Lack of Subsensitivity to Albuterol After Treatment with Salmeterol in Patients with Asthma

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1 Lack of Subsensitivity to Albuterol After Treatment with Salmeterol in Patients with Asthma HAROLD S. NELSON, ROBERT B. BERKOWITZ, DAVID A. TINKELMAN, AMANDA H. EMMETT, KATHLEEN A. RICKARD, and STEVEN W. YANCEY National Jewish Medical and Research Center, Denver, Colorado; Atlanta Allergy and Immunology Research Foundation, Atlanta, Georgia; and Glaxo Wellcome Inc., Research Triangle Park, North Carolina The development of tolerance to the bronchodilator effects of 2 -agonists used in asthma therapy has been the subject of debate. We conducted two placebo-controlled crossover studies to assess the bronchodilator response to a short-acting 2 -agonist before and after chronic therapy with salmeterol. Patients in one study were corticosteroid-naive; patients in the other study were using inhaled corticosteroids. Changes in FEV 1 after cumulative doubling doses of inhaled albuterol were assessed after a 2-wk -agonist washout period, before administering study medication on Day 1, and again after 28 d of therapy. Ipratropium bromide was provided as rapid-relief treatment for asthma, and use of any 2 -agonist except the study treatment was prohibited. On both assessment days for salmeterol, and during placebo administration periods, significant increases from predose FEV 1 values were observed beginning with the lowest dose of albuterol and continuing throughout the dose response assessment (p 0.001). These increases in FEV 1 were maintained for 6 h after the last dose of albuterol (p 0.05). There were no statistically significant differences in the albuterol dose response following salmeterol or placebo. These studies indicate that irrespective of concurrent corticosteroid treatment, chronic therapy with salmeterol does not result in tolerance to the bronchodilator effects of albuterol. Nelson HS, Berkowitz RB, Tinkelman DA, Emmett AH, Rickard KA, Yancey SW. Lack of subsensitivity to albuterol after treatment with salmeterol in patients with asthma. AM J RESPIR CRIT CARE MED 1999;159: (Received in original form July 24, 1998 and in revised form December 28, 1998) Supported by a grant from Glaxo Wellcome, Inc. Correspondence and requests for reprints should be addressed to Harold S. Nelson, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO Am J Respir Crit Care Med Vol 159. pp , 1999 Internet address: In the treatment of patients with asthma, the development of tolerance to the effects of short- and long-acting 2 -adrenoreceptor agonists after their prolonged use has been the subject of numerous reviews (1 5). Although tolerance to the extrapulmonary effects of 2 -agonists has been demonstrated in a number of studies (6 9), the potential for developing tolerance to the bronchodilator effects of these agents, resulting in a loss of therapeutic efficacy with their prolonged use, is of greater clinical concern. Salmeterol is a highly selective, potent, long-acting, inhaled 2 -receptor agonist indicated for the long-term maintenance treatment of asthma and prevention of bronchospasm in patients with reversible obstructive airway disease. A major advantage of salmeterol over other inhaled 2 -agonists is its longer duration of action. Salmeterol has been shown to be effective for 12 h after its administration, compared with 4 h to 6 h for the short-acting 2 -agonists (10, 11). In addition, the superior efficacy (as assessed by FEV 1, peak expiratory flow [PEF], and asthma symptom control) of therapeutic doses of salmeterol over those of the short-acting 2 -agonist albuterol for treatment periods of 12 wk to 12 mo has been demonstrated in numerous studies (12 16). These well-controlled studies have shown that the onset of activity, peak effect, and duration of activity of salmeterol are unchanged after its longterm use. Although there has been no evidence that prolonged use of salmeterol induces tolerance to its bronchodilator effects, its longer duration of action may raise concern about the potential development of tolerance to the 2 -agonist effects of short-acting -agonists as a result of -adrenergic receptor downregulation. Clinically relevant examples of the development of tolerance would be diminution of the onset, peak, or duration of bronchodilatation with additional 2 -agonist therapy. A recent study suggested that patients who received salmeterol twice daily for 4 wk became tolerant to the bronchodilator effects of albuterol (17). In that study, FEV 1 values before treatment with albuterol were notably higher after treatment with salmeterol than after administration of placebo; however, the analysis of the change from baseline did not control for this difference in baseline lung function between the two treatments, making the conclusions of the study questionable. The two studies presented here were similarly designed to further characterize the bronchodilator response to a shortacting 2 -agonist in patients with asthma who were receiving salmeterol as maintenance therapy. Because there has been some debate about whether corticosteroid treatment provides a protective effect against the development of tolerance to 2 -agonists (18, 19), two patient populations were evaluated: one study enrolled corticosteroid-naive patients, whereas the other required that patients be maintained on a stable regimen of inhaled corticosteroid treatment for their asthma be-

