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Repeated Dosing Effects of Mediator Antagonists in Inhaled Corticosteroid-Treated Atopic Asthmatic Patients^*

^* From the Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, UK.

Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK; e-mail: b.j.lipworth{at}dundee.ac.uk

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Background: The anti-inflammatory effects of repeated dosing with mediator antagonists as add-on therapy to that with inhaled corticosteroids (ICSs) in patients with asthma remain to be fully established.

Objective: We elected to evaluate the effects of repeated dosing with fexofenadine (FEX) and montelukast (ML) at clinically recommended doses in ICS-treated asthmatic patients using adenosine monophosphate (AMP) bronchial challenge as the primary outcome.

Methods: Eighteen atopic asthmatic patients receiving a mean (± SEM) dose of 631 ± 104 µg daily of ICSs, which remained unchanged throughout the entire study, were randomized in double-blind, cross-over fashion to receive FEX, 180 mg, ML, 10 mg, or placebo (PL) for 1 week. There was a 1-week washout period prior to each randomized treatment. Measurements of the provocative concentration of a substance (ie, AMP) causing a 20% fall in FEV₁ (PC₂₀) were made after each washout period and randomized treatment period.

Results: The values for AMP PC₂₀ after the washout period prior to each randomized treatment were not significantly different (FEX, 74 ± 15 mg/mL; ML, 73 ± 18 mg/mL; PL, 71 ± 19 mg/mL). There were significant improvements (p < 0.05) in AMP PC₂₀ with the use of FEX (127 ± 38 mg/mL) and ML (121 ± 27 mg/mL) compared to PL (78 ± 23 mg/mL). Spontaneous recovery after AMP challenge, as determined by area under the 60-min time-response curve, was significantly enhanced (p < 0.05) with the use of ML (352 ± 95%.min) and FEX (758 ± 140%.min) compared to PL (683 ± 134%.min). Both FEX and ML significantly suppressed (p < 0.05) the levels of exhaled nitric oxide, while only ML significantly reduced (p < 0.05) the peripheral blood eosinophil count compared to PL. Morning and evening peak expiratory flow were significantly higher (p < 0.05), and the frequency of salbutamol rescue was significantly reduced (p < 0.05) with FEX and ML compared to PL.

Conclusion: Repeated dosing with FEX and ML as add-on therapy improved AMP PC₂₀ and other surrogate inflammatory markers along with asthma diary outcomes in ICS-treated atopic asthmatic patients. Further studies are indicated to evaluate the long-term add-on effects of FEX on asthma exacerbations.

Key Words: adenosine monophosphate • antihistamine • asthma • fexofenadine • inhaled corticosteroid • leukotriene receptor antagonist • mediator antagonist • montelukast

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion References

 
The potential for inhaled corticosteroids (ICSs) to cause dose-related adverse systemic effects has driven the asthma guidelines toward the use of corticosteroid-sparing, second-line controller agents such as long-acting ß₂-agonists and leukotriene receptor antagonists. While H₁-antihistamines have an established role in the treatment of allergic rhinitis, they are not currently recommended in the treatment of asthma. It is recognized that treating allergic rhinitis may have a downstream effect on concomitant asthma.¹ A previous meta-analysis that focused on lung function parameters concluded that H₁-antihistamines were not effective in treating asthma.² However, it is appreciated that lung function is rather distant from the underlying inflammatory process, and consequently it is also important to evaluate the effects of H₁-antihistamines on surrogate inflammatory markers. We have previously shown that single doses of third-generation H₁-antihistamines as monotherapy significantly attenuated airway hyperresponsiveness to inhaled adenosine monophosphate (AMP) compared to placebo (PL).³ This is especially relevant as the results of indirect bronchial challenge with AMP have been shown to better correlate with allergic airway inflammation than those of a direct challenge with methacholine.⁴⁵⁶ AMP challenge may therefore be a suitable model for evaluating the potential anti-inflammatory activity of mediator antagonists.⁷

