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Occasional review

Functional antagonism: tolerance produced byinhaled 32 agonists

D W Cockcroft, V A Swystun

The development of tolerance to the beneficialeffects ofinhaled P2 agonists has been suggestedas one possible explanation for the deleteriouseffects of frequent use of these agents inasthma.' The two main beneficial phar-macological effects of inhaled 12 agonists inasthma are bronchodilation and functional ant-agonism.2 Although it has been difficult to showappreciable tolerance to the bronchodilatorefficacy of these agents,3 regular use of inhaled12 agonists predictably causes tolerance tothe functional antagonist (bronchoprotectiveeffect) of these drugs.' In this review we willdiscuss the topic of tolerance to the broncho-protective effect of inhaled 12 agonist and itspotential clinical relevance.

Division ofRespiratory Medicine,Department ofMedicine, RoyalUniversity Hospital,University ofSaskatchewan,Saskatoon,SaskatchewanS7N OW8, CanadaD W CockcroftV A Swystun

Correspondence to:Dr D W Cockcroft.

Received 13 May 1996Accepted for publication20 May 1996

Functional antagonismFunctional antagonism is a term used to des-cribe the ability of a pharmacological agentto prevent bronchoconstriction non-selectively.The term "non-selective" is used to contrastthis with "selective" inhibition of broncho-constriction - for example, inhibition ofcholinergic bronchoconstriction by anti-cholinergic drugs or inhibition of histaminebronchoconstriction by HI blockers. Func-tional antagonism is a property shared by thebronchodilator classes of medications. 12 agon-ists, particularly those administered via the in-haled route, are the most potent functionalantagonists in asthma.2 It has been suggestedthat tests of functional antagonism might bean alternative means of assessing the clinicaleffect and clinical duration of effect of inhaledP2 agonists.'

12 agonists prevent induced broncho-constriction predominantly by an effect on air-way smooth muscle P2 receptors.4 These are

the same receptors that are responsible forbronchodilation. It has been suggested that themechanism of bronchodilation and functionalantagonism are different, based on a poor cor-

relation between magnitude ofbronchodilationand magnitude of functional antagonism. Al-ternatively, the difference might be due to thedifference in the way in which these are meas-

ured. Bronchodilation is essentially a "closedend" scale where improvement in flow rates islimited by return to "normal" and may be near

maximal at relatively low doses of 12 agonist.By contrast, functional antagonism, as meas-

ured by dose response curves (see below), is amore "open ended" scale. Failure ofcorrelationbetween these two may be merely a result ofmeasurement differences rather than a differ-ence in mechanisms. Inhaled 12 agonists mayhave additional effects in protecting againstbronchoconstriction due to stimuli which in-volve mast cell mediator release. 12 agonistssuppress the release of mast cell mediators andprovide greater protection against mast cellstimuli such as AMP and allergen than they doagainst methacholine; this is probably due toan additive protective effect on mast cell andsmooth muscle 13 receptors in the former com-pared with smooth muscle only for the latter.4The functional antagonism effect of an in-

haled P2 agonist is assessed in the laboratoryusing bronchoprovocation tests performed be-fore and after administration of the inhaled 12agonist.24 The difference between the two testsrepresents the magnitude of the functional ant-agonism. Stimuli for bronchoprovocation canbe categorised as non-sensitising (histamine,methacholine, other chemical mediators, ex-ercise, cold air, non-isotonic aerosols, etc) orsensitising (allergens, occupational chem-icals).' Perhaps a more useful categorisation ofbronchoprovocative stimuli is that of direct andindirect.6 Direct stimuli provoke broncho-constriction by a direct effect on airway smoothmuscle receptors. Histamine, methacholine,and, probably, arachidonic acid metabolitesare examples of direct stimuli. Indirect stimuliprovoke bronchoconstriction by one or moreintermediate pathways such as mast cell me-diator release, neurological reflexes, etc. Thesensitising stimuli, the physical stimuli (ex-ercise, cold air, non-isotonic aerosols), and anumber of the chemical stimuli (AMP, 1 ad-renergic blockers) are felt to be indirect. Sincenaturally occurring bronchoconstriction inasthmatic subjects is indirect (exercise, coldair, irritants, allergens, etc), the results of chal-lenges with indirect stimuli has been hypo-thesised to have more clinical relevance forasthma.6There are two major different methodologies

for bronchoprovocation tests that lead totwo different ways to measure functionalantagonism. Most commonly, broncho-provocation tests are done by administeringdoubling doses of the bronchoconstrictor stim-ulus at appropriate time intervals to establish

