Duration of Protection by Inhaled Salmeterol in Exercise-induced Asthma

Duration of Protection by Inhaled Salmeterol in Exercise-induced Asthma* Sandra D. Anderson, Ph.D., D.Se.; L. L ROdwell, 8~Se. Grad. Dip.·Phty.; H. Young, Ph.D.

J Du Toit, B.Se.; and I.

P-Adreooceptor agonists such as albuterol are very effective in preventing exercise-induced asthma (EIA) when they are given as an aerosol immediately before exercise. However, their duration of protection against EIA is usually less than 2 h. This may be due partly to their rapid clearance from the airways. Salmeterol is a highly lipophylic compound that is thought to bind to an exoreceptor near the p. receptor. The objective of this study was to compare the protective effect of salmeterol with a1buterol against EIA. Exercise was performed 0.5, 2.5, 4.5, and 6.5 hours after administration of the active drugs. Subjects attended the laboratory on four days within six weeks and cycled for 8 min breathing dry compressed air. We studied 17 asthmatic subjects (aged 19 to 49 years) with moderate to severe EIA. Salmeterol (SO p.g) or albuterol (200 p.g) was given from a metered dose inhaler via a spacer (Volumatic). 00 the control day, the mean work load± 1 SD was 174±47 W, ventilation (VE) was 77.9 percent ± 11.2 percent of the target ventilation (60 percent maximum voluntary ventilation [MVV]), and heart rate was 170± 14 beats per minute. This intensity was maintained for all tests. FEV1 was measured before and after exercise and was expressed as percent predicted and as percentage of the preexercise

value (percentage of fall). Thirty minutes after treatment, both drugs were effective in inhibiting EIA-percentage of faD in FEVI ' 17 ± 12 after salmeterol; percentage of faD in FEV., 15 ± 15 after albuterol. At 2.5, 4.5, and 6.5 hours, the reduction in FEV. was significantly less (p
is a common stimulus for provoking an E xercise attack of asthma. Between 70 and 80 percent of

ance 12-14 and the hydrophilic nature of the agents. IS Salmeterol is a selective ~2-adrenoceptor agonist and is highly lipophilic. It has a prolonged duration of action compared with other ~-adrenoceptoragonists. 16 In a dose of 200 ~g, it has been shown to prevent histamine-induced bronchoconstriction in healthy subjects for at least 12 hours. 17 The aim of this study was to investigate the duration of action of salmeterol in the prevention of EIA and to compare its action with albuterol, a drug now commonly used to prevent EIA.

persons with clinically diagnosed asthma will have an attack provoked by 6 to 8 min of vigorous exercise in a temperate climate. 1 It has been recognized for many years that ~­ adrenoceptor agonists, when given as aerosols in the standard recommended dose, will prevent exerciseinduced attacks of asthma in about 90 percent of patients. l -3 However, the duration of the protection afforded by this dose is short and usually less than 2 h. 4-8 The duration of protection afforded by most ~-adrenoceptor agonists increases when twice the standard dose is used9 •10 or if they are used in combination with cromolyn8 • 11 or ipratropium bromide. 7 The short duration of action of aerosol agents given to prevent exercise-induced asthma (EIA) is thought to be due to their rapid clearance from the airway by the bronchial circulation and by mucociliary clear-

=

=

EIA exercise-induced asthma; FEV. forced expiratory volume in one second; MVV maximum voluntary ventilation; VE = ventilation

=

MATERIAL AND METHODS

*From the Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, NS~ Australia. Manuscript received December 18; revision accepted March 11. Reprint requests: Dr. Anderson, 1..£ve1 9, lbge Chest Pavillion, Royal Ptince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia

Eighteen subjects, including seven women, aged between 19 and 49 years, volunteered for the study. Their anthropometric data, predicted values for forced expiratory volume in 1 second (FEV.), and actual values for FEV. (percent predicted) on the days the active drugs were given, together with current medications, are given in Table 1. The subjects were selected on the basis ofa history of EIA that was sufficiently severe to warrant prophylactic medication. They all participated in regular vigorous exercise in their daily life and were able to perform multiple exercise tests on one da~ Their symptoms of asthma were well-controUed with inhaled and oral bronchodilators, cromolyn, and aerosol corticosteroids. Their asthma was required to be stable, with no change in medication, either over the preceding four weeks before the trial or during the trial. They were also required to manage without symptomatic inhaled medication for at least 6 h. To enter the trial, the subjects had to have a pretreatment FEV. greater than 65