We therefore elected to further evaluate the effects of repeated dosing with fexofenadine (FEX) and montelukast (ML) at clinically recommended doses as add-on therapy in atopic asthmatic patients who have been treated with ICSs using AMP bronchial challenge as the primary outcome. We also evaluated secondary outcomes, including exhaled nitric oxide level, peripheral blood eosinophil count, FEV₁, and domiciliary peak expiratory flow (PEF), asthma symptom score, and rescue use.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
Eligible patients were stable and had experienced mild-to-moderate persistent asthma for at least 3 months prior to the study, and none had received a course of therapy with oral corticosteroids or antibiotics during this period. All patients were required to be taking ICSs in a daily dose up to 2,000 µg for beclomethasone dipropionate/budesonide or 1,000 µg for fluticasone propionate. The ICS dose was kept constant throughout the entire study. All patients were recruited from our asthma database, and were required to exhibit a positive reaction to house dust mite and at least one other common aeroallergen on skin prick testing. None of our patients had any symptoms or any treatment that suggested the presence of concomitant allergic rhinitis, and the study was conducted outside of the pollen season in order to obviate any potential confounding effects in patients who were skin prick-positive for pollen. Patients had to demonstrate hyperresponsiveness to AMP on bronchial challenge testing with a provocative concentration of a substance (ie, AMP) causing a 20% fall (from baseline) in FEV₁ (PC₂₀) of < 200 mg/mL. All patients gave informed consent, and the study was approved by the Tayside Committee on Medical Research Ethics.

Study Design
The study was conducted in a randomized, double-blind, PL-controlled, crossover fashion (Fig 1 ). Patients receiving second-line controller therapy such as long-acting ß₂-agonists (six patients) and leukotriene receptor antagonists (one patient) stopped receiving them during a 1-week washout period prior to recruitment into the study. None of the patients were receiving H₁-antihistamine therapy or treatment for allergic rhinitis. Patients were randomized to receive either FEX, 180 mg (Telfast; Aventis Pharma Ltd; West Malling, UK), ML, 10 mg (Singulair; Merck Sharp & Dohme Ltd; Hoddesdon, UK), or PL for 1 week. All tablets were encapsulated and were identical in external physical appearance. Patients took the study capsules at 10:00 PM and went to the department the next morning at 10:00 AM. There was a washout period of 1 week prior to each randomized treatment during which patients continued with their usual dose of ICSs, which also remained unchanged during the randomized treatment period. Measurements for AMP PC₂₀ were made after each randomized treatment and after each washout period.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Study flow diagram with study visits (V) V1 to V7. Patients continued to receive their usual ICS dose throughout the entire study.

Spirometry:
Spirometry was performed according to the American Thoracic Society criteria⁸ using a compact spirometer (Vitalograph Ltd; Buckingham, UK) with a computer-assisted pneumotachograph head and pressure transducer. The spirometer was calibrated daily with a 1-L precision syringe (Vitalograph).

AMP Bronchial Challenge:
AMP bronchial challenge was performed as previously described.⁹ In brief, AMP was administered at 90-s intervals in doubling concentrations from 0.09 to 800 mg/mL until a 20% reduction in FEV₁ was recorded. Having achieved the PC₂₀, spontaneous recovery following AMP bronchial challenge was monitored with measurements of FEV₁ at 10-min intervals for 60 min.

Exhaled Nitric Oxide:
The measurement of exhaled breath nitric oxide was performed as previously described¹⁰ using an integrated clinical real-time nitric oxide gas analyzer (LR2000; Logan Research; Rochester, UK) with a flow rate of 250 mL/min and an accuracy of 2 parts per billion (ppb) nitric oxide with a response time of 2 s. The normal exhaled nitric oxide cutoff value in our laboratory is < 6 ppb for nonatopic nonasthmatic subjects, which is < 2 SDs from the mean.

Peripheral Blood Eosinophil Count:
Blood samples were taken for peripheral blood eosinophil count, which was measured using a hematology analyzer (SE9000; Sysmex UK Ltd; Milton Keynes, UK).

Domiciliary PEF, Symptom Score, and Rescue Diary:
Patients recorded morning and evening domiciliary PEF using a peak flowmeter (Mini-Wright; Clement Clarke International Ltd; Harlow, UK) along with documentation of asthma symptom scores (4-point scale: 0, no symptoms; 3, severe symptoms) and rescue inhaler use for the duration of the study.

Statistical Analysis
The study was powered at 80% with -error set at 0.05 (two-tailed) in order to detect a one doubling dilution difference in AMP PC₂₀ (the primary outcome) between randomized treatments, with a sample size of 16 completed patients in a crossover design. An overall multifactorial analysis of variance followed by multiple-range testing with Bonferroni correction set at 95% confidence interval (CI) was performed. To normalize distribution, data for AMP PC₂₀, exhaled nitric oxide, and peripheral blood eosinophil count were logarithmically transformed, and analyses were performed using a statistical software package (Statgraphics; STSC Software Publishing Group; Rockville, MD).

