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The beta agonist drug salmeterol can prevent pulmonary edema in mountain climbers, according to a study of 37 people. Pulmonary edema occurs when fluid collects in the lungs. It often occurs at high altitudes. It may be caused by a defect in the mechanism that removes excess water from the lungs.

Salmeterol may lose its effectiveness in preventing exercise-induced bronchoconstriction in asthma patients when it is taken long-term. Researchers measured lung function 30 minutes after the morning dose of salmeterol and nine hours later in 20 patients who took the drug or a placebo twice a day. Lung function was measured while the patients exercised on a stationary bicycle. Compared to placebo, the drug reduced the degree of bronchoconstriction, but as the 30-day study progressed, the drug became less effective.

Inhaled salmeterol may effectively control asthma in children, with no apparent effect on the child's growth. Salmeterol is a beta 2-agonist which was compared to the corticosteroid beclomethasone or a placebo in 241 patients. Beclomethasone reduced airway reactivity and effectively controlled asthma, but was associated with a smaller increase in height over one year. Salmeterol dilated breathing passages, but was less effective in reducing airway reactivity. However, it did not appear to affect height. Choosing medication in mild asthma may require balancing symptom control and height effects.

Salmeterol xinafoate appears to be more effective than albuterol as maintenance therapy for asthma. Salmeterol is a long-acting inhalant designed to inhibit asthma symptoms. Albuterol is a short-acting inhalant designed for the same purpose. A total of 322 asthmatics were randomly assigned to treatment with either two daily doses of salmeterol, four daily doses of albuterol or four daily doses of placebo. All patients used albuterol as needed to control breakthrough asthma symptoms. Those taking salmeterol twice daily for 12 weeks experienced more consistent ease of breathing between doses than those taking albuterol four times daily. Those taking salmeterol also experienced fewer nighttime breathing complications and no statistically significant change in heart rate. Furthermore, the effectiveness of salmeterol was the same at week 12 as it was in the beginning of treatment. The prevalence of adverse side effects such as palpitations, headaches and other body pains were similar for both salmeterol and albuterol., Objective.--To compare the efficacy and safety of inhaled salmeterol xinafoate, a long-acting [[beta].sub.2]-adrenoceptor agonist, with that of albuterol, a short-acting inhaled [[beta].sub.2]-agonist, in the treatment of asthma. Design.--Randomized, double-blind, placebo-controlled, parallel-group study. Setting.--Eleven outpatient clinical centers. Subjects.--A total of 322 male and female patients at least 12 years of age with chronic symptomatic asthma requiring daily therapy. Intervention.--Patients were treated with salmeterol xinafoate (42 [mu]g inhaled twice daily), albuterol (180 [mu]g inhaled four times daily), or placebo (four times a day) for 12 weeks; patients in all three groups could use inhaled albuterol as backup medication for breakthrough symptoms. Main Outcome Measures.--Serial 12-hour forced expiratory flow in 1 second ([FEV.sub.1]), peak expiratory flow (PEF), asthma symptoms, nocturnal awakenings due to asthma, episodes of asthma exacerbations, and electrocardiography. Results.--The mean area under the curve for [FEV.sub.1] throughout each 12-hour period was consistently greater after a single dose of salmeterol than after two doses of albuterol administered 6 hours apart (P

Giving asthma patients a beta-agonist drug in addition to an inhaled corticosteroid may allow doctors to reduce the dose of the corticosteroid, according to a study of 175 patients. However, eliminating the corticosteroid altogether may cause a worsening of symptoms.

Beta-agonist drugs may not be as effective as inhaled corticosteroids in the treatment of asthma, according to a study of 164 patients. The patients were randomly assigned to take either the beta-agonist drug salmeterol or the inhaled corticosteroid triamcinolone.

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.

