agonists in asthma - NCBI

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Journal of the Royal Society of Medicine Volume 86 February 1993

The current debate concerning ,-agonists in asthma:

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review

K F Chung MD FRCP Department of Thoracic Medicine, National Heart & Lung Institute, Royal Brompton National Heart & Lung Hospital; London SW3 6LY Keywords: (3-adrenoceptor agonists; asthma; airway hyper-responsiveness

Introduction Following the introduction of the selective ,B2-agonists in the therapy of asthma they rapidly became one of the most frequently prescribed drugs for this chronic condition. ,B-agonists are bronchodilator drugs and regarded as 'symptomatic' treatment, in contrast to 'anti-inflammatory' or 'prophylactic' treatment such as inhaled corticosteroids or sodium cromoglycate. The management of asthma consists of prevention with anti-inflammatory agents, with relief of breakthrough symptoms with ,8-agonists. While these drugs appear to be effective, there is some concern that the morbidity and mortality of asthma have risen in many countries. The whole question of the place of A-agonists in the management of asthma continues to be debated with recent studies linking ,3-agonist therapy with excess asthma deaths and with worsening asthma control. In this review, these studies are examined and the clinical implications discussed.

asthma death, particularly when analysed in subgroups defined by markers of asthma severity. What is not possible to determine is whether fenoterol directly contributed to the cause of death or whether the more severe and vulnerable patients were prescribed fenoterol because their asthma was difficult to control. These case-control studies raise the question as to whether this association is related specifically to fenoterol rather than to the whole class of ,B2-agonists. A case-control study in a cohort of 12 301 patients for whom asthma medications had been prescribed asthma medication in Saskatchewan between 1978 and 1987 indicated an increased risk of death or near death from asthma was related to fenoterol and salbutamol, especially fenoterol9. One limitation of the study is that the control group had milder asthma and the possibility that the risk of death or near-death was associated with the severity ofdisease still exists.

13-agonists and asthma deaths

6-agonists and asthma control Airway responsiveness Early studies on the effect of chronic regular treatment with ,B-agonists have concentrated on the measurement of bronchial responsiveness, typically using the PC20 as an index of the dose-response to inhaled histamine. Acute administration of 1-agonist improves PC20, an effect that parallels in time the bronchodilator effect'0. However, what has raised some concern is the increase in bronchial responsiveness that has been observed on several occasions at 12-23 h after stopping regular treatment with short-acting 13-agonists for 2 weeks or morell-'5. The inhaled 1-agonists used in these studies were terbutaline 500 tg three to four times a dayll-'3 up to 2000 lAg three times a day13, salbutamol 400 itg four times a day14 and fenoterol 400,ug four times a day'5 and no study has yet compared the effect of fenoterol with that of salbutamol or terbutaline in the same group. The increase in bronchial responsiveness observed has been of the order of 2-3 fold with a maimal transient effect at 23 h after stopping treatment13. The clinical significance of this transient, small increase in airway responsiveness induced by 13-agonist therapy is not clear. The study of Haahtela et al 16, by contrast, did not reveal any worsening of bronchial responsiveness to histamine or of asthma symptom score in patients with mild asthma using terbutaline at the unconventional dose of 375 isg twice a day. This study when placed in the context of the other reports"l-'3"5 suggests that the deterioration in bronchial responsiveness during 13-agonist therapy is dependent on the dose and frequency of administration. It is also possible that this is not seen in very mild asthmatic