2 Nelson, Berkowitz, Tinkelman, et al.: Lack of Tolerance with Salmeterol 1557 fore and throughout their participation in the study. An initial 2 -agonist washout period of 2 wk was included in both studies to control for the possibility of some patients having developed a degree of tolerance to 2 -agonists before study enrollment. Tolerance to the bronchodilator effects of albuterol was assessed with cumulative doubling doses of albuterol both before and after 28 d of treatment with salmeterol or placebo. Use of 2 -agonists during the placebo period was prohibited in order to ensure that no tolerance to 2 -agonists would develop as a result of the use of supplemental medications. METHODS Study Design and Patients Two randomized, double-blind, placebo-controlled, crossover clinical trials were conducted at two centers to examine bronchodilator subsensitivity in adult patients with asthma who had been receiving inhaled salmeterol xinafoate (Serevent Inhalation Aerosol; Glaxo Wellcome Inc., Research Triangle Park, NC) at a dose of 42 g twice daily for 4 wk. All patients provided written informed consent, and the trials were approved by institutional review boards. The two studies were identical in design with one exception: one study enrolled corticosteroid-naive patients, whereas the other enrolled patients who had been treated with daily inhaled corticosteroids (beclomethasone dipropionate 672 g d, flunisolide 2,000 g d, or triamcinolone acetonide 800 g d) for at least 30 d before enrollment and who were able to continue their inhaled corticosteroid regimen without adjustment for the duration of the study. Patients at least 18 yr of age were eligible for enrollment in each of the two studies if they had a diagnosis of asthma, as defined by the American Thoracic Society (20), that had lasted for at least 12 mo, had a baseline FEV 1 of 50% to 80% of Crapo and colleagues (21) predicted normal values after withholding of bronchodilators, and had at least a 12% increase in FEV 1 within 30 min after inhalation of 180 g albuterol. Eligibility criteria for both studies also specified that patients had required 2 -agonist therapy (on a fixed schedule or on an as-needed basis with at least one use daily) prior to enrollment. At the time of enrollment in either study, patients were supplied with supplemental ipratropium bromide (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) to treat breakthrough asthma symptoms, and were instructed to discontinue the use of all other bronchodilators for the duration of the study. Following a 2 -agonist washout period of 14 2 d, patients returned for their first day of randomized treatment with salmeterol or administration of placebo. Patients continued dosing with the study medication for 4 wk, entered a washout period of 7 2 d, and then received the alternative treatment for 4 wk in the second crossover period. Concurrent use of any oral or inhaled 2 -agonists (other than salmeterol) or of any -adrenergic receptor antagonists was prohibited throughout the washout and treatment periods. Eligible patients underwent screening assessments including medical history, physical examination and recording of vital signs, clinical laboratory assessments, pulmonary function testing that included an assessment of FEV 1 reversibility (after withholding of short-acting inhaled bronchodilators for at least 8 h, long-acting inhaled bronchodilators for at least 24 h, and any long-acting oral bronchodilators for at least 48 h), a 12-lead electrocardiogram (ECG), and an assessment of adverse events. During the screening visit, patients were instructed in and showed proficiency in the use of the metered dose inhalers (MDIs) and peak flow meters used in the study. Dose-response assessments for albuterol (Ventolin Inhalation Aerosol, Glaxo Wellcome) were conducted between 6:00 A.M. and 9:00 A.M. before the morning dose of study drug on the first treatment day and after 28 d of therapy during each study period (Study Days 1 and 28). Prior to testing, patients were to withhold ipratropium bromide for at least 8 h, abstain from caffeine consumption for at least 6 h, and avoid exercise or strenuous activity for at least 2 h. At each test session, doubling cumulative doses of inhaled albuterol were administered every 30 min, and pulmonary function tests (FEV 1, FVC, and FEF 25 75% ) were performed in triplicate 25 min after each doubling dose. Doses of albuterol ranged from 180 g to 1,440 g (for cumulative doses of 180, 360, 720, 1,440, and 2,880 g) unless significant signs of adverse events in response to albuterol prohibited further dosing. After the last dose of albuterol, pulmonary function tests were performed every hour for 6 