Zafirlukast

A Randomized Double-Blind, Placebo-Controlled Trial

* OBJECTIVE The objective of our study was to compare the efficacy and safety of fluticasone propionate (an inhaled corticosteroid) with zafirlukast (a leukotriene modifier) for persistent asthma.

* STUDY DESIGN In this randomized placebo-controlled, parallel-group, double-blind, double-dummy trial, patients underwent an 8- to 14-day run-in period followed by 12 weeks of treatment with inhaled fluticasone propionate (88 [micro]g twice daily by metered-dose inhaler), oral zafirlukast (20 mg twice daily), or placebo.

* POPULATION We included a total of 338 persistent asthma patients, 12 years of age or older, using short-acting [[Beta].sub.2]-agonists alone.

* OUTCOMES MEASURED Efficacy outcomes included changes in pulmonary function, asthma symptoms, rescue albuterol use, nighttime awakenings due to asthma, and quality of life. Safety outcomes included asthma exacerbations, adverse events, and clinically significant laboratory test results.

* RESULTS After 12 weeks of treatment, patients taking fluticasone propionate experienced significantly greater improvements in all clinical parameters (symptom scores, percentages of symptom-free and albuterol-free days, albuterol use, and nighttime awakenings) compared with patients taking zafirlukast (P [is less than] .05) or placebo (P [is less than] .05). Treatment with fluticasone propionate resulted in significantly greater improvements in pulmonary function compared with zafirlukast (P [is less than] .05) or placebo (P [is less than] .05). Fewer fluticasone propionate patients (4%) had an exacerbation requiring oral corticosteroids compared with those taking zafirlukast (12%) or placebo (10%).

* CONCLUSIONS Inhaled fluticasone propionate is more effective than zafirlukast in controlling asthma symptoms, improving pulmonary function, and improving quality of life for patients who are symptomatic with the use of short-acting [[Beta].sub.2]-agonists alone.

* KEY WORDS Persistent asthma; inhaled corticosteroids; fluticasone propionate; leukotriene modifier; zafirlukast. (J Fam Pract 2001; 50:595-602)

Asthma, a chronic inflammatory disorder of the airways, affects approximately 17.3 million people in the United States, with more than 5000 deaths per year attributed to the disorder.[1] National Institutes of Health (NIH) guidelines for asthma management recommend that patients with persistent asthma (ie, patients having symptoms more than twice weekly) receive daily medication for long-term control of asthma.[1] These guidelines consider inhaled corticosteroids the most effective controller medication for persistent asthma.

Recently, leukotriene modifiers have been introduced as a new class of asthma medications. NIH guidelines include leukotriene modifiers as potential alternative controller medications for mild, persistent asthma.[1] However, the guidelines also state that additional data are needed to establish the role and position of leukotriene modifiers in asthma therapy. To date, there have been few published reports of placebo-controlled clinical trials comparing the efficacy, safety, and quality of life in asthma patients treated with an inhaled corticosteroid versus a leukotriene modifier.

This study assessed the clinical benefits of an inhaled corticosteroid and a leukotriene modifier as first-line treatment for persistent asthma in patients who were symptomatic when using short-acting [[Beta].sub.2]-agonists alone.

METHODS

Patients

Patients aged 12 years old or older with asthma[2] were eligible if they had used a short-acting [[Beta].sub.2]-agonist (either scheduled or as-needed) for at least 6 weeks preceding the study, if they had a 1-second forced expiratory volume ([FEV.sub.1]) between 50% to 80% of predicted values,[3-5] and if they demonstrated reversibility of [FEV.sub.1] ([is greater than or equal to] 12% increase within 30 minutes after inhaling 180 [micro]g albuterol). Patients were excluded from the study if they had life-threatening asthma, significant and uncontrolled diseases (eg, chronic obstructive pulmonary disease, diabetes, coronary disease), used tobacco products within the preceding year, or had a smoking history of more than 10 pack-years. Patients were also excluded if they received any systemic corticosteroid within 6 months of screening, any inhaled corticosteroid within 1 month of screening, or any leukotriene modifier within 1 week of screening.

Study Design

This randomized double-blind, double-dummy, parallel-group study was conducted at 34 sites in the United States. All patients (or their parent or guardian) gave written informed consent before entering the study. The study was approved by institutional review boards for each site.

