James P. Kemp

Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription.

Five lipoxygenase (5-LO) is the first committed enzyme in the metabolic pathway leading to the synthesis of the leukotrienes. We examined genomic DNA isolated from 25 normal subjects and 31 patients with asthma (6 of whom had aspirin-sensitive asthma) for mutations in the known transcription factor binding regions and the protein encoding region of the 5-LO gene. A family of mutations in the G + C-rich transcription factor binding region was identified consisting of the deletion of one, deletion of two, or addition of one zinc finger (Sp1/Egr-1) binding sites in the region 176 to 147 bp upstream from the ATG translation start site where there are normally 5 Sp1 binding motifs in tandem. Reporter gene activity directed by any of the mutant forms of the transcription factor binding region was significantly (P < 0.05) less effective than the activity driven by the wild type transcription factor binding region. Electrophoretic mobility shift assays (EMSAs) demonstrated the capacity of wild type and mutant transcription factor binding regions to bind nuclear extracts from human umbilical vein endothelial cells (HUVECs). These data are consistent with a family of mutations in the 5-LO gene that can modify reporter gene transcription possibly through differences in Sp1 and Egr-1 transactivation.

The Effect of Inhibition of 5-Lipoxygenase by Zileuton in Mild-to-Moderate Asthma

Although intermittent episodic airway narrowing occurs in persons with asthma, the biochemical basis of this obstruction has not been elucidated. Nonetheless, inflammatory cells present in the airways of persons with asthma [1, 2] release various substances that narrow airways. Among these are cysteinyl leukotrienes, which are formed from arachidonic acid in part by the enzyme 5-lipoxygenase [3]. The evidence favoring a role for leukotrienes in asthma is that they are produced by various airway cells including eosinophils and mast cells [4, 5], they are potent bronchoconstrictor agonists [6-8], and they can be recovered from biological fluids during asthma attacks [9-11]. Recently, the salutary effects of specific leukotriene-receptor antagonists or synthesis inhibitors in persons with asthma have suggested that interventions in the 5-lipoxygenase pathway may be of therapeutic use in the treatment of asthma [12-20]. These observations are particularly interesting because of the increasing concerns about asthma therapies such as -agonists and theophylline [21-24] and the known toxicity of long-term steroid use [25, 26]. However, the conclusions about the efficacy of these new drugs in persons with asthma largely derive from studies in laboratory-induced, rather than spontaneously occurring, asthma. Because cases of spontaneously occurring asthma may differ from those of laboratory-induced asthma, in mechanism or in response to therapy, we examined the effects of zileuton (N-1-[benzo(b)thien-2-ylethyl]-N-hydroxyurea), an investigational inhibitor of 5-lipoxygenase [27] currently in phase III trials of efficacy, in persons with asthma. In a double-blind, placebo-controlled trial in patients with mild-to-moderate airflow obstruction, we investigated the effects of inhibition of 5-lipoxygenase with zileuton (Leutrol; Abbott Laboratories, North Chicago, Illinois), during a 4-week period, on airway function, asthma symptoms, and the bronchodilator response to -agonists. We found that a dose of 600 mg four times per day (2.4 g/d), which produces more than 35% inhibition of leukotriene production as indicated by excretion of leukotriene E4 (LTE4) in the urine, had a salutary effect on airway function and asthma symptoms. Methods Patient Selection Patients with mild-to-moderate asthma were recruited at 14 centers, which included university hospitals and private allergy and pulmonary practices. Patients with symptoms that corresponded with the American Thoracic Society definition of asthma [28] were screened. All patients had to have a forced expiratory volume in 1 second (FEV1) of 40% to 75% of predicted value and a 15% or greater increase in FEV1 30 minutes after inhalation of two puffs of albuterol. Additionally, patients were required to be 18 to 65 years old; women of childbearing potential were excluded. Before enrollment in the study, none of the patients had used oral or inhaled steroids or cromolyn sodium for 4 weeks. Beta-blockers, calcium-channel blockers, and nonsteroidal anti-inflammatory drugs could not have been used for at least 1 week before entry into the study. All patients were required to be able to achieve adequate symptomatic asthma control without using theophylline, oral -agonists, or antihistamines; none of these medications was permitted throughout the entire study period. Study Design and Intervention A randomized parallel design was used in this double-blind, placebo-controlled study. Patients were chosen randomly to receive either 600 mg of zileuton (four times a day), 800 mg of zileuton (twice a day), or placebo. A 1-week, single-blind, placebo lead-in qualification period (dummy lead-in period) was followed by random allocation to one of the three treatment groups for a 4-week, double-blind phase. During the single-blind, dummy lead-in and the double-blind study periods, all patients took capsules four times a day. Self-determined peak expiratory flow rates were recorded in the morning (before medication) and evening (2 hours after the third set of capsules) in a study diary. Albuterol inhaler use and asthma symptoms were recorded in the diary as well. Daytime asthma symptoms were self-rated on a scale of 1 to 5 (1 = no symptoms, 5 = severe symptoms; maximum weekly