Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma

Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma F. Estelle R. Simons, MD, FRCPC, N. Reeni Soni, MD, Wade T. A. Watson, MD, FRCPC, and Allan 6. Becker, MD, FRCPC Winnipeg,

Manitoba,

Canada

Background: In adults with asthma, the selective P,-adrenergic agonist salmeterol has a prolonged bronchodilator and bronchoprotective effect. To date, there are few published studies of salmeterol in children. Methods: We compared the bronchodilator and bronchoprotective effects of salmeterol, 25 and 50 pg, with salbutamol, 200 pg, and with placebo, administered via metered-dose inhaler, in a randomized, double-blind, within-patient, four-way crossover, single-dose study in 20 children. Results: Mean baseline forced expiratory volume in 1 second (FEV,) and PC, methacholine were not significantly different (p > 0.05) on the 4 study days, and did not change significantly after placebo. FEV, increased significantly from 5 to 30 minutes after salbutamol, and from 5 minutes to 12 hours after 25 pg or 50 pg salmeterol, compared with placebo. After 25 pg or 50 pg salmeterol, FEV, was significantly lower than after salbutamol at 5 and IO minutes, did not differ from salbutamol at 30 minutes, and was signijcantly greater than after salbutamol from 3 to I2 hours. No signiJcant difference occurred between the effect of 25 pg salmeterol and the effect of 50 pg salmeterol on FEV,. After salbutamol, there was a significant increase in PC,, only at 30 minutes. After 25 pg or 50 pg salmeterol, PC,, increased significantly from 30 minutes to 12 hours. Salmeterol, 25 pg and 50 pg provided significantly greater bronchoprotection than salbutamol from 3 to 12 hours and from 30 minutes to 12 hours, respectively. Salmeterol, 50 pg, provided significantly better bronchoprotection than 25 pg salmeterol from 30 minutes to 12 hours. The amount of change in PC,, accounted for by change in FEV, varied from 14% to 28%, indicating that protection against bronchoconstriction was not entirely dependent on bronchodilation. Conclusions: Salmeterol is a potent, long-acting bronchodilator, with a slower onset of bronchodilation than salbutamol. It provides significantly greater and longer-lasting protection against bronchoconstriction than salbutamol. (J ALLERGY CLINIMMUNOL1992;90:840-6.) Key words: Asthma, salmeterol, salbutamol, methacholine, bronchodilation, children

Salmeterol is a new, topically active, highly selective, &adrenergic agonist. Its long duration of action is attributed to its lipophilicity and to its unique long, nonpolar side chain (Fig. 1), which may bind to an exoreceptor site near the l& receptor and thus help

Abbreviations used FVC: FEV,: FEF 2596. 501.75%. 25% to75s:

PC,,: From the Section of Allergy and Clinical Immunology, Faculty of Medicine, the University of Manitoba. Supported by Glaxo Canada, Inc. Received for publication Dec. 3, 1991. Revised Feb. 20, 1992. Accepted for publication Feb. 20, 1992. Reprint requests: F. E. R. Simons, MD, Children’s Hospital of Winnipeg, 840 Sherbrook St., Winnipeg, Manitoba, Canada R3A 1Sl. l/1/41438

840

bronchoprotection,

Forced vital capacity Forced expiratory volume in 1 second Forced expiratory flow at 2.5%, 50%, 75%, and 25% to 75% of the FVC Provocative concentration of methacholine required to decrease FEV, by 20%

anchor the phenylethanolamine “head’ of the &-agonist to its receptor.lm4 In adults bronchodilation and protection against bronchoconstriction induced by methacholine, exer-

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cise, or allergen occur for at least 12 hours after a

SALBUTAMOL

single inhalation of 50 p,g salmetero1.5-‘XSalmeterol, SO kg twice daily, prevents asthma symptoms in patients with mild or moderate disease and improves nocturnal asthma,‘” sleep quality,16 and quality of life

METHODS The study protocol was approved by the University of Manitoba Faculty Committee on the Use of Human Subjects in Research, Before the study written informed consent was obtained from the patients and their parents. Patients were selected for inclusion in this study if they were 6 to 12 years of age. with chronic asthma diagnosed according to American Thoracic Society criteria. Patients were clinically stable for 30 days before the start of the study. During this time, and during the study itself, they were allowed to continue inhaled cromoglycate or inhaled corticosteroids such as beclomethasone or budesonide. They were excluded from the study if they had a history of adverse reaction to sympathomimetic medications, if they were likely to have an exacerbation of asthma as a result of seasonal allergies during the study, if they had had a viral upper respiratory tract infection in the month preceding the study, if they had required oral corticosteroids in the previous 30 days, or if they had any active systemic disorders other than well-controlled asthma.