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either a provocation dose (PD) or a provocationconcentration (PC) producing a given fall(usually 15% or 20%) in forced expiratoryvolume in one second (FEVI). The terms PD15,PC20 are used to describe these end points.The doubling "dose" can be achieved by doub-ling the concentrations of the stimulus (as isoften done with histamine,7 methacholine,47and other chemical mediators4), or by doublingthe duration of exposure as is frequently donewith non-isotonic aerosols.89 The early asth-matic response (EAR) to allergen can also beassessed as an allergen PC20.10 When usinga bronchoconstrictor stimulus for which theresults are expressed as a PC15 or PC20, func-tional antagonism produced by inhaled 12agonists is assessed by repeating thebronchoprovocation test at an appropriate timeafter the administration of the 12 agonist. ThePC15/PC20 is measured again. The degree ofbronchoprotection can be assessed log-arithmically by calculating the change in logPC20. The Alog1O PC20 is divided by the logof 2 (that is, Alog1o PC20/0.3) to express themagnitude of the functional antagonism in"doubling doses" of protection.4 An alternativemeans of expressing the shift in PC20 is non-logarithmically as, for example, fivefold, ten-fold, etc." Repeating an allergen challenge tomeasure PC20 after an inhaled P2 agonist canlead to a severe late asthmatic response(LAR).12 When examining the allergen-in-duced EAR in this way, we routinely administera single large dose of inhaled corticosteroid(beclomethasone dipropionate 500-1000 ,ug orequivalent) after completion of the EAR; thisis known to inhibit the LAR."3The second major bronchoprovocation

method involves administration ofa single max-imal or near maximal stimulus. This is thetraditional way in which exercise challengeshave been done.'4 Functional antagonism isassessed by repeating the "same dose" chal-lenge after inhaled P2 agonist and is expressedas the percentage reduction in the response - forexample, exercise induced bronchoconstriction(EIB) is usually measured as a fall in FEV1 -compared with the response to exercise fol-lowing placebo.'4 '5 Functional antagonism isexpressed as "percentage inhibition" by thefollowing formula:

% inhibition=

(EIB after placebo - EIB after drug)x100

EIB after placebo

The effect of pharmacological agents on theallergen induced LAR is also determined usinga "same dose" challenge; this method is alsooften used when studying the EAR.

Conventional P2 agonists and toleranceTolerance to the functional antagonism effectof inhaled 12 agonists has generally been as-sessed 10 hours (salbutamol, terbutaline) to 36hours (salmeterol) after discontinuing a 1-5week course ofthe agent. This is compared withthe functional antagonism measured before the

12 agonist treatment period4" '1 or after a cross-over blinded placebo period.'016 The per-centage change in functional antagonism, ascalculated in table 1, can be expressed by com-paring the shift in doubling doses (dd) beforeand after dosing by the formula:

[dd (pre) - dd (post)] x 100dd (pre)

For the same dose challenges - for example,exercise - this is expressed as:

A% inhibition (pre - post) x 100% inhibition (pre)