score of 35). After the 1-week dummy lead-in period, patients returned to their study center. Inhaled albuterol was withheld for at least 8 hours before the study visit. Spirometry was done on patients who had no clinically significant laboratory abnormalities, who had successfully completed their diary card, who had moderately symptomatic asthma (a total score of 12 but 28 in the previous 7 days), and who had used their albuterol inhaler at least 7 times during the dummy lead-in week. If the FEV1 was 40% to 75% of the predicted value, the patient was assigned randomly to a group according to a predetermined code. All patients took visually identical capsules four times per day that contained either 600 mg of zileuton four times daily, 800 mg of zileuton twice daily (active drug first and last dose daily), or placebo, which were supplied by Abbott Laboratories in a blind manner. The first dose of study medication was administered at the study center, and spirometry was done 30, 60, and 120 minutes later. In the 800-mg group, each days drug card contained both placebo and active drug, and as a result, on the first day, an undetermined number of patients received placebo instead of 800 mg of zileuton as their first dose of drug. Therefore, the 800-mg group was not included in the analysis of the acute response to the first dose of drug. During the 4-week double-blind period, patients returned to the study center at the same time of day on a weekly basis to have spirometry done and to review diary cards and medication use. During the second and third weeks of the double-blind randomization period, spirometry was also repeated 30 minutes after inhalation of two puffs of albuterol. Urine Collection and Analysis Urine was collected for 4 hours beginning at 8:00 a.m. before the dummy lead-in period and on day 28 of the study. Urinary LTE4 levels were determined by reverse-phase high-performance liquid chromatography and enzyme immunoassay using minor modifications of established procedures [29]. The recovery of the internal LTE4 standard was 74% 6%. The LTE4 content of the urine was expressed as picograms of immunoreactive LTE4 per milligram of creatinine. Adverse Events Routine complete blood counts, serum chemistries, urinalyses, and electrocardiograms were obtained throughout the study. Adverse symptoms were elicited daily through a diary question and were reviewed at the weekly visit to the study site. Statistical Analysis All values were expressed as means with associated 95% CIs; all outcome indicators were normally distributed. Paired t-tests were used to assess the statistical significance of any within-group changes from the baseline dummy lead-in phase. The statistical significance of differences among the placebo and active treatment groups during the 4 weeks of double-blind treatment was evaluated using a two-way analysis of variance model with effects for center, treatment, and center-treatment interaction. When statistical differences were noted among groups in the dummy lead-in, the groups were compared using an analysis of covariance adjusting for baseline differences. Available data were analyzed up to the point of withdrawal for patients who did not complete the study protocol. The Fisher test for the protected least significant difference was used to make pair-wise comparisons. Results Patients A total of 188 patients entered the single-blind dummy lead-in period; 143 fulfilled the enrollment criteria and were randomly assigned to receive study drug or placebo (46 patients received 2.4 g/d, 49 patients received 1.6 g/d, and 48 patients received placebo). Two patients withdrew during the first week of the double-blind study1 for personal reasons and the other because of worsening asthma (both received 1.6 g/d of zileuton). Two patients were not included in the final analysis, because they were enrolled in a center that did not have representation in all three treatment groups (1 received 1.6 g/d of zileuton and 1 received placebo). The characteristics of the 139 evaluated patients are given in Table 1. Of the 139 patients who were still in the trial after 1 week, 12 evaluated patients left the study before completing the trial protocol (all their data were included up to the point of termination): 4 patients because of worsening asthma (1 received 2.4 g/d, 2 received 1.6 g/d, and 1 received placebo); 2 patients because of upper respiratory infections (1 received 2.4 g/d and 1 received placebo); 1 patient because of sinusitis (placebo); 1 patient because of urticaria (1.6 g/d); 3 patients because of personal reasons (1 in each group); and 1 patient because of headaches that had begun before randomization (2.4 g/d). Table 1. Characteristics or Evaluated Patients* Acute Effects on Airway Obstruction A single 600-mg dose of zileuton produced rapid bronchodilation (Figure 1). Compared with the mean FEV1 measured just before study drug ingestion (0 minutes), the mean FEV1 improved 30 minutes after a single 600-mg dose of zileuton and remained increased for the entire 2-hour observation period (P < 0.005 for all observation points). The maximum increase (14.6%) in the mean FEV1 was 0.35 L (CI, 0.25 to 0.45 L) (P < 0.001), which occurred at 60 minutes. No improvement of the FEV1 occurred in the placebo group (0.09 L [CI, 0.01 to 0.19 L]; P = 0.075). The improvement in the mean FEV1 after zileuton was greater than that after placebo at 60 and 120 minutes (P < 0.001 and P = 0.01, respectively). Figure 1. Change in the forced expiratory volume during the 2 hours after administration of zileuton or placebo. P P P Effects of 4 Weeks of Zileuton Administration on Airway Obstruction All three groups of patients had an initial impr