Pulmonary

function

testing

All patients visited the Pediatric Allergy Laboratory at study entry (visit 1) for a flow-volume loop (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV J,. forced expiratory flow [ FEFzYa,FEF,,, FEF,,,, and FEF z,cr,,I;,.,I, and a methacholine challenge test (the provocative concentration of methacholine in milligrams per milliliter required to decrease the FEV, by 20% [PC,,,],.” !: For entry into the study they had to have an FEV, of at least 70% predicted for age. sex, and height, and a PC,,, methacholine of 14.0 mg/ml. The methacholine challenge test was performed as follows: patients inhaled methacholine chloride aerosol by breathing at tidal volume from a face mask for 2 minute‘.,” 2’ FEV, was assessed at 30 seconds, 90 seconds, and 5 minutes after completion of the methacholinc inhalation. The lowest FEV, from a technically acceptable flow-volume

CH ‘3

H i OH

in general. I’. ”

To date, few published studies exist of salmeterol in children with asthma, but preliminary evidence suggests that this medication is safe and effective when used in a dose of 25 or 50 kg twice daily in children and that it has a long duration of action in children. I” “’ We investigated the magnitude and duration of bronchodilation and of protection against methacholine-induced bronchoconstriction provided by 25 and SO pg inhaled salmeterol versus 200 Kg inhaled salbutamol and placebo, in this randomized, doubleblind. within-patient, four-way crossover, single-dose study in children with asthma.

8441

CHOH-CH2-NH-C----CH3 \ \\

SALMETEROL

FIG. 1. Illustration of chemical structures for salbutamol and salmeterol.

loop was considered to be the response to the methacholine inhalation. The FEV, after inhalation of 0.9% saline solution served as baseline for the dose-response to methacholine. At intervals of no less than 5 minutes, doubling doses of methacholine diluted in 0.9% saline solution were inhaled. The PC,,, was calculated by interpolation from a log-linear graph.

Study

protocol

Each patient was randomly allocated to receive. on four separate days (visits 2 to 5), one of the following treatments via metered-dose inhaler: salmeterol. two puffs of 12.5 pg: salmeterol, two puffs of 25 pg; salbutamol. two puffs of 100 Fg; or placebo two puffs. Patients arrived at the environmentally controlled Pediatric Allergy Laboratory between 7 AM and 8:30 AM. After a 30-minute rest, they had baseline tremor evaluated according to a 6-point scale (0 = no tremor, arms extended; 6 = marked tremor, arms flexed at side of body),‘,’ 12-lead electrocardiography with a 60-second rhythm strip was performed. blood pressure and pulse were measured, a Rowvolume loop for measurement of WC, FEV,. FEF,,., 1,,i(+, FEF,,., . FE&+, and FEF,,,., was made, and a methacholine challenge test was performed. Subsequent measurements were always made in this order for each patient: tremor. heart rate and rhythm, blood pressure, flow-volume loop, and methacholine challenge test. All assessments were made by the same investigator. On visits 2 to 5. FEV, and baseline PC,, methacholinc had to be within 10% and within one duubling; dose, rcspectively, of the values determined at visit 1. If t:hey were not within 10%. the visit was rescheduled. After measurement of PC,, and after recovery of the FEV, to within IO? of baseline, two inhalations of the study medication or placebo were administered in a technically correct manner. Spirometry (FVC. FEV,. FEF?,,-,,,,J4r FEl&, FEF,,+. and FEF,,,) was recorded at 5, 10. 15. and 30 minutes, and 3, 6,9, and 12 hours after medication inhalation. Mcthacholinc challenge tests were performed at 30 minutes and at 3. h.

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Time FIG. 2. Posttreatment FEV, to pretreatment FEV, ratio illustrated for inhalation of placebo (closed circlesj; 200 kg salbutamol (closed trianglesj; 25 kg salmeterol (open squares); and 50 pg salmeterol (closed squaresj in 20 patients. Each symbol represents mean * SEM. Asterisks denote a significant difference from placebo inhalation (*p < 0.05; **p < 0.01; ***p < 0.001). Crosses indicate a significant difference between salmeterol and salbutamol inhalations (‘p < 0.05; ++p < 0.01; +++p < 0.001).

