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A Bolus of Inhaled Budesonide Rapidly Reverses Airway Subsensitivity and ß₂-Adrenoceptor Down-regulation After Regular Inhaled Formoterol^*

^* From the Department of Clinical Pharmacology and Therapeutics and Department of Respiratory Medicine, Ninewells Hospital and Medical School, Dundee, Scotland, UK.

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: Subsensitivity of airway ß₂-adrenoceptors develops readily in asthmatics receiving regular long-acting ß₂-agonists. This subsensitivity may be rapidly reversed by using systemic corticosteroids. The purpose of the present study was to investigate whether the same acute facilitatory effects occur when using a bolus dose of inhaled corticosteroid.

Methods: Ten subjects with stable mild-to-moderate asthma, with a mean age of 27 years, mean (± SD) FEV₁ of 2.95 L (0.94 L), 81% (15%) of predicted, all receiving inhaled corticosteroids, reactive to adenosine monophosphate (AMP) with a provocative concentration producing a 20% fall in FEV₁ (PC₂₀) < 200 mg/mL, were recruited into a randomized double-blind crossover study. The subjects received two separate 1-week treatment periods with formoterol dry powder, 24 µg bid, with an initial 1-week run-in and a 1-week washout period between the treatments. A single dose of placebo or budesonide turbuhaler, 1,600 µg, was taken in conjunction with the last dose of both treatment periods. AMP challenge was performed 2 h after the first and last dose of formoterol. Blood for lymphocyte ß₂-adrenoceptor density (Bmax) was also measured before and after treatment with formoterol.

Results: There was no significant difference in the geometric mean PC₂₀ after the first dose of formoterol comparing the two treatment periods: 362 mg/mL vs 391 mg/mL. The PC₂₀ after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo: 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo: 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide: 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8). Lymphocyte ß₂-adrenoceptor density (geometric mean Bmax: fmol/10⁶ cells) also showed significant down-regulation (p < 0.05) by formoterol given with placebo: preformoterol 2.53 vs postformoterol 1.91, but not by formoterol given with budesonide: preformoterol 2.43 vs postformoterol 2.67. The Bmax was significantly higher (p < 0.05) with formoterol + budesonide as compared to formoterol + placebo, amounting to a 1.40-fold difference (95% CI, 1.09 to 1.80).

Conclusion: We have shown that a bolus dose of inhaled budesonide rapidly reverses subsensitivity to AMP bronchoprotection and associated ß₂-adrenoceptor down-regulation in asthmatics taking regular formoterol. Further studies are indicated to assess whether high-dose inhaled corticosteroids should be administered as soon as possible along with ß₂-agonists during an acute episode of bronchoconstriction.

Key Words: adenosine monophosphate • ß₂-adrenoceptor • bronchoconstriction • budesonide • formoterol • subsensitivity

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
National and international management guidelines have suggested the use of long-acting ß₂-agonists as additional therapy to low-dose inhaled corticosteroids for control of asthma instead of using monotherapy with high-dose inhaled corticosteroids.^{1 ,2} However, the regular use of long-acting ß₂-agonists is associated with development of subsensitivity to their bronchoprotective^{3 ,4 ,5} and bronchodilator^{6 ,7 ,8} effects. This airway subsensitivity has been shown to be associated with down-regulation of lymphocyte ß₂-adrenoceptors (ß₂-AR).^{6 ,7}

We have shown previously that the bronchodilator subsensitivity and down-regulation of ß₂-AR can be rapidly reversed by administration of systemic corticosteroids.⁹ As it is unlikely that most patients would have ready access to systemic corticosteroids at the time of an acute episode of bronchoconstriction, it is clinically important to know whether the same effect would also occur by short-term administration of inhaled corticosteroids. We have therefore investigated the effect of a bolus dose of inhaled corticosteroid (budesonide) on adenosine monophosphate (AMP) bronchial challenge in patients who are taking a long-acting ß₂-agonist (formoterol) on a regular basis. In everyday life as most bronchoconstrictor stimuli are indirectly acting, we chose to use AMP as it mediates bronchoconstriction via the activation of mast cells causing release of inflammatory mediators.¹⁰ We recruited patients into the study who were already taking inhaled corticosteroids, in line with the recommendations for the additive use of long acting ß₂-agonists in the management of asthma.^{1 ,2}

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
Ten asthmatic subjects (6 female and 4 male), mean age 27 years, all using inhaled corticosteroids, mean ± SD (range) dose 890 ± 731 (100 to 2,000) µg/d, were recruited to take part in a randomized, double-blind, crossover study (Table 1 ). Patients were required to be reactive to AMP with a provocative concentration producing a 20% fall in FEV₁ (PC₂₀) < 200 mg/mL. All were using inhaled ß₂-agonists for symptomatic relief (< 2 puffs/day), two were receiving oral theophylline, and three were receiving long-acting ß₂-agonist therapy with salmeterol. The subjects had stable asthma of mild-to-moderate severity according to the American Thoracic Society criteria¹¹ for at least 3 months prior to taking part in the study and no one had any oral corticosteroids during this period. Baseline spirometry showed mean (± SD) FEV₁ of 2.95 L (0.94 L), 81% (15%) predicted, and forced expiratory flow rate between 25% and 75% of vital capacity (FEF_25–75) of 2.57 L/s (1.0 L/s, 59% (22%) predicted. All gave written informed consent and the study was approved by the Tayside committee on medical research ethics.