A Comparison of Salmeterol with Albuterol in the Treatment of Mild-to-Moderate Asthma

BACKGROUND An effective, long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs. We compared a new long-acting, inhaled beta 2-adrenoceptor agonist, salmeterol, with a short-acting beta 2-agonist, albuterol, in the treatment of mild-to-moderate asthma. METHODS We randomly assigned 234 patients (150 male and 84 female patients 12 to 73 years old) to one of three treatment groups: one group received 42 micrograms of salmeterol twice daily, one received 180 micrograms of albuterol four times daily, and one received placebo. Treatment was assigned in a double-blind fashion, and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period. RESULTS Measurements of the forced expiratory volume in one second, performed hourly for 12 consecutive hours, showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart (6.3 vs. 4.9 liter.hr, P < 0.05). The difference was significant on day 1 and at week 4 of the study, but not at week 8 or 12. Salmeterol was also more effective than albuterol or placebo (with albuterol taken as needed) in increasing the morning peak expiratory flow rate: salmeterol induced a mean increase of 24 liters per minute over the pretreatment values, as compared with a decrease of 6 liters per minute with albuterol (P < 0.001) and an increase of 1 liter per minute with placebo (P = 0.002). The mean overall symptom score was improved most by salmeterol treatment (P < 0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively; there were no differences in results between albuterol treatment and placebo administration. We found no evidence of tolerance to the bronchodilating effects of salmeterol, and adverse reactions to all the treatments were infrequent and mild. CONCLUSIONS For the management of mild-to-moderate asthma, salmeterol given twice daily is superior to albuterol given either four times daily or as needed.

Montelukast once daily inhibits exercise-induced bronchoconstriction in 6- to 14-year-old children with asthma☆☆☆★★★

OBJECTIVE To determine whether montelukast, a leukotriene receptor antagonist, attenuates exercise-induced bronchoconstriction (EIB) in 6- to 14-year-old children with asthma. STUDY DESIGN Double-blind, multicenter, 2-period crossover study. Children (n = 27) with forced expiratory volume in 1 second (FEV1) > or =70% of the predicted value and a fall in FEV1 > or =20% after exercise on 2 occasions. Patients received montelukast (5-mg chewable tablet) or placebo once daily in the evening for 2 days in crossover fashion (at least 4 days between treatment periods). Standardized exercise challenges were performed 20 to 24 hours after the last dose in each period. End points included area above the postexercise percent fall in FEV1 versus time curve (AAC0-60 min), maximum percent fall in FEV1 from pre-exercise baseline, and time to recovery of FEV1 to within 5% of pre-exercise baseline. RESULTS Montelukast significantly reduced AAC0-60 min (265 vs 590% x min for montelukast and placebo, respectively, P < or = .05; approximately 59% protection relative to placebo) and the maximum percent fall (18% vs 26% for montelukast and placebo, respectively, P < or = .05). Montelukast treatment resulted in a shorter time to recovery (18 vs 28 minutes for montelukast and placebo, respectively, P = .079). CONCLUSIONS Montelukast attenuates EIB at the end of the dosing interval in 6- to 14-year-old children with asthma.