An increase in asthma deaths in the 1960s was recorded in several countries including the United Kingdom and New Zealand and inhaled high-dose isoprenaline came under suspicion",2. The epidemic occurred in countries where high dose isoprenaline aerosols had been introduced, and the increase in deaths and subsequent falls occurred at the same time as the rise and fall in isoprenaline sales2. The decline in mortality rates from asthma also followed warnings from the Committee of Safety of Drugs about the changes of overuse of isoprenaline aerosols and the removal from over-the-counter sales of high dose isoprenaline aerosols2. Whether isoprenaline was responsible in any way for the increase in asthma deaths was not fully determined, but a later interpretation of the 1960s epidemic pointed the finger at the delays and undertreatment of asthma, with isoprenaline only partly playing a role3. In 1976, a second increase in asthma deaths occurred in New Zealand4. Originally, a possible role for 13-agonists had been dismissed with more emphasis on undertreatment, particularly with corticosteroids was suggested5. Following the observation that fenoterol was used by a high proportion of asthmatics who have died, a series of case-control studies confirmed that such patients were more likely to have used fenoterol than any other 13-agonist, in particular salbutamol6-8. The later case-control studies7'8 attempted to answer criticisms levelled at differing sources for prescribed antiasthma drugs for the cases and controls, and at the validity of the choice of the control group and of the markers of severity of chronic asthma that had been used. In all these studies, fenoterol was associated with an overall risk of

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patients such as the newly-diagnosed ones of Haahtela et al. Further studies would be needed to resolve this question. One aspect of the dose-response curve of potential clinical significance is the maximal airway narrowing that can be achieved as can be measured by the plateau response. ,8-agonists while acutely improving PC20 does not significantly alter the plateau response'7.

Regular versus as required use of 3-agonists Sears et al.'5 recently addressed the question of asthma control and the regular use of fenoterol by comparing the effect of regular treatment with fenoterol (400,g 4 times a day) against that of an inhaled ,B-agonist of the patients' choice used only as when required15. Sixty-four subjects completed a 24-week crossover trial and were assessed using a standardized protocol that gave an indication of asthma control such as the use of short courses of oral steroids and peak flow diurnal variation. They found that in the 57 patients who did better with one of the two regimens, only 17 (30%) had better asthma control when receiving regularly administered bronchodilators, whereas 40 (70%) had better asthma control when they employed bronchodilators only when needed. Only one outcome variable, evening peak flow measurements, favoured routine use of (3-adrenergic agonists. Of 26 patients who developed a significant increase in bronchial responsiveness to methacholine, 22 were more responsive while receiving regular fenoterol. The results were similar whether or not the patients received inhaled corticosteroids. One criticism of the data from Sears et aL 15 is the expression of results into patients showing better control during each of the two treatment periods. There is no indication of the size of the differences or means of assessing their potential clinical significance. Similar to the case-control studies linking fenoterol to an increase in asthma deaths, the study of Sears et al.'5 begs the question as to whether similar results would have been obtained with other ,Badrenergic agonists such as salbutamol or terbutaline, which are prescribed at doses with significantly less 3-adrenergic stimulating effect. A recent study has on the other hand implicated regular bronchodilator therapy, irrespective of the class of bronchodilators'8. In a 2-year randomized controlled prospective cross-over study of 223 patients with either asthma or chronic bronchitis, the annual decline in FEV, was found to be 3 to 4 times higher in patients receiving continuous bronchodilator treatment (either salbutamol or ipratropium bromide) compared with those treated on demand18. However, no significant changes in bronchial responsiveness were observed in the asthmatic group. Other studies have not indicated worsening of asthma while taking regular ,3-agonist therapy. As mentioned above, a dose of terbutaline of 375 Ag twice daily did not worsen asthma symptoms or bronchial responsiveness in patients with mild asthma16. Shepherd et aL 19 studied the use of salbutamol (200 pg four times a day) against placebo in a crossover study in 18 asthmatics who required an average of 5.7 actuations (100 Ag per actuation) per day while on the placebo limb. They found better control of asthma during treatment compared with placebo, with both mean daily peak flow rates and peak flow rates on awakening higher during the regular

salbutamol treatment limb. Other similar results have been reported with salbutamol20'21. In a study of asthmatic patients established on theophyline, terbutaline at a dose of 500,pg four times daily improved asthma control, including symptom scores and use of as-needed inhaled bronchodilator, when compared with placebo22. These results raise the question of whether the data of Sears et aL is only applicable to fenoterol, or whether this is related to the dose used because a 200 jig of fenoterol per actuation is significantly greater in its (3-adrenergic stimulating properties than a 100 jig actuation of salbutamol or a 250 pg actuation of terbutaline23.

