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Inhibition of exercise-induced asthma by theophylline
Inhibition of exercise-induced by theophylline Elliot
F. Ellis, M.D. Buffulo, N.Y.
Although an association between exercise and provocation of asthma has been recognized for 300 yr, Jones et al., ’ pediatricians at Alder Hey Children’s Hospital in Liverpool, appear to have been the first to attempt to assess the effect of drugs as modulators of the exercise-induced bronchoconstriction phenomenon. Among the drugs they investigated was the choline salt of theophylline, a formulation that contains 64% anhydrous theophylline. In a single-dose study in which the subjects were administered anhydrous theophylline of the equivalent of between 4.5 and 5.8 mg/kg body weight several hours before exercise challenge, the postexercise fall in FEV, was completely or partially prevented in eight of nine subjects, and Jones et al. concluded that theophylline was protective against exercise-induced wheezing. In retrospect, it appears that the FEV, was measured before drug administration and not immediately before exercise and thus one does not know how much of the putative inhibition of exercise-induced asthma (EIA) was due to the bronchodilator effect of theophylline. Anderson et al.’ have emphasized the importance of measuring expiratory flow rate immediately before exercise so that the bronchodilating effect of the drug and its inhibitory effect on EIA can be considered separately. Nonetheless, in the study of Jones et al., the maximal FEV, after exercise was observed at a mean of 90 min after drug administration, which would coincide with the time of the peak serum theophylline concentration after administration of a rapidly absorbed product such as the one used. This was the first suggestion of a pharmacodynamic effect of theophylline in asthma. During the past decade there have been 10 additional studies2-” in which the efficacy of theophylline in the prevention of EIA has been investigated (Table I). While these studies are not strictly comparable because of a number of differences in experimental design and particularly in dose of theophylline, there are some generalizations that can be made. First, the results of these studies have uniformly shown that theFrom the Department of Pediatrics, at Buffalo, Buffalo, N.Y.
666
asthma
State University
of New York
ophylline is an effective bronchodilator at rest in individuals affected with asthma. Second, efficacy of theophylline as a bronchodilator does not predict efficacy in the prevention of EIA. There are a significant number of subjects with perennial asthma who obtain good bronchodilator effect and control of asthma with theophylline but in whom theophylline is only marginally effective in the inhibition of postexercise bronchoconstriction, a phenomenon also observed with aerosolized P-agonists. 6. 8. ” This finding has suggested to&me authors that the mechanism of bronchodilator drug action and protection against exerciseinduced bronchoconstriction may be independent of each other.6.8 Third, as in response to aerosolized pZagents, there is a heterogeneity of responsiveness among patients. With the exception of one study,‘j theophylline has been found to be effective in inhibiting EIA in about 80% of individuals tested. Some patients have no protection from EIA with theophylline. Fourth, all studies in which various agents are compared with each other show that theophylline is less effective than inhaled P-agonists in the modulation of the EIA phenomenon. Fifth, the differential effect of theophylline on airways of different calibers is unclear. Most investigators report good inhibition of EIA by theophylline as reflected in flow rates at both high and low lung volumes,3. ‘. * while a few find theophylline most effective in inhibiting exercise-induced airway narrowing involving the large airways.’ The pharmacodynamic effect of theophylline (i.e., the relationship between the logarithm of the serum concentration and the physiologic effect) is less clear in terms of inhibition of EIA6. 8. 9 than it is with bronchodilation, but it appears to exist. The general goal of asthma treatment is to provide control of airway reactivity around the clock. Theophylline is the only agent that can be said to provide bronchodilator activity around the clock on a reasonable dosing regimen that requires no more than three doses of drug in a 24-hr period. For this reason, and if the degree of preexisting airway obstruction is a determinant of severity of EIA, then theophylline is a useful drug.
VOLUME NUMBER
73 5 PART 2
TABLE I. Studies of theophylline
_-
in EIA
-----
Authors
Dose
Scale et al.,’ 1975 Bierman et al. ,I{ 1975 Badiei et al.,” 1975 Godfrey et al.,” 1975 Seale et al.,” 1977 Biennan et al..’ 1977
Pollock et al.,’ 1977 Chryssanthopoulos et al.,Y I979 Eggleston et al. ,I” I981 Phillips
*Individual
et al..”
data
of EIA by theophvlline
Inhibition
1981
375 mg 130 mg 6.5 mg/kg 64to 128mg I25 mg 8.0 mg/kg single and 4.0 mg/kg every 6 hr 7.5 mg/kg 4.6
mg/kg
Subjects (no.)
