treatment but not after S-albuterol or placebo treatment. This does not support the hypothesis that S-albuterol is involved in the induction of tolerance to bronchoprotective effects of albuterol and argues against the suggestion that less tolerance develops when R-albuterol is administered as the single enantiomer (levalbuterol) than when it is administered in a racemic formulation.Hypothesis: S-albuterol increases airway hyperresponsivenessIf true, this would result in less hyperresponsiveness after administration of levalbuterol than after administration of the racemic formulation. The study by Nelson et al showed that after 4 weeks of treatment there was a small increase in baseline FEV1 with placebo or levalbuterol but not with racemic albuterol. This was statistically significant only in a subgroup of subjects using inhaled corticosteroids. The authors suggested that this might have been due to an increase in airway responsiveness caused by the S-enantiomer.Four studies have directly tested this hypothesis using bronchoprovocation techniques.18Perrin-Fayolle M Salbutamol in the treatment of asthma [letter].Lancet. 1995; 346: 1101Abstract Full Text PDF PubMed Scopus (50) Google Scholar, 19Cockcroft 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: 845-848Crossref PubMed Scopus (70) Google Scholar, 20Ramsay 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: 353-359Crossref PubMed Scopus (49) Google Scholar, 21Cockcroft DW Davis BE Swystun VA Marciniuk DD. Tolerance to the bronchoprotective effect of β2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo.J Allergy Clin Immunol. 1999; 103: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar The brief report of Perrin-Fayolle18Perrin-Fayolle M Salbutamol in the treatment of asthma [letter].Lancet. 1995; 346: 1101Abstract Full Text PDF PubMed Scopus (50) Google Scholar indicated a significantly lower PC20 FEV1 to methacholine 3 hours after treatment with S-albuterol in comparison with placebo. However, the other 3 studies failed to find changes in responsiveness to methacholine or adenosine monophosphate from inhalation of single19Cockcroft 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: 845-848Crossref PubMed Scopus (70) Google Scholar, 20Ramsay 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: 353-359Crossref PubMed Scopus (49) Google Scholar or multiple21Cockcroft DW Davis BE Swystun VA Marciniuk DD. Tolerance to the bronchoprotective effect of β2-agonists: comparison of the enantiomers of salbutamol with racemic salbutamol and placebo.J Allergy Clin Immunol. 1999; 103: 1049-1053Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar doses of S-albuterol.Thus evidence in support of the hypothesis that S-albuterol increases airway hyperresponsiveness is at best inconclusive.Hypothesis: S-albuterol is responsible for inducing some or all of the paradoxical bronchospasm seen with racemic albuterolIf true, this would result in a lower incidence of paradoxical bronchospasm after treatment with R-albuterol than after treatment with R,S-albuterol. Unfortunately, there are no studies that directly test this hypothetical adverse effect of S-albuterol.Hypothesis: S-albuterol itself causes some of the systemic effects seen with inhaled albuterolNo authors of published preclinical studies or of papers that reviewed these studies have actually posed this hypothesis. Nonetheless, 2 other groups of authors have addressed this issue in normal volunteers.22Lipworth BJ Clark DJ Koch P Arbeeny C Pharmacokinetics and extrapulmonary beta 2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers.Thorax. 1997; 52: 849-852Crossref PubMed Scopus (46) Google Scholar, 23Pancu D Evans E LaFalmmer M Melanson S Stromski C Reed J How does the potassium-lowering effect of inhaled levalbuterol compare to that of standard albuterol?.Acad Emerg Med. 2001; 8: 496Google Scholar In addition, the current report by Lötvall et al4Lötvall 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: 726-731Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar addresses the issue in subjects with asthma. All of these reports concluded that all observed systemic effects of racemic albuterol are due to the R-enantiomer.So where are we now regarding a basis for decision-making? Although the preclinical data remain intriguing, available clinical data provide little support for the routine use of levalbuterol over the racemic formulation. Perhaps adverse effects of S-albuterol can be demonstrated in more severely ill asthmatic patients seen in the emergency room or intensive care unit when much larger doses are given for sustained periods. Studies in these clinical settings using appropriate methodology would be of interest.Table IRange of costs per usual dose for different formulations of albuterol aerosol preparations taken from 4 major online-pharmacy Web sitesProducePrice range per dose (US $)Xopenex (0.63 or 1.25 mg/3 mL)1.91 - 2.17Albuterol (2.5 mg/3 mL)0.80 - 0.88Albuterol MDI(200 inhalations, 2 inhalations/dose)0.14 - 0.20 Open table in a new tab In a 1998 report in the JACI, Nelson et al1Nelson HS Bensch G Pleskow WW. DiSantostefano R DeGraw S Reasner DS et al.Improved bronchodilation with levalbuterol compare with racemic albuterol in patients with asthma.J Allergy Clin Immunol. 