As bronchodilators, theophylline and ^-adrenergic agonists appear to have partially additive effects. Pulmonary function improves to a greater extent when the two drugs are given together than when the same doses are given separately. In vivo effects are not synergistic, as might be predicted from in vitro studies demonstrating that both agents act to increase intracellular cyclic AMP, and that their effects on both cyclic AMP and cellular function are synergistic.
In addition to their effects as bronchodilators, the therapeutic usefulness of β-adrenergic agonists and methylxanthines also depends on their ability to prevent attacks of asthma induced by a variety of stimuli. Asthmatic patients, because of their characteristic bronchial irritability, repeatedly have brief episodes of increased obstruction on encountering a variety of unavoidable stimuli, such as physical activity, cold air, pollutants, and allergens. In the context of their demonstrated ability to diminish the asthmatic patient’s characteristic hyperirritability, β-adrenergic agonists and methylxanthines act as modulators rather than bronchodilators.
For any asthmatic drug, bronchodilation and modulation of induced attacks may be distinct effects, as was first suggested by the clinical effectiveness of cromolyn sodium, a drug with no broncho-dilating effects. For β-adrenergic agonists specifically, higher doses seem to be necessary to modulate induced attacks than to produce significant bronchodilation.
The present study was conducted to examine the effects of a β-adrenergic agonist (fenoterol) and of theophylline both as bronchodilators and as modulators, and to determine whether their effects in preventing exercise-induced asthma are additive.
Subjects
Twenty subjects, aged 17 to 32 years, were studied. All had asthma as defined by the American Thoracic Society, and seven required regular medication for control of their disease. All had a history of asthma following exercise, and before entry into the study all demonstrated a 20 percent fall in FEVj after exercise. All subjects gave written, informed consent.
Subject Preparation
Before entry into the experiment, each subject had a history and physical examination. Blood was obtained for blood chemistries and hemogram, and urinalysis and ECC were performed. No abnormalities were detected.
Each subject received a theophylline dose titrated to produce serum levels greater than 10 mg/ml at two hours. A dose of 6 mg/kg of anhydrous theophylline 
solution was first administered. If the serum concentration measured two hours later by high-pressure liquid chromatography was not more than 10 mg/ml, the test dose was appropriately adjusted for use in the study.
Subjects excluded methylxanthines for eight hours before exercise testing and for 12 hours in the case of sustained-aotion formulation. Adrenergic agonists were excluded for 24 hours. Subjects taking corticosteroids every other day were tested on days off medication. Anyone who was wheezing was asked to return on another day for testing.
Exercise Testing
The response to exercise was measured according to a previously described protocol. Subjects exercised on a treadmill for five to six minutes, starting from a walk. Heart rate was monitored continuously, and exercise conditions were adjusted to increase heart rate to 90 percent of the age-predicted maximum, which was then maintained for five to six minutes. Forced vital capacity (FVC), one-second forced expiratory volume (FEVj), and forced expiratory flow from 25 to 75 percent of vital capacity (FEF25_75) were determined on a water-sealed, 9-L spirometer (Warren E. Collins, Inc) before exercise and at 1, 5, 10, 15, and 20 minutes after exercise. Values were compared with published normal values.
Each subject’s response to exercise was determined six times before entering the drug-testing protocol, in order to practice the procedures and to determine the reproducibility of their asthmatic response. Treadmill speed and inclination were varied during these runs to achieve maximal heart rates in the target range. Once optimal conditions were determined, they were maintained during drug testing. Many of the subjects’ responses to exercise had been measured within the previous three months. In those for whom this was not true, further runs were performed for evaluation.
Drug Testing
Fenoterol is the 4-hydroxyphenyl derivative of metapro-terenol. It is well absorbed orally, is effective for four to six hours, and has more potent bronchial effects than the parent compound. Selectivity for β-2 receptors is less than that seen with terbutaline and salbutamol, but greater than that with isoproterenol and metaproterenol.
The test drugs were supplied as fenoterol, 2.5-mg tablets, with matching placebo tablets, and as anhydrous theophylline solution containing 225 mg/30 ml with an identical solution without theophylline for a placebo (kindly supplied by Knoll Pharmaceutical Co). A liquid theophylline preparation was tested because greater dosage flexibility was possible.
Medications were administered in a randomized order in a double-blind, six-way crossover protocol. On each of the six test days, subjects received four tablets and the volume of liquid determined on the theophylline titration test day. The number of active fenoterol tablets, and die proportions of active and placebo theophylline solutions were varied to produce the doses listed in Table 1. Each treatment was separated by a washout period of at least 24 hours.
On testing days, two spirograms were recorded, pulse rate was measured, and a test medication administered. Two hours later, spirometry and pulse were remeasured and serum was obtained for theophylline determination. The subject then performed an exercise challenge at a rate and inclination identical to those established during the standardization period and with pulse rate and spirograms measured as before.
Statistics
Results were analyzed by Student’s t test unless otherwise stated.
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Table 1—Medications Administered
| Symbol | Description |
| Fio | Fenoterol, 10 mg |
| THi | Theophylline adjusted to produce serum levels greater than 10 Mg/ml |
| TiJO | Theophylline, 130 mg |
| T1IO F1.6 | Theophylline, 130 mg, -ffenoterol, 2.5 mg |
| Tl30 F* | Theophylline, 130 mg, -(“fenoterol, 5 mg |
| P | Placebo |