Route
691
.-----___ Protection vs. EIA _-
dose,
Oral Oral Oral Oral Oral Oral
IO Ih I6 15 I0 ‘I
‘J/ 16 I:/15 _, -: IO 1 I/‘_? it
2.2
Oral Oral
I2 ICI
I’il: q/Ills
Oral
I8
(mean);
to 7.2 mg/kg (range) 10.4 mg/kg
3.5 to
bwiv) 405 mg twice a day (mean), sustainedrelease product
_,I’ IO
x
9
Oral
3ioci ---___
not given.
tSixty percent or greater inhibition of PER, FEV,, *Forty percent or greater inhibition of fail in PEFR. $Less than 50% of fall in PEFR on placebo.
and FEF,,-r5.
There have been some recent findings on the extrapulmonary effects of theophylline that have impiications for the athlete with asthma. Theophylline has long been known to have an ionotropic effect on the heart and also to reduce pulmonary vascular resistance. Matthay et al. “. I3have shown that theophylline improves both right and left ventricular function in adults with chronic obstructive airways disease. In control subjects without cardiopulmonary disease, increases were also seen in right and left ventricular ejection fractions. In earlier studies of a similar patient population, 14-16 intravenous aminophylline was shown to decrease both pulmonary artery pressure and pulmonary vascular resistance. Of even greater relevance in competitive sports is the effect of theophylline on skeletal muscle. It has been known for some time from animal studies that xanthines strengthen the contractions of skeletal muscles that are elicited by electrical stimulation. Aubier et al. “. ‘* have shown recently that aminophylline improves diaphragmatic contractility in normal human subjects. This finding has been confirmed and extended to the intercostal muscles, at least in dogs.” If theophylline improves muscle contractility, it may also prevent development of fatigue, not only of respiratory muscles but also perhaps of other skeletal muscles as well. Methylxanthines are not presently on the list of drugs banned for use in international sports competition,20 but in view of the extrapulmonary effects of theophylline, one
could make the case that they should be added to the roster. REFERENCES I. Jones exercise
RS.
Wharton MJ, and bronchodilator
Buston MH: The place of physical drugs in the assessment of the
asthmatic child. Arch Dis Child 2. Scale, JP, Anderson SD, Lindsay 3.
ercise induced Bierman CW.
asthma. Pierson
asthma. Pharmacological combinations JAMA 6. Faciane
Aust WE.
38:539, 1963 DA: Drug evaluation
assessment
234:295,
of single
drugs
Badiei
5.
and their combination upon exercise-induced airway tion. Ann Allergy 35:32. 1975 Godfrey S, Kanig P: Suppression of exercise-induced theophyliine, asthmatic
and
drug
1975
4.
by salbutamol. in a group of
J. Sly RM:
in ex-
NZ J Med 5:466. I975 Shapiro GG: Exercise-induced
Effect
of theophylline,
ephedrine obstrucasthma
a&opine. cromotyn and p&&o children. Pediatrics 5h(suppl):930.
1975 6. Scale JP, Anderson SD. Lindsay theophylline and oral salbutamol I.
Aust NZ J Mad 7~270. Bierman CW. Shapiro
197-l GG,
and chronic theophylline spasm. Pedialrics 60:845. 8. Pollock
J, Kiechel
Pierson
therapy 1977
F. Cooper
of serum theophylline induced bronchospasm
DA: A comparison in exercise-induced WE,
Dorsett
of oral asthma. CS:
in exercise-induced D. Weinberger
M: Relationship
concentration to inhibition of exerciseand comparison with cromolyn. Pcdi-
attics 60:840, 1977 C, Bruns WT. Maksud MC. Galten 9. Chryssanthop3ulos Hause LL: Quantitative effect of theophylline anhydrous exercise-induced asthma after maximal physical effort. 10.
Allergy 42:355. Eggleston PA.
1979 Beasley
Acute
broncho-
PP. Kindle!