Tolerance to the functional antagonist effectof 1,3 agonists of conventional duration hasroutinely been found after their regular use.Gibson et al demonstrated that regular use ofingested salbutamol (4 mg four times daily for2-5 weeks) in six adult subjects resulted intolerance to the acute bronchoprotective effectof inhaled salbutamol against exercise inducedbronchospasm. Protection was 78% before and54% after treatment.'5 In the same study, in-haled salbutamol 800,g per day in six ado-lescents resulted in a slight and non-significantloss of the bronchoprotective effect against ex-ercise."' Vathenen et al studied airway re-sponsiveness to histamine and regular use ofinhaled terbutaline 750 jtg three times daily fortwo weeks. This study demonstrated reboundairway hyperresponsiveness to histamine max-imal 23 hours after stopping treatment, and asubstantial loss of bronchoprotective effect ofterbutaline against histamine which was greaterin the afternoon than in the morning. 6 A similarstudy from the same group examined brox-aterol 400,g three times daily and salbutamol200 gg three times daily for three weeks. Similarresults were seen with rebound histaminehyperresponsiveness maximal at 35 hours andlasting for up to 59 hours.'7 There was lessimprovement in histamine PD20 both in themorning and in the afternoon after the threeweek treatment period. Salbutamol initiallyshifted the histamine PD20 by about three doub-ling doses and, after completion of the study,this was reduced to a little over two doublingdoses. Broxaterol showed less protection atall times. This approximate 25% reduction inbronchoprotection of salbutamol against his-tamine was not statistically significant in these11 asthmatic subjects. O'Connor et al assessedairway responsiveness to methacholine andAMP before and after one week of treatmentwith terbutaline 500 jig four times daily in 12subjects.4 Their study design did not includere-establishing the baseline PC20 values aftereach treatment. The methacholine and AMPPC20 values were determined following a oneweek treatment period with terbutaline orplacebo and the PC20 value after a week ofterbutaline treatment was compared with thebaseline PC20 value following a week ofplacebo.Terbutaline initially produced a 2.7 doublingdose shift of methacholine PC20 compared witha 3.8 doubling dose shift of the AMP PC20

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Table 1 Functional antagonism before and after regular use of fl2 agonists

Functional antagonisnmt/2 agonist Stimulus n Duration Time Pre Post % loss Ref

Salbutamol (po) Exercise 6 2-5 wk 10 min -78% -54% -30% (*) 15(inhaled) Exercise 6 2-5 wk 10 min -95% .-82% - 13% (NS) 15

Terbutaline Histamine 8 2 wk 2 h am --2.9 dd - 1.7 dd 40% (**) 162 h pm --3.0 dd -0.5 dd 82% (**) 16

Salbutamol Histamine 11 3 wk 1 h am -3 dd -2 dd 33% (NS) 171 hpm -4 dd -3 dd 25% (NS) 17

Broxaterol Histamine 11 3 wk 1 h am -2 dd - 1.5 dd 25% (NS) 17lhpm -2dd -1.5dd 25%(NS) 17

Terbutaline Methacholine 12 1 wk 20 min 2.7 dd 2.2 dd 19% (*) 4AMP 12 1 wk 20 min 3.8 dd 1.7 dd 55%0(**) 4

Salbutamol Methacholine 12 2 wk 10 min 3.2 dd 2.6 dd 22% (*) 10Allergen 11 2 wk 10 min 3.7 dd 2.5 dd 27% (*) 10

Salbutamol (alone) Methacholine 13 1 wk 10 min 3.0 dd 2.0 dd 33% (**) 18(with budesonide) 10 min 2.9 dd 2.2 dd 24% (**) 18

Salbutamol200 pg/day Methacholine 10 1 wk 10 min 3.4 dd 2.6 dd 24% (**) 19400 pg/day 10 min 2.6 dd 24% (**) 19800 pg/day 10 min 2.5 dd 26% (**) 19

Salbutamol Exercise 10 1 wk 5 min 94% 85% 10% (?) 22Salmeterol Methacholine 12 4 wk 1 h 3.3 dd 1.0 dd 70% (**) 11

8 wk I h 1.0 dd 70%o(**) 11Salmeterol Methacholine 15 1 mo 12 h 1.7 dd 0.7 dd 59% (**) 25

2 mo 12 h 1.2 dd 29% (**) 253 mo 12 h 0.7 dd 59% (**) 254 mo 12 h 0.8 dd 53% (**) 25

Salmeterol Exercise 12 4 wk 6 h 66% 27% 54% 2612 h 40% 17% 58% 26

Salmeterol Allergen 8 1 wk 1 h 86% 13% 85% 27Salmeterol Methacholine 12 3.5 days 1 h 3.3 dd 1.6 dd 52% (**) 28

