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Interactions Between Corticosteroids and Β Agonists

Interactions Between Corticosteroids and Β Agonists

Thorax 2000;55:595–602 595

Occasional reviews

Interactions between and â agonists

Department of Medicine, Dunedin D R Taylor, R J Hancox School of Medicine, P O Box 913, Dunedin, New Zealand D R Taylor Inhaled corticosteroids and â agonists are the whereas long acting agents are indicated as a R J Hancox most frequently prescribed in the supplement to anti-inflammatory therapy if management of chronic . Current breakthrough symptoms persist.1 Thus, co- Correspondence to: prescribing is commonplace. However, despite Dr D R Taylor guidelines emphasise their complementary e-mail: robin.taylor@ role. Inhaled corticosteroids are the treatment dynamic interactions between endogenous stonebow.otago.ac.nz of choice for all but the mildest of disease. and catecholamines in vivo, it Received 5 January 2000 Short acting â agonists are recommended for is only recently that interest in the possibility of Accepted for publication “as required” relief of asthma symptoms, interactions has developed. Two topical 20 January 2000 and clinically relevant questions arise. Firstly, do positive interactions occur, thus providing s BA theoretical justification for current trends to use combination products incorporating a long Gs BR acting â agonist and a ? Sec- AC ondly, do negative interactions occur which might explain the apparent paradox that, HSP GR 1 ATP despite increasing use of the two therapies over the last 30 years, the overall burden of asthma cAMP HSP s 2 morbidity in most western countries has GR CREB continued to increase?2

TF 3 EVects of glucocorticoids on â receptor PKA 10 function s 4 Endogenous adrenal glucocorticoids have an GR CREB important facilitatory eVect on â receptor 6 function in vivo. In animals adrenalectomy 5 results in a generalised loss of responsiveness to CBP catecholamines.34 Conversely, the presence of RP GR 9 mRNA glucocorticoids enhances â receptor mediated responses: myocardial contractility, hepatic and DNA GRE CRE Gene voluntary muscle glucose , and 8 bronchial smooth muscle relaxation have been 4 7 BR shown to increase. These actions occur at mRNA physiological concentrations of . At least two mechanisms are proposed whereby glucocorticoids modify â receptor function. The first is by regulating the coupling Figure 1 Putative intracellular mechanisms for interaction between â agonists and of â receptors to G proteins and hence adenyl corticosteroids. (1) The steroid-glucocorticoid receptor complex upregulates â2 receptors by cyclase activation (fig 1). The degree of enhancing receptor coupling with G protein and/or preventing downregulation following â2 coupling determines cell responsiveness to â â2 receptor activation. (2) Binding between the activated glucocorticoid receptor and CREB 5 in the cytoplasm may inhibit translocation to the nucleus. (3) “Cross talk” between the receptor stimulation. Following exposure to glucocorticoid receptor, CREB, and other nuclear transcription factors. (4) “Cross talk” exogenous â agonist, uncoupling occurs rap- between the glucocorticoid receptor and CREB in the nucleus. (5) The glucocorticoid idly by phosphorylation of the receptor (desen- receptor and CREB may compete for or synergistically bind protein co-factors such as CBP which are required for coupling with RNA polymerase and activation of response elements sitisation). There are a number of phosphoryla- in the promoter regions of target genes. (6) Direct phosphorylation of protein co-factors such tion pathways, including â adrenoceptor kinase as CBP may alter their activity. (7) The presence of both GREs and CREs in the promoter (â-ARK),67 and these constitute the first step regions of target genes may mutually enhance or inhibit their eVects on gene transcription. towards the development of drug tolerance. (8) The promoter region of the â receptor gene contains GREs which may enhance or 2 Exposure to corticosteroids restores receptors suppress synthesis of the â2 receptor protein. (9) The promoter region of the glucocorticoid receptor gene contains CREs which may enhance or suppress synthesis of the glucocorticoid to their previously sensitised state.8 receptor protein. (10) A cAMP-dependent mechanism enhances the stability of messenger The second is that glucocorticoids can RNA for the glucocorticoid receptor increasing receptor levels.17 AC = adenylate cyclase; upregulate previously downregulated â receptor ATP = adenosine triphosphate; BA = â agonist; BR = â2 adrenoceptor; CBP = CREB binding protein; CRE = cAMP response element; CREB = cAMP response element binding function after chronic â agonist exposure. protein; cAMP = cyclic adenosine monophosphate; GR = glucocorticoid receptor; GRE = Downregulation is characterised by receptor glucocorticoid response element; Gs = stimulatory G protein; HSP = heat shock protein 90; 9 mRNA = messenger RNA; PKA = protein kinase A; RP = RNA polymerase; S = steroid internalisation and degradation, reversal of drug molecule; TF = transcription factor. which requires new receptor synthesis. Activa- 596 Taylor, Hancox

tion of glucocorticoid response elements factor NF-êB was reduced in bronchial mu- (GREs) in the promoter region of the â receptor cosa and GR binding increased with regular gene causes an increase in the rate of gene tran- inhaled , the simultaneous adminis- scription and hence of receptor numbers.10–15 tration of regular did not alter the binding activity of either.24 EVects of â agonists on glucocorticoid In other studies in human bronchial epithe- receptor function lial cells an inhibitory eVect of terbutaline on Inactive glucocorticoid receptors (GRs) are GR binding responses to budesonide has been bound to protein complexes (including heat shown, but occurred only when the â agonist shock protein, HSP-90) in the cytosol. After was administered simultaneously; the eVects of ligand binding, activated GRs dissociate and prior exposure to corticosteroid were unaf- translocate to the nucleus where they bind to fected by the subsequent addition of glucocorticoid response elements (GREs) in terbutaline.25 Thus, the timing of exposure to the promoter region of target genes. The eVect the two agents may be of relevance in of catecholamines on the normal function of determining possible interactions. In contrast, GRs and GREs has not been studied in detail. in another study both and sal- Forskolin, which increases intracellular cyclic meterol have been shown to enhance the

