Measuring the bronchial effects of bronchodilating drugs in healthy subjects with methacholine provocations: theophylline protects against induced bronchoconstriction in a dose-dependent manner.

To assess whether it would be possible to use methacholine (MCH) provocation tests with healthy subjects in the evaluation of bronchodilatory drugs, an intravenous infusion of theophylline ethylenediamine in increasing doses of 2.5, 5.0 and 7.5 mg/kg was given in random order to nine healthy non-smoking volunteers in a single-blind, placebo-controlled study. Dose response slope (DRS = maximal decline [%] in pulmonary function/the maximum dose of MCH [mumol]) was used to estimate airway reactivity. DRS was calculated to FEV1 (DRSFEV1) and to area under the flow-volume curve (AEFV, DRSAEFV). The bronchial reactivity was first tested with a standard MCH provocation method. An abbreviated, single-dose, method was used in the measurement of the effects of theophylline. The DRS-values obtained from the short method did not differ from those obtained from the standard one (p = 0.86, for DRSFEV1 and DRSAEFV), and correlation between these two methods was good (r = 0.93 and 0.98 for DRSFEV1 and DRSAEFV, respectively [p less than 0.001]). Serum theophylline concentrations achieved were (mean +/- SEM) 32.4 +/- 0.9, 63.7 +/- 3.3 and 93.4 +/- 3.3 mumol/l, which differed significantly from each other (p much less than 0.001). An inverse linear relationship between the serum theophylline concentration and the airway reactivity was observed with both indexes (r = -0.54, p less than 0.01 for DRSFEV1 and r = -0.65, p less than 0.001 for DRSAEFV). Even the lowest dose, which produced serum concentrations well under the therapeutic range, protected significantly (p less than 0.05) against MCH induced bronchoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)