24 htt 3.7 dd 1.9 dd 53% (**) 28Salmeterol and inhaled corticosteroid Methacholine 8 3.5 days 1 h 2.8 dd 1.6 dd 43% (**) 29

24 htt 2.6 dd 1.7 dd 35% (**) 29Formoterol Methacholine 17 2 wk 12 h 1.9 dd 0.6 dd 68% (*) 30Salmeterol Methacholine 10 4 wk 12 h 0.9 dd 1.2 dd (NS) 31

8 wk 12 h 0.7 dd (NS) 31

t Functional antagonism: Time = timing of assessment of functional antagonism; Pre before regular use of f2 agonist; % =% protection in "same dose" challenges;dd = doubling dose shift of PC20, PC,5, PD20, etc; - approximate (extrapolated from a graph); tt = 24 h after salmeterol completed, tested 10 min post-salbutamol.* p<0.05, ** p<0.01.

(p<0.001). This difference was attributed tothe combined effect of terbutaline on mast cellf3 receptors and smooth muscle 12 receptorsin protecting against AMP, and on smoothmuscle PI receptors only in protecting againstmethacholine.4 After the one week treatmentperiod terbutaline shifted the methacholinePC20 by 2.2 doubling doses; this 19% loss ofprotection was significant (p<0.05). By con-trast, there was a much greater loss ofbroncho-protective effect against AMP as terbutalinetreatment only shifted the AMP PC20 by 1.7doubling doses, a reduction of 55% from the3.8 doubling doses (p<0.001). The inter-pretation of this greater loss of protectionagainst inhaled AMP, a mast cell stimulus, wasthat P2 receptors on mast cells might be moresusceptible to tolerance than are the 32 re-ceptors on smooth muscle.4Using this study as a model we investigated

the effect of a two week course of salbutamol200,g four times daily on airway re-sponsiveness to methacholine (n= 12) andallergen (n = 11). 1 The study design wasdifferent from that of O'Connor et al in thatwe re-established methacholine and allergenPC20 baseline values following each treatmentperiod. We found that the methacholine PC20baseline did not change, but the initial pro-tection of 3.2 doubling doses was reduced to2.5 doubling doses after two weeks of sal-butamol (p = 0.026), a 22% loss of protection.The protection against allergen was initially 3.7doubling doses (greater than the protectionagainst methacholine but not significant) andit fell by 32% to 2.5 doubling doses after the

two week treatment period (p = 0.025). Themost striking finding in this study was theunexpected observation of a highly significantincrease in airway responsiveness to allergenafter two weeks of treatment with salbutamol.There was almost a doubling of airway re-sponsiveness to allergen (p=0.0009).10 In afollow up study we showed that salbutamol200 ,ug four times a day for seven days resultedin a loss of bronchoprotection against metha-choline from 2.9 doubling doses initially to 2.0doubling doses (31% loss) after one week ofsalbutamol.

In the same subjects, in a blinded crossovertrial, high dose budesonide (1600,g per day)was compared with high dose budesonide plussalbutamol. An equivalent tolerance to broncho-protection was found, with the initial pro-tection falling from 2.9 doubling doses to 2.25doubling doses, a 22% loss, not significantlydifferent from the comparison between placeboand salbutamol. In this same study, althoughbudesonide did improve the allergen PC,5, itdid not prevent the parallel increase in airwayresponsiveness to allergen when salbutamol andbudesonide were administered concurrently.'8We have investigated these two models in adouble blind randomised crossover study, com-paring placebo with salbutamol in doses of200 gg, 400 p.g, and 800 gg per day each forone week in 10 subjects. Salbutamol produceda 3.4 doubling dose improvement in metha-choline PC20 after placebo compared with a2.6 doubling dose improvement following the200 and 400 gg per day treatment periods, anda 2.5 doubling dose improvement following