AMP levels (thereby mimicking â2 receptor activation of GC receptors and their binding to activation), has been shown to increase rat nuclear GREs.26 hepatoma cell GR numbers and potentiate the The results of other laboratory studies production of induced neuro- designed to evaluate possible interactions tensin from the rat hypothalamic cells.16 between â agonists and glucocorticoids on Forskolin may also antagonise the downregula- inflammatory cells and their cytokines have tion of GRs induced by dexamethasone.17 also been inconsistent. has been These actions provide indirect evidence that â shown to enhance the steroid induced inhibi- agonists, which also enhance intracellular tion of activated monocytes27 and also cAMP levels, might enhance GR function. appears to potentiate fluticasone induced Glucocorticoids mediate many of their anti- apoptosis in activated human eosinophils (by a inflammatory eVects by either activating or factor of 2–3).28 Similarly, in airway smooth repressing gene transcription of cytokines. In muscle cells the inhibitory eVect of dexametha- addition to the binding of activated GRs to sone on tumour necrosis factor (TNF)-á GREs in the nucleus, this may also occur indi- mediated interleukin-8 production was poten- rectly when activated GRs interact with pro- tiated by simultaneous incubation with both inflammatory nuclear transcription factors—for salbutamol and salmeterol.29 In contrast, Sel- example, AP-1 or NF-kappa B (NF-êB)—to don et al have studied the eVect of salbutamol suppress their eVects on the upregulation of on dexamethasone induced inhibition of pro-inflammatory cytokine production (fig TNF-á and GM-CSF production from stimu- 1).18 19 Beta agonists modify gene transcription lated monocytes but, even at high concentra- by increasing intracellular levels of cAMP and tions of salbutamol, no important interaction activating the nuclear transcription factor was observed.30 Other in vitro data suggest that, cAMP response element binding protein at pharmacological concentrations, the pres- (CREB). In turn this binds to cAMP response ence of either or salbutamol may elements (CREs) on target genes. So-called actually impair the beneficial actions of steroid. “cross talk” between these transcription factors Nielson et al31 have shown that the eVects of has been postulated as a mechanism for dexamethasone on eosinophil superoxide pro- interactions between â agonist and cortico- duction and apoptosis are reduced in a dose steroid drugs. It is likely that “cross talk” dependent manner by both of these short includes competitive binding of protein co- acting â agonists. factors such as CREB binding protein (CBP) or A number of biological and pharmacological the related P300 which are necessary for the factors might account for the apparently activation of transcription factor response conflicting outcomes from these studies. They elements to GRs.20 Interactions between GREs include tissue dependent diVerences in recep- and closely related CREs in the promoter tor function, variations in the in vitro drug region of genes may also be important. concentrations used and the duration of expo- There is evidence that the eVects of â sure, and diVering pharmacological properties agonists and glucocorticoids on nuclear tran- of the drugs used—for example, partial versus scription factors are mutually inhibitory. Incu- full agonist or short acting versus long acting. bation of rat with salbutamol and Nevertheless, they provide some of the back- inhibits GR binding to GREs, while ground against which potential interactions incubation with dexamethasone inhibits the between â agonists and inhaled corticosteroids binding of CREB to CREs.21 The extent of in patients requiring chronic treatment have mutual inhibition is of the order of 40–50%. been investigated. Similar eVects have been described in the human lung.22 23 Despite this, in a clinical study Clinical interactions: designed to examine transcription factor REVERSING DESENSITISATION AND changes in bronchial mucosa during treatment DOWNREGULATION of mild asthma with terbutaline and budeso- Although the principal mode of action of nide singly and in combination, Hancox et al corticosteroids in acute asthma is to control found no evidence of a negative interaction.24 airway inflammation, several studies indicate Although DNA binding of the transcription that reversing â receptor desensitisation and Interactions between corticosteroids and â agonists 597

