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(Chest. 2000;118:321-328.)
© 2000 American College of Chest Physicians

Functional Antagonism With Formoterol and Salmeterol in Asthmatic Patients Expressing the Homozygous Glycine-16 ß2-Adrenoceptor Polymorphism*

Brian J. Lipworth, MD; Owen J. Dempsey, MBChB and Imran Aziz, MBBS

* From the Asthma and Allergy Research Group, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.

Correspondence to: Brian J. Lipworth, MD, Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; e-mail:b.j.lipworth{at}dundee.uk


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Formoterol and salmeterol differ in their relative intrinsic activity at airway ß2-adrenoceptors, with formoterol being a full agonist. The homozygous glycine-16 polymorphism of the ß2-adrenoceptor occurs in approximately 40% of patients and is known to predispose to agonist-induced downregulation and desensitization.

Objectives: To evaluate possible differences in intrinsic ß2-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction (the primary end point) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism.

Methods: Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were randomized to completion (mean [SEM] age, 35.8 [3.2] years; mean FEV1, 76.9 [2.5]% predicted). Patients received three different treatments for 1 week in randomized, double-blind, crossover fashion, with a 1-week washout period between treatments: formoterol, 12 µg bid; salmeterol, 50 µg bid; and placebo. For each of the randomized treatment periods, there were three separate methacholine challenges: baseline after washout, 12 h after the first dose, and 12 h after the last dose.

Results: Both salmeterol and formoterol exhibited significantly (p < 0.05) greater bronchoprotection than placebo for their effects after single or repeated dosing, although there was no significant difference between the two drugs. The geometric mean fold protection vs placebo (95% confidence interval [CI]) for the first dose was 1.6-fold (95% CI, 1.1 to 2.2) for salmeterol and 1.9-fold (95% CI, 1.1 to 3.2) for formoterol, and for last dose was 1.6-fold (95% CI, 1.2 to 2.3) for salmeterol and 1.9-fold (95% CI, 1.2 to 2.8) for formoterol. Salmeterol and formoterol produced significant (p < 0.05) increases in FEV1 and forced expiratory flow after 25 to 75% of vital capacity has been expelled, after the first but not the last dose compared to placebo, while there were significant (p < 0.05) improvements in domiciliary peak flows during treatment with both drugs.

Conclusion: Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype. There was a significant residual degree of bronchoprotection after 1 week of treatment, which was not significantly different compared to the first-dose effect.

Key Words: asthma • ß2-adrenoceptor • formoterol • methacholine • polymorphism • salmeterol


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled long-acting ß2-agonists such as formoterol or salmeterol have an established position in asthma management guidelines as second-line controller therapy in conjunction with inhaled corticosteroids.1 Their position is based on clinical studies showing that adding in a long-acting ß2-agonist to an inhaled corticosteroid is as effective as doubling the dose of inhaled corticosteroid in terms of controlling exacerbation rates.2 3 4 5 Inhaled long-acting ß2-agonists exhibit bronchodilator effects in the presence of resting bronchomotor tone, as well as exhibiting bronchoprotective effects in the presence of increased bronchomotor tone. The degree of intrinsic activity at airway ß2-adrenoceptors is conventionally evaluated by measuring the protection afforded against bronchoconstrictor stimuli such as carbachol or methacholine (ie, functional antagonism). For example, in an in vitro study with carbachol-contracted human airway, in comparison to isoprenaline (as 1.0) the relative intrinsic activity of formoterol and salmeterol was 0.84 and 0.36, respectively.6

Regular bid administration of long-acting ß2-agonists results in downregulation and desensitization of airway ß2-adrenoceptors, which is more marked for their bronchoprotective than bronchodilator effects.7 In vitro studies have shown that allelic polymorphisms of the ß2-adrenoceptor at codon 16 and 27 determine the degree of agonist-induced receptor downregulation and desensitization.8 The glycine polymorphism at codon 16 confers relative increased susceptibility to downregulation compared with the arginine polymorphism, whereas the glutamic acid polymorphism at codon 27 confers relative resistance compared with the glutamine polymorphism. The homozygous glycine-16 genotype is common in the general population, occurring with a prevalence of approximately 40%.9 In vivo studies have shown that the homozygous glycine-16 genotype predisposes to bronchodilator desensitization in asthmatic patients receiving regular bid inhaled formoterol, with the influence of the glycine-16 polymorphism dominating over any protective effects of the glutamic acid-27 polymorphism.10 In another study, formoterol-induced desensitization for peak bronchoprotection against methacholine was found to occur readily irrespective of ß2-adrenoceptor polymorphism at codon 16 or 27, although interpretation of the data was limited due to small sample size for the different genotypes and formoterol dosing regimes.11

