Theophylline and Fenoterol on Exercise-Induced Asthma Effects

On the theophylline titration day, serum theophylline levels ranged from 10.2 to 18.2 mg/ml, with a mean of 13.3 ±: 2.1 mg/ml. These levels were produced by doses ranging from 270 to 697 mg (3.5 to 10.4 mg/kg). When these doses were repeated during the experiment, the mean blood level was almost identical, 13.3 ± 3.3 mg/ml.

The lower theophylline dose, 130 mg, was administered on three testing days (on two of these days with fenoterol). Mean serum levels averaged 6.1, 5.9, and 6.0 /mg/ml, respectively, approximately one half the levels following high doses of theophylline. Following administration of 10 mg fenoterol and placebo, serum theophylline concentrations averaged 2.6 and 2.9 fig/ml, respectively.

On the two test days when test medications contained no theophylline, two subjects were found to have unusually high theophylline levels (11.3 and 12.5 mg/ml). Since these subjects used moderate doses of theophylline regularly to treat their asthma, and since their theophylline levels were also unusually high on other test days, it was assumed that theophylline clearance was slower in these subjects, and their data were excluded from subsequent analysis.

For the remaining 18 subjects, baseline pulmonary function before treatment on the six test days was similar. The mean values of FVC on the six days were identical (87 percent of predicted normal values) as were the mean FEVi values (91 percent of predicted). The mean values of FEF25-75 varied from 69 percent to 75 percent of predicted, but the values were not significantly different (P > 0.10; analysis of variance).

Bronchodilation

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Bronchodilation occurred following administration of all active medications as compared with placebo (Fig 1; Table 2). Improvement was most marked after fenoterol, 10 mg; FEVi increased.48 it.09 L (12 percent of predicted normal values and 14 percent above baseline values). Following administration of the higher dose of theophylline, FEVi increased.35 rt.06 L (9 percent of predicted and 10.5 percent above baseline).

The effects of theophylline and fenoterol were additive. Following 130 mg of theophylline alone, FEVi increased only 0.16 ±:.06 L (4 percent of predicted, 4.5 percent above baseline), as would be expected with the substantially lower serum levels. When a quarter dose of fenoterol was added, ie, 130 mg of theophylline and 2.5 mg of fenoterol, bronchodilation was somewhat greater. The FEVi increased 0.26 =t=.08 L (8.2 percent of predicted and 10 percent above baseline); the enhancement beyond theophylline alone approached statistical significance (P =.07). When 5 mg of fenoterol was added to 130 mg of theophylline, bronchodilation was significantly enhanced and was not significantly different from that seen with either theophylline or fenoterol given in full doses (P > .1).

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Changes in FEF25.75 were similar to, but slightly greater than those in FEVi.

Exercise-Induced Asthma

Exercise response is shown in Figure 2 and is compared statistically in Table 3. Maximal pulmonary function changes after exercise are compared with post-drug values, as well as being expressed as a percentage of predicted norms.

The modulating effects on exercise-induced asthma were not so clear as was bronchodilation. Only high-dose theophylline and 10 mg of f enoterol significantly inhibited exercise-induced asthma. On the day placebo was given, mean FEVi two hours after dosing (ie, post-drug value) was 3.54 L and fell to 2.37 L following exercise; thus, there was an exercise-induced decrease of 1.17 L (27 percent of predicted normal FEVi values, 32 percent of postdrug values). On the day high-dose theophylline was administered, FEVi decreased by.64 ±.09 L after exercise (17 percent of predicted, 17 percent of post-drug values), and on the day 10 mg of fenoterol was administered, FEVi decreased by.56 ± 0.08 L following exercise (14 percent of predicted values, 15 percent of post-drug values). These changes were significantly less than those following placebo (Table 3). Furthermore, they are similar to those seen with nonasthmatic patients exercised according to the conditions outlined.

Exercise-Induced AsthmaWhile there was a suggestion of additive inhibition of exercise-induced asthma by combinations of lower doses of fenoterol and theophylline, the changes were not statistically significant. As shown in Figure 2, exercise-induced changes in FEVi following theophylline, 130 mg (1.02 db.13 L; 27 percent of predicted values, 27 percent of post-drug values), were almost identical to those following placebo. Following 130 mg of theophylline with 5 mg of fenoterol, FEVi fell.79 ±.19 L after exercise (21 percent of predicted values, 18 percent of postdrug values); this change was not significantly different from that seen following either placebo (P =.07) or 130 mg of theophylline alone (P =.13).

None of the treatments significantly inhibited FEF25-75 changes when compared with placebo, although high-dose theophylline was effective when compared with 130 mg of theophylline (P =.03).

The net effects of bronchodilation and modulation of exercise-induced asthma are summarized in Figure 3. Comparing FEVi values before exercise with the lowest values after exercise showed that all active drugs had some effect on the net change. Following the three most effective regimens, the net change was only 2 percent (10 mg of fenoterol), 8 percent (high-dose theophylline), and 7 percent (130 mg of theophylline with 5 mg of fenoterol). It is apparent, however, that these effects were largely related to bronchodilation.

The seven subjects with more severe asthma, who required daily medication to control symptoms, more clearly benefited from active drugs. For instance, FEVi increased 16 percent following 10 mg FEV, BEFORE MEDICATION, AND BEFORE AND AFTER EXERCISE of fenoterol and 12 percent following high-dose theophylline, but decreased 3 percent following placebo. Additive effects were still demonstrable in that the 16 percent increase in FEVi seen following 130 mg of theophylline with 5 mg of fenoterol was significantly greater than either the 6 percent response to 130 mg of theophylline or the placebo response (P.05).