	Results

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Patients
Twenty patients were enrolled in the study, of whom 18 patients (10 men and 8 women) with mean (± SEM) age of 45 ± 3 years and FEV₁ of 78 ± 4% predicted completed the study per protocol. Two patients dropped out of the study due to personal reasons. The geometric mean AMP PC₂₀ at recruitment was 69 ± 11 mg/mL. All patients were skin prick-positive for house dust mite (18 patients) and at least one other common aeroallergen, such as grass (11 patients), tree (2 patients), weed (3 patients), aspergillus (6 patients), feather (3 patients), dog (15 patients), and cat (13 patients). The mean ICS dose was 631 ± 104 µg daily, comprising beclomethasone dipropionate (12 patients), budesonide (2 patients), and fluticasone propionate (4 patients).

AMP PC₂₀
Data for AMP PC₂₀ are shown in Figure 2 . The values for the geometric mean AMP PC₂₀ following each washout prior to randomized treatments were not significantly different (FEX, 74 ± 15 mg/mL; ML, 73 ± 18 mg/mL; and PL, 71 ± 19 mg/mL). Moreover, the mean washout AMP PC₂₀ values were not significantly different from the screening AMP PC₂₀ value at recruitment (69 ± 11 mg/mL). There were significant improvements (p < 0.05) in AMP PC₂₀ compared to PL (78 ± 23 mg/mL) with FEX (127 ± 38 mg/mL; 1.63-fold difference; 95% CI, 1.09 to 2.44) and ML (121 ± 27 mg/mL; a 1.55-fold difference; 95% CI, 1.01 to 2.39). There was no significant difference in AMP PC₂₀ comparing FEX and ML.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Geometric mean AMP PC20 with geometric SEM plotted on a log scale (top). Scatter plot depicting AMP PC20 values joined for each individual plotted on a log scale (bottom). AMP PC20 was significantly improved with therapy using FEX and ML compared to PL.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Time profile of spontaneous recovery following AMP challenge as a percentage of the mean reduction from baseline prechallenge FEV1 values. Recovery was significantly enhanced with ML therapy compare to those with FEX and PL.

Asthma Diary
Mean morning and evening PEF values were significantly higher (p < 0.05) when comparing FEX (442 ± 23 and 440 ± 23 L/min, respectively) and ML (444 ± 22 and 445 ± 22 L/min, respectively) to PL (425 ± 25 and 424 ± 25 L/min, respectively). Mean morning asthma symptom scores significantly improved (p < 0.05) with ML (0.2 ± 0.1) but not FEX (0.3 ± 0.1) compared to PL (0.4 ± 01). There were no significant differences in mean evening asthma symptoms scores when comparing all groups (FEX, 0.3 ± 0.1; ML, 0.3 ± 0.1; PL, 0.4 ± 0.1). Salbutamol rescue use in the morning and evening respectively were significantly reduced (p < 0.05) with FEX (0.4 ± 0.2 and 0.8 ± 0.2 puffs, respectively) and ML (0.4 ± 0.2 and 0.8 ± 0.2 puffs, respectively) compared to PL (0.8 ± 0.2 and 1.4 ± 0.6 puffs, respectively).

Inflammatory Markers
Mean exhaled nitric oxide levels were significantly reduced (p < 0.05) with both FEX (4.5 ± 0.7 ppb) and ML (4.3 ± 0.7 ppb) compared to PL (5.7 ± 0.7 ppb). Similarly, the mean peripheral blood eosinophil count was reduced (p < 0.05) with ML (240 ± 30 x 10⁶ cells/L) but not with FEX (290 ± 30 x 10⁶ cells/L) compared to PL (320 ± 30 x 10⁶ cells/L).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion References

 
Our results show that repeated dosing with FEX and ML as add-on therapy significantly improved AMP PC₂₀ and other surrogate inflammatory markers such as exhaled nitric oxide and peripheral blood eosinophil count, along with asthma diary outcomes in patients with persistent atopic asthma. Moreover, spontaneous recovery following AMP bronchial challenge was significantly shortened with ML.