9, and 12 hours after medication inhalation. Visits were scheduledat intervals of no less than 2 days. Patients were not allowed to take any l$-adrenergic agonists or ingest any methylxanthines, including dietary xanthines, for 12 hours before each visit and during each visit2“. 25Throughout the study patients avoided exposure to allergens to which they were sensitive, and patients using inhaled cromoglycate,beclomethasone,or budesonide continued to take these medications in a consistent manner. Data analysis The onsetof bronchodilation was determinedon the basis of differences between the pretreatment and posttreatment FEV, at 5, 10, 15, and 30 minutes. Assessmentof the duration of bronchodilation was basedon the posttreatment to pretreatmentFEV, ratio throughout the study. The bronchoprotective effect was assessedwith use of the posttreatment to pretreatmentPC, methacholine ratio at each time point for each patient. Data for bronchoprotectionwere also normalized for variation on the placebo day by use of the following formula at each time point for each patient: PosttreatmentPCJpretreatment PC,, PostplaceboPC,/preplacebo PC,, Enrollment of a minimum of 16 patients in this trial was calculated to provide a statistical power of 0.8 (p < 0.05) for a doubling of the PC, metbacholine.

Repeatedmeasuresanalysis of variance (ANOVA) were used to compare the treatment effect over time. Multiple t tests correctedwith Bonferroni adjustmentswere usedfor comparison at each time period between groups, because of a very significant interaction between treatments and time. Analysis of covariance was used to assessthe impact of bronchodilation on the bronchoprovocative airway responses.All data are reported as mean ? SEM; p 5 0.05 was considered significant.26 RESULTS Twenty patients (13 male) age 6 to 12 years (mean, 10.3 years) completed the study. Their mean height was 140.6 + 2.0 cm (mean + SEM), and their mean weight was 35.7 t 1.9 kg. Before the study and during the study, 17 patients required regular treatment with inhaled antiasthma medications (cromolyn, 1 patient; beclomethasone, 5 patients; and budesonide, 11 patients). Three patients were not taking any antiasthma medications regularly. All patients were permitted to use salbutamol two puffs as “rescue” medication except during the 12 hours before each visit and during each 1Zhour visit. Mean baseline FEV, was not significantly different on any of the study days (p > 0.05): placebo, 2.07 & 0.80 L (101% predicted); salbutamol, 2.02 t 0.74 L (100% predicted); 25 p,g salmeterol,

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2.06 21 0.87 L (99% predicted); and 50 kg salmeterol, 3.06 +- 0.81 L (101% predicted). After placebo inhalation FEV, did not change significantly ( Fig. 2). After salbutamol inhalation FEV, was significantly greater than after placebo inhalation from 5 to 30 minutes. reaching a peak at 15 to 30 minutes. but by 3 hours the difference was no longer significant. After inhalation of 2.5 pg or 50 pg salmeterol, FEV, peaked at 3 hours and was significantly greater than after placebo inhalation from 5 minutes to 12 hours, inclusive. After salmeterol. FEV, was significantly lower than after salbutamol at 5, 10, and 15 minutes (2.5 pg), and at 5 and 10 minutes (50 kg). FEV, did not differ significantly after 25 kg or 50 p.g salmeter01 or salbutamol at 30 minutes. After 25 Fg and 50 IJ-gsalbutamol FEV, was significantly greater than after salbutamol from 3 to 12 hours, inclusive. No significant difference occurred between the effect of 25 ~g salmeterol and 50 pg salmeterol on the FEV, When FEV, was normalized for baseline, the mean maximum FEV, did not differ significantly for the three medication regimens. Compared with placebo, all three active medications produced a significantly increased normalized FEV,. The maximum increase was 6.6% after placebo, 11.7% after salbutamol, I 1.7% after 25 big salmeterol and 12.7% after 50 pg salmeterol. After placebo, 200 kg salbutamol, and 25 pg and 50 kg salmeterol, the changes in FEFlsB, FEF,,,, FEF,,. and FEF,,, ,07icTiwere similar to the changes in FEV,. Mean PC,, methacholine was not significantly different (p > 0.05) at the beginning of each study day: placebo, 1.05 ? 0.19 mg/ml; salbutamol, 1.07 -r0.16 mg/ml; 25 kg salmeterol, 1.32 + 0.24 mg/ml; and 50 p,g salmeterol, 1.16 ? 0.23 mgiml. After placebo inhalation the PC,, did not change significantly. After salbutamol inhalation a 5.5-fold increase occurred in PC,, at 30 minutes. At 3, 6, 9, and 12 hours salbutamol did not increase the PC,, significantly (Fig. 3). After inhalation of 25 kg salmeterol, a significant increase in PC?” occurred from 30 minutes to 12 hours. It peaked at 3 hours when it was increased 4.9-fold (Fig. 3): at 12 hours it was still increased 4.2-fold. After inhalation of 50 pg salmeterol, PC,, increased 7.1 -fold by 30 minutes. The increase peaked at 7.4fold at 3 hours and was still 5.7-fold at 12 hours. Salmeterol (25 kg) provided significantly greater bronchoprotection than salbutamol from 3 to 12 hours, inclusive, and 50 Fg salmeterol provided significantly greater bronchoprotection than salbutamol from 30 minute5 to 12 hours, inclusive. Salmeterol (50 pg)