The objective of the present study was to evaluate possible differences in intrinsic ß2-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction in genetically susceptible patients who exhibit the homozygous glycine-16 polymorphism. In order to be consistent with the recommended guidelines, we evaluated the effects only in patients who were already receiving inhaled corticosteroid therapy, as well as evaluating usual recommended twice daily doses of both drugs. We also decided to perform the methacholine challenges at the end of the usual 12-h dosing interval, to coincide with the period when the airway is most vulnerable to bronchoconstrictor stimuli.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
We studied patients between the ages of 18 and 65 years who had an established diagnosis of stable mild-to-moderate persistent asthma, with a minimum duration of 12 months according to American Thoracic Society criteria12 and a FEV1 > 60% of predicted normal value. In all subjects, the provocative dose of methacholine causing a 20% fall in FEV1 (PD20) was required to be < 500 µg with at least a fourfold increase in PD20 30 min after inhaling 400 µg of salbutamol (two challenges performed on consecutive days). Patients were required to be taking inhaled corticosteroids at a constant dose for at least 3 months prior to the initial screening visit. Patients were excluded if they had been treated with oral corticosteroids in the past 6 months or had a history of recent respiratory tract infection within the past 3 months, or had smoked cigarettes within the previous 12 months. The patients were all using short-acting ß2-agonists (salbutamol or terbutaline) on an occasional on-demand basis at a dose less than four puffs per day. None were using long-acting ß2-agonists or theophyllines. All of the patients gave written informed consent for the study, which was approved by the Tayside Committee for Medical Research Ethics.

Study Design
Patients were enrolled into a randomized double blind cross-over design (Fig 1 ) to receive treatment for 1 week with each of the following: (1) salmeterol xinafoate, 50 µg bid (Serevent Accuhaler, 50 µg per actuation; Glaxo-Wellcome, Uxbridge, UK), (2) formoterol fumarate, 12 µg bid (Oxis Turbohaler, 12 µg per actuation; Astra Pharmaceuticals; Kings Langley, UK), and (3) placebo Turbohaler and placebo Accuhaler, both one puff bid. Patients were given a placebo Turbohaler to use in addition to their active salmeterol Accuhaler and were also given a placebo Accuhaler in addition to their active formoterol Turbohaler. All inhalers were dispensed by a third party in sealed boxes with their labels removed or masked. Patients were instructed to take their study inhalers at the same time in the morning between 8:00 AM and 10:00 AM, and in the evening between 8:00 PM and 10:00 PM. All study inhalers were withheld for 12 h prior to each methacholine challenge.



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  		Figure 1.. Schematic flow chart of study design. Arrow = laboratory visit for methacholine challenge and spirometry. These occurred at the end of the placebo run-in or washout (unprotected baseline, visit 1), 12 h after the first dose (visit 2), and 12 h after the last dose (visit 3) of each randomized treatment block. Asterisk = randomized treatments administered in crossover fashion were either salmeterol xinafoate, 50 µg bid via the Accuhaler; formoterol fumarate, 12 µg bid via Turbuhaler; and placebo, one puff bid.

 
Prior to the first randomized treatment and between the three randomized treatments, there was a 1-week washout period when all ß2-agonist therapy was withdrawn. Inhaled ipratropium bromide (two puffs; Atrovent Forte 40 µg per puff; Boehringer Ingelheim; Bracknell, UK) was used as required for symptomatic relief purposes as first-line rescue, with inhaled salbutamol (Ventolin 100 µg per puff, Glaxo-Wellcome, Uxbridge, UK) as second-line rescue. First or second-line rescue therapy was withheld for at least 12 h prior to each methacholine challenge.

