Am. J. Respir. Crit. Care Med.,
Volume 163, Number 2, February 2001, 474-477
Cumulative and Single-dose Design to Assess
the Bronchodilator Effects of 
2-Agonists in
Individuals with Asthma
DAVID
FISHWICK,
LISA
BRADSHAW,
CLAIRE
MACDONALD,
RICHARD
BEASLEY,
DIANA
GASH,
THOMAS
BENGTSSON,
EVA
BONDESSON,
and
LARS
BORGSTRÖM
Department of Medicine, Wellington School of Medicine, Wellington, New Zealand; AstraZeneca New Zealand, Auckland, New Zealand;
and AstraZeneca R&D Lund, Lund, Sweden
With the development of different chlorofluorocarbon (CFC)-free
metered dose aerosol and dry powder devices, it is necessary to
study and validate the methods used for assessing and comparing their efficacy. This study evaluated the cumulative dose design by
determining the bronchodilator response to salbutamol given according to either a high or a low cumulative dose regimen. Adults with asthma (n = 24) were studied in a placebo-controlled, randomized, double-blind, cross-over design. On separate days, cumulative doses of salbutamol (50+50+100+200 or 100+100+
200+400 or 400+0+0+0 or 0+0+0+0 µg) were given via Turbuhaler with 30 min between doses. The two cumulative dose regimens produced almost identical bronchodilator responses at each
time point. The relative dose-potency between the 800- and 400- µg cumulative dose regimens was 0.7 with a 95% confidence interval of 0.5-1.0, excluding the true value of 2. The 400-µg cumulative dose regimen resulted in a higher FEV1 at 115 min than the
400-µg single-dose regimen. There was no difference in the bronchodilator response to the single dose of 50, 100, or 400 µg of
salbutamol after either 5 or 25 min. Thus, care should be exercised
when using either a cumulative or single-dose design for comparing different 
2-agonists, or different inhalation devices, with respect to their relative dose-potency. In addition, this study provides further evidence that for short-acting 2-agonists such as
salbutamol, lower doses than those normally recommended may
be used, and that repeated self-administration of low doses over a
period of 60 min may give a better bronchodilator response than
a single administration of a high dose.