h. Statistical Analysis A sample size of at least 20 patients in each population completing both crossover periods was estimated to provide 80% power to detect a significant difference of 2.5% in the predicted FEV 1 at a significance level of Comparisons during treatment were done with t tests, with each patient s data paired with his or her baseline value for pulmonary function data as obtained during albuterol dose response assessments. Treatment comparisons at baseline were based on mean values, with an analysis of variance (ANOVA) crossover model (22). All other treatment comparisons were based on an ANOVA model of change from predose baseline values, with control for baseline and treatmentperiod effects. Pretreatment (Study Day 1) measurements of albuterol dose response with pulmonary function tests were also compared with measurements within each treatment group on study Day 28, using an ANOVA model. Frequencies of ECG results and adverse events were analyzed with Fisher s exact test (23). RESULTS A total of 24 corticosteroid-treated patients (16 females and eight males) and 27 corticosteroid-naive patients (13 females and 14 males) participated in the studies. Twenty-one corticosteroid-treated patients and 21 corticosteroid-naive patients completed both crossover periods; a total of nine patients were withdrawn from the studies prematurely. Asthma exacerbations led to premature withdrawal for one corticosteroid-treated and one corticosteroid-naive patient during administration of placebo, and of one corticosteroid-naive patient during salmeterol treatment. Two corticosteroid-naive patients were withdrawn because of adverse events during administration of placebo. Other reasons for withdrawal included withdrawal of consent, use of prohibited medication, and lack of efficacy. The mean age of the patients in the corticosteroid-treated group was 41 yr (range: 20 to 63 yr) and in the corticosteroidnaive group 32 yr (range: 20 to 56 yr). The majority of patients ( 90%) were white. In the corticosteroid-treated group, the mean prebronchodilation FEV 1 at screening was 2.33 L, the % predicted FEV 1 was 67.9%, and the percent reversibility was 27.9%. In the corticosteroid-naive group, the mean prebronchodilation FEV 1 was 2.68 L, the % predicted FEV 1 was 68.7%, and the percent reversibility was 29.0%. For both patient populations, pretreatment values for FEV 1 and PEF were similar in the salmeterol and placebo treatment periods (Table 1). Albuterol Dose Response There were no significant differences between the two crossover treatment periods in FEV 1, FVC, or FEF 25 75% at baseline for either patient population. Prior to either treatment with salmeterol administration of placebo (at study Day 1), significant increases in FEV 1 in response to inhalation of albuterol were observed in both the corticosteroid-treated and corticosteroid-naive patients after the first dose of albuterol (p 0.001) and continuing throughout dosing (p 0.001) (Figure 1), and for 6 h after the last dose of albuterol (p 0.003) (Figure 2). There were no significant differences in either patient population in the albuterol dose response before treatment with salmeterol or administration of placebo. During treatment with salmeterol, a significant increase in prealbuterol FEV 1 values from pretreatment on study Day 1 to Day 28 of therapy was noted in both the corticosteroidtreated (p 0.001) and corticosteroid-naive (p 0.003) pa-

3 1558 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 1 MEAN PRETREATMENT VALUES FOR LUNG FUNCTION Placebo Period Mean (SE) Salmeterol Period Mean (SE) Corticosteroid-treated pateints FEV 1, L, prealbuterol Treatment Day (0.20) 2.49 (0.20) Treatment Day (0.21) 2.70 (0.19)* PEF, L/min, A.M (26.5) (29.9) PEF, L/min, P.M (27.2) (29.1) Corticosteroid-naive patients FEV 1, L, prealbuterol Treatment Day (0.16) 2.76 (0.18) Treatment Day (0.14) 3.11 (0.16)* PEF, L/min, A.M (23.8) (23.0) PEF, L/min, P.M (24.2) (23.6) * Significant within-treatment difference from Day 1 to Day 28, p Significant between-treatment difference, p tients (Table 1); no differences were detected during administration of placebo. In the corticosteroid-treated patients, the change in prealbuterol FEV 1 from pretreatment on study Day 1 to Day 28 of therapy was significantly greater after treatment with salmeterol (mean change: 0.21 L) than after placebo ( 0.03 L; p 0.004). Likewise, in the corticosteroid-naive patients, the change in prealbuterol FEV 1 from pretreatment on study Day 1 to Day 28 of therapy was significantly greater after treatment with salmeterol (mean change: 0.36 L) than after placebo (0.000 L; p 0.020). After 4 wk of treatment with salmeterol or administration of placebo, albuterol produced significant increases in FEV 1 from predose values at all doses in both the corticosteroidtreated and corticosteroid-naive patient populations (p 0.001) (Figure 1). In both patient groups, significant increases from baseline values were maintained for 6 h after the last dose of albuterol with both treatment with salmeterol and administration of placebo (p 0.024) (with the exception of Hour 5 in the salmeterol group of corticosteroid-treated patients (p 0.055) (Figure 2). There were no significant differences in the albuterol dose response curves for changes in FEV 1 on study Day 1 versus Day 28 of therapy among recipients of salmeterol or placebo. There were also no significant differences between the salmeterol and placebo treatments for either patient population. Results for mean changes in FVC and FEF 25 75% in response to albuterol were similar to those for FEV 1 (data not shown). Asthma Exacerbations One corticosteroid-treated patient was withdrawn from the study because of an exacerbation of asthma during administration of placebo. The investigator reported that respiratory infection was the primary suspected cause of the exacerbation. Two corticosteroid-naive patients were withdrawn from the study because of asthma exacerbations, one during administration of placebo and one during salmeterol treatment. The investigator reported that respiratory infection was the primary suspected cause for the former withdrawal, whereas the latter was of unknown etiology. One additional corticosteroid-naive patient had an asthma exacerbation of unknown cause during administration of placebo, but was not withdrawn from the study. Heart Rate, Blood Pressure, and 12-Lead ECG There were no drug-related changes in patients heart rates or blood pressures during the study. There were also no overall clinically significant differences between treatments in ECG Figure 1. Mean SE FEV 1 (L) in response to cumulative doubling doses of albuterol before (Day 1) and after (Day 28) 4 wk of treatment with salmeterol (upper panel) or placebo (lower panel). ICS corticosteroid-treated; No ICS corticosteroid-naive; SAL salmeterol treatment; PBO placebo treatment. There were no significant differences between Day 1 and Day 28 in either group. results before treatment or after 28 d of treatment in either the corticosteroid-treated or corticosteroid-naive populations. After the final dose of albuterol on Day 28 of placebo administration, one corticosteroid-naive patient had an asymptomatic, nonspecific ST-T wave ECG abnormality that was considered clinically significant. Adverse Events The overall incidence of adverse events did not differ significantly with salmeterol treatment and placebo in either the corticosteroid-treated or corticosteroid-naive populations. The incidence of adverse events in the corticosteroid-treated population was 57% during administration of placebo and was 48% during salmeterol treatment. In the corticosteroid-naive population, the incidences of adverse events were 48% and 42% during placebo and salmeterol treatment, respectively. The

4 Nelson, Berkowitz, Tinkelman, et al.: Lack of Tolerance with Salmeterol 1559 Figure 2. Mean SE FEV 1 (L) for the 6 h after the last dose of albuterol. ICS corticosteroid-treated; No ICS corticosteroid-naive; SAL salmeterol treatment (upper panel); PBO placebo treatment (lower panel). There were no significant differences between Day 1 and Day 28 in either group. most frequently reported adverse event during the treatment periods was headache, 22% which occurred in and 26% of corticosteroid-treated patients during placebo and salmeterol treatment, respectively, and in 28% and 21% of corticosteroid-naive patients during placebo and salmeterol treatment, respectively. Dizziness was noted during administration of placebo and salmeterol treatment in 17% and 4% of corticosteroid-treated patients, respectively, and in 20% and 8% of corticosteroid-naive patients, respectively. There were no serious adverse events in either patient population. Two corticosteroid-naive patients were withdrawn because of adverse events (bronchitis and abnormal ECG, respectively) during administration of placebo. DISCUSSION The optimal assessment of tolerance to the bronchodilator effects of albuterol after treatment with salmeterol requires the

5 1560 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL inclusion of an adequate washout period for other 2 -agonists before beginning salmeterol treatment. This washout period ensures that tolerance has not already developed in response to previous treatment with other drugs of this class. The elimination of all 2 -agonists during such a study, including elimination of their use as rescue therapy, is also necessary to maintain a true placebo comparator. The inclusion of a cumulative dose response curve for assessing the bronchodilator response to a short-acting -agonist is also essential for thorough assessment of the peak and duration of response following prolonged treatment with salmeterol or administration of placebo. The studies reported here attempted to adequately control for several variables that could interfere with the assessment of bronchodilator tolerance. The design of the studies included a run-in period without 2 -agonist use, the use of cumulative doubling doses of albuterol, and the use of a non- 2 -agonist (ipratropium) as rescue medication. In addition, because of the data indicating a protective