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the 800 jig per day treatment period."9 Thisrepresents a 24-26% loss of the functionalantagonism effect, which was not significantlydifferent between the three doses ofsalbutamol.In the same study airway responsiveness toallergen did not change after 200 and 400 jigsalbutamol per day for a week but did increasesignificantly, again by almost twofold, after800 jig salbutamol per day for a week."8 In twoadditional studies which did not assess thefunctional antagonist effect, the late asthmaticresponse to allergen was shown to be almostdouble after a week of regular salbutamol treat-ment compared with placebo; these studieswere both done using the "same dose" allergenchallenge model.202'Inman et al studied the effect of salbutamol

200 jig four times daily and exercise. Followingsalbutamol there was a lower FEV, and a lowerFEVy after exercise, both with and withoutsalbutamol used immediately before exercise.22The protection against exercise induced bron-choconstriction was excellent both after a weekof placebo (94% protection) and a week ofsalbutamol (85% protection).

Long acting P2 agonists and toleranceTolerance has also been found with the longacting inhaled P2 agonists, salmeterol and for-moterol. After regular use of either of theseagents it is possible to demonstrate toleranceto bronchodilation as shown by a shift of the12 agonist dose-response curve to the rightwithout a loss ofmaximum bronchodilation.2324Tolerance to functional antagonism, however,appears to be greater than tolerance to bron-chodilation.Cheung et al performed a parallel placebo

controlled trial of salmeterol 50 pg twice dailyfor eight weeks with 12 subjects receiving pla-cebo and 12 receiving active drug. Followingthe first dose of salmeterol there was a tenfoldimprovement in methacholine PC20 (3.3 doub-ling doses). After a 36 hour washout period atfour and eight weeks there was no change inFEVI, no change in bronchodilation, but a doseof salmeterol at these two time periods offeredonly a twofold improvement in methacholinePC20 (that is, one doubling dose). This rep-resents approximately a 70% loss of broncho-protective effect. In this study there was norebound hyperresponsiveness after the eightweek treatment was discontinued." In a recentparallel study in children of salmeterol 50 jigtwice daily (n =15) versus salbutamol 200 jgtwice daily (n= 15) similar results were seen.25Twelve hours after the first dose of salmeterolthe methacholine PD20 increased by 1.7 doub-ling doses. After 1-4 months the methacholinePD20 was shifted, after a dose of salmeterol, by0.7, 1.15, 0.65, 0.76 doubling doses at one,two, three, and four months, respectively; thesewere significantly less than the protection afterthe first dose (p<0.001). Methacholine PD20measured 12 hours after salbutamol in theparallel group showed no changes at any time.Ramage et al studied the airway response to

exercise six and 12 hours after the first and lastdose of salmeterol, 50 jig twice daily for four

weeks. Since exercise was studied, a "samedose" challenge was used. The first dose ofsalmeterol produced a 66% reduction in theexercise induced fall in FEV, at six hours anda 40% reduction in the fall in FEV, at 12 hours.The last dose produced only a 27% reductionin exercise induced bronchoconstriction at sixhours and an 18% reduction at 12 hours, theresults with the last dose being not statisticallydifferent from those with placebo, despite atrend. These results represent a 55-60% lossof bronchoprotection.26

Gianinni et al, in a published abstract, stud-ied eight subjects who undertook a same doseallergen challenge one hour after the first andlast dose of salmeterol and placebo ad-ministered for one week in a crossover study.The first dose of salmeterol almost completelyinhibited the early asthmatic response (86%inhibition), whereas the last dose of salmeterolwas not significantly different (13% inhibition)from placebo. This represents a 77% loss ofbronchoprotection.27We have studied the time course of the

