Salmeterol and airway response to allergen

When conventional inhaled beta-agonists are used regularly, partial tolerance rapidly develops to the bronchoprotective effect of these agents (1-3). It has also been demonstrated that seven to 14 days of salbutamol 800 μg/day by inhalation increases both the early and late responses to inhaled allergen (3-5). Tolerance to the bronchoprotective effect of salmeterol is more pronounced than that seen with the short-acting beta-agonist (2), and occurs within 24 h of commencing the drug (6,7). The effect of salmeterol on airway response to allergen has not been addressed. ORIGINAL ARTICLE


Subjects:
Fourteen atopic asthmatic subjects were studied.Subjects were either patients in the Respiratory Clinic at the Royal University Hospital, Saskatchewan, Saskatchewan or volunteers (Table 1).The asthmatics were well controlled with (n=5) or without (n=9) inhaled corticosteroids.Subjects had not required inhaled beta-agonists for at least two weeks before the study and did not use them for the study's duration.Forced expiratory volume in 1 s (FEV1) was 70% of predicted or greater, methacholine PC20 (8) was 8 mg/mL or less, and all subjects were known to have an early asthmatic response to allergen challenge in the laboratory.Subjects had no allergen exposure or respiratory tract infections for four weeks before or during the study.The study was approved by the Ethics Committee at the University of Saskatchewan, and signed informed consent was obtained.Allergen challenge tests: Allergen challenges were done as previously outlined (3)(4)(5).After a rest period to ensure stability, FEV1 was measured in triplicate.Subjects then inhaled doubling concentrations of allergen for 2 mins of tidal breathing.Allergens were nebulized with a Wright nebulizer (Aerosol Ltd, Colchester, United Kingdom) calibrated to give an output of 0.13 mL/min (driving flow 7.5 to 9.5 L/min).The aerosols produced were passed into a Hans Rudolph valve (Hans Rudolph Inc, Missouri), and patients inhaled them though a mouthpiece.Two ventilator filters were placed on the expiratory side of the valve to capture the exhalate and uninhaled nebulizate, thus preventing allergen from entering the room air and minimizing exposure of both the subject and any other person in the laboratory to aerosolized allergen.FEV1 was repeated in duplicate 10 mins after each inhalation; inhalations were continued until the 10 min FEV 1 had fallen 13% or greater.FEV1 was then monitored every 10 mins until the maximum decrease in FEV1 had been recorded, generally at 20 or 30 mins.Following the assessment of the early asthmatic response, a single dose of fluticasone (Flovent, Glaxo Canada) or beclomethasone dipropionate (Becloforte, Glaxo Canada) 500 µg was administered by inhalation; this dose of inhaled corticosteroid is known to inhibit the late asthmatic response (9).The early asthmatic response was measured as an allergen PC15 calculated by an algebraic formula from the noncumulative log dose versus response curve.Study design: This study was a double-blind, randomized, crossover comparison of freon-propelled metered dose inhaled placebo two puffs twice daily for six days versus salmeterol 25 µg/puff two puffs twice daily for six days; there was a one week or longer washout.Subjects took their inhaler twice daily at approximately 12 h intervals.Subjects attended the laboratory 36 h after the last of the 12 doses of each drug, and spirometry followed by an allergen PC 15 was recorded.Subjects were supplied with ipratropium bromide 20 µg/puff (Atrovent, Boehringer Ingelheim) to use if rescue medication was required during the trial period so as to avoid the use of inhaled beta-agonists.Analysis: Major end-point for analysis was the allergen PC15 that was logarithmically transformed.A secondary end-point was the baseline FEV1 before allergen challenge.Results were analyzed by a computerized two-way (subject, treatment) ANOVA (Statistix 4.1 Analytical Software, Tennessee).

RESULTS
The trial was completed by all 14 subjects without adverse event.Ipratropium bromide was not required by any subject.Four subjects could accurately identify the active treatment, eight perceived no difference and two guessed incorrectly.Four subjects (patients 2,3,6,10) felt somewhat worse asthma control while using salmeterol; two suspected this was placebo, while two suspected this was active because they felt 'different'.All four had a lower FEV1 36 h after salmeterol versus after placebo (Table 2).
The allergen PC15 was significantly lower 36 h following discontinuation of salmeterol compared with the placebo.2).FEV1 was also slightly but significantly lower following discontinuation of the salmeterol.FEV 1 was 3.28±0.83L after salmeterol compared with 3.40±0.88L following placebo, P=0.032 (Table 2).The number of patients (patients 1,3,8,13,14) using inhaled corticosteroid was too small to analyze separately; however, there was no obvious difference compared with those not on inhaled corticosteroid (Table 2).