Protocol
Subjects were randomized to receive two 1-week treatment periods with inhaled formoterol, 24 µg twice daily. Formoterol was delivered by dry powder capsules, 12 µg per capsule (Foradil; Novartis Pharmaceuticals; Camberley, UK). There was an initial 1-week run-in period before randomization and a 1-week washout between each of the treatment periods. From the start of the run-in period until the end of the study, all oral theophylline and prescribed inhaled ß₂-agonist therapy was stopped and inhaled ipratropium bromide (Atrovent Forte; Boehringer Ingelheim; Brachnell, UK) was substituted for symptomatic relief purposes. Treatment with the patients' regular inhaled corticosteroid therapy was continued unchanged throughout the study.

Subjects attended the laboratory for the first visit between 8 and 9 AM, where they received the first dose of formoterol, after 40 mL of blood had been withdrawn for measurement of lymphocyte ß₂-AR parameters. AMP challenge was performed 2 h after the dose of formoterol. The subjects then went home and completed 7 days of treatment with formoterol before attending the laboratory for the second visit, having omitted the previous nighttime dose of their inhaled corticosteroid treatment. On this occasion, they received the last dose of formoterol along with either (1) 1,600 µg of budesonide using dry powder inhaler (Pulmicort Turbuhaler, 400 µg per actuation; Astra Pharmaceuticals; King's Langley, UK) or (2) inhaled placebo Turbuhaler. All subjects were given instruction with the Turbuhaler training device (Astra Draco; Lund, Sweden) in order to ensure correct technique and a peak inspiratory flow rate of at least 60 L/min. The second AMP challenge was performed 2 h after inhalation and blood for lymphocyte ß₂-AR parameters was withdrawn just before the AMP challenge. This was followed by the washout period before the next treatment cycle. Five patients received placebo first in sequence and five patients received budesonide first in sequence. The subjects brought back their respective formoterol inhalers at each study visit and compliance with treatment was checked by counting the used and unused formoterol capsules and was found to be > 95%.

AMP Bronchial Challenge Test
AMP bronchial challenge test was performed as previously described.¹² The test was continued until the FEV₁ had dropped by > 20% from the baseline level or the maximum concentration of 400 mg/mL had been given. The PC₂₀ was calculated using a computer-assisted curve-fitting package (Biolab Assistant 1.1; University of Dundee; Dundee, Scotland, UK). If the FEV₁ did not show a 20% fall after the maximum concentration had been given or if the curve fitting revealed an extrapolated value > 800 mg/mL, a censored PC₂₀ value of 800 mg/mL (double of the maximum concentration) was assigned for that test for the purpose of statistical analysis.¹³

Lymphocyte ß₂-AR Parameters
Lymphocyte ß₂-AR parameters ß₂-AR density (Bmax) and binding affinity (Kd) were measured as previously described, using ligand binding with (-) ¹²⁵I-iodocyanopindolol.^{6 ,7}

Identification of ß₂-AR Polymorphism
ß₂-AR polymorphisms at codons 16 and 27 were identified as previously described.¹⁴ In brief, genomic DNA was extracted from whole blood and a 234 base-pair fragment was generated by polymerase chain reaction that spanned the regions of interest. Genotype was determined by allele-specific oligonucleotide hybridization using probes homologous for the Arg-16, Gly-16, Gln-27, or Glu-27 forms of the receptor.

Statistical Analysis
The data for PC₂₀, Bmax, and Kd were log-transformed to normalize their distribution prior to analysis. The statistical analysis between treatments was performed by multifactorial analysis of variance followed by Duncans multiple-range testing, using subject, treatment, and visit as factors. The analysis was performed using a statistical software package (Statgraphics; STSC Software Publishing Group; Rockville, MD).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
All 10 recruited subjects completed the study. The bronchodilator response to formoterol was maintained with both treatments (Table 2 ). There was no significant difference in the geometric mean PC₂₀ after the first dose of formoterol comparing the two treatment periods: 391 mg/mL vs 362 mg/mL (Fig 1 ). The PC₂₀ after the last dose of formoterol was significantly higher (p < 0.05) in conjunction with budesonide than with placebo (formoterol + budesonide vs formoterol + placebo): 427 mg/mL vs 99 mg/mL, amounting to a 4.3-fold difference (95% confidence interval [CI], 1.1 to 16.6). For comparison within each treatment period, there was significant subsensitivity (p < 0.05) between the first and last dose of formoterol when the latter was given with placebo (first vs last dose): 391 mg/mL vs 99 mg/mL, a 3.9-fold fall (95% CI, 1.0 to 15.2), but not when the latter was given with budesonide (first vs last dose): 362 mg/mL vs 427 mg/mL, a 1.2-fold rise (95% CI, 0.5 to 2.8).