1254

Protection from Inhaled 5aJmeterol in Exercise-induced Asthma (Anderson st 81)

Table I-Anthropometric DatG, Current Medicationa and Daily Dote of Aerotol Steroid, PretlicIed Valuafor Forced &piratory Volume in 1 Second (FEVJ, and ftwcent PretlicIed FEV. BetJclaedfollotDirag lralatJlstion of Albuterol (A) and Salrneterol (S) for the 17 Subjecll StudiedHeight,

Weight,

Pred

'I> Pred FEV1

Subject No.lSex/Age, yr

em

kg

FEV., L

A

S

Rx

lIF121 2'M123 3IF124 4/M129 5IF129 6IMI22 7/M12O 8/F/19

168 175 166 183 166 181 193 168 172 166 178 167 184 170 182 165 183

63.0 62.0 67.0 68.0 68.0 87.0 80.5 54.0 79.0 52.0 60.0 68.5 87.0 68.0 66.0 76.0 90.0

3.45 4.28 3.34 3.56 3.20 4.55 5.08 3.50 3.78 3.25 4.45 3.40 4.20 4.05 4.60 2.65 4.29

98 77 74 91 93 88 66 66 87 71 83 72 83 95 76 102 97

101 70 73 80 92 88 72 68 79 76 79 69 82 96 92

A A,e A,B A,e,B A,T,B A A A,T,B A,T,B F, I A,B A A,e A,B A A A,B,e

9/MfJ5

101F127

Il1M/22 12/F121 131MfJ6 14/M125 151MI22 161F/49 17/MfJ4

*A = albuterol; 8 = heclomethasone; e

99

102

Steroid, fAogtd

400 800 200

800 800 600

800 250

= cromolyn; T = theophylline; 1= ipratropium; F = fenoterol; pred = predicted; and Rx =drug.

percent of the predicted normal value I" and a 20 percent reduction in that FEV1 after exercise. Each subject gave informed consent in writing after a full explanation of the protocol. The protocol was approved by the Ethics Review Committee of the Royal Prince Alfred Hospital. Each subject undelWent a medical examination carried out by the staff respiratory physician. The subjects withheld medication as follows: sustained-release theophylline and cromolyn for 24 h, oral bronchodilators for 12 b, aerosol broncbodilators for 6 h, and inhaled corticosteroids on the morning of the sltud~ The subjects attended the laboratory on four separate occasions. A period of at least six days separated each of the last three visits. The mean duration of the study was 23.8 ± 6.5 days, the minimum being 15 days and the maximum time being 38 days. The first visit was a familiarization day and the performance of the control exercise test. Patients were instructed how to perform spirometry and maximal expiratory volume maneuvers. The predicted FEV 1 was used to calculate the indirect maximum voluntary ventilation (MVV), ie, MVV = predicted FEV1 x 35. 19 This value was used as a guide to the maximum working capacity of the subject (see below). The exercise test was performed on a control day to determine the work load appropriate to reach 60 percent of predicted MVV (target ventilation). The second and third visits were all-day visits and the patients were given, in a random doubleblind crossover manner, either salmeterol or albuterol. The medication was given only once and usually between 8 and 10 AM. Four exercise tests were performed with an interval of 2 h between each test. On the fourth visit, the subjects received a placebo aerosol and performed exercise on two occasions 2 h apart. While the administration of the placebo was single-blind, many subjects presumed they had taken the placebo after the initial exercise test because they had moderate to severe EIA provoked by the exercise. The active drugs and the placebo were inhaled via a spacer (Volumatic) (Glaxo Group Research, UK). Two separate inhalations were made with 30 s separating each actuation of the metered dose inhaler. A dose of 50 fAog of salmeterol was delivered (2 x 25 fAog) and a dose of200 fAog ofalbuterol (2 x 100 fAog) was delivered. The subject was asked to breath hold for 10 s following each inhalation. The