Potential mechanisms or explanations of adverse effects of 8-agonists Although the results of the studies reviewed above do not allow one to state conclusively whether the adverse effects apply to all ,-agonists or to the degree of ,B2 receptor stimulation or to a particular severity of the disease, it is of interest to examine some of the potential mechanisms that may explain the potential link between (3-agonists, asthma deaths and deterioration of asthma control. Cardiac effects

02-adrenoceptor agents are known to cause dosedependent tachycardia, mainly as a reflex effect of peripheral vasodilation, and may also induce cardiac arrhythmias24. However, the extent to which 02agonists do so in the clinical setting of worsening asthma is not known. Clearly, the concomitant presence of hypoxaemia and tachycardia, the dose of (3-agonist inhaled the presence of myocardial disease and concomitant therapy, such as theophylline, has an important bearing on the likelihood of developing cardiac arrhythmias. In addition, ,8-agonists also can induce hypokalaemia, due to increased uptake of potassium into skeletal muscle25. Differences in their potential in causing side-effects do exist between various (3-agonists. Repeated inhalations of fenoterol was associated with a greater frequency of ventricular dysrhythmias in middle-aged patients with chronic airway obstruction, while salbutamol induced no dysrhythmias at equivalent doses24. Fenoterol also had significant chronotropic and hypokalaemic effects, with greater prolongation of the electrocardiographic QTc interval than salbutamol, isoprenaline and terbutaline23,26. Fenoterol may possess additive effects with hypoxaemia on the increase in heart rate and prolongation of the QTc interval in normal volunteers27. Although it is difficult to exclude completely any arrhythmias in patients who die suddenly of asthma at home, there was no evidence that arrhythmias were associated with near fatal attacks admitted to hospital28. While ventricular tachyarrhythmias may be involved in causing asthma deaths, they cannot be contributory to worsening of asthma control by chronic (3-agonist therapy. Mechanisms which may worsen asthma control may also contribute to asthma deaths. Tachyphylaxis The development of tachyphylaxis secondary to the down-regulation of (2-receptors can be readily demonstrated with the systemic effects of,-agonists (eg muscle tremor), but does not appear to occur readily to

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the bronchodilator effect of these drugs in mild asthmatic subjects29 30. Other investigators have found that although the peak bronchodilator effect may only be slightly reduced after prolonged 13adrenergic agonist usage (salbutamol or terbutaline), the duration of bronchodilation can be significantly reduced31 32. However, 02-adrenoceptor down-regulation as measured by ex vivo receptor ligand studies does not appear to be present in lung tissues of non-asthmatic patients who have received treatment with inhaled or oral terbutaline prior to surgery, despite a clear-cut reduction in the density of 02-adrenoceptors in circulating mononuclear cells33. However, information is not available as to whether tachyphylaxis could develop in those patients who take high doses of 1-agonists. Presumably any 13-agonist induced tachyphylaxis could enhance the response of the airways to endogenous or exogenous stimuli by reducing the protective effect of circulating catecholamines. Clearly, studies are needed on the effect of chronic ,B-agonist therapy on the functional state of the 132-receptors in the airway submucosa of the asthmatic patient.

