Thorax 1996;51:585-589 585 Effects of prior treatment with salmeterol and formoterol on airway and systemic 2 responses to fenoterol Thorax: first published as 10.1136/thx.51.6.585 on 1 June 1996. Downloaded from Alison Grove, Brian J Lipworth Abstract response curves to repeated doses of Background - Previous studies have fenoterol in stable asthmatic patients. shown that both salmeterol and formoterol (Thorax 1996;51:585-589) act as partial P2 receptor agonists in terms of antagonising the extrapulmonary re- Keywords: salmeterol, formoterol, fenoterol, partial sponses to fenoterol in normal subjects. agonist, bronchodilation, asthma. The aim ofthe present study was to extend previous observations in evaluating the Salmeterol and formoterol are both long acting effect of prior treatment with salmeterol P2 receptor agonists used in the treatment of and formoterol on bronchodilator re- asthma. It has been shown in vitro that sal- sponses to fenoterol, a full P2 receptor meterol is a partial 32 receptor agonist'2 and, agonist, in patients with asthma. even at high concentrations, it is unable to Methods - Ten stable asthmatic patients produce the maximal bronchorelaxant response of mean (SE) age 37 (3.7) years and forced elicited by a full agonist such as isoprenaline. expiratory volume in one second (FEV,) This difference can be expressed in terms of 59-5 (4-1)% of predicted completed the the intrinsic efficacy of the agonist, with a full study. One hour after inhaling single doses agonist such as isoprenaline nominally being ofplacebo, salmeterol 25 jg, or formoterol given an intrinsic activity of 1. Other agonists 12 jtg, dose-response curves to repeated can then be compared with this standard. In doses of inhaled fenoterol were con- vitro studies have shown that the intrinsic ac- structed (cumulative doses of100-3200 pg). tivity of salmeterol is of the order of 0 71 Measurements of airway and systemic P2 compared with isoprenaline.3 The intrinsic ac- receptor mediated responses were made tivity of formoterol is also lower than that at baseline, after inhalation of placebo, of isoprenaline with a value of 096,3 thus http://thorax.bmj.com/ salmeterol, or formoterol, and after each formoterol is also a partial agonist - albeit a dose of fenoterol. strong one. Results - Salmeterol and formoterol pro- From first principles it can be predicted that duced significant bronchodilation com- the presence of a partial agonist may inhibit pared with placebo (mean difference and the effects of an agonist with greater intrinsic 95% CI compared with placebo): FEV,, activity.4 In this respect we have previously salmeterol 0-41 (95% CI 0-13 to 0.69) 1, for- shown that oral salbutamol inhibits the effects moterol 0-47 (95% CI 0-19 to 0-75) 1. Sal- of endogenous adrenaline at extrapulmonary on October 2, 2021 by guest. Protected copyright. meterol and formoterol had no significant 12 receptors in normal subjects.5 In addition effect on systemic responses compared we have demonstrated that inhaled salmeterol with placebo. There were no significant and formoterol antagonise the extrapulmonary differences in peak airway responses to P2 receptor responses to endogenous adrenaline fenoterol after treatment with salmeterol and to exogenous inhaled fenoterol, also in or formoterol compared with placebo normal subjects.6 (mean (pooled SE)): FEV,, placebo The aim of the present study was to extend 2.84(0-03)1, salmeterol 2.87 (0.03)1, and the findings of these previous studies in order formoterol 2-88 (0.03)1. There were no sig- to assess whether prior treatment with sal- nificant differences in the area under the meterol or formoterol affects the airway and dose-response curve for any of the para- systemic 12 responses to repeated doses of in- Department of meters during the dose-response curve fol- haled fenoterol in asthmatic subjects. Fenoterol Clinical lowing treatment with salmeterol or was chosen to construct the dose-response Pharmacology, formoterol compared with There curves as it is known to be a full agonist with University of Dundee, placebo. intrinsic Ninewells Hospital and was no difference in the slope of the dose- greater activity than either salmeterol Medical School, response curves to fenoterol for FEVy or or formoterol. Low doses of salmeterol and Dundee DD1 9SY, UK forced expiratory flow after formoterol were used so as not to produce A Grove (FEF2575) maximal bronchodilator activity prior to ad- B J Lipworth treatment with salmeterol or formoterol ministering fenoterol. Correspondence to: compared with placebo, although there Dr A Grove. was a significant (p<005) attenuation of Received 15 August 1995 the slope in the dose-response curve for Methods Returned to authors 4 December 1995 the peak expiratory flow rate (PEFR). SUBJECTS Revised version received Conclusions - Prior treatment with low Ten stable asthmatic patients (five women) 10 January 1996 Accepted for publication doses of salmeterol or formoterol does not of mean (SE) age 37 (3 7) years and forced 18 January 1996 