Salmeteroi

I, 015 ; Time

A

in aslhmd

I;

843

Ii2

(hrs)

FIG. 3. Posttreatment-to-pretreatment ratio for PC*@ methacholine over time after inhalation of placebo (closed circles); 200 pg salbutamol (closed triangles); 25 kg salmeterol (open squares); and 50 pg salmeterol (closed squares) in 20 patients. Each symbol represents mean + SEM. Asterisks denote a significant difference from placebo inhalation (*p < 0.05; **p *c 0.01; *+*p -= 0.001). Crosses indicate a significant difference between salmeterol and salbutamol inhalations ( p c 0.05; '+p < 0.01; - "p < 0.001). Small triangles indicate a significant difference between 25 pg salmeteroi and 50 kg salmeterol (hp i 0.05; up < 0.01; up < 0.001).

provided significantly better bronchoprotection than 25 pg salmeterol from 30 minutes to 12 hours. inclusive. Analysis of covariance revealed that change in the baseline PC,<, was found to account for 13% of the change in the posttreatment PC2,. When “normalized” posttreatment to pretreatment PC, ratios were examined, 25 kg and 50 pg salmeter01 were noted to provide extremely marked, constant bronchoprotection from 3 to 12 hours, and from 30 minutes to 12 hours. respectively, in contrast to salbutamol. Normalized bronchoprotection provided by 50 pg salmeterol was significantly greater than that provided by 25 kg salmeterol , from 30 minutes to 12 hours, inclusive (Fig. 4). Analysis of covariance revealed a correlation between changes in FEV, and PC,,, but it was clear that the changes in FEV, were not responsible for all the changes in PCZO,that is, protection from bronchoconstriction was not dependent on bronchodilation. The amount of change in the PC,, accounted for by the change in FEV; varied from 14% to 28%

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g

I..

10.0

A Salbutamol 0 Salmetarol26 m Salmeterol 50

2 E

E

CLIN IMMUNOL NOVEMBER 1992

8.0

I

f SEM

iii

B 8 Et? o’25 E j I B

4.0

2.0

0 0

3

6

9

12

Time (hrs) FIG. 4. Data for posttreatment-to-pretreatment PCzOwere normalized by use of the formula in text. Each symbol represents mean k SEM. Asterisks denote a significant difference from placebo inhalation (*p < 0.05; **p < 0.01; *** p < 0.001). Crosses indicate a significant difference between salmeterol and salbutamol inhalations (‘p < 0.05; + ‘p < 0.01; + ++p < 0.001). Small triangles indicate a significant difference between 25 u,g salmeterol and 50 wg salmeterol (4, < 0.05; AAp < 0.01; -p < 0.001).

No increase in tremor followed treatment with placebo, salbutamol, 25 pg salmeterol, or 50 pg salmeterol. Pulse rate, normalized for the placebo experience, was not significantly increased after 200 pg salbutamol, but was significantly increased at 12 hours after 25 pg salmeterol and from 1 to 12 hours, inclusive, after 50 pg salmeterol. One patient had a single supraventricular premature beat 1 hour after placebo inhalation; and another patient had a supraventricular beat 3 hours after salbutamol and also 6 hours after 25 kg salmeterol. Systolic and diastolic blood pressures, normalized for the placebo experience, did not increase significantly at any time after 200 pg salbutamol, 25 kg salmeterol, or 50 kg salmeterol. DISCUSSION In this study in young patients with asthma, we have shown that inhalation of a single dose of salmeterol, 25 pg or 50 pg, has a statistically significant and clinically important bronchodilator and bronchoprotective effect for at least 12 hours, when the PC,, methacholine was still 4.2-fold and 5.7-fold greater than baseline (Fig. 3), respectively. In contrast, the bronchodilator and bronchoprotective effect of salbutamol was significant for less than 3 hours, and inhalation of placebo had no significant effect at any time. The doses of salmeterol used did not produce any clinically important adverse effects; however, the statistically significant increase in pulse rate from 1 to 12 hours, inclusive, after 50 kg salmeterol Suggests that this should be the maximum dose in preadolescents.