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Additive effects on exercise-induced asthma could also be demonstrated in this group. The exercise-induced reduction in FEVi following 10 mg of fenoterol (11 percent), high-dose theophylline (19 percent), 130 mg of theophylline (33 percent), 130 mg of theophylline with 2.5 mg of fenoterol (26 percent), and 130 mg of theophylline with 5 mg of fenoterol (16 percent) were all significantly less than that seen following placebo (44 percent). The response following 130 mg of theophylline with 5 mg of fenoterol was significantly less than following 130 mg of theophylline alone (P < .05).

Adverse Reactions

Fenoterol

Adverse reactions seen during the study are shown in Table 4. Ten mg of fenoterol was associated with side effects in more subjects (15 of 18) and with the greatest number of side effects (35 reports). Fewer side effects were seen following high-dose theophylline (21 reports) and following the combination of 130 mg of theophylline with 2.5 mg of fenoterol (21 reports) or with 5 mg of fenoterol (23 reports). Thus, all effective treatments were associated with side effects, and the combination of low doses of theophylline and fenoterol were associated with side effects just as frequently as was full-dose theophylline.

The reported side effects were also most severe following 10 mg of fenoterol. Of the 35 reports, 26 were considered moderately severe, and one (global anxiety and inability to concentrate) was considered severe. Following high-dose theophylline, only six of 21 reports were considered moderately severe, and following 130 mg of theophylline with 2.5 mg or 5 mg of fenoterol, only 5 of 21 and 10 of 23 reports, respectively, were considered moderately severe; none was considered severe. All of the reported side effects following low-dose theophylline were mild.

Gastrointestinal symptoms were seen primarily following high-dose theophylline, with tremor and CNS symptoms seen more frequently when fenoterol was given. Although side effects were both more frequent and more severe with the higher dose of theophylline, the individual occurrence of side effects did not correlate with serum theophylline levels.

Treatment effects on heart rate are shown in Table 5. Resting heart rates were almost identical on the six testing days. Two hours following 10 mg of fenoterol, heart rate had increased 23 beats/min (range, —8 to 5 beats/min). These changes were significantly different from the placebo response (P < .001), as were the smaller increases seen following 130 mg of theophylline with 5 mg of fenoterol (P =.003). The changes following high-dose theophylline, 130 mg of theophylline, or 130 mg of theophylline with 2.5 mg of fenoterol were not significantly different from those following placebo. Maximal heart rates during exercise were not affected, nor were heart rates following recovery from exercise.

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Changes in pulmonary functionFigure 1. Changes in pulmonary function from values before medications to values 2 hours afterward for 18 subjects. Values expressed as percentage of predicted normal (17), and brackets drawn at 1 SE.

Changes from values before exercise
Figure 2. Changes in pulmonary function from values just before exercise (2 hours after medications) to lowest values after exercise for 18 subjects. Values expressed as percentage of predicted normal (17), and brackets drawn at 1 SE.

mean FEV
Figure 3. Summary of mean FEVj values before medication, 2 hours later, and the lowest after exercise, expressed as percentage of predicted normal (17). Bronchodilation (comparing baseline values to 2 hours) indicated by length of die arrow. Exercise-induced asthma (comparing values just before exercise to lowest after exercise) indicated by length of batched bar. Mean serum theophylline levels 2 hours after dosing.

Table 2—Brcnchodilation: Statistical Comparison of Data in Figure 1

« FEVi FEF*6-76
F10 <.001* <.001
Тш <.001 <.001
P vs Ti* .011 .025
Tiio-fFj.5 <.001 <.001
k Tuo Fs <.001 <.001
F10 .004 .004
Тш <.001 .027
Tito vs ‘ Tiio F*.6 NSf NS
Tuo F6 .003 .02
I f F10 .014 NS
Tiio Fi.b vs \ THi NS NS
1 [ Tiao Fs .031 NS

Table 3—Modulation of Exercise-Induced Asthmas Statistical Comparison of Data in Figure 2

FEVt FEFm.7»
Fio <.001* NS
THt .006 NS
P vs • T,« NSt NS
TlM Ft.8 NS NS
k Тцо F» NS NS
Fio <.001 NS
Ti» vs ( Thi <.001 .03
Ti»oH-Fi.6 NS NS
k Tuo F* NS NS
( Fio NS NS
Geo Fj.» vs * THi NS NS
( Tiso Fft NS NS

Table 4—Advene Reaction» Following Test Medications

Fio Th! Two Tuo Fj .5 Tuo-fFfi P
Total no. of subjects reporting adverse reactions 15 12 5 11 11 0
Total no. of adverse reactions reported Systems involved 35 21 5 21 23 0
Central nervous 8 4 2 10 6 0
Neuromuscular 15 7 0 7 7 0
Gastrointestinal 1 6 2 1 3 0
Palpitations 0 1 1 0 0 0
Miscellaneous* 11 3 0 3 7 0

Table 5—Effect of Medications on Heart Rate

Fio THi Ti,0 Tno Fj.6 Tiso Fs P
Baseline 77* 78 77 77 77 76
Increase after medication 23 6 2 10 15 6
Maximum during exercise 177 179 175 178 177 174
5 minutes following exercise 115 109 98 107 111 100