Eligible patients entered an 8- to 14-day run-in period to establish baseline respiratory function. Patients who met the study criteria were randomly assigned to receive 1 of the following double-blind, double-dummy treatments every morning and evening for 12 weeks: (1) 88 [micro]g fluticasone propionate (FP [Flovent Inhalation Aerosol], 2 puffs of 44 [micro]g each) administered by metered-dose inhaler (MDD and a placebo capsule; (2) oral zafirlukast 20 mg (Accolate over-encapsulated tablet) and 2 puffs of placebo by MDI; or (3) a placebo capsule and 2 puffs of placebo by MDI. The zafirlukast dosage (20 mg twice daily) is the currently recommended dosage for patients aged 12 years or older, and 88 [micro]g FP twice daily is the lowest FP dosage delivered by MDI approved for use in adolescents and adults. Treatment assignments were generated by computer in blocks of 6 so that each of the 3 treatments was represented twice in random order.

Before initiating the study, comparative dissolution testing was performed to determine whether overencapsulation would affect the bioequivalence of the blinded zafirlukast tablets. The dissolution profiles were the same for the over-encapsulated (blinded drug) and the trade product. Empty capsules were also tested, and complete dissolution and disintegration of the capsules occurred within 5 minutes.

Patients were instructed to inhale 2 puffs from their study MDI each morning and evening and to swallow 1 study capsule each morning at least 1 hour before breakfast, and each evening at least 2 hours following dinner. The timing of administration of study capsules was based on the limited absorption of zafirlukast when given with food. Patients were instructed to rinse their mouths with water after using the MDI. Patients were not allowed to take any asthma medication during the study other than the study medication, albuterol (Ventolin Inhalation Aerosol) as needed for symptom relief, or oral or parenteral corticosteroids for asthma exacerbations. The use of medications that interact with inhaled corticosteroids or leukotriene modifiers was not allowed. Patients who experienced 2 exacerbations (eg, required a second burst of oral corticosteroids) or received oral or parenteral corticosteroids for more than 14 consecutive days were withdrawn from the study.

Assessments of Efficacy and Safety

The primary physiologic efficacy measure was morning predose [FEV.sub.1]. Other efficacy measures included patient-recorded morning (AM) and evening (PM) peak expiratory flow (PEF). Patient-oriented outcomes included asthma symptom scores, percentage of symptom-free days, albuterol use, percentage of albuterol-free days, and nighttime awakenings due to asthma symptoms; physicians' overall assessment of medication effectiveness, and patient questionnaires concerning asthma-specific quality of life, productivity, and satisfaction with study medication. Safety assessments included the incidences of asthma exacerbations, adverse events, and pre-defined, clinically significant, laboratory test results.

[FEV.sub.1] was assessed at each clinic visit between 6 AM and 10 AM.[6] Morning doses of study medications were withheld before each clinic visit, and the visit was rescheduled if the patient used albuterol within 6 hours preceding the visit. Before taking study medications, patients recorded on a diary card any asthma symptoms experienced, using a 6-point scale (where 0 = no symptoms and 5 = symptoms caused severe discomfort and prevented normal activities). After recording symptoms, patients measured and recorded their PEF, along with the number of puffs of albuterol used and the number of nighttime awakenings due to asthma. Patients reported study medication compliance daily on the diary card. Adverse events, concurrent medications, and diary cards were reviewed at each clinic visit. Laboratory tests were performed at the beginning of the run-in period and at the patient's last visit.

At the last clinic visit, following a review of diary cards and the status of each patient, physicians rated the overall effectiveness of each patient's blinded study medication using a 4-point scale (where 0 = ineffective and 3 = very effective). At weeks 2 and 12, patients assessed their overall satisfaction with study medication using a 7-point scale (where 0= very dissatisfied and 6 = very satisfied) and completed the Asthma Quality of Life Questionnaire (AQLQ),[7] which measures the impact of asthma on patients' daily functioning. At weeks 2, 4, 6, 8, and 12, patients documented their productivity (days missed from work or school and days with symptoms at work or school) over the previous 2 weeks.

Statistical Analyses

The sample size ([is greater than or equal to] 100 patients completing each treatment) provided [is greater than or equal to] 80% power to detect a difference in [FEV.sub.1] of 0.25 L between treatment groups, according to a 2-sample t test with a significance level of 0.05 and a standard deviation of 0.55 L. All patients randomly assigned to the Study drug were included in the safety analyses. Nine patients at 1 site were excluded from the efficacy analyses because of significant deviations from good clinical practice standards.

