Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: Dose response,☆☆,,★★

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Abstract

BACKGROUND: Two adverse effects of inhaled β2-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of β2-agonists versus bronchoconstrictors (e.g., methacholine). OBJECTIVE: We studied three doses of inhaled salbutamol, 200, 400, and 800 μg/day, to determine dose-response curves for these two adverse effects. METHODS: Ten atopic patients with mild, stable asthma free of all asthma medications, allergen exposure, and respiratory tract infection for at least 4 weeks participated in a double-blind, random-order, crossover study. There were four 1-week treatment periods with a 1-week washout period: placebo, salbutamol 200 μg, 400 μg and 800 μg per day. After each treatment, we assessed FEV 1, bronchodilation 10 minutes after administration of 200 μg of salbutamol, methacholine PC 20, methacholine dose-shift after administration of 200 μg of salbutamol, and allergen PC 20. RESULTS: There was no significant difference in baseline FEV1, bronchodilation, or methacholine PC 20. The methacholine dose shift was maximum after the placebo (3.4 ± 0.22 doubling doses) and was significantly greater (p < 0.01) than all salbutamol regimens (2.2 to 2.6), which were not significantly different from each other (p > 0.05). Allergen PC 20 was significantly lower (p < 0.02) after salbutamol 800 μ g/day (geometric mean = 288 protein nitrogen units [PNU]/ml) than each of the other treatments (447 to 550 PNU/ml), which were not significantly different from each other (p >0.05). CONCLUSION: Significant increase in airway responsiveness to allergen occurred only with the largest dose of inhaled salbutamol (800 μg/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 μ g/day. This suggests different mechanisms may be operative in producing these two effects. (J ALLERGY CLIN IMMUNOL 1996;97:47-52.)

Section snippets

Subjects

Ten atopic volunteers with stable asthma and an FEV1 ≥ 70% of that predicted were included in the study. Subjects did not take asthma medications for at least 4 weeks and had no allergen exposure or respiratory tract infection for at least 4 weeks and during the study period. All had at least one allergen to which there were both historical and skin test evidence of high degree of type I sensitivity. This study was approved by the University of Saskatchewan Advisory Committee on Ethics in Human

RESULTS

The anthropometric data, details of lung function, and allergen challenge are given in Table I. There was one protocol violation. Subject 6, with an initial screening allergen PC20 of 1:8, did not respond by more than 10% to allergen at 1:4 dilution after the first treatment. No further allergen challenges were done with this individual; however, the remainder of the study was completed and data were analyzed for FEV1, Δ FEV1, methacholine PC20, and dose shift.

The four baseline FEV1 values

DISCUSSION

The present study confirms our earlier finding of increase, almost doubling, in airway responsiveness to allergen after regular use of inhaled salbutamol for 1 week. This increase in responsiveness was significant only after use of inhaled salbutamol 800 μg per day. Although there was a slight increase (less than one quarter of a doubling concentration) after salbutamol 200 and 400 μg/day, it failed to achieve statistical significance compared with the placebo period. Seven of the 10 had not

Acknowledgements

We thank Jacquie Bramley for assistance in the preparation of the manuscript.

References (21)

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From the Division of Respiratory Medicine, Department of Medicine, Royal University Hospital, Saskatoon, Saskatchewan, Canada.

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Supported by a grant from the Saskatchewan Lung Association.

Reprint requests: Donald W. Cockcroft, MD, Division of Respiratory Medicine, Royal University Hospital, 103 Hospital Drive, Ellis Hall, 5th Floor, Saskatoon, Saskatchewan S7N 0W8 Canada.

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