MARY BETH BOLLINGER, DO Baltimore, [...], Purpose of the Study. To compare inhaled salmeterol powder to oral montelukast in patients with persistent asthma who are not well-controlled on inhaled corticosteroids (ICS). Study Population. Male and nonlactating, nonpregnant females ≥ 15 years of age with the diagnosis of asthma for at least 6 months were recruited from 71 private and university clinics in the United States and Puerto Rico. The group included 948 subjects (61% female, 85% Caucasian). All subjects were symptomatic with their asthma for at least 6 weeks before screening and at a constant dose of ICS for 30 days before screening. Baseline forced expiratory volume in 1 second (FE[V.sub.1]) was 50% to 80% and all subjects had at least 12% improvement in FE[V.sub.1] postbronchodilator. Methods. Two multicenter, randomized, double-blind, parallel-group clinical trials were conducted comparing 50 µg bid of salmeterol by dry powder inhaler (n = 476) versus 10 mg po daily of montelukast (n = 472). All subjects underwent baseline history and physical, and pulmonary function tests including FE[V.sub.1] reversibility. After a 7-to 14-day run-in period to assess symptoms, diary card completion, and patient proficiency with inhaler use, patients whose FE[V.sub.1] remained within 50% to 80% of normal were eligible for enrollment. Subjects also had to meet at least 1 of the following criteria during the 7 days before randomization: use of an average of ≥ 4 puffs per day of albuterol, a symptom score of ≥ 2 on ≥ 3 days, and/or ≥ 3 nights of nocturnal asthma symptoms. The subjects remained on their current ICS dose throughout the study and rescue albuterol, but no other asthma medications were allowed other than study drug. Subjects were asked to record am and pm peak flows (PEF), nocturnal awakenings, albuterol use, asthma symptoms, and daily study drug use. Symptoms were rated using a 5-point scale and were targeted to affects on activity level. Subjects returned for assessments at 1, 4, 8, and 12 weeks of treatment. The subjects completed a satisfaction survey at the end of the 12-week study. Results. A total of 476 subjects received inhaled salmeterol and 472 received montelukast. The treatment groups had similar demographics and disease characteristics at baseline, with 61% women, >80% Caucasian, >70% with asthma ≥ 10 years, mean baseline FE[V.sub.1] 68% of predicted, and mean baseline PEF of 370 1/m. Morning PEF in the salmeterol treated group increased more significantly (mean = 35 l/m) than the montelukast treated group (mean = 21.7 l/m). The bronchodilator properties of salmeterol were superior than montelukast over all treatment weeks. Patients in the salmeterol group had a significantly greater increase in symptom-free days than the montelukast group (24% vs 16%; P < .001). Symptom scores for all parameters except wheezing were significantly improved in the salmeterol group vs the montelukast group. Subjects in the salmeterol group used significantly less rescue albuterol than the montelukast group. Regarding patient satisfaction with the drug, the salmeterol group had greater satisfaction other than in how long the medication worked, where there was no difference in scores. The number of asthma exacerbations and the number of adverse events was similar in both groups, with 13 in each group withdrawing from the study because of adverse events. Conclusion. The addition of salmeterol in moderate to severe persistent adult asthmatics poorly controlled on ICS was superior to the addition of montelukast in improvement in PEF and overall symptom control. Reviewer's Comments. The addition of inhaled salmeterol in subjects who were not adequately controlled on ICS showed significantly greater improvement in lung function and control of symptoms (other than wheezing) compared with oral montelukast. Other groups have compared salmeterol as an additive agent versus doubling the ICS dose and versus another leukotriene modifier, but not all in that study were on baseline ICS. Future studies are needed to determine if these findings will hold true over longer study periods and whether either long-acting β-agonists or leukotriene modifiers have a bearing on the natural history of asthma. In addition, similar studies in children are needed to see if the same patterns of response occur in all age groups. Fish JE, Israel E, Murray JJ, et al. Chest. 2001;120:423-430