Change from baseline was calculated at each clinic visit and at the last available observation for [FEV.sub.1]. For each subject-recorded assessment from the diary card, weekly means were calculated for each patient, and change from baseline (baseline = mean of last 7 days' data from run-in) was calculated at each week and at the endpoint (endpoint = mean of last available weekly data). Onset of effect was evaluated as change in daily AM PEF from day of randomization. Changes from baseline in global AQLQ and the individual domain scores were computed at the endpoint (endpoint = last available questionnaire). Analyses of covariance adjusted for investigator effect and included the baseline value as a covariate. Analysis of covariance F tests were used to evaluate treatment differences in all change from baseline values.

Cochran-Mantel-Haenszel tests, controlling for investigator, were used to determine treatment differences in physicians' overall assessment of efficacy (at endpoint), in patient satisfaction with study medication (at week 2 and endpoint), and in the number of patients in each treatment group with at least 1 asthma exacerbation requiring oral or parenteral corticosteroids. Van Elteren tests were used to assess patient productivity.

RESULTS

Patients

A total of 338 patients, 12 to 75 years of age, were randomly assigned to treatment (113, FP; 111, zafirlukast; 114, placebo). Equal numbers of men and women were enrolled in the study, and the majority of patients were non-Hispanic white (86%) or African American (10%). Baseline pulmonary function (% of predicted [FEV.sub.1]) was similar across treatment groups (66%-57% predicted). The majority of patients in each treatment group had moderate asthma (77%, FP; 82%, zafirlukast; 18%, placebo), and most patients in each treatment group had asthma diagnosed for at least 10 years (64%-73%). A post hoc survey of patients revealed that the majority of respondents (149 of 286 patients; 52%) were recruited from primary care practices for the purpose of the study or were treating their asthma with over-the-counter bronchodilators. Similar numbers of patients in each group completed the study (81%, 86% of patients). The most common reasons for discontinuation were lack of efficacy (2%-5%) and withdrawn consent (3%-5%). Median compliance was 93% in each group for both inhaled and oral study medication.

Efficacy

Treatment with FP significantly improved pulmonary function more than zafirlukast or placebo. At the endpoint (Table 1) and at individual points as early as day 4 (Figure 1), mean improvements in [FEV.sub.1] and in AM PF and PM PEF were significantly greater in the FP group compared with the zafirlukast or placebo group (P [is less than] .05). When stratified by baseline pulmonary function (% predicted [FEV.sub.1]), mean changes in [FEV.sub.1] and PM PEF were significantly greater in FP patients than in zafirlukast or placebo patients, regardless of baseline pulmonary function (Table 2).

[GRAPH OMITTED]

At the endpoint, treatment with FP significantly improved all clinical parameters (mean symptom scores, percentages of symptom-free and albuterol-free days, albuterol use, and nighttime awakenings due to asthma) compared with placebo (P [is less than or equal to] .006, Table 1). In contrast, treatment with zafirlukast resulted in significant improvements in albuterol use and the percentage of symptom-free and albuterol-free days (P [is less than or equal to] .040, vs placebo), but not in mean symptom scores or the number of nighttime awakenings. Compared with zafirlukast at the endpoint, FP produced significantly greater improvements in mean symptom scores, the percentages of symptom-free and albuterol-free days, albuterol use, and the number of nighttime awakenings due to asthma (P [is less than or equal to] .038). When compared with placebo at individual time points, FP produced significantly greater improvements in each clinical parameter at most or all time points (P [is less than or equal to] .039). In contrast, treatment with zafirlukast resulted in fewer time points with significantly different improvements in these parameters compared with placebo. Compared with zafirlukast, FP produced significantly greater improvements in mean symptom scores, the percentages of symptom-free and albuterol-free days, albuterol use, and nighttime awakenings due to asthma at the majority of time points from week 2 through week 12 (P [is less than or equal to] .050).

At the endpoint, physicians' overall assessments of study medication efficacy and patients' overall satisfaction with study medication both significantly favored FP over zafirlukast (P [is less than or equal to] .025) or placebo (P [is less than] .001; Figure 2). More physicians rated FP "effective" or "very effective" compared with zafirlukast or placebo. Likewise, more FP patients were "satisfied" or "very satisfied" with their study medication than were patients taking zafirlukast or placebo. The patient productivity questionnaire data showed that the mean number of days that patients attended work or school with asthma symptoms was significantly higher in the zafirlukast and placebo groups than the FP group (3.8, 4.4, and 1.8 days, respectively, P [is less than or equal to] .03).