development of tolerance to the broncho-protective effect of salmeterol against metha-choline. Methacholine PC20 was measured onehour after the first, third, fifth, and seventhdoses of twice daily salmeterol in a double blindplacebo crossover study. Twenty four hoursafter salmeterol was discontinued the metha-choline PC20 was measured 10 minutes after200 jg inhaled salbutamol. By the third doseof salmeterol the bronchoprotective effect wasreduced from 3.3 to 2.4 doubling doses (p =0.009) and continued to fall to a protection ofonly 1.5 doubling doses after the seventh dose.The PC20 after salbutamol on day 5 was alsoreduced from a 3.7 doubling dose shift 24hours after the seventh dose of placebo to 1.9doubling dose shift 24 hours after the seventhdose of salmeterol.28 Similar findings were re-ported in a subsequent study of identical designin eight subjects with more severe asthma whorequired regular inhaled corticosteroids.29 Theinitial dose of salmeterol provided an im-provement of approximately three doublingdoses in methacholine PC20, while the last doseprovided less than 1.5 doubling dose pro-tection. The loss of protection was again sig-nificant by the second day (p=0.031) andagain extended to salbutamol given 24 hoursafter the last dose.

Yates et al assessed methacholine PC20 afterthe first and last dose of a two week treatmentperiod of formoterol 24 jig twice daily. Twelvehours after the first dose of formoterol therewas a 1.9 doubling dose improvement inmethacholine PC20 compared with a 0.5 doub-ling dose increase 12 hours after the last dose.This represents a 74% loss of broncho-protection. This study also failed to show anysignificant rebound hyperresponsiveness at36 hours, 60 hours, 108 hours, and two weeksafter the two week course of formoterol.30 TheFEV, was lower 36 hours after formoterol thanafter placebo, but was not lower at other timeperiods.The one contradictory study published was

that by Booth et al who studied 26 asthmatic

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patients, 19 of whom were on maintenanceinhaled corticosteroids. They were allowed freeaccess to inhaled 32 agonist before and duringthe trial as "rescue" medication, so any tol-erance may have been present at the beginningof the study. The study was a parallel, doubleblind, eight week trial with 10 subjects com-pleting the salmeterol arm and 12 the placeboarm. Methacholine PC20 was measured 12hours after the first dose and repeated 12 hoursafter a dose at four and eight weeks. Thefunctional antagonism effect after the first dosewas less than one doubling concentration ofmethacholine and there was no loss over time.3'It is likely that the negative results in this trialwere caused by the pre-trial (and continued)use of rescue inhaled 32 agonist.The results of all of the trials quoted are

summarised in table 1. Whereas the short actingP2 agonists generally appear to result in a 20-30% loss of bronchoprotection, the longer act-ing P2 agonists consistently seem to cause a50-75% loss of bronchoprotection. Althoughstill difficult to demonstrate tolerance to bron-chodilation, this is easier for the longer actingthan for the conventional P2 agonists.2324

ConclusionsThe published studies are very consistent. Tol-erance to the functional antagonist effect ofinhaled 132 agonists develops with all agents andto all stimuli (table 1). Significant tolerancecan be seen at very low doses (salbutamol200 1.g per day for seven days)'9 and can de-velop very rapidly (by the third dose of twicedaily salmeterol) .28 29 Corticosteroids do notprevent development of this tolerance.'829 Themast cell stimuli (AMP, allergen, possibly ex-ercise) appear to be more prone to tolerancethan are the direct chemical stimuli.4 In ad-dition to tolerance to the bronchoprotectiveeffect, regular use of inhaled (32 agonists in-creases baseline airway responsiveness to al-lergens - both earlyl08'l9 and late202' - suchthat the post-salbutamol allergen PC20 after twoweeks of salbutamol was almost two doublingdoses lower than after placebo.'0The clinical relevance of these findings re-

mains uncertain. Even when tolerance de-velops, particularly with the short actinginhaled 132 agonists, there remains a con-siderable functional antagonist effect. How-ever, inhaled 132 agonists are often used clinicallyfor their functional antagonist effect - for ex-ample, before exercise, exposure to cold air,and exposure to allergens. It therefore seemslikely that the important loss of broncho-protection against allergen and exercise seenparticularly with the long acting inhaled 132agonists might have important clinical rel-evance. The enhanced airway response to aller-gen, particularly the late response, may beassociated with increased allergen induced air-way inflammation.2' This may explain the ob-servation of Manolitsas et al of increased levelsof eosinophils in bronchial biopsy specimenstaken after regular treatment with salbutamol."2These findings may also explain the appearance

of increased airway responsiveness (or reboundairway responsiveness) seen in somestudies'6173334 but not in others. 10 1 181930

The authors would like to thank Jacquie Bramley for assistingin the preparation of this manuscript.