In our laboratory, using identical study design, equipment, and technique, in a similar patient population, we have previously shown a long-lasting bronchodilator and bronchoprotective effect for another new &-agonist, formotero1,22 which, 12 hours after administration, improved PC,, methacholine 3.3fold and 4.4-fold after doses of 12 l.r,g and 24 p.g, respectively. Protection against bronchoconstriction induced by chemical factors such as methacholine or histamine or by physical factors such as exercise or cold, dry air inhalation, is a useful measure of the antiasthma effect of inhaled P,-agonists. An increase in airway responsiveness is related to the presence of airway inflammation, as demonstrated by bronchoalveolar lavage, biopsy, and sputum analysis.” Repeatedly challenging patients with methacholine to evaluate the protection afforded by an antiasthma medication is a much more relevant and exacting test of an antiasthma medication than is merely measuring bronchodilation.22, ** Nonspecific bronchial responsiveness in asthmatic children depends on severity of disease and relates in a complex way to natural stimuli such as exercise challenge. 29,3oThis study provides additional evidence that protection from bronchoconstriction, as measured by the PCZo, does not primarily occur because of concomitant bronchodilation,3’, 32as the patients achieved maximal bronchodilation from both the 25 +g and 50 p,g doses of salmeterol, yet had an obvious and significant bronchoprotective dose response, as measured by the PC,.

VOLUME RlUMBER

Salmeterol

90 5

Although salmeterol is a potent functional antagonist with a long-acting bronchodilator and bronchoprotective effect in patients with asthma,5-2” it is too early to precisely define its role in asthma management. In patients with moderate or severe asthma, it is likely to be useful in reducing nocturnal symptams. I” In patients with mild asthma, for some hours after inhalation, it may play some role in prevention of symptoms induced by exercise or other factors.” Salmeterol has a less rapid onset of bronchodilator effect than salbutamol and is therefore not recommended for relief of “breakthrough” asthma symptoms or for the treatment of acute asthma episodes.‘” In consideration of the evidence that treatment with a short-acting &adrenergic agonist alone on a regular daily basis may increase nonspecific bronchial hyperresponsiveness to substances such as methacholine or histamine.“-” and that regular use of a shortacting (J,-adrenergic agonist may worsen asthma contrO].3s w studies of regular salmeterol use versus “as needed” &-adrenergic agonist use are urgently required We acknowledge the excellent supportof J. L. Lukowski. BN. D. Dilay, RN, M. Cheang. MMath, F. A. Jonker, MSc, and A. Haukioja, MSc. REFERENCES

1. Brittain RT. Approaches to a long-acting, selective p2-adrenoceptor stimulant. Lung 1990;168(suppl):111-4. 2. Ball DI. B&din RT, Coleman RA, et al. Salmeterol, a novel and in vivo long-acting P,-adrenoceptor agonist: characterization of pharmacological activity in vitro. Br J Pharmacol 1991;104:665-71, 3. Johnson M. The pharmacology of salmeterol. Lung 1990: 168(suppl): 115-9. 4. Jack D. A way of looking at agonism and antagonism: lessons from salbutamol, salmeterol and other P-adrenoceptor agonists. Br J Clin Pharmacol 1991;31:501-14. 5. Ulhnan A, Svedmyr N. Salmeterol, a new long-acting inhaled &adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax 1988;43:674-8. 6. Ullman A. Hedner J. Svedmyr N. Inhaled salmeterol and salbutdmol in asthmatic patients. Am Rev Respir Dis 1990;132:571-5. 7. Palmer JBD. Inhaled salmeterol-single dose studies. Eur Respir J 1989;2(suppl. 8):6765. 8. Bierman CW, Kemp JP. Sharpe MJ, Georgens J. Salmeterol, a &agonist Induces bronchodilation for 12 hours or greater: a placebo-controlled single dose study. J ALLERGY CLAN IMMLKOI. 1990:85: 198. 9. Ullman A, Svedmyr N. A dose-response comparison of inhaled aerosol and dry powder formulations of salmeterol in asthmatic patients. Am Rev Respir Dis 1988;137:435. 10. Sandstrijm T, Frederiksen B, Rosenhall L, Sandstriim B. Salmeterol -a dose-response study with a long-acting inhaled PIagonist. Am Rev Respir Dis 1990; 139:A64. I 1. Boyd G, Anderson K, Carter R. A 12-hour placebo-controlled comparison of the bronchodilator performance of salmeterol and albuterol. Am Rev Respir Dis 1990;141:A206. 12. Maconochie JG, Forster JK. Fowler P, Thomas M. An initial