spacer was used to provide visual proof that the metered dose inhaler had actuated correctly and an observer was present to confirm that the drug, or its placebo, was administered on each occasion. Exercise was performed for 8 min on a bicycle ergometer (ElemaShonander, Solna, Sweden). Subjects breathed by mouth from a cylinder of compressed and dry medical air via a demand valve (CIG Medishield Demand Resuscitator, Sydne~ Australia) that was attached to the inspiratory port ofthe breathing valve (Hans Rudolph No. 2700, Kansas ei~ MO). The temperature of the inspired air ranged between 2re and 2frC. Expired air passed into a gasomet~r (350L Tissot, WE Collins, Braintree, Mass) and ventilation was recorded during the 5th, 6th, and 7th min of exercise (Watanabe Miniwriter WrR 771A, Watanabe Instrument Corporation, Japan). The oxygen consumption required to stimulate the target ventilation and the work load producing this oxygen consumption were calculated." During the 8rst 3 min of exercise, the work load was increased from 60 percent, to 75 percent, to 90 percent, and finally in the 4th min to 100 percent of the work load calculated to produce the target ventilation. II This work load was usually then maintained for 4 min. The ventilation recording was chedced during this test and the work load was adjusted accordingl~ For each subsequent exercise test, minor adjustments in the work load were made to ensure similar ventilations on all test days. Heart rate was also measured throughout each exercise test. FEV1 was measured using a calibrated hot wire anemometer (Minato Autospirometer, AS8OO, Osaka, Japan). At the start of each visit, measurements of FEV. were made in triplicate, on two occasions, 10 min apart. These measurements were required to vary by less than 10 percent on the day of the study for the study to proceed. Measurements of FEV. were made in duplicate immediately before and after exercise, and at 1, 3, 5, 7, 10, 15, and 30 min following completion of the exercise test. The highest value of each pair was used in calculations. The severity of EIA and the benefit afforded by albuterol and salmeterol were assessed in a number of ways. The percent fall index was calculated as follows: A - B x 100/A, where A =FEV1 measured immediately before exercise, and at 0.5, 2.5, 4.5, and 6.5 hours after the active drugs, and 0.5 and 2.5 hours after placebo; B =the lowest FEV. recorded within 30 minutes CHEST I 100 I 5 I NOVEMBER, 1891

1251

after each exercise test. If the value for the percent fall index was less than 10, it was considered that the patient had complete protection from EIA. The patient was considered to have clinical protection afforded by the active drug if the percent fallon the active ag~nt was equal to, or less than, 50 percent of the value observed on the first test on the placebo day. This value is based on previously published data on the reproducibility of the test. 3 To compare the effects ofsalmeterol and albuterol, the percentage of fall index recorded for each exercise test was compared at the same time interval after administration of the drug. As the percentage offall index is not a guide to the clinical state of the subject after exercise and as it does not reflect ~e bronchodilating properties of a drug, absolute values of FEV I are also given. The values are expressed as a percentage of normal predicted and those given include values measured before medication, immediately before exercise (that is 0.5, 2.5, 4.5, and 6.5 hours after medication), and the lowest value for FEV I recorded after exercise. Analysis of Data

Statistical analysis was made using an analysis of variance to compare values for FEV I and exercise intensi~ Salmeterol and a1buterol were compared by analyzing the values for FEV I and exercise intensity (work load, ventilation, and heart rate) measured before and 0.5, 2.5, 4.5, and 6.5 hours after the administration of both drugs. Values were considered signi6cant at p
Seventeen of the 18 subjects completed the four 8-