Effects on airway inflammation Several mechanisms have been proposed by which ,8-agonists could exacerbate the airways inflammation of asthma, which runs counter to the hypothesis that 1-agonists may have a beneficial effect airways inflammation (see below). Bronchodilation of the airways could increase the exposure of the lower airways to inhaled particles such as allergens and thereby increase the degree of airway inflammation, late phase reactions and airway hyperresponsiveness 5. This mechanism would apply to all bronchodilators irrespective of class or type. Another hypothesis proposes that 13-agonists inhibit the release from mast cells of heparin, a highly charged molecule which may neutralize the damaging effect of other mediators such as eosinophil basic proteins and which may prevent some of the structural abnormalities of the asthmatic airway24. However, the contribution of heparin and the amount released in the airways are not known. Little is known about the effect of chronic exposure of inflammatory cells to 13-adrenergic agonists on their state of activation. The significance of the increases in PC20 observed during 13-agonist therapy in terms of airway inflammation is not known. The studies of 13-agonists on allergen challenge may provide an indirect assessment of their effects on airway inflammation. Administration of a single dose of inhaled salbutamol (200,g) prior to allergen challenge abated the early asthmatic response but had no significant effect on the late response or the associated increase in histamine responsiveness measured at 7 h post challenge35. However, studies using a higher dose of salbutamol (2.5 mg inhaled from a nebulizer) and the long-acting 13-agonists, salmeterol and eformoterol, have shown inhibition of the late phase response and the associated increase in histamine responsiveness36-38. The interpretation of such data is confounded by the continuing functional antagonism of the 13-agonist, which could counteract airway smooth muscle contraction induced by inflammatory mediators released during the late phase response. For example, the late response to antigen appears to be of a similar magnitude following placebo compared with the post salmeterol response although from a higher baseline. In the

study with eformoterol, it was concluded that the apparent protective effect against allergen-induced increases in bronchial responsiveness was due to functional antagonism rather than to any antiinflammatory effects38.

Other explanations One potential explanation for the increased risk of asthma deaths associated with 13-agonists is that patients for whom asthma medications are prescribed are more likely to die from more severe disease. In the study of Spitzer et aL3, there was no apparent increase in risk of deaths associated with the use of inhaled and oral steroids, suggesting that severity of asthma (as would be indicated by the need for such medication) was not determined by severity. It is possible that 1-agonists may interact in a selected group of more symptomatic or severe asthmatics to result in asthma deaths or loss of control. Over-reliance on 13-agonist therapy to relieve symptoms of wheeze may lead to a false sense of security on the part of both the clinician and patient that the patient's underlying asthma (eg as expressed by the inflammatory process) is stable. Essential antiinflammatory treatment may be withheld until the patient's disease becomes life-threatening. Such an explanation has been previously provided for the increase in asthma deaths in the 1960s and in New Zealand3'5. Long-acting ,8-agonists and airway inflammation Long-acting 1-agonists have been introduced amid the current discussions concerning the place of 13-agonists in the treatment of asthma. Salmeterol and formoterol are both more potent and selective at the 12-receptor than the short-acting 1-agonists, and have a duration of bronchodilator and protective effect of at least 12 h39. Sustained clinical benefit has been observed over a one year period with eformoterol and salmeterol, with maintenance of high peak flow values and with lack of evidence of tachyphylaxis to salbutamolinduced bronchodilation in several studies in which the majority of patients were on steroid therapy40-42. One preliminary report shows that regular usage of salmeterol did not impair its protection against constrictor stimuli or augment bronchial responsiveness to histamine43. Data obtained by Glaxo Group Research showed that the number of patients on regular salmeterol reporting exacerbations over a one year period remained constant and that there was no difference between regular salmeterol and salbutamol, and salbutamol on demand only44"45. These observations suggest that the new-long acting 1-agonists may not possess the disadvantages that have been described with some of the short-acting agents. However, further careful observations are necessary. One issue which has been rekindled by the introduction of the long-acting 13-agonists is whether these drugs possess any 'anti-inflammatory' effect. In addition to relaxation of airway smooth muscle, ,8-agonists have been demonstrated to inhibit mediator release from mast cells46 and reduce plasma exudation in the airways47'49. The new long-acting 1-agonists have proven to be much more potent that salbutamol in inhibiting release of histamine from sensitized human lung fragments or mast cells in vitro48-50. Inhibition of eosinophil activation in vitro and of eosinophil accumulation in the lungs of sensitized guinea pigs

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have also been reported51'52. Although (3-agonists can inhibit T-lymphocyte proliferation in vitro53, a recent study showed that salmeterol had no effect on the number of activated T-lymphocytes in airway biopsies from patients with asthma54.

