ASTHMA: ß-ADRENERGIC AGONIST THERAPY |
Tolerance to the Protective Effect of Salmeterol on Allergen Challenge Can be Partially Restored by Withdrawal of Salmeterol Regular Treatment
Baltimore, MD
Purpose of the Study. To determine if withdrawal of salmeterol for 3 days can restore its bronchoprotective ability on specific bronchial provocative testing with allergen that was completely lost after 1 week of regular treatment with salmeterol.
Study Population. Ten nonsmoking subjects (8 men/2 women), mean age 24 ± 8 years with stable mild intermittent asthma (mean baseline forced expiratory volume in 1 second [FEV1] = 90%) without previous regular ß-agonist treatment. All subjects had had previous early airway response (EAR) to screening allergen challenge to dust mite by bronchoprovocation.
Methods. All subjects had FEV1, skin testing to dust mite and specific bronchial provocation testing (sBPT) at baseline (T0). They then underwent sBPT with the same allergen after a single dose of inhaled salmeterol, 50 µg (T1), followed by sBPT with allergen after 1 week of regular treatment of salmeterol 50 µg bid (T2). They then continued on salmeterol 50 µg bid for 4 days and then changed to inhaled placebo 2 puffs bid for 3 days, after which they underwent sBPT (T3). The treatments were single-blinded and the technicians performing the pulmonary function tests were not aware of the treatment periods. All sBPTs were performed 1 hour after the last drug inhalation with the same dose of allergen as T0 determined by the dose required to cause a decrease in FEV1 of >20%.
Results. The 4 mean baseline FEV1 before the allergen challenges (T0–T3) were not significantly different. At T0, the mean drop in FEV1 was 39% (range: 29–45) and this decrease was almost completely abolished by a single dose of salmeterol 50 µg (T1), (mean drop = 3%, range: 0%–13%). However, after 1 week of regular salmeterol treatment, the sBPT drop in FEV1 (T2) was not prevented (mean drop = 29.5%, range: 18%–49%). If salmeterol was then dropped 3 days before sBPT (T3), the drop in FEV1 was again not prevented (mean drop = 23%, range: 4%–41%), but the drop was lower than when subjects remained on regular salmeterol before sBPT (T2).
Conclusions. The bronchoprotective effect of salmeterol on sBPT was lost after 1 week of regular treatment in a group of mild intermittent asthmatics. The withdrawal of inhaled salmeterol for 3 days before challenge only slightly improved its bronchoprotective ability on sBPT with allergen. Additional studies are needed to evaluate whether a longer period of withdrawal in such patients would completely restore the bronchoprotective effect of salmeterol on sBPT to allergen.
Reviewer’s Comments. Regular use of short-acting ß-agonists may cause increased bronchial reactivity and loss of asthma control. Others have shown that regular use of salmeterol or formoterol may reduce the ability to block bronchoconstriction to methacholine. Inhaled steroids are known to reduce tolerance and their concurrent use with salmeterol could minimize the occurrence of tolerance. The results of this study also bring into question the washout periods used for ß-agonists for many study protocols. For example, many study protocols will hold meds for 1 to 6 months, but allow ß-agonist use without any washout period. Regular use of either short- or long-acting ß-agonists before sBPTs may affect the degree of bronchoconstriction. It is not clear what is a sufficient washout period for ß-agonists, because in this study 3 days of withdrawal of salmeterol was not sufficient.
REFERENCES
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Giannini D, Di Franco A, Bacci E, et al.
Chest.2001; 119
:1671
–1675
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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