min exercise tests on the two days the active treatments were given. One subject developed a chest infection and had an exacerbation of his asthma after visit 2. He was withdrawn from the study and the results are presented on the remaining 17 patients. On the day they received placebo, all ~ubjects completed the initial exercise challenge, but two subjects had such severe attacks of asthma that rescue medication was required and they were unable to be included for the second challenge 2 h later. Th~re was ~either a significant difference in the work load, level of ventilation (expressed as a percentage of th~ target ventilation), or heart rate achieved during exercise for each test on the days the active medication was taken, nor was there a significant difference from the control day. On the day salmeterol was given, the mean ± 1 SD work load was 177 ± 45 W and on the albuterol day it was 175 ± 46 W. The ventilation reached on the salmeterol day was 87.6± 14.5 percent of the target ventilation rate and for albuterol it was 86.3 ± 18.1 percent. Heart rate was 168 ± 12 beats per minute for salmeterol and 166 ± 12 beats per minute for albuterol. The work load on the control day was 174±47 W with 'a ventilation of 77.9± 11.2 percent of the target ventilation and a heart rate of 170± 14 beats per minute. Pulmonary Function before Drug

The values for FEV1 before each treatment were not significantly different, indicating that the lung function remained similar throughout the study. At the beginning of each test day, the values for FEV1

Table 2-MeGn ± 1 SEM Value. for (1) FEV. (Percent Predicted) Meaaured before Exercise and at Various Times after Medication; (2) the lDwat Value for FEV. (Percent Predicted) ~etJBUred After Each Exercise Tat; and (3) the Fall in FEV. &preaed aa a Percentage of the Ab.olute Value for FEV. MetJBUred Immediately before Exerci8e Before Drug Control 1

81.6±3.1

2

3 Salmeterol 1 2 3 Albuterol 1 2 3 Placebo 1 (n= 17) (0= 15) 2 (0= 17) (n= 15) 3 (n= 17) (n=15)

Hours after Medication 0.5

2.5

4.5

6.5

51.4±3.3 36.2±3.2

83.5±2.8

94.3±2.7 78.1±3.5 17.3±2.9

98.3±2.3* 85.6±2.6* 12.9± 1.8*

98.5±2.3* 83.1±3.4* 15.9±2.6*

95.8±2.5* 76.8±3.2* 19.9±2.4*

83.4±2.8

96.6±2.5 81.8±3.7 14.8±3.6

95.3±2.5 68.4±4.3 28.6±3.4

88.4±3.0 59.1 ±3.6 33.5±2.7

83.9±3.0 54.1±3.9 36.3±3.0

84.4±2.7 85.2±3.1

82.8±3.0 84.7±3.2 52.3±4.4 55.2±4.6 37.4±4.1 35.1 ±4.0

84.4±3.2 56.9±4.4 33.2±3.3

*p
1258

Protection from Inhaled Salmeterol in Exerdse-induced Asthma (Anderson et aJ)

100 90 Q

W

80

~

u

is

w

70

II:

Q.

0.5 HOURS

~~

100 90 80

2.5 HOURS

~

100 90

#. 70

70

C

60

.;

... W

60

60

0-4

1ft

C

50

50

40

40

• SALMETEROL .ALBUTEROL

100 90 Q

W

~

(,)

80

is

w

II: Q.

~

70

100 90 80 70

50 40 ~CONTROL

APLACEBO

~

Pulmonary Function after Ex:.,>rcise

100 90 80

..,

1ft

~

#. 70

"0 :II

1ft

#.

.; W

"0 :II

1ft

~

...

..,

1ft

80 -<

C

60

60

60

50

50

50

40

4.5 HOURS

40

6.5 HOURS

values for FEV. were still significantly higher compared with values observed immediately before treatment with albuterol (p
0

-4

1ft

c

40

F.GI'IIE I. Mean values ± 1 SEM for forced expiratory volume in one se<.,md (FEY,) measured before and 0.5 h after treatment. immediately before exercise. and the lowest value recorded after exercise. expressed as a percentage of the predicted normal value.

were greater than 65 percent ofpredicted and repeated maneuvers varied by less than II percent. Pulmonary Function after Treatment and before Exercise