At the endpoint, treatment with FP produced significantly greater improvements in global and individual domain AQLQ scores compared with zafirlukast or placebo (P [is less than or equal to] .033; Figure 3). Furthermore, treatment differences between FP and placebo for global and most individual domain AQLQ scores are considered clinically meaningful ([is greater than or equal to] 0.5).[8] In contrast, zafirlukast did not achieve clinically meaningful differences compared with placebo for any AQLQ endpoint.

Safety

The percentages of patients who experienced at least 1 adverse event were similar across treatment groups (67% to 72%). More FP patients reported sinusitis (12%, vs 4% with zafirlukast and 4% with placebo), and more zafirlukast patients reported chest congestion (5%, vs [is less than] 1% with FP and 0 with placebo). Oropharyngeal candidiasis was reported for 2 placebo recipients and 3 FP patients. Few patients experienced adverse events potentially related to study medication (12% to 13% of each group). The most common adverse events considered potentially related to study medication were throat irritation (FP: 4% of patients; zafirlukast and placebo: 3% each) and headache (FP: 3%; placebo and zafirlukast: 2% each). Two patients in the FP group and 1 patient in the zafirlukast group and 1 patient in the placebo group discontinued study treatment because of adverse events possibly related to study medication (FP: diarrhea, coughing and hoarseness; zafirlukast: increase in [Gamma]-glutamyltransferase [GGT; other hepatic enzyme levels were not elevated]; placebo: light-headedness and shakiness). The only adverse events requiring hospitalization occurred in the placebo group. Few clinically significant laboratory abnormalities ([is less than or equal to] 3% for any assay) were reported; none were considered related to study medication. Fewer FP patients experienced asthma exacerbations that required treatment with oral corticosteroids compared with zafirlukast or placebo patients (4%, 12%, and 10% of patients, respectively); treatment differences, however, were not statistically significant.

DISCUSSION

The goals of asthma therapy are to prevent asthma symptoms, maintain normal activity levels, normalize lung function, meet patients' expectations and satisfaction, and provide optimal therapy with minimal adverse effects.[1] For patients with persistent asthma, daily controller medications are recommended.[1] The results of our study indicate that, compared with zafirlukast or placebo, treatment with FP resulted in greater improvements in patients' symptoms, quality of life, and overall satisfaction, as well as less albuterol use, fewer nighttime awakenings, and better pulmonary function. Furthermore, fewer FP patients experienced an asthma exacerbation compared with zafirlukast or placebo patients. Improvements in the zafirlukast group were generally similar to improvements reported in previous placebo-controlled trials with zafirlukast.[9,10]

In our study, differences between FP and zafirlukast were seen early, and those differences generally persisted throughout the 12-week treatment. Treatment effects that favored FP were seen for all clinical endpoints by week 2, while differences in pulmonary function that favored FP were noted by day 4 of treatment. The rapid improvements noted with FP in our study are consistent with previously published results.[11] In the current study, patients treated with FP continued to improve with each subsequent week of treatment, while improvements with zafirlukast generally peaked after 2 weeks, of treatment. Although the percentage of symptom-free days in the zafirlukast group appeared to increase in the last 4 weeks of the study, this may be related to the higher withdrawal rate during this period. Patient-rated outcomes support the clinical findings. Significant differences between FP and zafirlukast occurred by week 2 with quality of life, patient satisfaction, and days worked with asthma symptoms. The treatment effects noted in this study may be related to the rapid onset of action of fluticasone[11] and may result in improved compliance and better long-term asthma control.