Allergic Rhinitis and its Impact on Asthma (ARIA) 2008

J. Bousquet, N. Khaltaev, A. A. Cruz, J. Denburg, W. J. Fokkens, A. Togias, T. Zuberbier, C. E. Baena-Cagnani, G. W. Canonica, C. van Weel, I. Agache, N. A t-Khaled, C. Bachert, M. S. Blaiss, S. Bonini, L.-P. Boulet, P.-J. Bousquet, P. Camargos, K.-H. Carlsen, Y. Chen, A. Custovic, R. Dahl, P. Demoly, H. Douagui, S. R. Durham, R. Gerth van Wijk, O. Kalayci, M. A. Kaliner, Y.-Y. Kim, M. L. Kowalski, P. Kuna, L. T. T. Le, C. Lemiere, J. Li, R. F. Lockey, S. Mavale-Manuel , E. O. Meltzer, Y. Mohammad, J. Mullol, R. Naclerio, R. E. O Hehir, K. Ohta, S. Ouedraogo, S. Palkonen, N. Papadopoulos, G. Passalacqua, R. Pawankar, T. A. Popov, K. F. Rabe, J. Rosado-Pinto, G. K. Scadding, F. E. R. Simons, E. Toskala, E. Valovirta, P. van Cauwenberge, D.-Y. Wang, M. Wickman, B. P. Yawn, A. Yorgancioglu, O. M. Yusuf, H. Zar Review Group: I. Annesi-Maesano, E. D. Bateman, A. Ben Kheder, D. A. Boakye, J. Bouchard, P. Burney, W. W. Busse, M. Chan-Yeung, N. H. Chavannes, A. Chuchalin, W. K. Dolen, R. Emuzyte, L. Grouse, M. Humbert, C. Jackson, S. L. Johnston, P. K. Keith, J. P. Kemp, J.-M. Klossek, D. Larenas-Linnemann, B. Lipworth, J.-L. Malo, G. D. Marshall, C. Naspitz, K. Nekam, B. Niggemann, E. Nizankowska-Mogilnicka, Y. Okamoto, M. P. Orru, P. Potter, D. Price, S. W. Stoloff, O. Vandenplas, G. Viegi, D. Williams

Common characteristics of upper and lower airways in rhinitis and asthma: ARIA update, in collaboration with GA(2)LEN.

This update aimed to review the new evidence available to support or refute prior Allergic Rhinitis and its Impact on Asthma (ARIA) statements. A Medline search of publications between 2000 and 2005 was conducted, with articles selected by experts. New evidence supports previous ARIA statements, such as: (i) allergic rhinitis (AR) is a risk factor for asthma; (ii) patients with persistent rhinitis should be evaluated for asthma; (iii) most patients with asthma have rhinitis; (iv) a combined strategy should be used to treat the airways and (v) in low‐ to middle‐income countries, a different strategy may be needed. The increased risk of asthma has also been found among sufferers from non‐AR. Recent reports show AR is a global problem. Many studies demonstrated parallel increasing prevalence of asthma and rhinitis, but in regions of highest prevalence, it may be reaching a plateau. Factors associated with a reduced risk of asthma and AR have been identified, confirming previous findings of protection related to exposure to infections. Treatment of rhinitis with intranasal glucocorticosteroids, antihistamines, leukotriene antagonists or immunotherapy may reduce morbidity because of asthma. To take advantage of the paradigm of unified airways, there is a need to rationalize diagnosis and treatment to optimize management.