The values for FEV, (expressed as a percentage of predicted) at the various times after the administration of the treatments are summarized in Table 2. There was a significant improvement in FEV. 30 min after inhalation of both drugs (p
All subjects recorded a fall in FEV, greater than 21 percent of their preexercise value on the control day. There was no significant difference in the percent fall for FEV. observed on the control and placebo days and the coefficient of variation for the percent fall index was 20.9 percent (Table 2, Fig 2). Thus, over the period of the study, these subjects all remained responsive to exercise. In four subjects, percent fall in FEV. was 12, 14, IS, and 16 percent on the first run on the placebo day. For the second exercise test, 2 h later, the falls were 17, 42, 9, and 33 percent, respectively. For the other 11 subjects who performed both exercise tests on the placebo day, there was good reproducibility of the response, and the coefficient of variation was 17.9 percent and for the group of 15 it was 23.2 percent. Although some individuals had a lesser response on the second exercise test, this was generally small, and only one subject became unresponsive. Even so, no subject had a fall after the second exercise test with placebo that was less than 50 percent of that recorded on the first test. Thus, the exercise-induced reduction in FEV. was reproducible 40.0 35.0

.;

...w ...et ..J ..J

~

30.0 25.0 20.0 15.0 10.0 5.0

CON 'ROl 0.5hr •

SALMETEROL

n

=17

T

2.5hr

4.5hr

D

ALBUTEROL

6.5hr PLACEBO

SEM

FIGUIIE 2. Mean values ± 1 SEM for percent fall in forced expiratory volume in one se<.,md (FEY,) re<.'>rded on the control and placebo days. and at various times after treatment. CHEST I 100 I 5 I NOVEMBER. 1991

1257

for individuals, not only over the four weeks of the study, but also within one study day 2 h apart (Table 2). The severity of the asthma provoked bY' "exercise was fairly consistent in that the lowest value for FEV. (percent predicted) recorded after exercise was similar on the control da~ after the placebo, and the last two tests after albuterol (Table 2, Fig 1). Thus, the lowest absolute value in FEV. reached by each individual was reproducible over the study period. the values for percent fall in FEV1 are illustrated in Figure 2. Thirty minutes after medication, the two drugs had a similar protective effect. At all other times, salmeterol was superior to albuterol in reducing the fall in FEVl after exercise (p<0.01). The lowest values for FEV1 (percent predicted) are given in Table 2 and are illustrated in Figure 2. There was no significant difference 0.5 h after medication. However, at all other times the lowest values for FEV. were significantly higher after salmeterol compared with albuterol (p<0.01). After salmeterol, there was a Significant reduction in the severity ofEIA compared with the FEV. values following the initial challenge on the placebo day. Six of the 17 subjects had complete protection from EIA at 0.5 h, seven had protection at -2.5 h, and six had protection at 4.5 h. Even at 6.5 h, three subjects recorded a fall in FEV. less than 10 percent of the prechallenge level. When assessed as clinical protection, the best results were obtained at 2.5 h when 14 of the 17 subjects had less than 50 percent of the fall in FEV. that was recorded with placebo. Eleven subjects still had clinical protection at 6.5 h (Table 3). By contrast, albuterol was only effective in inhibiting EIA 0.5 h after the drug was taken. Ten subjects were completely protected at this time and 14 had clinical protection. At 2.5 h, only two subjects were completely protected and only three had clinical protection (Table 3). DISCUSSION

The results of this study clearly demonstrate that Table 3-Number of Subject8 and Percentage of Total

Protectionfrom EDrciBe-lnduced Asthma at 0.5, 2.5, 4.5, 6.5 Houn after Inhalation

Hours

Complete protection Salmeterol Albuterol Clinical protection Salmeterol Albuterol

1258

2.5

0.5 (If,)

(%)

6 (35) 10 (59)

7 (41) 2 (12)

10 (59) 14 (82)

14 (82) 3 (18)

4.5 (If,)

6.5

(%)

6 (35) (0)

3 (18) 1 (6)

13 (77) o (0)