AMP acts as an indirect stimulus by releasing inflammatory mediators from primed mast cells and has been shown to more closely reflect the acute inflammatory processes involved in allergic airways disease compared to direct-acting bronchial stimuli such as methacholine.⁴⁵⁶ Long-term dosing with FEX and ML attenuated AMP hyperresponsiveness to a similar degree. These effects are in keeping with previous observations about the effects of monotherapy with FEX and ML on AMP PC₂₀.³¹¹ Moreover, add-on therapy with ML to that with ICSs is known to attenuate AMP PC₂₀.¹²¹³

To our knowledge, this is the first study to demonstrate that H₁-antihistamines improve AMP PC₂₀ as add-on therapy to ICSs. In a previous study,¹⁴ the combination of therapy with histamine and leukotriene receptor antagonists shifted AMP PC₂₀ by 3.9-fold, which is comparable to the total 3.2-fold shift seen in the present study with FEX and ML therapy in the presence of ICSs. A further study is indicated to compare the combination of histamine and leukotriene receptor antagonism with each agent alone to assess the potential additive effects on AMP PC₂₀. It is also noteworthy that prechallenge FEV₁ values were not significantly different after each randomized treatment period, thus excluding changes in airway geometry as a possible mechanism for improvements in AMP PC₂₀. It is also pertinent that there was no carryover effect between randomized treatments, as highlighted by numerically similar nonsignificant AMP PC₂₀ values after each washout period.

Unlike ML, FEX did not enhance AMP recovery compared to PL. This is likely to be an artifact due to the higher AMP PC₂₀ value, which would have resulted in more cysteinyl leukotrienes being released, thus prolonging recovery. This hypothesis is supported by previous data¹⁴ showing that the concomitant administration of ML and desloratadine resulted in shortened recovery despite a higher AMP PC₂₀. We have also shown that in ICS-treated patients the addition of ML shortened AMP recovery in conjunction with a higher AMP PC₂₀.¹³ To truly evaluate the effects of FEX on recovery compared to PL, one would have to perform a study in which the same AMP PC₂₀ was given on each occasion. It has been shown previously that by using this methodology, recovery was markedly enhanced by terfenadine.¹⁵

Although none of our patients had any symptoms or treatment to suggest concomitant allergic rhinitis, in order to limit any potential confounding effects in patients who were skin prick-positive for pollen, we conducted the study outside of the pollen season. Nonetheless, we cannot completely exclude the possibility that some of our patients may have had asymptomatic nasal inflammation due to perennial aeroallergens, and that treating the upper airway may have had a concomitant downstream effect on the lower airway.¹ In terms of subjective asthma symptoms, our patients conditions appeared to be well-controlled throughout the study, with the significant improvement in morning asthma symptom score following ML having no clinical relevance. Nevertheless, both antagonists significantly improved PEF and reduced rescue therapy requirements. This demonstrates the potential for the use of both antagonists in a clinical setting. The lack of any significant improvement in laboratory FEV₁ values despite an increase in domiciliary PEF can be explained by the greater sensitivity of repeated measures with the latter.

Levels of exhaled nitric oxide were already suppressed prior to enrollment due to the effects of preexisting ICS therapy. The significant fall in exhaled nitric oxide levels with therapy using both antagonists on top of ICS therapy is unlikely to be clinically relevant, but is in keeping with the results of other ML studies in ICS-treated patients.¹²¹³ Likewise, reductions in peripheral blood eosinophil count with ML are consistent with other data.¹²¹³ Further studies would be indicated to compare the effects of mediator antagonists on induced sputum and bronchial biopsy specimens.

Mediator antagonism with FEX and ML exhibited additive effects to moderately high doses of ICSs when used as add-on therapy in the treatment of persistent atopic asthmatic patients. Although the role of leukotriene receptor antagonists is well-established in treating asthma, future long-term larger studies will be required to evaluate the effects of H₁-antihistamines on asthma exacerbations.

	Footnotes

 
Abbreviations: AMP = adenosine monophosphate; CI = confidence interval; FEX = fexofenadine; ICS = inhaled corticosteroid; ML = montelukast; PC₂₀ = provocative concentration of a substance causing a 20% fall in FEV₁; PEF = peak expiratory flow; PL = placebo; ppb = parts per billion

This study was supported by a University of Dundee departmental grant and received no support from the pharmaceutical industry.

Received for publication July 30, 2003. Accepted for publication November 6, 2003.

	References

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This Article Abstract Full Text (PDF) Free Erratum (v130,p308) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Lee, D. K. C. Articles by Lipworth, B. J. Search for Related Content PubMed PubMed Citation Articles by Lee, D. K. C. Articles by Lipworth, B. J.