downregulation caused by prior â agonist Clinical interactions: chronic asthma treatment may be important. In animal studies PROTECTION AGAINST THE DEVELOPMENT OF a bolus of corticosteroid reverses tolerance to TOLERANCE the protective eVects of isoprenaline against If corticosteroids are of benefit in restoring â non-specific airway responsiveness.32 However, receptor numbers and function in acute at least in vitro, the magnitude of this eVect asthma, the question arises: do they oVer appears to diVer depending on which drugs are protection against the development of toler- used.33 In humans, single doses of either intra- ance when administered as chronic therapy? venous prednisolone34 or even inhaled Unfortunately, since no firm relationship has beclomethasone35 have been shown to restore been established between â agonist tolerance the response to isoprenaline during long term use of either short or long and fenoterol, respectively. Similarly, Tan et al36 acting agents and asthma control, the clinical have shown that tolerance to the broncho- relevance of this question is speculative. Nevertheless, a number of studies have been dilator eVects of inhaled may be carried out to establish whether inhaled rapidly reversed by a single dose of intravenous corticosteroids may have a prophylactic role in corticosteroid. The apparently short time preventing â agonist tolerance. frame for this change contrasts with that for the The results of most studies indicate that formation of cytokines and inflammatory cell inhaled corticosteroids do not modify the infiltration in the late asthmatic response, sug- development of tolerance during treatment gesting that the initial benefits of steroid with short acting agents.46–49 In a recent study therapy in acute asthma are due to their by Hancox et al50 clear evidence of tolerance to permissive eVect on â receptor function rather the bronchodilator action of inhaled â agonist than suppression of pro-inflammatory path- was seen in 34 asthmatic patients following six ways. This might also explain the clinical weeks treatment with regular inhaled terbuta- observation that, in acute severe asthma, the line in a dose of 1 mg four times daily. After co-administration of corticosteroid either sys- inducing with metha- temically or by the inhaled route results in an choline, the acute response to sequential doses enhanced rate of recovery of lung function of inhaled salbutamol was significantly reduced compared with â agonist or corticosteroid compared with placebo but the addition of alone.37 38 regular budesonide to terbutaline in a dose of Although interactions between â agonists 400 µg twice daily did not prevent this eVect. In and corticosteroids in acute asthma are likely one in vitro study some protection against the to be beneficial, there are theoretical reasons development of tolerance was achieved with why this might not always be the case. A the administration of dexamethasone,15 which number of hypotheses have been advanced to is arguably a more potent corticosteroid. How- explain the relationship between the use of ever, in a clinical study by Molema et al in inhaled â agonists and the two recent “epidem- which a range of doses of inhaled beclometha- ics” of asthma mortality.39 Among them is the sone was given, tolerance to the acute eVects of possibility that, in association with the inhaled salbutamol remained unchanged.47 It of acute severe asthma, overuse of â agonists therefore seems unlikely that the use of even might precipitate death by cardiac high doses of inhaled corticosteroids will arrhythmia.40 In patients who have been taking confer protection, even if avoiding tolerance â agonists frequently or regularly, administer- were deemed to be clinically desirable. ing systemic corticosteroids might re-sensitise A similar picture has emerged for the long myocardial as well as bronchial smooth muscle acting â agonists, particularly with regard to â receptors, thus theoretically increasing the the loss of protective eVect against broncho- possibility of arrhythmias. In laboratory ani- constrictor stimuli aVorded by single doses of a mals corticosteroid administration has been short acting drug during long term treatment with a long acting agent.51–56 In general, inhaled shown to increase the cardiac toxicity of corticosteroids do not prevent the advent of catecholamines.41 Recently, Aziz et al have tolerance, although here the evidence is shown that downregulation of human perhaps less clear. Recently, Giannini et al have rate responses to salbutamol during treatment reported that inhaled beclomethasone partially with the long acting â agonist formoterol was reverses the loss of protective eVect of salm- modified by concomitant use of inhaled 57 42 eterol against allergen challenge. In another steroid. Likewise, cardiovascular responses to study with healthy volunteers Tan et al found emergency â agonist drugs may be increased in that oral steroid prevented downregulation of patients who have previously received treat- systemic responses to salbutamol during long 43 ment with inhaled corticosteroids. In con- term treatment with formoterol.58 trast, in healthy volunteers the use of oral pred- nisone failed to potentiate the eVects of â CLINICAL INTERACTIONS: SHORT ACTING 44 agonist on heart rate or QTc interval. Given â AGONISTS that death from acute severe asthma is more In the late 1980s case control studies carried likely to be the result of than out in New Zealand identified an association cardiac causes,45 it seems unlikely that recovery between asthma mortality and the prescription or even enhancement of the downregulated of the â agonist fenoterol. The risk of death was cardiovascular eVects of â agonist by cortico- greatest among those requiring continuous steroid during acute severe asthma is clinically treatment with oral prednisone.59–61 This may important. not be surprising since these patients had more 598 Taylor, Hancox

Median ment with regular salbutamol, reduced after IQR treatment with budesonide, and intermediate when both drugs were used in combination. Range 3 Given this background, there has been a need for appropriately designed studies to con- 2 firm whether these observations are relevant to 1 asthma control during long term combined therapy with inhaled corticosteroids and â 0 agonists. A number of investigations have com- pared the addition of inhaled corticosteroids to 70–75 _1 â agonist treatment alone. Their results antigen (doubling doses)

20 have been consistent: symptoms, pulmonary

PC _2 function, bronchial hyperresponsiveness, and exacerbation rates are improved using com- bined therapy. However, comparisons between Placebo Terbutaline Terbutaline + Budesonide budesonide combined treatment and inhaled cortico- steroids alone, which are much more relevant Figure 2 Changes in PC20 allergen (doubling doses) 33 hours after cessation of treatment with placebo, terbutaline, to answering the question of a possible adverse

budesonide, and their combination. The increase in PC20 interaction between the two drugs, have been which occurred with budesonide was significantly greater fewer. Their results are summarised in table than for the combination of terbutaline and budesonide. 63 76–81 Shaded areas = interquartile ranges. Reproduced from 1. Wong et al68 with permission. We have recently reported the results of two placebo controlled, four way, crossover studies severe asthma, but it did raise the possibility of designed to evaluate interactions between â an adverse interaction. Further, the results of agonists and inhaled corticosteroids.63 81 Nei- several investigations have found that airway ther investigation provided evidence that short inflammation may be increased during mono- acting â agonists reduced the clinical benefits therapy with a short acting â agonist.62–64 Thus, of inhaled corticosteroids. In the larger study individual case reports have suggested that comprising 61 patients with mild to moderate reducing, or even withdrawing, short acting â asthma81 combined treatment with inhaled agonist treatment may result in clinical im- terbutaline (1 mg four times daily) and inhaled provement and a significant reduction in budesonide (800 µg daily) over six weeks was steroid requirements.65–67 These data have gen- ranked best of the four treatments, and erated the hypothesis that the benefits of achieved significant improvements in asthma corticosteroid treatment may be compromised control compared with budesonide alone. A or, alternatively, that the need for anti- similar positive interaction was noted for inflammatory therapy may be increased as a morning peak flows which showed a greater result of â agonist use and an adverse increase during combined treatment (com- interaction between the two drugs. pared with placebo) than the sum of the Other clinical studies have oVered support increases for terbutaline or budesonide given for this possibility. Wong et al68 showed that the alone (fig 3) although, interestingly, this

addition of regular terbutaline treatment re- pattern was not true for FEV1. A simple expla- sulted in significant impairment of the reduc- nation for these results is that terbutaline tion in bronchial hyperresponsiveness to aller- enhanced airway deposition of the budesonide gen resulting from inhaled budesonide (fig 2). and hence overall improvement. However, Similarly, in a controlled crossover study given the in vitro evidence already cited, a more Cockcroft et al69 showed that bronchial respon- complex interaction seems likely. The possi- siveness to allergen was increased after treat- bility that inhaled steroid may have oVered Table 1 Studies comparing short acting â agonists in combination with inhaled corticosteroids with inhaled corticosteroid alone