11 (65) o (0)

o

salmeterol, when given by aerosol in a dose of 50 J-Lg, 30 min before exercise, is effective in protecting against EIA in a majority of subjects. The extent of the protection provided by salmeterol 30 min after administration was similar to that provided by albuterol (200 J-Lg). However, the duration of the protective effect ofsalmeterol was considerably greater compared with albuterol. While most subjects had no protection afforded by albuterol2.5 h after administration, 11 of 17 subjects had more than 50 percent protection afforded by salmeterol for as long as 6.5 h after its administration. On the basis of these findings, it may be expected that the salmeterol could afford protection against EIA for a much longer period. Salmeterol also had a long action as a bronchodilator. Even after repeated exercise challenge, the resting FEVl measured 6.5 h after salmeterol was 95.8±2.5 percent of the predicted value. Thus, salmeterol has a long duration of action, both as a bronchodilator and as a protective agent against EIA. It is the most effective of all agents we have studied in inhibiting EIA at 4.5 and 6.5 h after inhalation. It is more effective at these times than the combination of a ~­ adrenoceptor agonist and either cromolyn or ipratropium bromide. 7 ,8 The maximum protective effect afforded by salmeterol occurred later than with albuterol. For salmeterol, the maximal protective effect was observed 2.5 h after administration while for albuterol it was 0.5h. This study demonstrates that quite severe EIA can occur when good lung function is documented before exercise and confirms our earlier findings. 2 ,3,8.9 Thus, 2.5 h after the administration of albuterol, when values for FEV. were 95.3±2.5 percent of the predicted nonilal, only two subjects had complete protection and 11 had falls in FEV. greater than 20 percent. For the same time interval after administration of salmeterol, the FEV. was very similar at 98.3 ± 2.3 percent of the predicted normal value with seven patients having complete protection and only one having a fall in FEV. greater than 20 percent. If protection against EIA was simply a function of the presence of the drug on the ~-receptor of the bronchial smooth muscle, one may have expected a similar level of protection afforded by the drugs 2.5 h after administration when the lung function was similar. Concentrations ofthe drug at the receptor site are likely to be important. 23 However, on the day salmeterol was given, the FEV. (percent predicted) recorded before the third exercise challenge was 98.5 ± 2.3, implying that the concentration of the drug at the smooth muscle was still high at that time, yet more EIA occurred after this challenge than during the first or second challenges. Thus, the concept that an aerosol J3-adrenoceptor agonist acts at sites other Protection from Inhaled Salmeterol in Exercise-induced Asthma (Anderson et aI)

than bronchial smooth muscle is in keeping with the findings of this study.2,9,24,25 The novel manner whereby the long side chain of salmeterol is thought to bind to an exoreceptor26 close to the (3-receptor may help to explain these other modes of action. (3-Receptors are known to be on the airway epithelium27 and on human lung mast cells. 28 Salmeterol could act to stimulate CI ion secretion and thus enhance water transport to the airway lumen. 29 Enhanced water transport could modify the cooling and drying effects from evaporative water loss - both of which are thought to be important stimuli to EIA.30,31 Further, salmeterol may act to prevent the release of mediators from mast cells lying superficially in the airways. The presence of a high concentration at these sites for many hours could explain the prolonged duration of action of salmeterol. By contrast, the albuterol molecule will move from the airway lumen at a faster rate, thus failing to provide adequate protection for more than an hour. The magnitude of the bronchodilation was similar between the two drugs and although 11 of 17 had a higher maximum FEV1recorded with salmeterol, the difference was not significant. The time course for the two drugs was different, however, with 15 of the 17 subjects reaching their maximum, or close to it, within 30 min after albuterol. By contrast, the maximum FE VI was reached only in one subject 30 min after salmeterol with 11 subjects recording the maximum, or close to it, at 2.5 h. It is not precisely understood how exercise provokes airway narrowing. It is clear that the severity of the airway response relates to the loss of water from the airways in humidifying the air to alveolar conditions. 32 ,33 It is not certain whether the cooling or drying and hyperosmolar effects of water loss is the mechanism. 31 Recently, it has been suggested that rapid rewarming of the airways, and a vascular engorgement and edema from the bronchial circulation is the mechanism whereby loss ofwater from the respiratory tract leads to EIA.30,34 This contrasts with an earlier hypothesis suggesting that hyperosmolarity of the periciliary fluid is the stimulus to EIA.35 The mechanism whereby hyperosmolarity causes EIA is thought to be in a degranulation of mast cells36 ,37 with the released mediators acting to cause airway narrowing, either directly by contraction of smooth muscle and edema from the bronchial circulation, or indirectly via sensory nerves. If the bronchial circulation alone is causing airways to narrow via vascular engorgement and edema, the protective effect of agents such as salmeterol and albuterol must be explained in terms of their effects in preventing the reactive hyperemia ofthis circulation and the edema. By preventing vasoconstriction, reactive hyperemia of the vessels cannot occur and thus