DISCUSSION
These results show that 36 h after a six-day course of twice daily salmeterol, airway responsiveness to allergen assessed by the early asthmatic response was significantly greater.The difference was slightly less than a half a doubling concentration.FEV 1 was also significantly lower.
Our previous studies with salbutamol and the early asthmatic response have shown that a seven-to 14-day course of salbutamol 200 µg four times daily caused a fall in allergen PC15 or PC20 of between one-half and one doubling concentration (3)(4)(5).We are aware of only one publication that addresses the chronic use of salmeterol and allergen, an abstract by Giannini et al (10).This study assessed the bronchoprotective effect at 1 h after the first and last dose of salmeterol administered twice daily for a week.The first dose of salmeterol completely inhibited the early asthmatic response to allergen.At the end of one week, the last dose of salmeterol no longer provided any protection against the allergen-induced early asthmatic response.
Regular use of salmeterol produces a greater tolerance to the bronchoprotective effect of beta-agonist than does shorter-acting beta-agonists.Cheung et al (2) demonstrated that 50 µg of salmeterol initially shifted the methacholine PC 20 by 10-fold (3.3 doubling doses), whereas after weeks 4 and 8, the shift was reduced to twofold (one doubling dose) (2).By contrast, conventional beta-agonists produce a smaller degree of tolerance.Terbutaline used for one week caused a reduction in the terbutaline-induced methacholine dose-shift from 2.7 to 2.2 doubling doses (1), while salbutamol for two weeks caused a reduction from 3.2 to 2.6 doubling doses (3).This tolerance occurs within 24 h after starting salmeterol and results in a reduction in salbutamolinduced inhibition of methacholine (6,7).Salmeterol-induced tolerance to the bronchoprotective effect is particularly marked when studying indirect stimuli, such as exercise (11) and allergen (10).Salmeterol also produces lessened bronchodilator response to salbutamol and the reduction in nonpulmonary beta-agonist effects, such as tremor, hypokalemia and tachycardia (12).The clinical relevance of the loss of bronchoprotection is uncertain, particularly with reference to artificial stimuli, such as methacholine, adenosine monophosphate, etc. Natural stimuli (eg, exercise, allergen) are more clinically relevant, and there is greater loss of bronchoprotection against such stimuli when beta-agonists have been used regularly (3,10,11), particularly in the case of salmeterol (10,11).
Because salmeterol produces greater loss of bronchoprotection than does salbutamol, we had anticipated that we might observe a greater increase in responsiveness to allergen.This seemed particularly likely because the allergen-induced early asthmatic response assessed 1 h after the last dose of salmeterol (twice daily for one week) in Giannini's study was not different from placebo.The increased response to allergen in the current study, slightly less than half a doubling concentration, is similar to, or slightly less than, that produced by salbutamol.In three studies, we have shown falls in allergen PC15 or PC20 ranging between 0.6 and 0.9 doubling concentrations after seven to 14 days salbutamol 800 µg/day (3)(4)(5).It is reassuring that the allergen effect produced by regular use of salmeterol is relatively small.
The mechanism of the increased airway response to allergen remains obscure.It appears to be a separate issue to the loss of protection of beta-agonists.In addition, increased allergen responsiveness requires a larger daily dose of betaagonist than that associated with lessened bronchoprotection (5).It is attractive to speculate that, after regular use of beta-agonists, allergen exposure results in a greater (50% to 100%) release of mast cell mediators.Perhaps subsequent greater degrees of airway inflammation could explain the enhanced late response (4,13).Both increased mediators and increased inflammation are testable hypotheses and are being investigated (13).Allergen exposure (likely via allergen-induced airway inflammation) is important in the pathogenesis of asthma (14).We feel that the beta-agonist-induced increase in airway responsiveness to allergen is probably more important than tolerance to beta-agonist.Others share this view (15).The extremely long duration of action of salmeterol made selecting a time of measurement difficult.The goal was to study allergen PC15 as soon as reasonably possible outside the duration of salmeterol's pharmacological effect.We selected 36 h because this is the time interval used by others (3,12), and 36 h is 12 h beyond salmeterol's known 12 to 24 h duration of action.
A six-day course of salmeterol produced a significant but small decline in FEV 1 and a significant modest increase in airway responsiveness to allergen.Although it is reassuring that the allergen effect is not greater, the data support the view that frequent use of inhaled beta-agonists, including salmeterol, should be avoided, particularly in allergic asthmatics.

TABLE 1 Anthropometric and challenge data
BDP Beclomethasone dipropionate; BUD Budesenide; F Female; FEV1 Forced expiratory volume in 1 s; M Male

Salmeterol and airway response to allergen
Can Respir J Vol 4 No 1 January/February 1997