No. of Reference patients Study design Results Comments

Dahl et al76 37 DB, crossover, 3 weeks. Oral Higher peak flows + fewer nocturnal Oral terbutaline used. Small diVerences terbutaline/inhaled budesonide/both awakenings with combination between treatments 77 Bennati et al 30 DB, parallel group, 1 month. PC20 (methacholine) higher after Salbutamol used prn in beclomethasone Salbutamol/beclomethasone/both combination than beclomethasone group. Small numbers of subjects alone (NS) 78 Selroos et al 12 DB, crossover, 3 weeks. Terbutaline + FEV1 higher with combination. No Abstract report. Small numbers of subjects budesonide/budesonide diVerence in peak flow or PD20 () Wilding et al79 16 DB, crossover, 2 weeks. Terbutaline + Evening peak flow higher with Small diVerences only. Small numbers of budesonide/budesonide combination. Morning peak flow also subjects higher (NS). Barnes et al80 74 DB, crossover, 4 weeks. Peak flow higher with combination. Fewer Very low dose terbutaline used. â agonist Terbutaline/budesonide/ both symptoms with combination used prn throughout Hancox et al81 61 DB, placebo controlled, crossover, 6 Combination treatment was highest High doses of terbutaline used weeks. With/without ipratropium used as ranked. Morning peak flows higher with (4000 µg/day) to maximise any possible supplement. Terbutaline/budesonide/ combination than sum of increments adverse interaction. both/placebo with single treatments. Aldridge et al63 34 DB, placebo controlled, crossover, 6 BHR to hypertonic and sputum Pro-inflammatory actions of terbutaline weeks. Ipratropium used as supplement. eosinophils increased with terbutaline not modified by combination of Terbutaline/budesonide/ both/placebo budesonide with terbutaline

DB = double blind; NS = not statistically significant; BHR = bronchial hyperresponsiveness; FEV1 = forced expiratory volume in one second; PD20 = provocative dose causing fall in FEV1 of 20% or more. Interactions between corticosteroids and â agonists 599

470 and lung function than increasing the dose of Morning peak flow inhaled corticosteroid.84–90 460 Evening peak flow Although in some studies these outcomes do not appear to translate into a reduction in 450 asthma exacerbations,91 92 this is perhaps be- cause these studies were not primarily designed 440 to evaluate this clinical end point. In contrast, in the FACET study93 the addition of regular 430 formoterol in a dose of 12 µg twice daily to either low dose (200 µg/day) or high dose

Peak flow (I/min) 420 (800 µg/day) budesonide reduced severe exac- erbation rates by 26% in each instance. 410 However, the reduction in severe asthma episodes for patients on low dose steroid was 400 Placebo Terbutaline Budesonide Budesonide + still best achieved by increasing the anti- terbutaline inflammatory therapy (49%). Even in patients on maintenance treatment with inhaled Figure 3 Mean morning and evening peak flow rates during six weeks treatment with corticosteroids and whose asthma is consid- regular inhaled terbutaline, budesonide, their combination, and placebo. Morning peak flows ered to be stable, further benefits may be were higher when terbutaline was added to budesonide (p<0.002) whereas, when compared achieved by adding a long acting â agonist. In with placebo, terbutaline alone conferred no significant improvement. Reproduced from Hancox et al81 with permission. the study by Taylor et al the use of salmeterol resulted in a 45% reduction in major exacerba- protection against the development of toler- tions among patients with stable asthma, 92% ance has been investigated and discounted.50 of whom were already taking inhaled Similar clinical outcomes were obtained in a corticosteroids.94 Leblanc et al have reported second separate study comprising 34 patients.63 that the benefits of long acting â agonists are However, in that investigation there was a greater in patients already receiving inhaled

significant reduction in PD15 for hypertonic corticosteroids than in those who are not saline and a significant increase in the percent- already on anti-inflammatory therapy.95 Sal- age of eosinophils in induced sputum during meterol has also been shown to permit a treatment with terbutaline, indicating that monotherapy with the short acting â agonist 18 A had a permissive eVect on airway inflammation (fig 4). This adverse outcome was not modified 16 by the addition of budesonide. Indeed, the 14 pattern of results for these end points was simi- lar to that previously described by Wong et al68 12 and Cockcroft et al69—namely, there was some impairment of the benefits of treatment with 10 inhaled corticosteroids when the â agonist was

saline (ml) 8

added without apparently aVecting asthma 15

control. PD 6 Taken together, the results of these recent studies suggest that, even though inhaled 4 corticosteroids do not appear to prevent the pro-inflammatory eVects of short acting â ago- 2 nists, this is unlikely to be of clinical signifi- 0 cance, at least in patients with mild or moder- Placebo Terbutaline Budesonide Combined ate asthma taking “normal” doses of either 50 drug. In fact, a beneficial interaction appears to B occur in most patients. The results suggest that a â agonist facilitates the actions of inhaled 40 corticosteroids, perhaps simply by improving airway drug deposition or, alternatively, by 30 enhancing the anti-inflammatory eVects of inhaled corticosteroids at a subcellular level.26–28 20