Clinical implications The latest studies which continue to question the safety of ,8-agonists have served to reinforce the recommendations of our national guidelines for the management of asthma55. ,8-agonists should only be used as when dictated by the occurrence of symptoms and should be considered only as a symptom-relieving medication. An increasing need for (-agonists should be considered as a sign of worsening disease and an urgent indication for introducing or stepping-up anti-inflammatory therapy, usually in the form of inhaled or systemic corticosteroids. Prescription of ,B-agonists on a regular basis is not recommended until further trials show conclusively that (3-agonists other than fenoterol do not increase asthma morbidity and symptoms. There is enough doubt raised about the safety of fenoterol that it is best to avoid the 400 jig dose altogether. One area in need of investigation is the use of lower doses of 3-agonists for clinical use. There is continuing debate about the place of the long-acting inhaled and slow-release oral ,B-agonists in the management of asthma. An extension of the guidelines for the use of short-acting f3-agonist would not recommend the continuous twice daily usage of the long-acting j3-agonists unless the patient is still symptomatic (particularly at night) despite being on an adequate dose of inhaled corticosteroid. It is not clear whether steroid therapy may prevent any potentially deleterious effects of chronic ,3-agonist therapy although the study of Sears et aL suggests that it may not. A small subgroup of more symptomatic patients have over the years grown accustomed to using large amounts of ,3-agonists such as a metered-dose canister of 200 puffs every week, sometimes in conjunction with ,3-agonist delivered by nebulizer or in oral form or a long-acting 13-agonist. A withdrawal of,-agonist to a level of use as when necessary with adequate anti-inflammatory therapy should be tried. Such a protocol has been suggested56 but its value has not been assessed.

Conclusions The potential deleterious effects of f3-agonists clearly needs further definition as to whether this is shared by all f3-agonists, whether there is a dose-dependent effect and whether they are related to the severity of asthma. Such information will obviously have clinical implications. Perhaps the greatest area where information is currently deficient is that concerning the mechanism(s) by which chronic ,B-agonist therapy may worsen asthma control or airway hyper-responsiveness. The effect of 02-agonist therapy on airway inflammation in asthma is not known. Research in this area may uncover some of the basic mechanisms by which airway inflammation modulates airway function and the recent cloning of the 13-receptor should lead to an increased understanding of potential mechanisms at the molecular level. In the midst of all the current debate surrounding the use of (3-agonists in asthma, it must be remembered that ,B-agonists remain the most effective and potent bronchodilator available for asthma at therapeutic

doses that is relatively devoid of short-tern side-effects and that they are particularly effective in treating acute severe asthma. The benefits of symptom relief when ,8-agonists are used according to the guidelines outweigh considerably any potential long-term disadvantages. The overall risk-benefit ratio for /3agonists do not indicate that 3-agonists should be discontinued; however, we need to establish how best to use them to maximal benefit with minimum risks. Acknowledgments: I thank Patricia Murphy for her help in the preparation of this manuscript. References 1 Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. BMJ 1968;i:335-9 2 Inman WHW, Adelstein AM. Rise and fall -of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1969;ii:279-85 3 Editorial. Fatal asthma. Lancet 1979i-:337-8 4 Wilson JD, Sutherland DC, Thomas AC. Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma? Lancet 1981i:1235-7 5 Sears MR, Rea HH. Patients at risk of dying of asthma: New Zealand experience. J Allergy Clin Immunol 1987;80:477-81 6 Crane J, Pearce N, Flatt A, et aL Prescribed fenoterol and death from asthma in New Zealand, 1981-83: case-

control study. Lancet 1989i:917-22 7 Pearce N, Grainger J; Atkinson M, et aL Case control study of prescribed fenoterol and death from asthma in' New Zealand, 1977-81. Thorax 1990;45:170-5 8 Grainger J, Woodman K, Pearce N, et aL Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study. Thorax 1991; 46:105-11 9 Spitzer WO, Suissa S, Ernst P, et aL The use of ti-agonists and the risk of death and near death from asthma. N Engl J Med 1992;326:501-6 10 Salome CM, Schoeffel RE, Woolcock AJ. Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects. Thorax 1983;36:580-4 11 Kraan J, Koeter GH, Van der Mark TW, Sluiter HJ, De Vries K. Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J Allergy Clin Irtmunol