Preventing recurrent exacerbations and minimizing the need for emergency department visits or hospitalizations is an important goal in asthma therapy.[1] The low incidence of exacerbations in the FP group in our study is consistent with data from previous clinical trials.[12-14] With regard to the frequency of asthma exacerbations in patients receiving leukotriene modifiers, available data demonstrate that zileuton, zafirlukast, and montelukast each significantly decrease the risk of asthma exacerbations compared with placebo.[10,15-17] Although leukotriene modifiers are superior to placebo in reducing the risk of asthma exacerbations, the results of our study indicate that patients receiving an inhaled corticosteroid had fewer asthma exacerbations than those receiving a leukotriene receptor antagonist. These data are in agreement with an earlier placebo-controlled, comparative study.[17]

A significant placebo effect was seen with [FEV.sub.1] in our study and is similar to observations from other FP studies.[18,19] In our study, the placebo effect was larger in patients with a percent predicted [FEV.sub.1] of more than 70% at baseline. One possible explanation for this is regression to the mean, since patients typically present for care when their symptoms are worst. Another is that milder patients are affected more by the additional medical attention received in clinical studies or that participation in a clinical study influenced patients to avoid asthma-triggering events. The placebo effect was strongest with the spirometric endpoints, for reasons that are unclear. Regardless of the magnitude of the placebo response, the differences in our study between placebo and each active treatment are consistent with the differences seen in other studies involving FP or zafirlukast.[18,20]

Because asthma involves chronic inflammation of the airways, the NIH guidelines recommend long-term controller medications with anti-inflammatory effects. In the present study, an inhaled corticosteroid and a leukotriene modifier both led to improvements in pulmonary function. However, FP continued to improve pulmonary function throughout the 12-week study, while the benefits of zafirlukast tended to plateau by week 2 of treatment. Although the precise mechanism of action of glucocorticoids in asthma is unknown, the greater degree of effectiveness seen with FP in the present study may be related to the multiple effects of inhaled corticosteroids on airway inflammation.[21] A post hoc analysis of the patient population stratified by baseline pulmonary function (% predicted [FEV.sub.1] of 50% to 70% or 70.1% to 80%) showed that, regardless of baseline lung function, FP was more effective than zafirlukast or placebo with regard to improvement in albuterol use and pulmonary function. These data are consistent with asthma guidelines, which recommend inhaled corticosteroids as first-line treatment for all levels of persistent asthma.[1]

Limitations

The design of our study has several potential limitations. First, several studies indicate that dosages of zafirlukast higher than 20 mg twice daily may result in greater pharmacologic results.[22-26] Our study, however, was performed in the United States, where this is the only approved dosage for zafirlukast. Second, outcomes were measured at the end of the dosing interval, before administration of morning dosages of study medication. The timing of these tests may have introduced a potential bias in favor of FP, since there is evidence to support bronchodilatory activity with leukotriene modifiers.[27] The lesser effect of zafirlukast could be explained if the drug has a duration of action that is shorter than the recommended 12-hour dosing interval. However, the procedures and timing used in this study are similar to those used in other studies of leukotriene modifiers.[9,10,17] Third, a large number of efficacy measures were collected at multiple time points, which potentially increases the likelihood of finding significant treatment differences. However, many of the differences noted in this study were highly significant, and all of the measures were in agreement. This suggests that treatment differences seen in this study were valid. Finally, zafirlukast tablets were over-encapsulated for the purpose of blinding. The over-encapsulation did not appear to affect the performance of zafirlukast, because over-encapsulated and nonencapsulated tablets exhibited similar dissolution profiles. This conclusion is reinforced by the fact that the efficacy profile of zafirlukast in our study is similar to that seen in previous studies.[9,10]

CONCLUSIONS

Treatment with FP 88 [micro]g twice daily was more effective than zafirlukast 20 mg twice daily or placebo in improving asthma control and patient-rated outcomes in patients with persistent asthma who were previously receiving short-acting [[Beta].sub.2]-agonists alone.

ACKNOWLEDGMENTS

We acknowledge the important contributions made by the clinical investigators in this study: Thomas Bell, MD, Missoula, MT; Robert Berkowitz, MD, Atlanta, GA; David Bernstein, MD, Cincinnati, OH; Paul Chervinsky, MD, North Dartmouth, MA; Jonathan Corren, MD, Los Angeles, CA; David Coutin, MD, Bend, OR; David Denmead, MD, Danville, CA; James Fish, MD, Philadelphia, PA; Charles Fogarty, MD, Spartanburg, SC; Pinkus Goldberg, MD, Indianapolis, IN; Marshall P Grodofsky, MD, West Hartford, CT; Jay Grossman, MD, Tucson, AZ; Alan Heller, MD, San Jose, CA; Harold Kaiser, MD, Minneapolis, MN; Edward Kent, MD, South Burlington, VT; Kathy Lampl, MD, Rockville, MD; Allen Lieberman, MD, Austin, TX; Richard Lockey, MD, Tampa, FL; Stephen McGeady, MD, Philadelphia, PA; Jon Musmand, MD, Portland, ME; Anjuli Nayak, MD, Normal, IL; Gregory Neagos, MD, Ypsilanti, MI; John Oppenheimer; MD, Springfield, NJ; Frank Picone, MD, Tinton Falls, NJ; Jacob Pinnas, MD, Tucson, AZ; Gordon Raphael, MD, Bethesda, MD; Guy Settipane, MD, Providence, RL; William Sokol, MD, Newport Beach, CA; James Taylor, MD, Tacoma, WA; Robert Townley, MD, Omaha, NE. We also acknowledge the assistance of Cheryl Beale, MA, and Richard A. Rogers, MS, in the preparation and editing of this manuscript.