CLINICAL INTERACTIONS: LONG-ACTING 10 â AGONISTS % sputum eosinophils Current guidelines for the management of 0 chronic asthma support the addition of a long acting â agonist in patients whose asthma remains inadequately controlled with anti- Placebo Terbutaline Budesonide Combined inflammatory therapy and “as required” Figure 4 Changes in (A) bronchial hyperresponsiveness bronchodilator.1 As monotherapy, inhaled to hypertonic saline (PD15 saline) and (B) percentage of corticosteroid achieves greater control of eosinophils in induced sputum at the end of six weeks asthma than long acting â agonist alone.82 83 treatment with inhaled terbutaline (1 mg four times daily), budesonide (400 µg twice daily), combined treatment, and However, the addition of a long acting agent placebo given to 34 subjects in a randomised crossover results in greater improvements in symptoms sequence. Reproduced from Aldridge et al63 with permission. 600 Taylor, Hancox

reduction in maintenance dosage of inhaled studies designed specifically to evaluate airway corticosteroid (median reduction of 400 µg inflammation and bronchial hyperresponsive- beclomethasone per day compared with 0 µg ness indicate that short acting â agonists may per day during the placebo period) without any have pro-inflammatory eVects and that their apparent increase in symptoms or adverse magnitude is not modified by treatment with change in lung function although, again, exac- inhaled corticosteroids. It remains possible erbation rates were not reported as a study end that, in patients with more severe asthma or point.96 those using higher doses of drug or for longer Although the design of most of these studies periods of time, the pro-inflammatory actions may not permit final conclusions to be drawn, of short acting â agonists counterbalance the their results suggest that the benefits of long benefits of inhaled corticosteroids. There are acting â agonists are likely to be greatest among suYcient in vitro data to support this possi- patients already taking inhaled corticosteroids, bility. This might explain the adverse eVect of â thus raising the possibility that a positive inter- agonists on asthma control that has been action may be occurring. This seems more observed in some studies despite concomitant plausible than that long acting â agonists have anti-inflammatory treatment when a potent intrinsic anti-inflammatory eVects, clear evi- agent at relatively high doses has been used.97 98 dence for which has not emerged. These data have formed the basis upon which the role of 1 British Thoracic Society. The British guidelines on asthma fixed dose combination products is now being management: 1995 review and position statement. Thorax 1997;52(Suppl 1):S1–21. investigated. 2 Sears MR. Epidemiology of asthma. In: Barnes PJ, Rodger IWB, Thomson NC, eds. Asthma: basic mechanisms and clinical management. 3rd ed. San Diego: Academic Press, Conclusions 1998: 1–33. Both positive and negative interactions be- 3 Davies AO, DeLean A, Lefkowitz RJ. Myocardial beta- receptors from adrenalectomised rats: impaired tween corticosteroids and â agonists may formation of high-aYnity agonist-receptor complexes. occur; both have been demonstrated in vitro. Endocrinology 1981:108:720–2. 4 Davies AO, Lefkowtiz RJ. Regulation of beta-adrenergic On the one hand, â agonists may potentiate receptors by steroid hormones. Ann Rev Physiol 1984;46: steroid induced repression of some cytokines 119–30. 5 Torphy TJ. Beta-receptors, cAMP and airway smooth mus- while corticosteroids upregulate â receptor cle relaxation: challenges to the dogma. Trends Pharmacol mRNA transcription, thus restoring â receptor Sci 1994;15:370–4. 6 Hausdorf WP, Caron MG, Lefkowitz RJ. Turning oV the function. On the other, mutual inhibition of the signal: desensitisation of beta- function. binding of nuclear transcription factors has FASEB J 1990;4:2881–9. 7 McGraw DW, Liggett SB. Heterogeneity of the â-adrenergic been shown. These apparently divergent re- receptor kinase expression in the lung accounts for sults may be the result of methodology; there cell-specific desensitisation of the â2-adrenergic receptor. J Biol Chem 1999;272:7338–44. have been important diVerences between tissue 8 Hui KKP, Conolly ME, Tashkin DP. Reversal of human preparations, drug concentrations, and dura- lymphocyte beta-adrenoceptor desensitization by glucocor- ticoids. Clin Pharmacol Ther 1982;32:566–71. tion of drug exposure in the various studies. As 9 Barnes PJ. Beta-adrenergic receptors and their regulation. yet we cannot conclude that these Am J Respir Crit Care Med 1995;152:838–60. 10 Kobilka BK, Dixon RAF, Frielle T, et al. cDNA for the interactions—whether positive or negative— human beta-adrenergic receptor: a protein with multiple occur consistently or whether these in vitro membrane spanning domains and encoded by a gene whose chromosomal location is shared with that of the data are relevant to the in vivo situation. receptor for derived growth factor. Proc Natl Acad In clinical studies interactions between â Sci USA 1987;84:46–50. 11 Emorine LJ, Marullo S, Delavier-Klutchko C, et al. agonists and corticosteroids appear to be Structure of the gene for human beta-2 adrenergic predominantly positive. In acute severe asthma receptor: expression and promoter characterisation. Proc Natl Acad Sci USA 1987;84:6995–9. the interaction is beneficial: the administration 12 Hadcock JR, Malbon CC. Regulation of beta-adrenergic of corticosteroid enhances the bronchodilator receptors by permissive hormones: glucocorticoids in- crease steady state levels of receptor mRNA Proc Natl Acad response to â agonist by reversing desensitisa- Sci USA 1988;85:8415–9. tion and downregulation of â receptors. In 13 Malbon CC, Hadcock JR. Evidence that glucocorticoid response elements in the 5'-non-coding region of the ham- chronic asthma there is little evidence that ster beta-2 adrenergic receptor are obligate for glucocorti- corticosteroid prevents â receptor downregula- coid regulation of receptor mRNA levels. Biochem Biophys Res Commun 1988;154:676–81. tion. Despite this, combinations of the two 14 Mak JCW, Nishikawa M, Barnes PJ. Glucocorticoids drugs have been found to improve asthma con- increase beta-2 adrenergic receptor transcription in human lung. Am J Physiol 1995;268:L41–6. trol and reduce exacerbation rates. This is par- 15 Mak JCW, Nishikawa M, Shirasaki H, et al. Protective ticularly true for long acting â agonists. The eVects of a glucocorticoid on down-regulation of pulmo- nary beta-2 adrenergic receptors in vivo. J Clin Invest 1995; exact mechanism remains unclear. There is 96:99–106. also the possibility that, because of a positive 16 Scarceriaux V, Pelaprat D, Forgez P, et al.EVects of dexam- ethasone and forskolin on neurotensin production in rat interaction, long acting â agonists may have hypothalamic cultures. Endocrinology 1995;136:2554–60. “steroid enhancing” or “steroid sparing” ef- 17 Dong Y, Aronsson M, Gustafsson JA, et al. The mechanism of cAMP-induced glucocorticoid receptor expression. J fects. However, the use of these terms ought to Biol Chem 1989;264:13679–83. be very cautiously applied: the minimum dose 18 Adcock IM, Shirasaki H, Gelder CM, et al. The eVects of glucocorticoids on phorbol ester and cytokine stimulated requirement for inhaled corticosteroids in transcription factor activation in human lung. Life Sci combination therapy remains to be defined 1994;55:1147–53. 19 Van der Saag PT, Caldenhoven E, Van der Stolpe A. and, given that the use of long acting â agonists Molecular mechanisms of steroid action: a novel type of as monotherapy is less eVective than inhaled crosstalk between glucocorticoids and NF-kappa B tran- scription factors. Eur Respir J 1996;9(Suppl 22):146–52s. corticosteroids alone, it is certainly not zero. 20 Janknecht R, Hunter T. A growing co-activator network. Current clinical data provide reassurance Nature 1996;383:22–3. 21 Peters MJ, Adcock IM, Brown CR, et al. Beta-adrenoceptor that in most patients the benefits of inhaled agonists interfere with glucocorticoid receptor DNA bind- corticosteroids are not being compromised by ing in rat lung. Eur J Pharmacol 1995;289:275–81. 22 Peters MJ, Adcock IM, Brown CR, et al. Beta-agonist inhi- â agonist use and, at least for long acting bition of steroid-receptor DNA binding activity in human agents, are likely to be enhanced. Nevertheless, lung. Am Rev Respir Dis 1993;147:A772. Interactions between corticosteroids and â agonists 601