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Geometric mean (SE) values. Top: PC20 for AMP challenge. Bottom: lymphocyte ß2-AR density (Bmax). The data for PC20 are graphed on a log2 scale to show doubling concentrations of AMP. Asterisk denotes significant difference between first and last dose of formoterol (FM), while cross denotes significant difference between the last dose of FM with placebo (PL) and the last dose of FM with budesonide (BUD).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Geometric mean PC20 for individual responses for formoterol with placebo and formoterol with budesonide. The responses are shown according to individual genotype at codon 16 of the ß2-AR. The data are shown on a log10 scale. First and last dose PC20 values for each individual are joined.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The results of the present study showed that within 2 h of inhalation, a bolus dose of inhaled budesonide reversed subsensitivity to AMP bronchoprotection and down-regulation of lymphocyte ß₂-AR produced by regular treatment with inhaled formoterol. We have shown previously that systemic administration of corticosteroid acutely reversed bronchodilator subsensitivity and up-regulated the lymphocyte ß₂-AR in patients receiving the same dose and formulation of formoterol.⁹ It would therefore appear that a bolus high dose of inhaled corticosteroids may be used instead of systemic corticosteroid to achieve rapid restoration of ß₂-AR function, although it may not be possible to extrapolate our findings to what happens in acute asthma. A 1,600-µg dose of budesonide was chosen to represent the highest licensed daily dose for administration by Turbuhaler. Another important finding was that although the bronchodilator effects of formoterol were maintained, bronchoprotective subsensitivity had developed after regular treatment. This is in keeping with a recent study also with formoterol in which there was dissociation in subsensitivity between methacholine protection and bronchodilator activity.¹⁵ This might conceivably lull patients into a false sense of security in that their peak flow would be maintained while their airways would become more vulnerable to bronchoconstrictor stimuli. In this respect, regular long-acting ß₂-agonist therapy has been shown to mask underlying inflammation in patients who experience an exacerbation of asthma due to inhaled steroid reduction.¹⁶

The short-term effect of budesonide in reversing airway subsensitivity was mirrored by effects on lymphocyte ß₂-AR density. This therefore suggests that the short-term facilitatory effects of budesonide are modulated by a process of up-regulation, rather than its anti-inflammatory activity on mast cells, which would be expected to take much longer to recover. Indeed it has been shown in vitro that dexamethasone increases gene transcription of ß₂-AR messenger RNA within 1 h of administration.¹⁷ Our findings are similar to a previous report by Pansegrouw¹⁸ in which acute resistant asthma caused by excessive ß₂-agonist use was reversed by inhaled beclomethasone dipropionate, 200 µg, in terms of restoration of the bronchodilator response to fenoterol within 60 min after corticosteroid administration. We did not include a treatment limb with inhaled budesonide alone in the absence of formoterol, and so we cannot say whether budesonide would have shown the same short-term effect on AMP challenge as we observed in the present study. Preliminary data have shown that 6 h after a single 2.4-mg bolus dose of inhaled budesonide, there was a significant improvement in airway hyperreactivity and airway eosinophils.¹⁹ O'Connor and colleagues²⁰ have showed 1.6 mg/d of budesonide Turbuhaler to produce significantly greater protective effect on the bronchoconstrictor response to AMP as compared to challenge with methacholine (a direct stimulus) or sodium metabisulphite (a neuronal stimulus), although this effect occurred after 4 weeks. Yates et al²¹ evaluated steroid-naive asthmatics showing a 3.2-fold loss of AMP protection with regular terbutaline, 500 µg qid, with a 1.7-fold increase (nonsignificant) in protection when regular terbutaline was administered 12 h after a single 800-µg bolus dose of budesonide. It might be informative in future studies to look at the time course for possible acute anti-inflammatory effects of budesonide using another surrogate marker such as exhaled nitric oxide, as well to see whether this is influenced by prior treatment with formoterol.