significantly alter bronchodilator dose- expiratory volume in one second (FEV,) 2'04 586 Grove, Lipworth (0 23) 1,59 5 (4 1)% ofpredicted normal, com- acic Society criteria' using a Vitalograph com- pleted the study. All patients were diagnosed as pact spirometer with pneumotachograph head having asthma according to American Thoracic and pressure transducer, and on-line computer Society criteria.8 At an initial screening visit assisted determination of FEVL, FEF2, ,-, and patients were required to have an FEV, of PEFR. Forced expiratory manoeuvres were Thorax: first published as 10.1136/thx.51.6.585 on 1 June 1996. Downloaded from less than 80% of predicted normal, and to performed from total lung capacity to residual demonstrate at least 15% reversibility to in- volume with measures being taken according haled fenoterol 200 jg (Berotec 200 metered to best test criteria. dose inhaler; Boehringer Ingelheim, Bracknell, Berkshire, UK). In addition, all subjects were required to have a normal physical ex- Extrapulmonary responses amination, 12 lead ECG, haematology and A standard lead II electrocardiogram was mon- biochemical screen. All subjects gave written itored and recorded with a Hewlett-Packard informed consent to participate in the study ECG monitor and printer (Palo Alto, California, which had been approved by the Tayside com- USA) with paper speed set at 25 mm/s. Heart mittee for medical ethics. At the time of the rate was calculated from the mean of five con- study all 10 patients were using inhaled cortico- secutive R-R intervals. steroids in doses of400-2400,g daily, together Finger tremor was recorded by a previously with inhaled short acting bronchodilators on validated method10 using an accelerometer an as required basis. In addition, four patients transducer (Entran Ltd, Ealing, UK). Four were oral recordings were made at each measurement taking theophylline preparations. and the results were stored on computer for subsequent analysis of total tremor power >2 Hz (mg2/s) using computer assisted auto- PROTOCOL Patients attended the laboratory between 08.00 covariance. The mean of three consistent re- and 09.00 hours on three occasions separated cordings was subsequently used in the analysis. by at least one week. Before each visit broncho- Serum potassium levels were measured by dilators were withheld for an appropriate period flame photometry (IL943 analyser, Instru- of time (that is, 48 hours for theophylline pre- mentation Laboratory Ltd, Warrington, UK) parations and eight hours for short acting 32 with analysis being performed in batches at the agonists). A cannula was inserted into a forearm end of the study, and samples being assayed vein to facilitate venous blood sampling. After in duplicate. The coefficients of variation for 30 minutes supine rest, baseline measurements analytical imprecision within and between as- of heart rate, postural finger tremor, serum says were 0 41% and 1-04%, respectively. The potassium levels, and spirometric parameters normal reference range for serum potassium were performed. was required to be levels in our laboratory is 3 5-555 mmol/l. FEV, http://thorax.bmj.com/ within 15% of that recorded at the initial screening visit. Subjects were then randomised STATISTICAL ANALYSIS to receive inhaled placebo, salmeterol 25 jtg Data for finger tremor were transformed using (Serevent metered dose inhaler, 25 jtg per actu- logarithm to base 10 to achieve conformation ation; Allen and Hanburys, Uxbridge, Middle- with a normal distribution. Data were then sex, UK), or formoterol 12,ug (Foradil metered analysed using a Statgraphics software package dose inhaler, 12 gg per actuation, Ciba Geigy (STSC Software Publishing Group, Rockville, AG Basel, Switzerland) in a single blind cross- USA). Baseline values, and values following over fashion. All drugs were administered via inhalation of placebo, salmeterol, and for- on October 2, 2021 by guest. Protected copyright. a large volume spacer device in an attempt to moterol, were compared by multifactorial anal- maximise lung delivery. After one hour further ysis ofvariance (MANOVA). Where the overall measurements of airway and systemic para- MANOVA was significant, Duncan's multiple meters were made. A dose-response curve to range testing was used to establish where inhaled fenoterol (Berotec metered dose in- differences were significant. Peak values halers, 100 jig and 200 jig per actuation) was achieved during the dose-response curve by constructed using doses of 100 jig, 100 pg, each individual were obtained, regardless of 200 jg, 400 jig, 800 jg, and 1600 jg- that the doses at which they occurred, and were is, a total cumulative dose of 3200,g. The compared by MANOVA and Duncan's mul- fenoterol was also administered via the large tiple range testing. Analysis of the responses at volume spacer device. Dose increments were individual doses from the dose-response curve given at 20 minute intervals with measurements was not performed in order not to confound being made 15 minutes after each dose.