Oral Montelukast Compared with Inhaled Salmeterol To Prevent Exercise-Induced Bronchoconstriction: A Randomized, Double-Blind Trial

Exercise-induced bronchoconstriction is common in patients with chronic asthma (1). Airway cooling or desiccation during exercise may trigger activation of mast cells and release of such mediators as histamine and cysteinyl leukotrienes, resulting in bronchospasm (1, 2). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4), synthesized from arachidonic acid through the 5-lipoxygenase pathway, are potent bronchoconstrictors, with an effect greater than 1000 times that of histamine (3-5). Several researchers have demonstrated an increase in urinary concentrations of LTE4 after exercise (6, 7). Prophylaxis against exercise-induced bronchoconstriction with inhaled mast cell-stabilizing agents and short-acting -agonists must be administered 15 to 30 minutes before exercise. The long-acting inhaled -agonist salmeterol protects against exercise-induced bronchoconstriction for up to 12 hours, thus providing more flexibility in the dosing schedule for active patients with asthma (8, 9). However, in some patients, tolerance to salmeterol develops with long-term use, and the level of bronchoprotection diminishes by 6 to 9 hours (10-12). Montelukast sodium, a leukotriene receptor antagonist, is a potent oral medication for the treatment of asthma. The leukotriene receptor antagonists have demonstrated a significant bronchoprotective effect with exercise after one or two doses (13, 14). In patients with exercise-induced bronchoconstriction, short-term treatment with montelukast (Singulair, Merck & Co., Inc., Whitehouse Station, New Jersey) given once daily diminished the postexercise response, as described by the area under the FEV1 time curve (AUC0-60 min), by more than 50%, even at the end of the dosing interval (20 to 24 hours after administration) (15, 16). Furthermore, tolerance to the bronchoprotective effects of montelukast did not occur with long-term administration (17). We sought to test the hypothesis that the bronchoprotective effects of montelukast were greater than those of salmeterol in patients with chronic asthma who experienced exercise-induced bronchoconstriction. Methods Design We conducted a randomized, parallel-group study consisting of a 2-week, single-blind placebo baseline period followed by an 8-week, double-blind treatment period with montelukast sodium (10-mg tablet taken orally once in the evening) or inhaled salmeterol (50-g aerosol formulation [2 puffs] taken twice daily). Seventeen clinical study sites participated in the trial. To mask formulation differences, a double-dummy treatment regimen was used. Each patient received one tablet daily (active agent or matching placebo) or one inhaler twice daily (active agent or matching placebo) for both the single-blind and double-blind treatment periods. A computer-generated allocation schedule with a blocking factor of 4 was produced by the statistician. Each center was given a block of allocation numbers that were assigned sequentially to consecutive randomly assigned patients. Spirometric measurements were obtained before and after standardized exercise challenges at the beginning and end of the baseline period, within the first 3 days of the double-blind treatment period, and at weeks 4 and 8 of the treatment period. Additional measurements were physical examination, vital signs, electrocardiography, chest radiography, and laboratory tests (hematology, chemistry profile, and urinalysis). At each visit, all spontaneously reported adverse events were recorded. The protocol was approved by the institutional review board of each site, and written informed consent was obtained from each patient. Inclusion Criteria Male and female patients 15 to 45 years of age with a history of chronic asthma were enrolled. All patients had an FEV1 of at least 65% of the predicted value at rest and a decrease in FEV1 of at least 20% after a standardized exercise challenge on two occasions during the baseline period. All patients had been nonsmokers for at least 1 year and had a smoking history of less than 15 pack-years. Exclusion Criteria Persons who had upper respiratory infection or exacerbation of asthma requiring emergency care within the past month or were hospitalized for asthma in the past 3 months were excluded. Use of oral or inhaled corticosteroids, theophylline, cromolyn sodium, nedocromil, oral -agonist, and long-acting antihistamines was prohibited before and during the study. Use of inhaled albuterol for symptomatic relief of asthma and use of short-acting antihistamines were permitted. Evaluations A standard spirometer (Puritan-Bennett PB100/PB110, Puritan-Bennett, Wilmington, Massachusetts) was used to obtain all spirometric measurements according to American Thoracic Society standard criteria (18). Patients had to have discontinued use of inhaled short-acting -agonists for 6 hours before the visit. Exercise testing was done in the early afternoon near the trough of effect for