effect of corticosteroids in the development of tolerance to -agonists (18, 19), we evaluated bronchodilator tolerance in both corticosteroid-treated and corticosteroid-naive patients. The results of our studies indicate that tolerance to the bronchodilator response to albuterol does not develop after 4 wk of treatment with salmeterol at a dose of 42 g twice daily, irrespective of concurrent corticosteroid treatment. In this study neither the peak nor the duration of the albuterol dose-response as measured with the FEV 1 was significantly different at Day 28 of salmeterol treatment from the respective pretreatment baseline values on study Day 1 in either the corticosteroid-treated or corticosteroid-naive patient populations. The comparison of the albuterol response of salmeteroltreated subjects and those given placebo after 28 d of treatment also showed no significant difference. These results were very similar to those in a 6-mo study by Wilding and associates (24) that showed an identical final FEV 1 achieved with salmeterol and with placebo in an albuterol dose-response study, indicating that bronchodilator responsiveness is maintained after regular salmeterol treatment. Furthermore, significant increases in FEV 1 in response to cumulative doubling doses of albuterol persisted for 6 h after the last cumulative dose of albuterol in both the salmeterol and placebo treatment periods for both patient populations. Although the prospective albuterol dose-response assessments in our study found no significant differences in the change from baseline with salmeterol or placebo on Day 1 and Day 28, or in the change within treatments from Day 1 to Day 28, we also conducted a more sensitive, post hoc repeatedmeasures analysis (data not shown) in which we compared the areas under the albuterol dose response curves for placebo and salmeterol treatment on Day 1 and Day 28. These results also showed no difference in the curves. We therefore conclude that the response after 28 d of salmeterol therapy was not different from that on the pretreatment dose response curve, and that the albuterol dose-response following salmeterol was not different from that following placebo. These results are in contrast to those of a similarly designed study by Grove and Lipworth (17), which reported development of tolerance to the bronchodilator effects of albuterol after 4 wk of treatment with salmeterol in corticosteroid-treated patients, as assessed by a shift to the right in the albuterol dose response curve for changes from baseline in FEV 1. However, in their study, the mean baseline FEV 1 before the start of the albuterol dose-response assessment was higher after salmeterol treatment than after placebo. Because the amount of change in FEV 1 is physiologically limited by the maximal degree of bronchodilation that can occur, the analysis of change in FEV 1 from baseline on the same day, as done in Grove and Lipworth s study, may not reflect tolerance after salmeterol treatment, but rather a more limited potential for response in the salmeterol-treatment period. That the peak level of pulmonary function following administration of albuterol did not differ significantly in the placebo and salmeterol treatment periods also suggests this possibility. The present study analyzed the absolute value of FEV 1 at each point on the dose response curve, as well as for 6 h after the last dose of albuterol. No significant differences within treatments between Days 1 and 28 or between salmeterol and placebo were observed at any time, indicating that tolerance did not develop to the bronchodilator effects of albuterol after treatment with salmeterol. The findings in our studies support those in other controlled clinical trials in which the significant bronchodilator effects of salmeterol were maintained throughout 8 wk to 12 mo of treatment (14 16, 25 28). Salmeterol treatment for 4 wk was well-tolerated in our studies. No clinically notable differences were observed in the effects of salmeterol and placebo on heart rate, blood pressure, or 12-lead ECGs. The use of salmeterol is currently recommended in conjunction with inhaled corticosteroids (29), and previous studies have supported the use of salmeterol in conjunction with inhaled corticosteroids as a more effective alternative to increasing the inhaled corticosteroid dose alone (30, 31). The findings of the present studies support the safe and effective use of inhaled corticosteroids in conjunction with salmeterol. In conclusion, the results of these studies indicate that 4 wk of treatment with salmeterol does not produce tolerance to the bronchodilator effect of albuterol in patients with asthma, irrespective of concurrent corticosteroid treatment. The results of the present studies are particularly reassuring because of the frequency with which short-acting 2 -agonists such as albuterol are used in the treatment of acute, or breakthrough, asthma attacks. References 1. Taylor, D. R., M. R. Sears, and D. W. Cockcroft The beta-agonist controversy. Med. Clin. 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