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18 Van Schayck CP, Dompeling E, Van Herwaarden CL, Folgering H, Verbeek ALM, Van der Hoogen HJM, Van Weel C. Bronchodilator treatment in moderate asthma or chronic bronchitis: continuous or on demand? A randomised controlled study. BMJ 1991;303:1426-31 19 Shepherd GL, Hetzel MR, Clark TJH. Regular versus symptomatic aerosol bronchodilator treatment of asthma. Br J Dis Chest 1981;75:215-17 20 Beswick KBJ, Power GM, Sampson S. Long-term regularly inhaled salbutamol. Curr Med Res Opin 1986;10:228-34 21 Patakas D, Maniki E, Tsara V, Daskalopoulou E. Intermittent and continuous salbutamol rotacaps inhalation in asthmatic patients. Respiration 1988;54:174-8 22 Vandewalker ML, Kray KT, Weber RW, Nelson HS. Addition of terbutaline to optimal theophylline therapy: double-blind cross-over study in asthmatic patients. Chest 1986;90:198-203 23 Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990;336:1396-9 24 Tandon MK. Cardiopulmonary effects of fenoterol and salbutamol aerosols. Chest 1980;77:429-31 25 Scheinin M, Koulu M, Laurikainen E, Allonen H. Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled doseresponse study in healthy volunteers. Br J Clin Pharmacol 1987;24:645-53 26 Crane J, Burgess C, Beasley R. Comparison of the vascular and hypokalaemic effects of inhaled salbutamol, fenoterol and isoprenaline. Thorax 1989;44:136-40 27 Bremner P, Woodman K, Beasley R, et aL Hypoxaemia increases the cardiovascular effects offenoterol. Am Rev Respir Dis 1991;143:A648 28 Molfino NA, Nannini LJ, Martelli AN, Slutsky AS. Respiratory arrest in near-fatal asthma. NEngl J Med 1991;324:285-8 29 Tattersfield AE. Tolerance to beta agonists. Bull Eur Physiopathol Respir 1985;21:15-55 30 Harvey JE, Tattersfield AE. Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic and asthmatic subjects. Thorax 1982; 37:280-7 31 Weber RW, Smith JA, Nelson HS. Aerosolized terbutaline in asthmatics: development of subsensitivity with longterm administration. J Allergy Clin Immunol 1982; 70:417-22 32 Repsher LH, Anderson JA, Bush RW, et aL Assessment of tachyphylaxis following prolonged therapy of asthma with inhaled albuterol aerosol. Chest 1984;85:34-8 33 Hauck RW, Bohm M, Gengenback S, Sunder-Plasmann L, Fruhmann G, Erdmann E. i32-adrenoceptors in human lung and peripheral mononuclear leukocytes of untreated and terbutaline-treated patients. Chest 1990; 98:376-81 34 Page CP. Inhibition of natural anti-inflammatory mechanism by fl2-agonists. Lancet 1991;337:717-19 35 Cockroft DW, Murdoch KY. Comparative effects of inhaled sabutamol, sodium cromoglycate and BDP on allergen-induced early asthmatic responses, late asthmatic responses and increased bronchial responsiveness to histamine. J Allergy Clin Immunol 1987; 79:734-40 36 Twentyman OP, Finnerty JP, Holgate ST. The inhibitory effect of nebulised albuterol on the early and late asthmatic reactions and increase in airways responsiveness provoked by inhaled allergen in asthma. Am Rev Respir Dis 1991;144:782-7 37 Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 1990;336:1338-42 38 Wong BJO, Kamada DH, Ramsdale EH, et aLW Effect of formoterol compared with beclomethasone and placebo