both drugs according to a method described elsewhere (17). Measurements were obtained 20 and 5 minutes before exercise (prechallenge period). Exercise challenge was performed only if the average FEV1 in the prechallenge period was greater than 65% of predicted; otherwise, the test was rescheduled. Patients exercised on a treadmill while inhaling room temperature, compressed, dry air. During the first test, the speed and gradient of the treadmill were adjusted to achieve 80% to 90% of the patients age-predicted maximum heart rate. The settings were maintained for a total of 6 minutes; the same settings were used for future tests. This level of exercise has been used to quantify the level of bronchoconstriction associated with regular exercise (19). Serial spirometric measurements were obtained at 0, 5, 10, 15, 30, 45, and 60 minutes after exercise (postexercise period). Additional measurements were carried out at 15-minute intervals for up to 90 minutes if the patients FEV1 had not returned to within 5% of the prechallenge value by 60 minutes. If the patients FEV1 did not return to the prechallenge value by 90 minutes after exercise, a rescue dose of inhaled -agonist was administered at the discretion of the study investigator. Statistical Analysis An all-patients-treated analysis, which included patients with a baseline visit and at least one post-randomization visit, was performed. The change from baseline in the maximal percentage decrease in FEV1 after exercise at the end of 8 weeks of treatment was the primary end point. Analysis of variance was used to compare the two treatment groups. The analysis of variance model included terms for treatment, center, and the interaction of treatment and center. Ninety-five percent CIs for within-group means and the difference between groups were constructed to assess the magnitude of the treatment effect. Analysis of variance on the ranked data was used to analyze percentage inhibition for all end points. In the event of early termination of the exercise challenge because of administration of rescue medication, the largest percentage decrease in FEV1 achieved before administration of rescue medication was used in the analysis. Secondary end points were change from baseline for maximal percentage decrease in FEV1 at days 1 to 3 and week 4, the time required after maximal decrease in FEV1 to return within 5% of prechallenge values (time to recovery), and the AUC0-60 min at all visits. The mean of the 20- and 5-minute prechallenge measurements was used as the pre-exercise FEV1 value. If a patient required rescue with inhaled -agonist during the postexercise period, the last recorded FEV1 value was used and carried forward for all subsequent readings and 100 minutes was entered for the end point of time to recovery. The AUC0-60 min was calculated by using the trapezoidal method. If a patients FEV1 did not decrease below 95% of the prechallenge value, the time to recovery was assigned a value of zero. The persistence of effect over time was assessed by using a repeated-measures fixed-effects model with terms for center, treatment group, time, and the interaction of treatment group and time to calculate the rate of change over the treatment period. Persistence of effect was defined as a slope of zero. The magnitude of the slopes for each treatment group was estimated, and 95% CIs were calculated. An overall test of equal slopes between the treatment groups was examined, and a 95% CI on the difference in slopes between treatment groups was provided. The number and percentage of patients requiring rescue medication during or at the end of the exercise test were summarized by treatment group at each time point. In addition, the number and percentage of patients whose decrease in FEV1 from pre-exercise levels was less than 10%, 10% to 20%, 20% to 40%, and greater than 40% were summarized by treatment group for each visit. The overall incidence of adverse events and laboratory abnormalities was assessed by using the Fisher exact test, and within-group changes in the number of laboratory abnormalities were assessed by using the McNemar test. Descriptive statistics were provided by treatment group for patient demographic characteristics, clinical characteristics, and baseline profile. The study was designed with a sample size of 160 patients (80 patients per treatment group) to have 95% power (two-sided test at =0.05) to detect a 7% difference in the mean change in maximal percentage decrease in FEV1 between treatments. All statistical analyses were performed by using SAS software, version 6 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source Funding for this trial was provided by Merck & Co., Inc., Whitehouse Station, New Jersey. Personnel from Merck U.S. Human Health, Clinical Development department played a significant role in the design, conduct, and analysis of the trial. The trial was conducted in accordance with guidelines for clinical trials of investigational agents established by U.S. regulatory authorities. Results Pati