1998; 102: 943-952Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar concluded that levalbuterol (the generic name for R-albuterol administered as a single enantiomer) had a better therapeutic ratio than racemic albuterol (which contains both the R- and S-enantiomers of albuterol). The following year, Gawchik et al2Gawchik 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: 615-621Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar likewise concluded that levalbuterol had fewer β-agonist–mediated side effects than racemic albuterol when administered in doses that produce similar efficacy. Handley et al3Handley DA Tinkelman D Noonan M Rollins TE Snider ME Caron J Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.J Asthma. 2000; 37: 319-327Crossref PubMed Scopus (37) Google Scholar also reported that nebulized levalbuterol, in doses yielding comparable bronchodilation, had fewer β-agonist–mediated side effects than nebulized racemic albuterol (R,S-albuterol). All 3 reports implied that levalbuterol had a therapeutic advantage over racemic albuterol because less R-albuterol was required to produce the same degree of efficacy when administered as levalbuterol than when administered in a racemic formulation. Negative effects of the Senantiomer were proposed as the explanation for this. The lower dose of R-albuterol (levalbuterol), in turn, resulted in fewer systemic effects for the same degree of bronchodilator efficacy (ie, a better “therapeutic ratio”). However, in a report appearing in this month's issue of the Journal, Lötvall et al4Lötvall 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: 726-731Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar arrived at a different conclusion. They failed to find any difference between the therapeutic ratios for levalbuterol and the racemic formulation. Specifically, they found that all pharmacologic effects of racemic albuterol reside with levalbuterol (the R-enantiomer) and that the S-albuterol was clinically inactive. Why the difference, and which conclusion should guide therapeutic decision-making? Concerns about potential adverse effects of S-albuterol were first supported by results obtained from preclinical animal and in vitro models.5Mazzoni L Naef R Chapman ID Morley J. Hyperresponsiveness of the airways following exposure of guinea-pigs to racemic mixtures and distomers of β2 selective sympathomimetics.Pulm Pharmacol. 1994; 7: 367-376Crossref PubMed Scopus (79) Google Scholar, 6Leff RA 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: 97-104Crossref PubMed Scopus (42) Google Scholar, 7Handley DA McCullough JR Crowther SD Morley J Sympathomimetic enantiomers and asthma.Chirality. 1998; 10: 262-272Crossref PubMed Scopus (37) Google Scholar These studies, previously reviewed in the pages of this Journal,8Waldeck B. Enantiomers of bronchodilating β2-adrenoceptor agonists: is there a cause for concern?.J Allergy Clin Immunol. 1999; 103: 742-748Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 9Nelson HS Clinical experience with levalbuterol.J Allergy Clin Immunol. 1999; 104: S77-S84Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 10Handley D The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists.J Allergy Clin Immunol. 1999; 104: S69-S76Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar indicated that S-albuterol had proinflammatory effects, increased airway smooth muscle responsiveness to LTC4 and histamine, and acted in opposition to the airway protective effects of R-albuterol (levalbuterol) against antigen-induced bronchospasm. On the basis of these preclinical studies, clinically relevant adverse effects of S-albuterol in human beings were postulated.10Handley D The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists.J Allergy Clin Immunol. 1999; 104: S69-S76Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar These included the following: diminution of the efficacy of R,S-albuterol by working in opposition to the bronchodilator and bronchoprotective effects of R-albuterol; the development of tolerance to beneficial effects of R,S-albuterol with repeated use, based on the preferential accumulation of S-albuterol versus R-albuterol in the lung; increased airway responsiveness, possibly due to proinflammatory effects of S-albuterol; and the potential for producing paradoxical bronchospasm. The potential for these clinically important adverse effects from S-albuterol provided the rationale for clinical development of a nebulized formulation of relatively pure R-albuterol (levalbuterol) and its marketing under the trade name Xopenex. Because the conclusions of Lötvall et al4Lötvall 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: 726-731Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar in this issue of the Journal conflict with those in the other publications noted above,1Nelson HS Bensch G Pleskow WW. DiSantostefano R DeGraw S Reasner DS et al.Improved bronchodilation with levalbuterol compare with racemic albuterol in patients with asthma.J Allergy Clin Immunol. 1998; 102: 943-952Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 2Gawchik 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: 615-621Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 3Handley DA Tinkelman D Noonan M Rollins TE Snider ME Caron J Dose-response evaluation of levalbuterol versus racemic albuterol in patients with asthma.J Asthma. 2000; 37: 319-327Crossref PubMed Scopus (37) Google Scholar it is appropriate to reexamine the weight of evidence from all of the published clinical trials that have attempted to test the hypothesized" @default.
• W1973148624 created "2016-06-24" @default.
• W1973148624 creator A5053429396 @default.
• W1973148624 creator A5057739578 @default.
• W1973148624 date "2001-11-01" @default.
• W1973148624 modified "2023-10-14" @default.
• W1973148624 title "Levalbuterol and racemic albuterol: Are there therapeutic differences?" @default.
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