ALAN B. GOLDSOBEL, MD San Jose, [...], Purpose of the Study. To determine whether inhaled corticosteroid (ICS) therapy can be reduced or eliminated in patients with persistent asthma after adding a long-acting [β.sub.2]-agonist to their treatment regimen. Study Population. Four hundred twenty-two patients ages 12 through 65 years, entered a common 6-week run-in period for 2 companion studies--Salmeterol or Corticosteroids (SOCS) and Salmeterol ± Inhaled Corticosteroids (SLIC). Three hundred sixty-one patients completed the run-in period of treatment with inhaled triamcinolone acetonide (400 µg twice daily). One hundred sixty-four patients achieved good asthma control according to preestablished clinical and pulmonary function criteria and were entered into the SOCS trial. One hundred seventy-five patients did not achieve good asthma control and were entered into the SLIC trial. Methods. This was a 24-week, randomized, controlled, blinded, double-dummy, parallel group trial conducted at 6 National Institutes of Health (NIH)-sponsored, university-based ambulatory care centers over a 2-year period. Patients continued on triamcinolone therapy in the same dose of 400 µg twice daily. Blinded, add-on therapy was then done with either placebo (n = 21) or salmeterol 42 µg twice daily (n = 154) for 2 weeks at stable doses. Next was an ICS reduction phase over the next 8 weeks as all 21 patients on triamcinolone plus placebo were assigned to receive half the dose of triamcinolone 200 µg twice daily plus continued placebo (placebo-minus group). Patients on full dose ICS plus salmeterol were randomized to either continue on that same dose (salmeterol-plus group) or to continue on salmeterol with half the dose of ICS 200 µg daily (salmeterol-minus group). Last was an 8-week ICS elimination phase. The placebo-minus group (previously on ICS 200µg bid plus placebo salmeterol) were assigned to receive placebo ICS and placebo salmeterol. The salmeterol-minus group (receiving a half dose of ICS plus salmeterol) were changed to placebo ICS plus salmeterol. The salmeterol-plus group (receiving a full dose of ICS plus a full dose of salmeterol) continued on that same dose (active control group). The main outcome measure was timed to asthma treatment failure (specifically defined by parameters of pulmonary function and/or clinical deterioration) in patients receiving salmeterol. Results. Treatment failure occurred in 8.3% of the salmeterol-minus group 8 weeks after ICS treatment was reduced compared with 2.8% of the salmeterol-plus group (active control group, full dose) when the dose of ICS was not changed. Subsequent treatment failure occurred in 46.3% of the salmeterol-minus group 8 weeks after ICS therapy was eliminated compared with 13.7% of the salmeterol-plus group (active control group, full dose). The relative risk of treatment failure at the end of the ICS elimination phase in the salmeterol-minus group (plus placebo ICS) was 4.3% compared with the salmeterol-plus group (active control group, full dose). Secondary outcome measures included a lower mean presalmeterol forced expiratory volume in 1 second (FE[V.sub.1]) in the salmeterol-minus group versus the salmeterol-plus group and decreased salmeterol-protected methacholine response was less in the salmeterol minus versus the salmeterol plus group. Conclusions. In patients with persistent asthma suboptimally controlled by triamcinolone therapy alone, but whose asthma symptoms improve after addition of salmeterol, a 50% reduction in ICS dose can occur without a significant loss of asthma control. However, total elimination of ICS therapy results in a significant deterioration of asthma control as well as decline in pulmonary function and loss of bronchoprotection. Reviewer's Comments. This study is entirely consistent with the current consensus that although salmeterol may improve asthma control when given along with an inhaled steroid and provide significant steroid-sparing effects. In addition, it supports the notion that salmeterol should not be used as monotherapy for persistent asthma. Lemanske R, Sorkness C, Mauger E, et al. JAMA. 2001; 285:2594 -2603