Zafirlukast for symptomatic mild-to-moderate asthma : A 13-week multicenter study

The efficacy of the oral leukotriene-receptor antagonist zafirlukast was assessed as maintenance therapy for patients with mild-to-moderate asthma. A total of 762 patients aged 12 to 76 years were enrolled in a 13-week, multicenter, double-masked, placebo-controlled, parallel-group trial and randomly assigned to receive either zafirlukast (20 mg twice daily) or placebo. Patients were maintained on as-needed beta-agonist therapy throughout the study and had to have a cumulative daytime asthma symptoms score > or = 8 (on a daily scale of 0 to 3) over 7 consecutive days before randomization. Efficacy was assessed by changes in symptoms, beta-agonist use, and pulmonary function. Safety was assessed by adverse experiences, laboratory test results, physical examination, and electrocardiography. Zafirlukast significantly decreased daytime asthma symptoms scores (-26.5%), nighttime awakenings (-19.8%), mornings with asthma (-29.0%), and beta-agonist use (-22.3%) and significantly increased morning peak expiratory flow rate (6.9%) and forced expiratory volume in 1 second (6.3%) compared with placebo. Changes in symptoms, beta-agonist use, and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial. Zafirlukast was well tolerated. Pharyngitis and headache were the most common adverse events, occurring with similar frequency in both the zafirlukast and placebo groups. No clinically significant changes were observed in laboratory test results, findings on physical examination, or electrocardiographic findings. We conclude that zafirlukast produces early and sustained effects in the treatment of mild-to-moderate asthma.

Once-daily budesonide inhalation suspension for the treatment of persistent asthma in infants and young children

BACKGROUND Inhaled glucocorticosteroids (GCS) are the most effective long-term controller medications for the treatment of persistent asthma. Currently, however, available delivery devices limit their use in young children. A nebulized formulation of budesonide has been developed to address the needs of infants and young children. OBJECTIVE To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS. METHODS Three hundred fifty-nine children were randomized to receive once-daily budesonide inhalation suspension (0.25 mg, 0.50 mg, or 1.0 mg) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks. Efficacy assessments included nighttime/daytime asthma symptoms, pulmonary function (subset of patients), rescue medication use, and treatment discontinuations. Safety was based on adverse events and assessment of HPA-axis function. RESULTS Demographics, baseline characteristics, asthma symptoms, and pulmonary function were similar across treatment groups. Mean nighttime/daytime asthma symptom scores were 1.19 +/- 0.63 and 1.34 +/- 0.53, respectively. Mean duration of asthma was 36.3 months and mean FEV1 was 81.3% of predicted with 27.7% reversibility. Following 12 weeks of treatment, all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms (P < or = .049) and significant decreases in rescue medication use (P < or = .038) compared with placebo. Significant improvements (P < or = .044) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups. There were no differences between doses of budesonide inhalation suspension. Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups. CONCLUSION Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments.

Administration of budesonide once daily by means of Turbuhaler to subjects with stable asthma

BACKGROUND Optimal management of chronic, mild-to-moderate asthma with inhaled steroids may include use of the lowest possible doses, as recommended in guidelines, and a reduction in the frequency of daily administration for greater convenience. Lower doses and once daily treatment with inhaled steroids must be rigorously evaluated in controlled clinical trials. OBJECTIVES The objective of this study was to assess the efficacy and safety of once daily treatment with budesonide in subjects with stable asthma. METHODS Once daily budesonide was assessed in 309 adult subjects, including those who were and were not using an inhaled steroid at baseline. The subjects were stratified by inhaled steroid use and randomly assigned to one of 3 treatments: 200 microgram budesonide, 400 microgram budesonide, or placebo administered by means of Turbuhaler once daily in the morning for 6 weeks. Beyond this point, treatment was continued unchanged for another 12 weeks (maintenance) in those receiving 200 microgram budesonide once daily and placebo. In those who received 400 microgram budesonide once daily, the dose was reduced to 200 microgram once daily at week 6 and held constant for the remaining 12 weeks (400/200 microgram group). Primary efficacy endpoints were mean change from baseline in FEV1 and morning peak expiratory flow. RESULTS Once daily budesonide was well tolerated and resulted in significant improvements in all efficacy endpoints, even though baselines were well stabilized. Baseline lung function was elevated with little room for improvement; however, mean increases in FEV1 during the maintenance period were 0.10 L and 0.11 L in the 200 microgram and 400/200 microgram groups, respectively, versus a decrease of -0.09 L in the placebo arm (P <.001). Results for peak expiratory flow were similar. Significant improvements in secondary endpoints, including symptoms, beta-agonist use, and quality of life, also developed with budesonide 200 and 400 microgram once daily. CONCLUSION Inhaled budesonide, in doses as low as 200 microgram, may be an appropriate introductory or maintenance dose in subjects with stable, mild-to-moderate asthma.