Asthma, Rhinitis, Other Respiratory Diseases
The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients,☆☆

https://doi.org/10.1067/mai.2001.119152Get rights and content

Abstract

Background: It has been suggested that R-albuterol produces bronchodilation that is comparable with that of racemic albuterol (RS-albuterol) on a 4:1 dose-for-dose basis but systemic side effects on a 2:1 basis, implying better therapeutic ratio for R-albuterol. Objective: We sought to carefully compare the bronchodilating and systemic effects of R- and RS-albuterol by using a crossover study design. Methods: Twenty asthmatic patients (15.1%-28.7% FEV1 reversibility) were given R-albuterol (6.25-1600 μg), S-albuterol (6.25-1600 μg), RS-albuterol (12.5-3200 μg), or placebo in a crossover, double-blind, placebo-controlled fashion. Cumulative doses were given with a Mefar dosimeter, and FEV1, heart rate, and plasma K+ levels were measured 20 minutes after each dose. Results: Both R- and RS-albuterol produced dose-related improvement in FEV1 and, at higher doses, increased heart rate and decreased plasma K+ levels. Neither placebo nor S-albuterol had any significant effect. Individual estimates of the potency ratio for R-albuterol/RS-albuterol were calculated and summarized across all subjects. The geometric mean potency ratio for effects on FEV1 was 1.9 (95% CI, 1.3-2.8), on HR of 1.9 (95% CI, 1.3-2.9), and on K+ level of 1.7 (95% CI, 1.3-2.1). Conclusion: All pharmacologic effects of RS-albuterol reside with the R-enantiomer, and S-albuterol is clinically inactive. The R-albuterol/RS-albuterol potency ratios for local (FEV1) and systemic effects (heart rate and K+) are similar, suggesting a comparable therapeutic ratio for R-albuterol and RS-albuterol in asthmatic subjects. (J Allergy Clin Immunol 2001;108:726-31.)

Section snippets

Methods

The study was approved by the Göteborg University Ethics Committee, and all patients gave their full written informed consent before entry into the study. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Trial Practice, and prior approval was obtained from the Swedish Medical Products Agency. The sponsor (GlaxoWellcome) monitored the study.

Pharmacodynamics

Both R- and RS-albuterol (6.25-3600 μg) produced significant and dose-dependent increases in FEV1 (Fig 1).

. Mean effect of inhaled R-albuterol (6.25-1600 μg), S-albuterol (6.25-1600 μg), RS-albuterol (12.5-3200 μg), and placebo on FEV1 in 20 patients with mild asthma.

All doses significantly improved FEV1 versus the effects of placebo. The dose-response curve did not consistently plateau at the higher doses of R- and RS-albuterol tested. At the highest doses of R- and RS-albuterol (ie, 1600 and

Discussion

This study, using a more than two-10log cumulative dose-response design, shows that R- and RS-albuterol have a 2:1 potency ratio for improvement in FEV1 in asthmatic patients and shows that S-albuterol is clinically inactive. Because the RS-albuterol mixture contains only 50% R-albuterol, it is clear that the clinical effect of albuterol resides with the R-enantiomer. Furthermore, the therapeutic ratios of R- and RS-albuterol are very similar, suggesting that the S-enantiomer of albuterol does

Acknowledgements

We thank Drs Karina Joyce and Stephen Pleasance (International Bioanalysis) and Dr Malcolm York (Clinical Pathology), Glaxo-Wellcome R&D Ltd, Ware, United Kingdom) for their bioanalytic support. We also thank Helen Törnqvist, Eva Karlgren, and Marianne Robertsson of the Lung Pharmacology Group, Göteborg University, Sweden, for their help with the clinical phase of the study.

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Supported by a grant from Glaxo Wellcome Research & Development Limited.

☆☆

Reprint requests: Jan Lötvall, MD, PhD, Department of Respiratory Medicine and Allergology, Göteborg University, S-413 45 Gothenburg, Sweden.

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