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on allergen induced airway response. Thorax 1991; 46:770 Lofdahl CG, Chung KF. Long-acting j32-adrenoceptor agonists: a new perspective in the treatment of asthma. Eur Respir J 1991;4:218-26 Wallin A, Melander B, Rosenhall L, Sandstrom T, Wahlander L. Formoterol, a new long acting beta2 agonist for inhalation twice daily, compared with salbutamol in the treatment of asthma. Thorax 1990; 45:259-61 Ullman A, Hedner J, Svedmyr N. Inhaled salmeterol and salbutamol in asthmatic patients. An evaluation of asthma symptoms and the possible development of tachyphylaxis. Am Rev Respir Dis 1990;142:571-5 Arvidsson P, Larsson S, Lofdahl CG, Melander B, Svedmyr N, Wahlander L. Inhaled formoterol during 1 year in asthma: a comparison with salbutamol. Eur Respir J 1991;4:1168-73 Beach JR, Young CL, Haskawat R, Neill P, Walters EH, Hendrick DJ. Measurement of airway responsiveness during regular treatment with salneterol and salbutamol. Eur Resp J 1991;4(suppl 14):199s-200s Jenkins MM, Hilton CJ, De Kock JC, Palmer JBD. Exacerbations of asthma in patients on salmeterol. Lancet 1991;337:913-14 Shepherd GL, Jenkins WJ, Alexander J. Asthma exacerbations in patients taking regular salmeterol, or salbutamol for symptoms. Lancet 1991;337:1424 Butchers PR, Skidmore JF, Vardey CJ, Wheeldon A. Characterization of the receptor mediating the antianaphylactic effects of 13-adrenoceptor agonists in human lung tissue in vitro. Br J Pharmacol 1980;71:663-7 Persson CGA, Ekman M, Erjefalt I. Vascular antipermeability effect of 3-receptor agonists and theophylline in the lung. Acta Pharmacol Toxicol 1979;44:216-20 Tokuyama K, Lotvall JO, Lofdahl CG, Barnes PJ, Chung KF. Inhaled histmine-induced airflow obstruction and airway microvascular leakage in guinea-pig. Eur J Pharmacol 1991;193:35-40 Subramanian N. Inhibition of immunological and nonimmunological histamine release from human basophils and lung mast cells by formoterol. ArzneimittelForsch 1986;36:502-5 Butchers PR, Cousins SA, Vardey CJ. Salmeterol: a potent and long-acting inhibitor of the release of inflammatory and spasmogenic mediators from human lung. Br J Pharmacol 1987;92:745 Rabe K, Dent G, Giembycz MA, Ravenall S, Barnes PJ, Chung KF. Effects of long acting beta adrenoceptor agonist formoterol vs albuterol on LTB4 induced CA2+ mobilisation, H202 and TxB2 release in guinea pig eosinophils. Am Rev Respir Dis 1990;141:A29 Sanjar S, McCabe PJ, Reynolds LH. Salmeterol, a longacting 132-agonist inhibits antigen-induced bronchial eosinophil accumulation. Am Rev Respir Dis 1991; 143:A755 Feldman RD, Hunninghake GW, McArdle WL. fl-adrenergic receptor-mediated suppression of interleukin-2 receptors in human lymphocytes. J Immunol 1987; 139:3355-9 Roberts JA, Bradding P, Walls AF, Britten KM, Wilson S, Holgate ST, Howarth Ph. The influence of salmeterol xinafoate in mucosal infla tion in asthma (Abstract). Am Rev Respir Dis 1992;45:A418 British Thoracic Society. Guidelines for management of asthma in adults: I - Chronic persistent asthma. BMJ 1990;301:651-3 Sears MR. Dose reduction of beta-agonists in asthma. Lancet 1991;338:1331-2

(Accepted 16 June 1992)