23 Stevens DA, Barnes PJ, Adcock IM. Beta-agonists inhibit responses after regular twice daily treatment with eformot- DNA binding of glucocorticoid responses in human erol dry powder in asthmatic patients Thorax 1995;50:497– pulmonary and bronchial epithelial cells. Am J Respir Crit 504. Care Med 1995;151:A195. 52 Grove A, Lipworth BJ. Bronchodilator subsensitivity to 24 Hancox RJ, Stevens DA, Adcock IM, et al.EVects of inhaled salbutamol after twice daily salmeterol in asthmatic beta-agonist and corticosteroid treatment on nuclear tran- patients. Lancet 1995;346:201–6. scription factors in bronchial mucosa in asthma. Thorax 53 Kalra S, Swystun VA, Bhagat R, et al. Inhaled cortico- 1999;54:488–92. steroids do not prevent the development of tolerance to the 25 Korn SH, Wouters EFM, Wesseling G, et al. Interaction bronchoprotective eVect of salmeterol. Chest 1996;109: between glucocorticoids and beta-2-agonists: alpha and 953–6. beta glucocorticoid-receptor mRNA expression in human 54 Yates DH, Kharitonov SA, Barnes PJ. An inhaled cortico- bronchial epithelial cells Biochem Pharmacol 1998;56: steroid does not prevent tolerance to the bronchoprotective 1561–9. eVect of a long-acting inhaled beta-agonist. Am J Respir 26 Eickelberg O, Roth M, Lorx R, et al. Ligand-binding activa- Crit Care Med 1996;154:1603–7. tion of the glucocorticoid receptor by beta-2 adrenergic 55 Booth H, Bish R, Walters J, et al. Salmeterol tachyphylaxis in receptor agonists in primary human lung fibroblasts and steroid treated asthmatics. Thorax 1996;51:1100–4. vascular smooth muscle cells. J Biol Chem 1999;274:1005– 56 Simons FER, Gerstner TV, Cheang MS. Tolerance to the 10. bronchoprotective eVect of salmeterol in adolescents with 27 Oddera S, Silvestri M, Testi R, et al. Salmeterol enhances exercise-induced asthma using concurrent inhaled gluco- the inhibitory activity of dexamethasone on allergen- corticoid treatment. Pediatrics 1997;99:655–9. induced mononuclear cell activation. 57 Giannini D, Bacci E, Dente FL, et al. Inhaled beclometha- 1998;65:199–204. sone dipropionate reverts tolerance to the protective eVects 28 Anenden V, Egemba G, Kessel B, et al. Salmeterol faciliata- of salmeterol. Chest 1999;115:629–34. tion of fluticasone-induced apoptosis in eosinophils of 58 Tan KS, McFarlane LC, Lipworth BJ. Concomitant admin- asthmatics pre- and post-antigen challenge. Eur Respir J istration of low dose protects against in vivo 1998;12:157s. beta-2 adrenoceptor subsensitivity induced by regular for-

