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Villaran C, O'Neill SJ, Heibling A, et al. J Allergy Clin Immunol. 1999;104:547-553 ROBERT A. WOOD, MD Baltimore, [...], Purpose of the Study. Both montelukast, a leukotriene receptor antagonist, and salmeterol, a long-acting [Β.sub.2]-agonist, have been show to protect against exercise-induced bronchoconstriction (EIB) in short-term studies. This study was designed to compare these 2 agents in a longer term fashion for the treatment of EIB. Study Population. One hundred ninety-seven patients between the ages of 14 and 45 years with mild asthma and a positive response to an exercise challenge, defined as a postexercise decrease in forced expiratory volume in 1 second ([FEV.sub.1]) of at least 18%. Methods. Patients were randomized in a double-blind protocol to receive either montelukast 10 mg once-daily or salmeterol 50 µg twice-daily for 8 weeks. Exercise challenges were repeated at day 3 and weeks 4 and 8. The primary efficacy endpoint was the maximal percent decrease in postexercise [FEV.sub.1] at week 8. Results. The 2 drugs provided similar protection at day 3 but thereafter montelukast was superior. For example, at week 8 the maximal fall in [FEV.sub.1] after exercise was 15.9% for montelukast and 20.2% for salmeterol (P [is less than] .001), compared with 33.1% and 30.9% at baseline. In addition, clinical adverse events were significantly less common in the montelukast group. Conclusions. Montelukast was more effective than salmeterol in the chronic treatment of EIB over an 8-week period in patients with mild asthma. Montelukast may be a better alternative than salmeterol for the chronic treatment of EIB, especially in view of the lower rate of adverse events. Reviewer's Comments. For many years [Β.sub.2]-agonists have been considered the gold standard for the prevention of exercise-induced asthma. Although this should not be considered the final answer for all patients (and a similar study in children is absolutely necessary), the results of this comparative trial appear very significant. The control of EIB should be a goal for every child with asthma and the leukotriene antagonists may play an important role in achieving that goal. In addition, it is important to note that the most likely reason that the drugs were comparable at day 3 but different by week 4 is that patients may develop a tolerance to the effects of salmeterol with long-term use. This has been demonstrated in several previous studies and although there has been debate as to how clinically significant this may be, it certainly may be relevant to at least some of your patients.

Korosec M, Novak RD, Myers E, Skowronski M, McFadden ER Jr. Am J Med. 1999;107:209-213 ALLEN ADINOFF, MD Aurora, [...], Purpose of the Study. The present study was undertaken to determine whether regular use of salmeterol reduces the emergency effectiveness of albuterol. Patients and Methods. Acutely ill asthmatic patients chronically taking salmeterol, and similar patients who were not taking salmeterol, were treated with albuterol, either as 3 aerosols of 2.5 mg every 20 minutes for 1 hour or 2 doses of 5.0 mg every 20 minutes. Peak expiratory flow measurements were monitored before and after each treatment. The time to disposition and the number of return visits were also recorded. Results. One hundred fourteen patients, 57 who took salmeterol and 57 who served as control patients, completed the study. Thirty-three patients in each group received the lower dose of albuterol, and 24 were given the larger amount. There were no significant pretreatment differences between the salmeterol and control groups in the severity of symptoms or the degree of airway obstruction. Both albuterol regimens improved peak flow. Responses in the control group and in the salmeterol group were similar (low-dose albuterol increase in peak flow = 49%, control = 35%, P = .37; high-dose albuterol increment in peak flow = 43%, control = 41%, P = .81). There were no significant differences between the control group and the salmeterol group in the mean length of stay, the proportion of subjects admitted to the hospital, or the number of return visits. Conclusions. In patients with asthma, chronic use of salmeterol does not interfere with the effects of standard doses of albuterol for the treatment of acute decompensations. Reviewer's Comments. This study addresses important mechanistic and clinical questions which remain of concern to some: dose the prolonged use of long-acting Β-agonists impair the effectiveness of short-acting Β-agonists? The answer would appear to be: no. The clinical importance is obvious. Patients using long-acting Β-agonists such as salmeterol should receive similar benefit from short-acting bronchodilators for the treatment of attacks of asthma as those not previously taking salmeterol. Further comment on this study are found in an editorial in the same journal issue (Am J Med. 1999;107:283-285).

Condemi J, Goldstein S, Kalberg C, Yancey S, Emmett A, Rickard K, Salmeterol Study Group. Ann Allergy Asthma Immunol. 1999;82:383-389 HELEN SKOLNICK, MD ROBERT A. WOOD, MD Baltimore, [...], Purpose of the Study. To evaluate the efficacy and safety of adding salmeterol to patients who remain symptomatic while receiving fluticasone propionate (FP) as compared with increasing the dose of FP. Study Population. Four hundred thirty-seven patients, aged 12 years or older, who had reversible airways disease as demonstrated by a 15% or greater increase in forced expiratory volume in 1 second ([FEV.sub.1]) from baseline after inhalation of 180 µg of albuterol, or an [FEV.sub.1] of 40% to 80% of predicted value. The patients were enrolled if they had asthma for at least 6 months and had used a short-acting bronchodilator on a regular basis for at least 3 months. Methods. Thirty-six research centers enrolled the 437 patients whom, after a 2- to 4-week screening, participated in a 24-week randomized, double-blind, double-dummy parallel-group treatment period. During the screening, all patients used 88 µg of open-label FP twice daily and albuterol as needed. After, this dose of FP was continued and the patients were randomly assigned to receive either salmeterol (42 µg twice daily) or FP 220 µg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures including [FEV.sub.1], symptom scores, nighttime wakenings, and supplemental albuterol use. Safety was assessed by adverse events and asthma exacerbations. Results. The addition of salmeterol resulted in a significantly greater improvement in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline as compared with 24 L/min with FP 220 µg twice daily (P [is less than] .001), while the percent of symptom-flee days increased from baseline by 26% as compared with 10% of days (P [is less than] .001). The adverse event profiles were similar between groups while fewer exacerbations were reported with salmeterol treatment. Conclusions. The addition of salmeterol is clinically and statistically superior to increasing the dose of FP in patients who remain symptomatic while using low-dose FP. Reviewer's Comments. This was a well-done study that examined the clinical benefits of adding salmeterol to low-dose FP versus increasing the dose of FP. The addition of salmeterol was clearly superior to increasing the dose of FP. Because higher dose inhaled corticosteroids may reduce growth rates, it is important to consider additive therapy in children and adolescents rather than simply increasing steroid doses. Similar effects may be seen with leukotriene antagonists and theophylline, although no studies comparing these different medications have been done. Although compliance may suffer when additional medications are added, this disadvantage of combination therapy will soon be overcome by the introduction of inhalers that combine inhaled steroids and long-acting Β-agonists. The first of those, which will be available later this year, actually combines the 2 medications used in this study.