The patients attended the laboratory for an unprotected challenge on one occasion after each of the three washout periods and subsequently on the next day for a protected challenge 12 h after the first dose (having been taken the previous evening). Patients also had a protected challenge 12 h after the last dose of each of the 1-week treatment periods. Hence, each of three randomized treatment periods comprised three separate challenges: unprotected baseline (visit 1), protected first dose (visit 2), and protected last dose (visit 3), a total of nine challenges. All methacholine bronchial challenges were performed at the same time in the morning for each subject between 8:00 AM and 10:00 AM, to coincide with 12 h after the previous first or last dose of each randomized treatment. Patients also kept a diary card during each washout and treatment period to record their peak flow (AM and PM) and rescue inhaler use.

Patients received written and verbal instructions on proper inhaler technique at screening and at each of the study visits. For this purpose in order to ensure an adequate peak inspiratory flow-rate, an inhaler assessment device (In-check; Clement Clarke International Limited; Harlow, UK) was used with both Turbohaler and Accuhaler impedance attachments. Patients were also requested to mark the time of taking each study drug on their diary card, and at least 90% compliance was required to be considered as to be evaluable data for the purposes of analysis. Treatments were randomly allocated in three balanced blocks.

Measurements
Spirometry was performed according to American Thoracic Society criteria13 using a Vitalograph compact spirometer (Vitalograph Limited; Buckinghamshire, UK), with a pneumotachograph head and pressure transducer and on-line computer-assisted determination of best test values for FEV1 and forced expiratory flow after 25 to 75% of vital capacity has been expelled (FEF25–75). The procedure for the methacholine challenge protocol was previously validated and has been described elsewhere.14 In brief, methacholine was administered in cumulative doubling doses from 3.125 to 6,400 µg with a microprocessor controlled dosimeter, at 5-min intervals until a 20% fall in FEV1 was recorded. The PD20 value was determined by computer-assisted logarithmic linear interpolation of the dose-response curve.

ß2-adrenoceptor polymorphisms were identified as described previously.16 In brief, genomic DNA was extracted from whole blood and a 234 base-pair fragment that spanned the regions of interest was generated by the polymerase chain reaction. The genotype was determined by allele-specific oligonucleotide hybridization with probes homologous for the arginine-16, glycine-16, glutamic acid-27, and glutamine-27 forms of the receptor.

Statistical Analysis
The data for PD20 were logarithmically transformed to normalize the distribution before analysis. The study was designed with at least 80% power to detect a twofold (one doubling dose) difference in PD20 (the primary end point) between active treatments and placebo using a crossover design. The PD20 value was calculated as a geometric mean (expressed in micrograms), and the geometric mean fold protection ratio was also calculated for both active treatments in comparison to placebo, for each visit (ie, baseline, first, or last dose). The statistical analysis was performed by multifactorial analysis of variance using subject, treatment, sequence and visit as factors. This was followed by Bonferroni multiple-range testing set at 95% confidence limits in order to investigate pairwise comparisons without confounding the {alpha} error. A probability value of p < 0.05 (two tailed) was considered to be significant. Results are given as being significant (p < 0.05) or nonsignificant (from the multiple-range test). The analysis was performed on a Statgraphics statistical software package (STSC Software Publishing Group; Rockville, MD).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All 18 randomized patients completed the nine study visits. There were 10 female patients, with mean (± SEM) age of 35.8 ± 3.2 years. Values at the initial screening visit (prior to the first washout) were as follows: mean FEV1, 2.54 ± 0.17 L, 76.9 ± 2.5 percent predicted; and mean FEF25–75, 2.26 ± 0.21 L/s, 56.1 ± 4.2 percent predicted. The geometric mean (± SEM) PD20 at the initial screening visit (before salbutamol, 400 µg) was 54 ± 14 µg and (after salbutamol, 400 µg) was 559 ± 170 µg. This amounted to a geometric mean 10.3-fold difference (95% confidence interval [CI], 4.6 to 23.0-fold) for after-before protection.

The mean daily dose of inhaled corticosteroid was 644 ± 118 µg, median dose 450 µg (interquartile range, 400 to 800 µg). Fourteen patients were taking beclomethasone dipropionate, 2 patients budesonide, and 2 patients fluticasone. At codon 16, all patients were homozygous for the glycine allele, while at codon 27, there were 10 patients who were homozygous for glutamic acid, 4 patients homozygous for glutamine, with the remaining 4 patients being heterozygous (ie, glutamic acid/glutamine).