1 Taylor DR, Sears MR, Cockcroft DW. The beta-agonistcontroversy. In: Cockcroft DW, Dosman JA, eds. Ob-structive lung diseases Part II: Asthma, sleep, occupationalexposures and AIDS. Med Clin North Am 1996;80:719-48.

2 Ahrens RC, Bonham AC, Maxwell GA, Weinberger MW.A method for comparing the peak intensity and durationof action of aerosolized bronchodilators using broncho-provocation with methacholine. Am Rev Respir Dis 1984;129:903-6.

3 Tattersfield AE. Tolerance to beta-agonists. Bull Eur Physio-pathol Respir 1985;21:1-5s.

4 O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to thenonbronchodilator effects ofinhaled 02-agonists in asthma.N EnglJ Med 1992;327:1204-8.

5 Cockcroft DW, Hargreave FE. Airway hyperresponsiveness:definition, measurement, and clinical relevance. In:Kaliner MA, Barnes PJ, Persson CGA, eds. Asthma: itspathology and treatment. New York: Marcel Dekker, 1991:51-72.

6 Pauwels R, Joos G, Van Der Straeten M. Bronchial hyper-responsiveness is not bronchial hyperresponsiveness is notbronchial asthma. Clin Allergy 1988;18:317-21.

7 Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE.Bronchial reactivity to inhaled histamine: a method andclinical survey. Clin Allergy 1977;7:235-43.

8 Finnerty JP, Wilmot C., Holgate ST. Inhibition ofhypertonicsaline-induced bronchoconstriction by terfenadine andflurbiprofen. Am Rev Respir Dis 1989;140:593-7.

9 Anderson SD, Schoeffel RE, Finney M. Evaluation of ultra-sonically nebulised solutions for provocation testing inpatients with asthma. Thorax 1983;38:284-91.

10 Cockcroft DW, McParland CP, Britto SA, Swystun VA,Rutherford BC. Regular inhaled salbutamol and airwayresponsiveness to allergen. Lancet 1993;342:833-7.

11 Cheung D, Timmers MC, Zwinderman AH, Bel EH, Dijk-man JH, Sterk PJ. Long-term effects of a long-acting ,B,-adrenoceptor agonist, salmeterol, on airway hyper-responsiveness in patients with mild asthma. N Engl JMed 1992;327:1188-203.

12 Lai CKW, Twentyman OP, Holgate ST. The effect of anincrease in inhaled allergen dose after rimiterol hydro-bromide on the occurrence and magnitude of the lateasthmatic response and the associated change in non-specific bronchial responsiveness. Am Rev Respir Dis 1989;140:917-23.

13 Cockcroft DW, McParland CP, O'Byrne PM, Manning P,Friend JL, Rutherford BC, et al. Beclomethasone givenafter the early asthmatic response inhibits the late responseand the increased methacholine responsiveness and cro-molyn does not. JfAllergy Clin Immunol 1993;91:1163-8.

14 Anderson S, Seale JP, Ferris L, Schoeffel R, Lindsay DA.An evaluation of pharmacotherapy for exercise-inducedasthma. J Allergy Clin Immunol 1979;64:612-24.

15 Gibson GJ, Greenacre JK, Konig P, Conolly ME, PrideNB. Use of exercise challenge to investigate possible tol-erance to beta-adrenoceptor stimulation in asthma. BrJDis Chest 1978;72:199-206.

16 Vathenen AS, Knox AJ, Higgins BG, Britton JR, TattersfieldAE. Rebound increase in bronchial responsiveness aftertreatment with inhaled terbutaline. Lancet 1988;i:554-7.

17 Wahedna I, Wong CS, Wisniewski AFZ, Pavord ID, Tat-tersfield AE. Asthma control during and after cessationof regular beta2-agonist treatment. Am Rev Respir Dis1993;148:707-12.