29 Pang L, Knox AJ. Synergistic inhibition by â2 agonists and moterol. Chest 1998;113:34–41. corticosteroids on TNFá induced IL-8 release from 59 Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and cultured human airway smooth muscle cells. Am J Respir death from asthma in New Zealand, 1981–83: case control Cell Mol Biol 2000 (in press). study. Lancet 1989;i:917–22. 30 Seldon PM, Stevens, Adcock IM, et al. Albuterol does not 60 Pearce N, Grainger J, Atkinson M, et al. Case-control study antagonize the inhibitory eVect of dexamethasone on of prescribed fenoterol and death from asthma in New monocyte cytokine release. Am J Respir Crit Care Med Zealand, 1977–81. Thorax 1990;45:170–5. 1998;157:803–9. 61 Grainger J, Woodman K, Pearce N, et al. Prescribed 31 Nielson CP, Hadjokas NE. Beta-adrenoceptor agonists fenoterol and death from asthma in New Zealand, block corticosteroid inhibition in eosinophils. Am J Respir 1981–87: a further case control study. Thorax 1991;46: Crit Care Med 1998;157:184–91. 105–11. 32 Geddes BA, Jones TR, Dvorsky RJ, et al. Interaction of glu- 62 Gauvreau GM, Jordana M, Watson RM, et al.EVect of cocorticoids and on isolated guinea-pig regular inhaled albuterol on allergen-induced late re- tracheal and human bronchial smooth muscle. Am Rev sponses and sputum eosinophils in asthmatic subjects. Am Respir Dis 1974;110:420–7. J Respir Crit Care Med 1997;156:1738–45. 33 Stephan WC, Chick TW, Avner BP, et al. Tachyphylaxis to 63 Aldridge RE, Hancox RJ, Taylor DR, et al.EVects of terbu- inhaled isoproterenol and the eVect of methylprednisolone taline and budesonide on sputum inflammatory cells. Am J in dogs. J Allergy Clin Immunol 1980;65:105–9. Respir Crit Care Med 2000 (in press). 34 Ellul-Micallef R, Fenech FF. EVect of intravenous pred- 64 Manolitsas ND, Wang J, Devalia JL, et al. Regular albuterol, nisolone in asthmatics with dimished adrenergic respon- sodium and bronchial inflammation in asthma. siveness. Lancet 1975;ii:1269–71. Am J Respir Crit Care Med 1995;151:1925–30. 35 Pansegrouw DF, Weich DJV, LeRoux FPJ. Beta-adrenergic 65 Jones SA, Taylor DR. Excessive use of salbutamol: the receptor tachyphylaxis in acute severe asthma. SAfrMedJ potential benefits of dose reduction. A case report. NZ Med 1991;80:229–30. J 1999;112:448–50. 36 Tan KS, Grove A, McLean A, et al. Systemic corticosteroid 66 Van Metre TE. Adverse eVects of of excessive rapidly reverses bronchodilator subsensitivity induced by amounts of nebulised isoproterenol in status asthmaticus. J formoterol in asthmatic patients. Am J Respir Crit Care Med Allergy 1969;43:101–13. 1997;156:28–35. 67 Reisman RE. Asthma induced by adrenergic aerosols. J 37 Arnaud A, Charpin J. Interaction between corticosteroids Allergy 1970;46:162–7. and beta-2 agonists in acute asthma. Eur J Respir Dis Suppl 68 Wong CS, Wahedna I, Pavord ID, et al.EVect of regular 1982;122:126–31. terbutaline and budesonide on bronchial reactivity to aller- 38 Rodrigo G, Rodrigo C. Inhaled flunisolide for acute severe gen challenge. Am J Respir Crit Care Med 1994;150:1260– asthma. Am J Respir Crit Care Med 1998;157:698–703. 70. 39 Pearce N, Crane J, Burgess C, et al. Beta-agonists and 69 Cockcroft DW, Swystun VA, Bhagat R. Interaction of asthma mortality: déjà vu. Clin Exp Allergy 1991;21:401– inhaled beta-2 agonist and inhaled corticosteroid on airway 10. responsiveness to allergen and methacholine Am J Respir 40 McDevitt DG, Shanks RG, Swanton JG. Further observa- Crit Care Med 1995;152:1485–9. tions on the cardiotoxicity of isoprenaline during hypoxia. 70 Haahtela T, Alanko K, Muittari A, et al. The superiority of Br J Pharmacol 1974;50:335–44. combination beclomethasone and salbutamol over stand- 41 Guideri G, Barletta M, Lehr D. Extraordinary potentiation ard dosing of salbutamol in the treatment of chronic of isoproterenol cardiotoxicity by corticoid pre-treatment. asthma. Ann Allergy 1989;61:63–6. Cardiovasc Res 1974;8:775–86. 71 Horn CR, Clark TJH, Cochrane GM. Can the morbidity of 42 Aziz I, McFarlane LC, Lipworth BJ. Concomitant inhaled asthma be reduced by high dose inhaled therapy? A corticosteroid resensitises cardiac beta-2 adrenoceptors in prospective study. Respir Med 1990;84:61–6. the presence of long-acting beta-2 agonist therapy. Eur J 72 Waalkens HJ, Gerritsen J, Koeter GH, et al. Budesonide and Clin Pharmacol 1998;54:377–81. terbutaline or terbutaline alone in children with mild 43 Lin RY, Newman TG, Sauter D, et al. Association between asthma: eVects on bronchial hyper-responsiveness and reported use of inhaled and diVerential diurnal variation in peak flow. Thorax 1991;46:499–503. short-term responses to aerosolised albuterol in an 73 Van Essen Zandvliet EE, Hughes MD, Waalkens HJ, et al. setting. Chest 1994;106:452–7. EVects of 22 months treatment with inhaled corticosteroid 44 Taylor DR, Wilkins GT, Herbison GP, et al. Interaction and/or beta-2 agonists on lung function, airway responsive- between corticosteroid and beta-agonist drugs: biochemi- ness and symptoms in children with asthma. Am Rev Respir cal and cardiovascular eVects in normal subjects. Chest Dis 1992;146:547–54. 1995;102:519–24. 74 Kerstjens HAM, Brand PLP, Hughes MD, et al. A compari- 45 Molfino NA, Nannini LJ, Martelli AN, et al. Respiratory son of bronchodilator therapy with or without inhaled arrest in near-fatal asthma. N Engl J Med 1991;324:285–8. corticosteroid therapy for obstructive airways disease. N 46 Harrison AR, Richards R, Howarth P, et al. Interaction of Engl J Med 1992;327:1413–9. inhaled corticosteroids and beta-2 agonists in asthmatic 75 Dompeling E, Van Schayck CP, Van Grunsven PM, et al. subjects. Thorax 1984;39:710–1. Slowing the deterioration of asthma and chronic obstruc- 47 Molema J, Lammers J-WJ, Van Herwaarden CLA, et al. tive pulmonary disease observed during bronchodilator EVects of inhaled beclomethasone dipropionate on beta-2 treatment by adding inhaled corticosteroids. Ann Intern receptor function in the airways and adrenal responsiveness Med 1993;118:770–8. in bronchial asthma. Eur J Clin Pharmacol 1988;34:577–83. 76 Dahl R, Pedersen B, Hagglof B. Nocturnal asthma: eVect of 48 Wempe JB, Postma DS, Breederveld N, et al. Separate and treatment with oral sustained-release terbutaline, inhaled combined eVects of corticosteroids and bronchodilators on budesonide, and the two in combination. J Allergy Clin airflow obstruction and airway responsiveness in asthma. J Immunol 1989;83:811–5. Allergy Clin Immunol 1992;89:679–87. 77 Bennati D, Piacentini GL, Peroni DG, et al. Changes in 49 Hjemdahl P, Zetterlund A, Larsson K. Beta-2 agonist treat- bronchial reactivity in asthmatic children after treatment ment reduces beta-2 sensitivity in alveolar macrophages with beclomethasone alone or in association with salbuta- despite corticosteroid treatment. Am J Respir Crit Care Med mol. J Asthma 1989;26:359–64. 1996;153:576–81. 78 Selroos O, Nyholm J-E. Influence of a budesonide- 50 Hancox RJ, Aldridge RE, Cowan JA, et al. Tolerance to terbutaline combination on bronchial reactivity. Clin Exp beta-agonists during acute bronchoconstriction. Eur Respir Allergy 1990;20:76. J 1999;14:283–7. 79 Wilding PJ, Clark MM, Oborne J, et al.EVect of regular 51 Newnham DM, Grove A, McDevitt DG, et al. Subsensitiv- terbutaline on the airway response to inhaled budesonide. ity of bronchodilator and systemic beta-2 adrenoceptor Thorax 1994;51:989–92. 602 Taylor, Hancox