Methacholine Bronchial Challenge
There were no significant differences between unprotected baseline PD20 values prior to each of the randomized treatments (ie, visit 1 values after washouts). Furthermore when first or last dose PD20 values were analyzed (Fig 2 ), there were no significant sequence effects when comparing values for the three randomized treatments. For between-treatment comparisons, there was a significant (p < 0.05) improvement in geometric mean PD20 after the first dose (ie, visit 2) of salmeterol or formoterol as compared to placebo. This amounted to a geometric mean 1.6-fold difference (95% CI, 1.1 to 2.2-fold) for salmeterol vs placebo, and a 1.9-fold difference (95% CI, 1.1 to 3.2-fold) for formoterol vs placebo. Likewise, after 1 week of regular treatment (ie, visit 3) the protection afforded by salmeterol and formoterol remained significant (p < 0.05) as compared with placebo. This amounted to a 1.6-fold difference (95% CI, 1.2 to 2.3-fold) for salmeterol vs placebo, and a 1.9-fold difference (95% CI, 1.3 to 2.8-fold) for formoterol vs placebo. There was no significant difference between the two active drugs for first or last dose effects. For within-treatment comparisons (ie, first vs last dose protection) there was no significant difference for either placebo, salmeterol, or formoterol.



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  		Figure 2.. Geometric mean (SEM) values for methacholine challenge, as PD20 value plotted on a log2 scale to depict doubling doses. Values to be shown for each treatment are as follows: baseline (after run-in or washouts), 12 h after the first dose and last dose. PL = placebo; FM = formoterol; SM = salmeterol. There were no significant differences between formoterol and salmeterol for first or last dose. There were no significant differences between baseline values.

 
Prechallenge Spirometry
Spirometry values (as FEV1 and FEF25–75) for visit 1 baseline prior to each randomized treatment showed no significant differences (Fig 3 ). There were no significant sequence effects when comparing values for the three randomized treatments. For between-treatment comparisons, there were significant (p < 0.05) differences between both drugs and placebo for the first (visit 2) but not the last dose (visit 3). For within-treatment comparisons, there were no significant differences between first and last dose effects for any of the three randomized treatments. There were no significant differences between the two drugs at first or last dose.



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  		Figure 3.. Mean (SEM) prechallenge values for FEV1 (top) and FEF25–75 (bottom). See Figure 2 for abbreviations.

 
Diary Cards
Values for both morning and evening peak flow were significantly (p < 0.05) higher during treatment with formoterol or salmeterol compared with placebo (Fig 4 ). Use of first-line (ipratropium bromide) or second-line rescue therapy was not significantly different when comparing the three treatments (data not shown).



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  		Figure 4.. Mean (SEM) values for domiciliary peak flow diary cards during each of the three randomized treatments. See Figure 2 for abbreviations.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The results of the present study showed that both salmeterol and formoterol exhibited significantly greater bronchoprotection than placebo for their effects at 12 h after single or repeated dosing, although there was no significant difference between the two drugs. These findings suggest that even in genetically predisposed individuals with the homozygous glycine-16 polymorphism, differences in intrinsic agonist activity between formoterol and salmeterol are not important in terms of the functional antagonism against methacholine-induced bronchoconstriction. These results may be reassuring for clinicians in that 40% of patients who have the homozygous glycine-16 genotype would be expected to exhibit the greatest propensity for developing airway ß2-adrenoceptor subsensitivity.8 In a previous study of unselected asthmatics, we have reported no differences between regular treatment with formoterol and salmeterol in their effects on lymphocyte ß2-adrenoceptor regulation at the end of a 12-h dosing interval.16

Our protocol reflected the recommended guidelines,1 in that all of our patients were already receiving inhaled corticosteroids before receiving additional therapy with long-acting ß2-agonists. We believe that our results looking at trough protection are relevant, as this represents the period when the airways will be most susceptible to bronchoconstrictor stimuli. The validity for performing the methacholine challenge at 12 h is supported by a study where a single 50-µg dose of salmeterol afforded significant bronchoprotection against methacholine for up to 24 h and for up to 20 h after 12 µg of formoterol.17

