The effect of tiotropium-bromide on deep inspiration-induced bronchodilation and airway responsiveness in asthma.

In healthy subjects deep inspirations can protect against airway narrowing
(bronchoprotection) and can also reverse induced bronchoconstriction
(bronchodilation). These effects of deep inspiration are impaired or even
absent in patients with asthma. In vitro work on the airway smooth muscle cell
has shown that periodical stretching is in particular necessary to keep the
muscle cell flexible and in a less contractile state. Stretching of the airway
smooth muscle cell, or the response to stretch, might be altered in patients
with asthma. Chronic blockage of muscarinic receptors of airway smooth muscle
by tiotropium bromide may change the fixed state of the airway smooth muscle
cell in asthma into a more flexible and less contractile state. This would
allow stretches implied by breathing to be effective in reducing smooth muscle
cell contraction and enhancing deep inspiration induced bronchodilation. We
therefore hypothesize that a three-week treatment with the anti-cholinergic
agent tiotropium-bromide will improve the degree of bronchodilation following
deep inspiration. In addition we hypothesize that the maximal response of the
airways to histamine will decrease.

1) To examine the effect of 3 weeks of 18*g tiotropium bromide once daily on
the degree of bronchodilation following deep inspiration at a given level of
bronchoconstriction.
2) To examine the effect of 3 weeks of 18*g tiotropium bromide once daily on
the maximal response of the airways to histamine.

Lung function, Resistance of the respiratory system, airway
hyperresponsiveness, maximal dose response curves and deep inspiration induced
bronchodilation will be measured before, 7 days, and 21 days after treatment
with tiotropium-bromide 18 mcg once daily or placebo. All measurements will be
performed 180 minutes post tiotropium-bromide or placebo inhalation. The
maximal dose response curve will be stopped at a fall in FEV1 of more than 50%
or when reaching the last dose (32 mg/ml). During the challenge lung function
will be measured using both maximal and partial flow volume curves to measure
deep inspiraiton induced bronchodilation (M/P ratio). After the last dose
resistance of the respiratory system will be measured before, during and after
a deep inspiration.

One group will receive 18mcg tiotropium-bromide once daily for 21 days. The
other group will receive placebo.

In total 4 histamine challenges with lungfunction and resistance measurements
will be performed per patient over 4 visits. One skin prick test will be
performed and medical history will be asked. Each patient will attend the
department for 17 hours over a period of 4 weeks.
There are no appreciable risks during this study. All tests are regularly
performed at the department for diagnostic reasons. No invasive measurements
are done.