We recognize and accept the limitations of our study. The bolus dose of budesonide was given, having withheld previous nighttime dose of the patients' usual inhaled corticosteroid therapy, so as to avoid any carryover effect on the short-term response. We could have chosen to use steroid-naive subjects, although this would not have been clinically relevant in terms of accepted guidelines for use of combined therapy with long-acting ß₂-agonists and inhaled corticosteroids.¹ We used a relatively small sample size and although we found significant changes in AMP challenge and ß₂-AR, there was a degree of variability in individual responses that may relate to the effect of ß₂-AR polymorphism.⁸ However, it was evident from the post hoc genotype analysis that even in patients with the Gly-16 homozygous polymorphism who are predisposed to desensitization, budesonide was still able to resensitize ß₂-AR. We used lymphocyte ß₂-AR as a surrogate to look at lung ß₂-AR, although there is controversy as to its validity in this respect.^{22 ,23} The use of AMP for the challenge was chosen as this represents an indirect acting bronchoconstrictor agent as is the case for stimuli that occur in everyday life. However, the use of AMP does not assess nonspecific bronchial hyperactivity as such, which would require the use of a direct smooth muscle stimulus such as histamine or methacholine. We did not perform a dose-response curve to formoterol and so we cannot exclude the possibility that bronchodilator subsensitivity may have occurred, as demonstrated in previous studies.^{6 ,7}

We chose to use inhaled budesonide via the Turbuhaler as it has rapid onset to peak concentration, with a pharmacokinetic profile similar to an IV injection.²⁴ It has been shown previously that a 1.6-mg daily dose of budesonide via Turbuhaler produces 34% adrenal suppression,²⁵ suggesting perhaps that the observed short-term effects on ß₂-AR function cannot be explained on the basis of its systemic activity. Whether we would have observed the same effect with a lower dose of budesonide is unclear, although Pansegrouw¹⁸ reported a facilitatory effect with 200 µg of beclomethasone in acute asthma. It is conceivable that using another inhaled corticosteroid such as fluticasone propionate might not have achieved the same effect, as it has a much longer onset to peak concentration than budesonide.²⁶ In this respect, we have shown previously in asthmatic patients that lymphocyte ß₂-ARs were not up-regulated by 10 h after administration of a single 2-mg bolus dose of inhaled fluticasone propionate, in contrast to a significant increase in ß₂-AR density at the same time after a single oral dose of prednisolone, 50 mg, while both drugs exhibited marked adrenal suppression.²⁷ However, it should be pointed out that these patients were not receiving regular long-acting ß₂-agonists, and they had similar ß₂-AR density in comparison to values obtained from normal control subjects. Thus, further studies with different inhaled corticosteroids in patients receiving regular long-acting ß₂-agonists are required to evaluate whether similar facilitatory effects are observed, as with budesonide in the present study.

What are the possible clinical implications of our findings? It should be emphasized that we evaluated the effects of budesonide in a controlled experimental setting with AMP, in patients with stable asthma of mild-to-moderate severity. The implication of our results is that a bolus high-dose inhaled corticosteroid should be taken as early as possible during an episode of acute bronchoconstriction, in order to restore normal airway ß₂-AR sensitivity while taking inhaled ß₂-agonists as reliever therapy. It is likely that the degree of airway subsensitivity and ß₂-AR down-regulation would be more relevant in patients with more severe airflow obstruction and particularly in patients predisposed to desensitization who have the Gly-16 polymorphism of ß₂-AR.⁸ It is also conceivable that peripheral airway deposition of inhaled corticosteroid might be reduced as a consequence of the bronchoconstriction that occurs in acute severe asthma. However, in a recent study, it was reported that repeated administration of high-dose flunisolide with albuterol in acute severe asthma improved the bronchodilator response as compared with albuterol alone.²⁸ Whether this was secondary to acute bronchodilatation by flunisolide or a facilitatory effect on albuterol ß₂-AR response is unclear. Thus, further studies are indicated to assess whether a higher dose of inhaled budesonide might be required in the setting of an acute attack in order to achieve the same local airway concentration required to desensitize ß₂-AR.

	Acknowledgements

 
ACKNOWLEDGMENT: The authors wish to thank Dr. I. P. Hall, Department of Therapeutics, University Hospital, Nottingham, UK, for performing the genotype analysis.

	Footnotes

 
Supported by a University of Dundee Research Grant.

Correspondence to: Brian J. Lipworth, MD, Ninewells Hospital and Medical School, Dundee DD1954, Scotland, UK; e-mail: b.j.lipworth@dundee.ac.uk

Abbreviations: AMP = adenosine monophosphate; Arg = arginine; ß₂-AR = ß₂-adrenoceptor; Bmax = lymphocyte ß₂-adrenoceptor binding density; CI = confidence interval; FEF_25–75 = forced expiratory flow rate between 25% and 75% of vital capacity; Gln = glutamine; Glu = glutamic acid; Gly = glycine; Kd = lymphocyte ß₂-adrenoceptor binding affinity as dissociation constant; PC₂₀ = provocation concentration producing a 20% fall in FEV₁

Received for publication July 28, 1998. Accepted for publication October 16, 1998.

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