EIA is inhibited. It has been suggested34 that the vasodilating properties of (3-adrenoceptor agonists prevent the vasoconstriction brought about by airway cooling. Such an effect has not been demonstrated for this drug or albuterol in vitro, although older agents such as isoproterenol are known to have a vasodilator action. Persson38 has reported that the (3-adrenoceptor agonist may prevent microvascular leakage and this could be an important mode of action at the level of the bronchial circulation. In relation to the hyperosmolarity theory, it could also be argued that by preventing vasoconstriction, there is an improved water delivery to the airways allaying the dehydrating effects from conditioning inspired air. However, none of the mechanisms ofaction of these drugs necessarily imply that the airway narrowing in EIA results from vascular engorgement of the bronchial circulation and we think that it is unlikely that this was the mode of action of either drug in preventing EIA. The patients in this study had reasonably good lung function at rest and many of them did not seek medical attention for their asthma. Seven were taking 400 to 800 JLWQ of aerosol corticosteroids, but could be still judged as having moderate to severe EIA. These patients serve to demonstrate some relevant factors for the management of asthma. First, subjects with good lung function can have moderate to severe EIA. This means that documentation oflung function in the surgery or at home does not predict the severity of an attack provoked by exercise. The severity of EIA should be measured, either in a laboratory or by the patient using a flow meter. Second, regular treatment with aerosol beclomethasone diproprionate may improve resting lung function but does not necessarily improve the subject's response to exercise. Finall~ the protective effect of albuterol and other drugs commonly used to prevent EIA is short. We have previously proposed that clearance of the drug from the airway lumen is likely to account for the short duration of action most drugs have in protecting against EIA. The findings in this study that salmeterol has a prolonged duration of action against EIA is consistent with this concept. The reason for the superior duration of action of salmeterol may be due to slower clearance from the airways as a result of its binding to exoreceptors in the vicinity of the 13receptor. This property would reduce chances of it being cleared by the mucociliary escalator or absorbed by the bronchial circulation and, together with its high lipophilicity, may explain why it remains in the mucosa or on the bronchial smooth muscle. In this study, salmeterol has been shown to be effective in inhibiting or preventing exercise-induced asthma for up to 6.5 h. This is 4 h longer than any other drugs previously investigated. Complete prevention of EIA did not occur in all subjects in this study. CHEST I 100 I 5 I NOVEMBER. 1991

1259

For subjects in whom any reduction in FEVl is a problem, such as those who are competing in sport, it may be useful to add a drug such as cromolyn in order to completely prevent EIA. Although the" same 'effect may be achieved by increasing the dose of a padrenoceptor agonist,9.lo this approach to controlling EIA is not recommended for those who exercise many times in a da~

14 Richards R, Fowler C, Simpson SF, Renwick AG, Holgate S1: Deep inspiration increases the absorption of inhaled sodium cromoglycate. Br J Clin Pharmacoll989; 27:861-65 15 Jeppsson A-B, Lofdahl C-G, Waldeck B, Widmark E. On the predictive value of experiments in vitro in the evaluation of the effect duration of bronchodilator drugs for local administration. Pulmon Pharmaooll989; 2:81-5

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1280

Protection from Inhaled SaImeteroI in Exercise-induced AsIhma (Anderson et 81)

ACKNOWLEDGMENT: The authors would like to thank Dr. Ann Dyke of Glaxo Australia Ply Ltd for her assistance with the design orthe protocol and her help and advice during the stud~ REFERENCES

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