In some respects, our results may be considered to be surprising, as we did not detect any significant bronchoprotective desensitization when comparing first and last dose effects of either salmeterol or formoterol (ie, for within-treatment comparisons). On inspecting the degree of first-dose protection, this amounted to a shift in PD20 of 1.6-fold for salmeterol, 50 µg, and 1.9-fold for formoterol, 12 µg, as assessed 12 h after inhalation. This compares with a previous study from our laboratory in genetically unselected patients where there was a 4.1-fold shift in PD20 1 h after a single 12-µg dose of formoterol dry powder and a 3.4-fold shift after a 50-µg dose of salmeterol dry powder.18 This, in turn, suggests that the lower degree of protection that was seen in the current study was due to the timing of the methacholine challenge, which coincided with the trough effect at the end of the usual 12-h dosing interval. The magnitude of the first-dose protection that we observed with formoterol or salmeterol is unlikely to be due to a carryover effect of airway ß2-adrenoceptor desensitization, as there was a 1-week washout period without ß2-agonists in between the randomized treatment arms, with baseline values after washout being not significantly different. Furthermore, there was good evidence to show that airway ß2-adrenoceptor responsiveness was not impaired at the initial screening visit, as there was a 10.3-fold protective effect on PD20 at 30 min after a 400-µg dose of inhaled salbutamol.

Our findings for trough effects contrast with a previous study in patients receiving inhaled corticosteroid therapy, where methacholine protection 1 h after inhalation of formoterol, 12 µg qd, was associated with 6.4-fold protection for the first dose and 1.5-fold residual protection after 14 days, with corresponding values for formoterol, 24 µg bid, being 10.2-fold and 1.4-fold protection.19 In another study with salmeterol, 50 µg bid, there was a 10-fold methacholine protection after the first dose and twofold protection after 8 weeks.20 This suggests the possibility that there is a reduced propensity for tolerance to develop for trough than peak bronchoprotection, which might be due to a lower degree of receptor occupancy toward the end of the dosing interval. The 1-week duration of treatment in the present study is unlikely to be relevant, as we have shown no difference in protection loss when comparing PD20values after 1 week and 2 weeks with formoterol, compared with the first-dose effect.19 Indeed, there is good evidence to show that with salmeterol, bronchoprotective desensitization occurs after two doses within 24 h after initiating treatment.21 22

Our data revealed a numerically higher degree of residual last-dose protection with formoterol (1.9-fold) than salmeterol (1.6-fold), although there was no significant difference between the drugs. One might expect the higher degree of intrinsic agonist activity with formoterol to result in a greater degree of downregulation and desensitization of airway ß2-adrenoceptors, particularly in genetically predisposed subjects. It is possible that differential desensitization between formoterol and salmeterol might become evident if peak rather than trough bronchoprotection was evaluated after chronic dosing.

We elected to use patients who exhibited the homozygous glycine-16 genotype, as this has been shown to predispose to agonist-induced downregulation and desensitization in vitro.8 Bronchodilator desensitization does not occur readily with regular long-acting ß2-agonist therapy, although there are data to suggest that patients with the homozygous glycine-16 genotype have a greater tendency toward bronchodilator desensitization when receiving formoterol bid.10 As bronchoprotective desensitization occurs more readily, it is perhaps not surprising that the degree of desensitization in response to long-acting ß2-agonist exposure occurs irrespective of ß2-adrenoceptor polymorphism at codon 16. For example, in a previous study, patients with the homozygous glycine-16 genotype exhibited a uniform degree of protection loss (first vs last dose) > 30% when treated for 2 weeks with either formoterol, 6 µg bid; formoterol, 12 µg qd; formoterol, 24 µg qd; or terbutaline, 500 µg four times daily, in terms of methacholine protection 1 h after inhalation.11

We have also shown that genetic polymorphism at codon 16 or codon 27 does not influence basal or stimulated adenylyl-cyclase activity in lymphocyte ß2-adrenoceptors, and similarly does not influence the degree of peak bronchoprotection exhibited by a single 24-µg dose of formoterol against methacholine-induced bronchoconstriction.23 There are, however, other data to suggest that patients with the homozygous glycine-16 genotype have a diminished bronchodilator response to inhaled salbutamol, although the patients in that study were instructed to stop their ß2-agonist for only 6 h prior to the bronchodilator test, which may have resulted in a carryover effect due to ß2-adrenoceptor downregulation and desensitization.24