80 Barnes PJ, O’Connor BJ. Use of a fixed combination beta-2 than inhaled corticosteroid dose increases. Allergy Asthma agonist and steroid dry powder in asthma. Am J Proc 1999;20:173–80. Respir Crit Care Med 1995;151:1053–7. 90 Baraniuk J, Murray JJ, Nathan RA, et al. alone 81 Hancox RJ, Cowan JO, Flannery EM, et al. Randomised or in combination with salmeterol vs. triamcinolone in trial of an inhaled beta-agonist, inhaled corticosteroid and asthma. Chest 1999;116:625–32. their combination in the treatment of asthma. Thorax 91 Russell G, Williams DAJ, Weller P, et al. Salmeterol 1999;54:482–7. xinafoate in children on high dose inhaled steroids. Ann 82 Verberne AAPH, Frost C, Roorda RJ, et al. One year treat- ment with salmeterol compared with beclomethasone in Allergy Asthma Immunol 1995;75:423–8. children with asthma. Am J Respir Crit Care Med 1996;156: 92 Van der Molen T, Postma DS, Turner MO, et al.EVects of 688–95. the long-acting beta-agonist formoterol on asthma control 83 Simons FE. A comparison of beclomethasone, salmeterol in asthmatic patients using inhaled corticosteroids. Thorax and placebo in children with asthma. N Engl J Med 1996;52:535–9. 1997;337:1659–65. 93 Pauwels RA, Lofdahl C-G, Postma DS, et al.EVect of 84 Greening AP, Ind PW, Northfield M, et al. Added salmeterol inhaled formoterol and budesonide on exacerbations of versus higher dose corticosteroid in asthma patients with asthma. N Engl J Med 1997;337:1405–11. symptoms on existing inhaled corticosteroid. Lancet 1995; 94 Taylor DR, Town GI, Herbison GP, et al. Asthma control 344:219–24. during long-term treatment with regular inhaled salbuta- 85 Woolcock A, Lundback B, Ringdal N, et al. Comparison of mol and salmeterol. Thorax 1998;53:744–52. addition of salmeterol to inhaled steroids with doubling of 95 Leblanc P, Knight A, Kreisman H, et al. A placebo- the dose of inhaled steroids. Am J Respir Crit Care Med controlled, cross-over comparison of salmeterol and 1996;153:1481–8. 86 Pearlman DS, Stricker W, Weinstein W, et al. Inhaled salm- salbutamol in patients with asthma. Am J Respir Crit Care eterol and fluticasone: a study comparing monotherapy Med 1996;154:324–8. and combination therapy in asthma. Ann Allergy Asthma 96 Pedersen B, Faurschou P, Madsden F, et al. Salmeterol Immunol 1999;82:257–65. treatment reduces the need for inhaled steroid in 87 Van Noord JA, Schreurs AJM, Mol SJM, et al. Addition of steroid-dependent asthmatics: a randomised, double-blind salmeterol versus doubling the dose of fluticasone propion- placebo-controlled parallel-group study. Eur Respir J 1996; ate in patients with mild to moderate asthma. Thorax 1999; 9:50s. 54:207–12. 97 Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta- 88 Weersink EJ, Douma RR, Postma DS, et al. Fluticasone agonist treatment in bronchial asthma. Lancet 1990;336: propionate, salmeterol xinafoate, and their combination in 1391–6. the treatment of nocturnal asthma. Am J Respir Crit Care 98 Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled Med 1997;155:1241–6. beta-agonist: eVects on exacerbations and lung function. 89 Murray JJ, Church JL, Anderson WH, et al. Concurrent use of salmeterol with inhaled corticosteroids is more eVective Thorax 1993;48:134–8.

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