RT:
The
eifccrs
WJ. on Ann of oml
692
I I.
12.
13.
14.
15.
Ellis
doses of theophylline and fenoterol on exercise-induced asthma. Chest 79:399, 1981 Phillips MJ, Oilier S, Trembath PW. Boobis SW. Davies RJ: The effect of sustained-release aminophylline on exercise-induced asthma. Br J Dis Chest 75:181, 1981 Matthay RA, Berger HJ. Loke J. Gottschalk A, Zaret BL: Effects of aminophylline upon right and left ventricular performance in chronic obstructive pulmonary disease: Noninvasive assessment by radionuclide angiocardiography. Am J Med 65:903, 1978 Matthay RA, Berger HJ, Davies R, Loke I, Gottschalk A, Zaret BL: Improvement in cardiac performance by oral longacting theophylline in chronic obstructive pulmonary disease. Am Heart J 104:1022, 1982 Parker JO, Ashekian PB, DiGiorgi S, West RO: Hemodynamic effects of aminophylline in chronic obstruction pulmonary disease. Circulation 35:365, 1967 Parker JO, Kelkar K, West RO: Hemodynamic effects of aminophylline in COT pulmonale. Circulation 33: 17, 1966
J. ALLERGY
CLIN.
IMMUNOL. MAY 1984
16. Murphy GW. Schreiner BF Jr, Yu PN: Effects of aminophylline on the pulmonary circulation and left ventricular performance in patients with valvular heart disease. Circulation 37:3hl. 196X 17. Aubier M. DeTroyer A. Sampson M. Macklem PT. Rou,bob C: Aminophylline improves diaphragmatic contracrility. N Engl J Med 305:249, 1981 18. Aubier M. Murciano D. Viires N. Lecocguic Y. Palaciob S. Pariente R: Increased ventilation caused by improved diaphragmatic efficiency during aminophylline infusion. Am Rev Respir Dis 127:148, 1983 19. Sigrist S. Thomas D, Howell S. Roussos CH: The effect of aminophylline on inspirarory muscle contractility. Am Rev Respir Dis 126:46. 1982 20. Guidelines for doping controls and antidoping work. The Norwegian Confederation of Sports, 1983
F. Ellis, M.D. Buffulo, N.Y.
Although an association between exercise and provocation of asthma has been recognized for 300 yr, Jones et al., ’ pediatricians at Alder Hey Children’s Hospital in Liverpool, appear to have been the first to attempt to assess the effect of drugs as modulators of the exercise-induced bronchoconstriction phenomenon. Among the drugs they investigated was the choline salt of theophylline, a formulation that contains 64% anhydrous theophylline. In a single-dose study in which the subjects were administered anhydrous theophylline of the equivalent of between 4.5 and 5.8 mg/kg body weight several hours before exercise challenge, the postexercise fall in FEV, was completely or partially prevented in eight of nine subjects, and Jones et al. concluded that theophylline was protective against exercise-induced wheezing. In retrospect, it appears that the FEV, was measured before drug administration and not immediately before exercise and thus one does not know how much of the putative inhibition of exercise-induced asthma (EIA) was due to the bronchodilator effect of theophylline. Anderson et al.’ have emphasized the importance of measuring expiratory flow rate immediately before exercise so that the bronchodilating effect of the drug and its inhibitory effect on EIA can be considered separately. Nonetheless, in the study of Jones et al., the maximal FEV, after exercise was observed at a mean of 90 min after drug administration, which would coincide with the time of the peak serum theophylline concentration after administration of a rapidly absorbed product such as the one used. This was the first suggestion of a pharmacodynamic effect of theophylline in asthma. During the past decade there have been 10 additional studies2-” in which the efficacy of theophylline in the prevention of EIA has been investigated (Table I). While these studies are not strictly comparable because of a number of differences in experimental design and particularly in dose of theophylline, there are some generalizations that can be made. First, the results of these studies have uniformly shown that theFrom the Department of Pediatrics, at Buffalo, Buffalo, N.Y.