MARY BETH BOLLINGER, DO Baltimore, [...], Purpose of the Study. To evaluate the effect of salmeterol on allergen-induced airway inflammation. Study Population. Sixteen atopic patients with mild asthma (10 male, 6 female) >18 years (mean 25.2) old with diagnosis of asthma for at least 6 months. The subjects had stable asthma for at least 1 month and baseline forced expiratory volume in 1 second (FE[V.sub.1]) >70% (mean: 95%). Subjects had to have a late asthmatic response (LAR) to an allergen inhalation challenge, defined as a 15% decrease in FE[V.sub.1] between 2 and 8 hours after challenge. Patients had to be off of oral or inhaled steroids and any other antiinflammatory medications for at least 1 month before the study. Methods. The study was a randomized, double-blind, cross-over trial. The subjects underwent baseline allergen skin testing with titration to determine the specific allergen and dose to use for the inhalation challenge. Baseline FE[V.sub.1] was performed and inhalation challenge was performed to document early asthmatic response (EAR) and LAR. After a 2-week run-in without medication other than rescue albuterol, the subjects underwent a saline challenge a day before randomization. Subjects were randomized to receive either salmeterol 50 µg daily or 1 week of inhaled placebo. They were also allowed to use rescue salbutamol and record the use on diary cards. A 2-week washout period separated the 2 cross-over treatment periods. Subjects recorded asthma symptoms and medication usage on diary cards and had spirometry and methacholine (Mch) challenges before and at the end of each treatment period 24 hours after holding the study medication. They also underwent bronchoalveolar lavage (BAL) and bronchial biopsies 24 hours after an allergen challenge. The allergen challenges were performed before the run-in period and each allergen challenge was preceded the day before by an Mch challenge. Salmeterol or placebo was given on the day of the challenge and bronchoscopy. Allergen challenges were performed with increasing allergen doses until the FE[V.sub.1] dropped >15% or until the maximum dose was reached, and subjects had repeated spitrometry up to 8 hours postchallenge. Results. All 16 subjects completed the study. The mean baseline Mch PC20 (Mch dose causing a 20% decrease in FE[V.sub.1]) was 1.53 ± 1.28. The mean percentage drop in FE[V.sub.1] after allergen challenge for EAR was 28.7 ± 1.7% and for LAR was 24.6 ± 1.8%. Mean PC20 after placebo was 1.15 ± 1.34 and after salmeterol was 2.20 ± 1.31 (P = .009). Salmeterol significantly inhibited the decrease in FE[V.sub.1] during EAR compared with placebo, but LAR was similar between the 2 groups. There was no significant difference in BAL macrophage, lymphocyte, neutrophil, and eosinophil counts 24 hours after allergen challenge in the 2 treatment groups. However, the salmeterol treated group showed an increase in a number of inflammatory cells on bronchial biopsies after allergen challenge compared with placebo. Conclusion. This study found an increase in lung mast cells and total leukocyte counts from bronchial biopsies obtained 24 hours after allergen exposure from allergen sensitized asthmatics taking salmeterol regularly for 1 week versus those taking placebo. Reviewer's Comments. This study showed an increase in inflammatory cells from bronchial biopsy 24 hours after antigen challenge in asthmatic subjects taking salmeterol for 1 week as monotherapy, versus those taking placebo control. Although salmeterol can improve baseline spirometry and reduce airway responsiveness to allergen, this study suggests that when used alone, salmeterol may be associated with mild increased allergen-induced airway cellular responses. Others studies have found some conflicting effects of salmeterol on various inflammatory markers, both in the serum, BAL fluid, and bronchial biopsies. Compared with inhaled corticosteroids, when used as monotherapy, long-acting β-agonists have been associated with increased frequency of asthma exacerbations. These results support the concomitant use of inhaled corticosteroids with long-acting β-agonists. Boulet L-P, Chakir J, Milot J, Boutet M, Laviolette M. Clin Exp Allergy. 2001;31:430-437