18 Cockcroft DW, Swystun VA, Bhagat R. Interaction of in-haled 2 agonist and inhaled corticosteroid on airwayresponsiveness to allergen and methacholine. Am J RespirCrit Care Med 1995;152:1485-9.

19 Bhagat R, Swystun VA, Cockcroft DW. Salbutamol-inducedincreased airway responsiveness to allergen and reducedprotection vs. methacholine: dose-response. J Allergy ClinImmunol 1996;97:47-52.

20 Cockcroft DW, O'Byrne PM, Swystun VA, Bhagat R. Reg-ular use of inhaled albuterol and the allergen-induced lateasthmatic response. _Allergy Clin Immunol 1995;96:44-9.

21 Gauvreau GM, Watson RM, Jordana M, Cockcroft D,O'Byrne PM. The effect of regular inhaled salbutamol onallergen-induced airway responses and inflammatory cellsin blood and induced sputum. AmJ Respir Crit Care Med1995;151:A39.

22 Inman MD, O'Byrne PM. The effect of regular inhaledalbuterol on exercise-induced bronchoconstriction. Am JRespir Crit Care Med 1996;153:65-9.

23 Newnham DM, Grove A, McDevitt DG, Lipworth BJ.Subsensitivity of bronchodilator and systemic 02 ad-renoceptor responses after regular twice daily treatmentwith eformoterol dry powder in asthmatic patients. Thorax1 995;50:497-504.

24 Grove A, Lipworth BJ. Bronchodilator subsensitivity tosalbutamol after twice daily salmeterol in asthmaticpatients. Lancet 1995;346:201-6.

25 Verberne AAPH, Hop WCJ, Creyghton FBM, van RooijRWG, van den Berg M, de Jongste JC, et al. Airwayresponsiveness after a single dose of salmeterol and during

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four months oftreatment in children with asthma. JAllergyClin Immunol 1996;97:938-46.

26 Ramage L, Lipworth BJ, Ingram CG, Cree JA, Dhillon DP.Reduced protection against exercise induced broncho-constriction after chronic dosing with salmeterol. RespirMed 1994;88:363-8.

27 Giannini D, Carletti A, Dente FL, Bacci E, Bancalari L,Di Franco A, et al. Tolerance to salmeterol in allergeninduced bronchoconstriction. Am Respir Crit Care Med1995;151:A39.

28 Bhagat R, Kalra S, Swystun VA, Cockcroft DW. Rapid onsetof tolerance to the bronchoprotective effect of salmeterol.Chest 1995;108:1235-9.

29 Kalra S, Swystun VA, Bhagat R, Cockcroft DW. Inhaledcorticosteroids do not prevent the development of tol-erance to the bronchoprotective effect of salmeterol. Chest1996;109:953-6.

30 Yates DH, Sussman HS, Shaw MJ, Barnes PJ, Chung KF.Regular formoterol treatment in mild asthma: effect on

bronchial responsiveness during and after treatment. Am_Respir Crit Care Med 1995;152:1170-4.

31 Booth H, Fishwick K, Harkawat R, Devereux G, HendrickDJ, Haydn Walters E. Changes in methacholine inducedbronchoconstriction with the long acting P2 agonist sal-meterol in mild to moderate asthmatic patients. Thorax1993;48:1121-4.

32 Manolitsas ND, Wang J, Devalia JL, Trigg CJ, McAulayAE, Davies RJ. Regular albuterol, nedocromil sodium,and bronchial inflammation in asthma. Am _7 Respir CritCare Med 1995;151:1925-30.

33 Kraan J, Koeter GH, Van Der Mark Th W, Boorsma M,Kukler J, Sluiter HJ, et al. Dosage and time effects ofinhaled budesonide on bronchial hyperreactivity. Anm RevRespirDis 1988;137:44-8.

34 Kerribijn KF, van Essen-Zandvliet EEM, Neijens HJ. Effectsof long-term treatment with inhaled corticosteroids andbeta-agonists on the bronchial responsiveness in childrenwith asthma. IAllergy Clin Immunol 1987;79:653-9.

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