666
asthma
State University
of New York
ophylline is an effective bronchodilator at rest in individuals affected with asthma. Second, efficacy of theophylline as a bronchodilator does not predict efficacy in the prevention of EIA. There are a significant number of subjects with perennial asthma who obtain good bronchodilator effect and control of asthma with theophylline but in whom theophylline is only marginally effective in the inhibition of postexercise bronchoconstriction, a phenomenon also observed with aerosolized P-agonists. 6. 8. ” This finding has suggested to&me authors that the mechanism of bronchodilator drug action and protection against exerciseinduced bronchoconstriction may be independent of each other.6.8 Third, as in response to aerosolized pZagents, there is a heterogeneity of responsiveness among patients. With the exception of one study,‘j theophylline has been found to be effective in inhibiting EIA in about 80% of individuals tested. Some patients have no protection from EIA with theophylline. Fourth, all studies in which various agents are compared with each other show that theophylline is less effective than inhaled P-agonists in the modulation of the EIA phenomenon. Fifth, the differential effect of theophylline on airways of different calibers is unclear. Most investigators report good inhibition of EIA by theophylline as reflected in flow rates at both high and low lung volumes,3. ‘. * while a few find theophylline most effective in inhibiting exercise-induced airway narrowing involving the large airways.’ The pharmacodynamic effect of theophylline (i.e., the relationship between the logarithm of the serum concentration and the physiologic effect) is less clear in terms of inhibition of EIA6. 8. 9 than it is with bronchodilation, but it appears to exist. The general goal of asthma treatment is to provide control of airway reactivity around the clock. Theophylline is the only agent that can be said to provide bronchodilator activity around the clock on a reasonable dosing regimen that requires no more than three doses of drug in a 24-hr period. For this reason, and if the degree of preexisting airway obstruction is a determinant of severity of EIA, then theophylline is a useful drug.
VOLUME NUMBER
73 5 PART 2
TABLE I. Studies of theophylline
_-
in EIA
-----
Authors
Dose
Scale et al.,’ 1975 Bierman et al. ,I{ 1975 Badiei et al.,” 1975 Godfrey et al.,” 1975 Seale et al.,” 1977 Biennan et al..’ 1977
Pollock et al.,’ 1977 Chryssanthopoulos et al.,Y I979 Eggleston et al. ,I” I981 Phillips
*Individual
et al..”
data
of EIA by theophvlline
Inhibition
1981
375 mg 130 mg 6.5 mg/kg 64to 128mg I25 mg 8.0 mg/kg single and 4.0 mg/kg every 6 hr 7.5 mg/kg 4.6
mg/kg
Subjects (no.)
Route
691
.-----___ Protection vs. EIA _-
dose,
Oral Oral Oral Oral Oral Oral
IO Ih I6 15 I0 ‘I
‘J/ 16 I:/15 _, -: IO 1 I/‘_? it
2.2
Oral Oral
I2 ICI
I’il: q/Ills
Oral
I8
(mean);
to 7.2 mg/kg (range) 10.4 mg/kg
3.5 to
bwiv) 405 mg twice a day (mean), sustainedrelease product
_,I’ IO
x
9
Oral
3ioci ---___
not given.
tSixty percent or greater inhibition of PER, FEV,, *Forty percent or greater inhibition of fail in PEFR. $Less than 50% of fall in PEFR on placebo.
and FEF,,-r5.
There have been some recent findings on the extrapulmonary effects of theophylline that have impiications for the athlete with asthma. Theophylline has long been known to have an ionotropic effect on the heart and also to reduce pulmonary vascular resistance. Matthay et al. “. I3have shown that theophylline improves both right and left ventricular function in adults with chronic obstructive airways disease. In control subjects without cardiopulmonary disease, increases were also seen in right and left ventricular ejection fractions. In earlier studies of a similar patient population, 14-16 intravenous aminophylline was shown to decrease both pulmonary artery pressure and pulmonary vascular resistance. Of even greater relevance in competitive sports is the effect of theophylline on skeletal muscle. It has been known for some time from animal studies that xanthines strengthen the contractions of skeletal muscles that are elicited by electrical stimulation. Aubier et al. “. ‘* have shown recently that aminophylline improves diaphragmatic contractility in normal human subjects. This finding has been confirmed and extended to the intercostal muscles, at least in dogs.” If theophylline improves muscle contractility, it may also prevent development of fatigue, not only of respiratory muscles but also perhaps of other skeletal muscles as well. Methylxanthines are not presently on the list of drugs banned for use in international sports competition,20 but in view of the extrapulmonary effects of theophylline, one
could make the case that they should be added to the roster. REFERENCES I. Jones exercise
RS.