Although our study was not powered on spirometry, the bronchodilator effects on resting airway tone (ie, prior to methacholine challenge) showed significant improvements in FEV1 and FEF25–75, compared to placebo for both drugs with the first but not the last dose. Furthermore, our patients showed significant improvements in domiciliary morning and evening peak flow during treatment with salmeterol or formoterol, compared to placebo. There are data from a large multicenter study with formoterol Turbohaler, 12 µg bid, given in addition to inhaled budesonide, where there was a marked reduction in bronchodilator efficacy in terms of morning peak flow response during the first 2 weeks of treatment, pointing to the development of bronchodilator tolerance.4 There is also evidence to show a small but significant rightward shift in the formoterol bronchodilator dose-response curve for peak and duration of effect after treatment with regular bid formoterol in patients receiving inhaled corticosteroid therapy.25 26 27 Studies with salmeterol have yielded conflicting results in terms of the propensity for inducing a rightward shift in the salbutamol or terbutaline dose-response curve.28 29 30 31 32

In conclusion, our results have shown no difference between salmeterol and formoterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 polymorphism. There was a significant residual degree of bronchoprotection after 1 week of treatment, which was not significantly different compared to the first-dose effect. These data may be reassuring for patients who require combination therapy with inhaled corticosteroids and long-acting ß2-agonists.


   Acknowledgements
 
The authors wish to acknowledge the technical assistance of Mss. Erika Sims, Michelle Paterson, and Wendy Coutie in performing the methacholine bronchial challenges; Dr. Ian Hall (University of Nottingham) for performing the genotype assays; and Dr. R.A. Brown (Department of Mathematical Sciences, University of Dundee) for statistical advice.


   Footnotes
 
Abbreviations: CI = confidence interval; FEF25–75 = forced expiratory flow after 25 to 75% of vital capacity has been expelled; PD20 = provocative dose of methacholine causing a 20% fall in FEV1

This study was funded by University of Dundee Anonymous Trust Research Grant and received no support from the pharmaceutical industry.