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comparison of salmeterol and salbutamol agal:!% histammeinduced bronchoconstriction in healthy quhre<:\ Rr I (‘lin Pharmacol 1988;25:115P. 13. Derom E, Pauwels R. Van der Straeten M. The etiect of mhaled salmeterol on methacholine responsiveness 117 ,ubpxts with asthma up to 12 hours. J ALLERGY CI.I~ IFVLWvji 1997,PY: 811-S.

14. Gongora HC, Wisniewski AFZ, Tattersheld AE. 4 str~gic-dots comparison of inhaled albuterol and two fc>rmulatzonb ot \almeter01 on airway reactivity in asthmatic .subjccts Am Kc\ Respir Dis 1991; 144:626-9. 15. Twentyman OP, Finnerty JP, Han% A, Palmer f. Holga!e ST. Protection against allergen-induced asthma by baimereroi Lsncet 1990:336:1338-42. 16. Fitzpatrick MF. Mackay T. Driver H. Douglas h.i. Salmeterol in nocturnal asthma: a double-blind, placebo-ctilntrolled trial of a long-acting inhaled p: agomst. BMJ 199O:.iOi: l ih.i-8 17. Dahl R. Salmeterol-one-month studies in asthn:atic Datrents. Eur Respir J 1989:2(suppl 8):6773. 18. Bousquet J. How do we optimize asthma asz+ksnlcnth’ 1:ur Respir J 1991:4(suppl 14):39%. 19. Green CP, Price JF. Prevention of exerclsc-rnduced asthma by inhaled salmeterol xinafoate. Arch Dis i‘h:ld !992:67: 1014.7. 20. Verbeme AAPH, Bos AB, Hop WCJ, dr Jongste .iC, Kerrehljn KF. The duration of the bronchodilating and protective effects of salmeterol in asthmatic children. Eur Resp I 109 1.4(>uppl 14):403S. 21. Cockcroft DW, Killian DN, Mellon JJA. Hargreal,e I-,I:. Brnnchial reactivity to inhaled histamine: a nlethclcr and cfincral survey. Clin Allergy 1977;7:235-43 22. Becker AB. Simons FER. Formoterol. a new long-acting selective &-adrenergic receptor agonist: double-bhnd comparison with salbutamol and placebo in children svilh asthma. J ALLERGY CLIN IMMUNOL. 1989:84:X9

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23. Thiringer G, Svedmyr N. Evaluation of skeletal muxcle tremor due to bronchodilator agents. Stand J Recp~r Dts 1975;5h93IO?.

24. Becker AB, Simons KJ, Gillespie CA, SinIons FER. The bronchodilator effects and pharmacokinetica of caffeine in :lathma. N Engl J Med 1984;310:743-6. 25. Simons FER. Becker AB. Simons KJ, Gillespie C.\. The hronchodilator effect and phdrmacokinetics of theobromine in young patients with asthma. J ALI.I;K(:Y C’I.!U IhlMIw)i. 1985;76:703-7. 26. Steel RDG, Torrie JH, eds. Principles and proccdurea of xtatistics: a biometrical approach. New York: McGrau -Hill. 19X0. 27. Beasley R. Roche WR, Roberts IA. Holgate ST. Cellular events in the bronchi in mild asthma and after hrclnchial provocation. Am Rev Respir Dis 1989; 139:X06- 17 28. Ahrens RC, Bonham AC, Maxwell GA. Weinherger MM. A method for comparing the peak intensity and duration of actron of aerosolized bronchodilators using bronchoprorocarion \nrth methacholine. Am Rev Respir Dis 1984: 12Y:YO3.I\ 1991;144:36-8. 30. Clough JB. Hutchmson SA, Williams JD. I-Iolgatc ST Arrway response to exercise and methacholinc in children with respiratory symptoms. Arch Dis Child 1991;66:579-82 31. Britton J, Hanley SP, Garrett HV, Hadtield JW. Tattersfield AE. Dose-related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subiecra with asthma. Thorax I988;43:300-5. 32. Epgleston PA, Beasley PP. Bronchodilaimn ~nc! rnhibltion rrf