Wharton MJ, and bronchodilator
Buston MH: The place of physical drugs in the assessment of the
asthmatic child. Arch Dis Child 2. Scale, JP, Anderson SD, Lindsay 3.
ercise induced Bierman CW.
asthma. Pierson
asthma. Pharmacological combinations JAMA 6. Faciane
Aust WE.
38:539, 1963 DA: Drug evaluation
assessment
234:295,
of single
drugs
Badiei
5.
and their combination upon exercise-induced airway tion. Ann Allergy 35:32. 1975 Godfrey S, Kanig P: Suppression of exercise-induced theophyliine, asthmatic
and
drug
1975
4.
by salbutamol. in a group of
J. Sly RM:
in ex-
NZ J Med 5:466. I975 Shapiro GG: Exercise-induced
Effect
of theophylline,
ephedrine obstrucasthma
a&opine. cromotyn and p&&o children. Pediatrics 5h(suppl):930.
1975 6. Scale JP, Anderson SD. Lindsay theophylline and oral salbutamol I.
Aust NZ J Mad 7~270. Bierman CW. Shapiro
197-l GG,
and chronic theophylline spasm. Pedialrics 60:845. 8. Pollock
J, Kiechel
Pierson
therapy 1977
F. Cooper
of serum theophylline induced bronchospasm
DA: A comparison in exercise-induced WE,
Dorsett
of oral asthma. CS:
in exercise-induced D. Weinberger
M: Relationship
concentration to inhibition of exerciseand comparison with cromolyn. Pcdi-
attics 60:840, 1977 C, Bruns WT. Maksud MC. Galten 9. Chryssanthop3ulos Hause LL: Quantitative effect of theophylline anhydrous exercise-induced asthma after maximal physical effort. 10.
Allergy 42:355. Eggleston PA.
1979 Beasley
Acute
broncho-
PP. Kindle!
RT:
The
eifccrs
WJ. on Ann of oml
692
I I.
12.
13.
14.
15.
Ellis
doses of theophylline and fenoterol on exercise-induced asthma. Chest 79:399, 1981 Phillips MJ, Oilier S, Trembath PW. Boobis SW. Davies RJ: The effect of sustained-release aminophylline on exercise-induced asthma. Br J Dis Chest 75:181, 1981 Matthay RA, Berger HJ. Loke J. Gottschalk A, Zaret BL: Effects of aminophylline upon right and left ventricular performance in chronic obstructive pulmonary disease: Noninvasive assessment by radionuclide angiocardiography. Am J Med 65:903, 1978 Matthay RA, Berger HJ, Davies R, Loke I, Gottschalk A, Zaret BL: Improvement in cardiac performance by oral longacting theophylline in chronic obstructive pulmonary disease. Am Heart J 104:1022, 1982 Parker JO, Ashekian PB, DiGiorgi S, West RO: Hemodynamic effects of aminophylline in chronic obstruction pulmonary disease. Circulation 35:365, 1967 Parker JO, Kelkar K, West RO: Hemodynamic effects of aminophylline in COT pulmonale. Circulation 33: 17, 1966
J. ALLERGY
CLIN.
IMMUNOL. MAY 1984
16. Murphy GW. Schreiner BF Jr, Yu PN: Effects of aminophylline on the pulmonary circulation and left ventricular performance in patients with valvular heart disease. Circulation 37:3hl. 196X 17. Aubier M. DeTroyer A. Sampson M. Macklem PT. Rou,bob C: Aminophylline improves diaphragmatic contracrility. N Engl J Med 305:249, 1981 18. Aubier M. Murciano D. Viires N. Lecocguic Y. Palaciob S. Pariente R: Increased ventilation caused by improved diaphragmatic efficiency during aminophylline infusion. Am Rev Respir Dis 127:148, 1983 19. Sigrist S. Thomas D, Howell S. Roussos CH: The effect of aminophylline on inspirarory muscle contractility. Am Rev Respir Dis 126:46. 1982 20. Guidelines for doping controls and antidoping work. The Norwegian Confederation of Sports, 1983