Received for publication September 7, 1999. Accepted for publication April 18, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Institutes of Health, April 1997; Publication No. 97–4051
  2. Greening, AP, Ind, PW, Northfield, M, et al (1994) Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 344,219-224[CrossRef][ISI][Medline]
  3. Woolcock, A, Lundback, B, Ringdal, N, et al (1996) Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 153,1481-1488[Abstract]
  4. Pauwels, R, Lofdahl, CG, Postma, D, et al (1997) Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 337,1405-1411[Abstract/Free Full Text]
  5. Van Noord, JA, Schrereus, AJM, Mol, SJM, et al (1999) Addition of salmeterol versus doubling the dose of fluticasone propionate in patients with mild to moderate asthma. Thorax 54,207-209[Abstract/Free Full Text]
  6. Molimard, M, Naline, E, Zan Zhang, Y, et al (1998) Long and short-acting ß2-adrenoceptor agonist: interactions in human-contracted bronchi. Eur Respir J 11,583-588[Abstract]
  7. Lipworth, BJ (1997) Airway subsensitivity with long-acting ß2-agonists: is there cause for concern? Drug Safety 16,295-308[ISI][Medline]
  8. Green, SA, Turki, J, Vegarno, P, et al (1995) Influence of ß2-adrenergic receptor genotypes on signal transduction in human airways smooth muscle cells. Am J Respir Cell Mol Biol 13,25-33[Abstract]
  9. Dewar, J, Wilkinson, J, Wheatley, A, et al (1997) The glutamine 27 ß2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol 100,261-265[CrossRef][ISI][Medline]
  10. Tan, KS, Hall, IP, Dewar, J, et al (1997) Association between ß2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitization in moderately severe stable asthmatics. Lancet 350,995-999[CrossRef][ISI][Medline]
  11. Lipworth, BJ, Hall, IP, Aziz, I, et al (1999) ß2-adrenoceptor polymorphism and bronchoprotective sensitivity with regular short and long-acting ß2-agonist therapy. Clin Sci 96,253-259[Medline]
  12. . American Thoracic Society. (1997) Standards for diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 136,225-244
  13. . American Thoracic Society. (1987) Standardization of spirometry: update. Am Rev Respir Dis 136,1285-1298[ISI][Medline]
  14. Beach, JR, Jung, CL, Avery, HA, et al (1993) Measurement of airway responsiveness to methacholine: relative importance of the precision of drug delivery and the method of assessing response. Thorax 418,239-243
  15. Dewar, J, Wheatley, A, Venn, A, et al (1998) ß2-adenoceptor polymorphisms are in linkage disequilibrium but are not associated with asthma in an adult population. Clin Exp Allergy 28,442-448[CrossRef][ISI][Medline]
  16. Aziz, I, McFarlance, LC, Lipworth, BJ (1999) Comparative trough effects of formoterol and salmeterol on lymphocyte ß2-adrenoceptor regulation and bronchodilation. Eur J Clin Pharmacol 55,431-436[CrossRef][Medline]
  17. Rabe, KF, Jorres, R, Nowak, D, et al (1993) Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma. Am Rev Respir Dis 147,1436-1441[ISI][Medline]
  18. Lipworth, BJ, Aziz, I (1999) A high dose of albuterol does not overcome bronchoprotective subsensitivity in asthmatic patients receiving regular salmeterol or formoterol. J Allergy Clin Immunol 103,88-92[CrossRef][ISI][Medline]
  19. Lipworth, B, Tan, S, Devlin, M, et al (1998) Effects of treatment with formoterol on bronchoprotection against methacholine. Am J Med 104,431-438[CrossRef][ISI][Medline]
  20. Cheung, D, Timmers, MC, Zwindermann, AH, et al (1992) Long-term effects of a long-acting ß2-adrenoceptor agonist, salmeterol on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 327,1198-1203[Abstract]
  21. Kalra, S, Swyston, VA, Bhagat, R, et al (1996) Inhaled steroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 109,953-956[Abstract/Free Full Text]
  22. Drotar, DE, David, EE, Cockcroft, DW (1998) Tolerance to the bronchoprotective effect of salmeterol 12 hours after starting twice daily treatment. Ann Allergy Asthma Immunol 80,31-34[ISI][Medline]
  23. Lipworth, BJ, Hall, IP, Tan, S, et al (1999) Effects of genetic polymorphism on ex vivo and in vivo function of ß2-adrenoceptors in asthmatic patients. Chest 115,324-328[Abstract/Free Full Text]
  24. Martinez, FD, Graves, PE, Baldini, M, et al (1997) Association between genetic polymorphisms of the ß2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest 100,3184-3188[ISI][Medline]
  25. Newnham, DM, Grove, A, McDevitt, DG, et al (1995) Subsensitivity of bronchodilator and systemic ß2-adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 50,497-504[Abstract]
  26. Newnham, DM, McDevitt, DG, Lipworth, BJ (1994) Bronchodilator subsensitivity after chronic dosing with eformoterol in patients with asthma. Am J Med 97,29-37[CrossRef][ISI][Medline]
  27. Tan, KS, Grove, A, McLean, A, et al (1997) Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients. Am J Respir Crit Care Med 156,28-35[Abstract/Free Full Text]
  28. Grove, A, Lipworth, BJ (1995) Bronchodilator subsensitivity to inhaled salbutamol after twice daily salmeterol in asthmatic patients. Lancet 346,201-216[CrossRef][ISI][Medline]
  29. Langley, SJ, Masterson, CM, Batty, EP, et al (1998) Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo. Eur Respir J 11,1081-1085[Abstract]
  30. Wilding, P, Clark, M, Coon, J, et al (1997) Effects of long term treatments with salmeterol and asthma control: a double blind randomised crossover study. BMJ 314,1441-1446[Abstract/Free Full Text]
  31. Fuglsang, G, Vikre-Jorgensen, J, Pedersen, S (1998) Effect of salmeterol treatment on nitric oxide level in exhaled air and dose-response to terbutaline in children with mild asthma. Pediatr Pulmonol 25,314-321[CrossRef][ISI][Medline]
  32. Nelson, HS, Berkowitz, RB, Tinkleman, DA, et al (1999) Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. Am J Respir Crit Care Med 159,1556-1561[Abstract/Free Full Text]



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