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induced asthma by adrenergic agonists. Clin Pharmacol Ther 1981;29:505-10. 33. Lofdahl CG, Chung KF. Long-acting B,-adrenoceptor agonists: a new perspective in the treatment of asthma. Em Respir J 1991;4:218-26. 34. Kerrebijn KF, van Essen-Zandvliet EEM, Neijens HJ. Effect of long-term treatment with inhaled corticosteroids and betaagonists on the bronchial responsiveness in children with asthma. J ALLERGY CLIN IMMUNOL 1987;79:653-9. 35. Kraan I, Koeter GH, van der Mark TW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J ALLERGY CLIN IMMUNOL 1985;76:628-36.

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36. Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tatterstield AE. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988;1:554-8. 37. van Schayck CP, Graafsma SJ, Visch MB, van Herwaarden CLA, Dompeling E, Van Wee1 C. Increased bronchial hyperresponsiveness after inhaling salbutamol during 1 year is not caused by subsitization to salbutdmol. J ALLERGY CLIN IMMUNOL 1990;86:793-800. 38. Sears MR, Taylor DR, Print CG, et al. Regular inhaled betaagonist treatment in bronchial asthma. Lancet 1990;336: 1391-6. 39. Spitzer WO, Suissa S, Ernst P, et al. The use of B-agonists and the risk of death and near death from asthma. N Engl J med 1992:326:501-6.

The protective effect of low-dose inhaled fenoterol against methacholine and exercise-induced bronchoconstriction in asthma: A dose-response study Helgo Magnussen,

MD, and Klaus F. Rabe, MD Grosshansdor$

Germany

We compared in a randomized, double-blind study the protective effect of low doses offenoterol on the airway response to exercise during cold air breathing and an inhalation challenge with methacholine. In six asymptomatic asthmatic persons (mean age, 20.3 years) exercise and methacholine challenges were perjormed under control conditions and 15 minutes after the inhalation from a metered-dose inhaler of either placebo or 30, 50, 100, and 200 pg fenoterol, resulting in 12 separate study sessions within a 3-week period. Airway response was determined by measuring specijc airway resistance (sRaw). Exercise tests were standardized by maintaining a constant respiratory heat exchange, with an average (range) of 1.28 (I .I5 to 1.45) kcallmin. Methacholine was inhaled at increasing doses until sRaw had doubled (PD,dRaw). Mean postexertional increase of sRaw (SD) after control conditions, placebo, and 30, SO, 100, and 200 pg fenoterol aerosol was 27.8 (6.9), 28.9 (lO.O), 7.20 (2.7), 9.33 (3.8), 5.57 (2.3), and 5.28 (I .6) cm H,O . s. Fenoterol aerosol was equally effective at all doses administered, whereas methacholine-induced bronchoconstriction was attenuated in a dose-dependent manner. From these observations we suggest that low-dose fenoterol protects against bronchoconstriction induced by exercise, a naturally occurring stimulus reflecting airway hyperresponsiveness. (J ALLERGY CLINLMMLJNOL 1992;90:846-51.) Key words: Asthma,

exercise,

low-dose fenoterol,

From the Grosshansdorf Hospital, Center for Pneumology and Thoracic Surgery, Grosshansdorf. Received for publication Aug. 13, 199 1. Revised Nov. 12, 1991. Accepted for publication Nov. 18, 1991. Reprint requests: Prof. Dr. med. Helgo Magnussen, Wohrendamm 80, D-2070 Grosshansdorf, Germany. l/1141437

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airway

hyperresponsiveness

Fenoterol aerosol is a selective and widely used p2adrenoceptor agonist, usually inhaled from a metereddose inhaler, with one puff containing 200 pg (Berotec; Boehringer Ingelheim, Ingelheim am Rhein, Germany) or 100 pg (Berotec mite). Both doses of fenoterol produce effective bronchodilation and protect against a variety of stimuli.‘-5 However, because