This study was supported by a grant from Glaxo Wellcome Inc., Research Triangle Park, North Carolina.

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[14.] Donahue JG, Weiss ST, Livingston JM, Goetsch MA, Greineder DK, Platt R. Inhaled steroids and the risk of hospitalization for asthma. JAMA 1997; 277:887-91.

[15.] Israel E, Cohn J, Dube L, Drazen JM, for the Zileuton Clinical Trial Group. JAMA 1996; 275:931-36.

[16.] Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. J Allergy Clin Immunol 1996; 98:859-71.

[17.] Malmstrom K, Rodriguez-Gomez G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, controlled trial. Ann Intern Med 1999; 130:487-95.

[18.] Sheffer AL, LaForce C, Chervinsky P, Pearlman D, Schaberg A. Fluticasone propionate aerosol: efficacy in patients with mild to moderate asthma. Fluticasone Propionate Asthma Study Group. J Fam Pract 1996; 42:369-75.

[19.] Galant SP, Lawrence M, Meltzer EO, Tomasko M, Baker KA, Kellerman DJ. Fluticasone propionate compared with theophylline for mild-to-moderate asthma, Ann Allergy Asthma Immunol. 1996; 77:112-18.

[20.] Kemp JP, Minkwitz MC, Bonuccelli CM, Warren MS. Therapeutic effect of zafirlukast as monotherapy in steroid-naive patients with severe persistent asthma. Chest 1999; 115:336-42.

[21.] Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. Am J Respir Crit Care Med 1998; 157:S1-53.

[22.] Hofstra WB, Sterk PJ, Neijens HJ, van der Weij AM, van Zoest JG, Duiverman EJ. Two weeks treatment with zafirlukast (Accolate), sodium cromoglycate or placebo on exercise-induced bronchoconstriction in asthmatic adolescents. Am J Resp Crit Care Med 1997; 155:A665.

[23.] Bateman ED, Aitchison JA, Summerton L, Harris A. The early onset of action of zafirlukast (Accolate) in patients with asthma. Am J Resp Crit Care Med 1997; 155:A663.

[24.] Laitinen LA, Naya IP, Binks S, Harris A. Comparative efficacy of zafirlukast and low dose steroids in asthmatics on prn [[Beta].sub.2]-agonists. Eur Resp J 1997; 10(suppl):419S-20S.

[25.] Richter K, Speckin P, Koschyk S, Jorres RA, Magnussen H. Efficacy and duration of action of zafirlukast on cold air-induced bronchoconstriction in patients with asthma. Eur Resp J 1997; 10(suppl):419S.

[26.] Lockhart A, Djaballah K, Dessanges JF, et al. The protective effect of zafirlukast against exercise-induced asthma. Eur Resp J 1997; 10(suppl):419S.

[27.] Lipworth BJ. Leukotriene-receptor antagonists. Lancet 1999; 353:57-62.

(*) Submitted, revised, March 23, 2001.

This paper was presented, in part, at the annual meeting of the American College of Chest Physicians, Toronto, Ontario, November 8 - 12, 1998.

From the University of Wisconsin Hospital and Clinics, Madison, Wisconsin (W.B.); the Allergy and Asthma Associates, Santa Clara Valley Research Center, San Jose, California (J.W.); Allergy and Asthma Associates, Colorado Springs, Colorado (W.S., S.S.); and Glaxo Wellcome Inc., Research Triangle Park, North Carolina (L.E., M.J., B.W.B., P.R.R, and K.R.)

All requests for reprints should be addressed to William W. Busse, MD, University of Wisconsin Hospital and Clinics, H6/367 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-2454. E-mail: wwb@medicine.wisc.edu.

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