Distinct relationships of intramuscular and subcutaneous fat with cortical bone: findings from a cross-sectional study of young adult males and females.

CONTEXT: Intracellular fat within muscle and visceral tissue has been suggested to adversely influence bone development. OBJECTIVE: The aim of the study was to evaluate associations between im fat, as reflected by muscle density as measured by peripheral quantitative computed tomography, and cortical bone parameters in young adults. DESIGN/SETTING/PARTICIPANTS: We conducted a cross-sectional analysis of 1703 males and 2243 females aged 17.8 years from the Avon Longitudinal Study of Parents and Children. OUTCOME MEASURES: We measured cortical bone parameters from midtibial peripheral quantitative computed tomography scans. RESULTS: Muscle density (inversely related to im fat) was inversely associated with periosteal circumference (PC) (beta = -0.07 [95% confidence interval (CI), -0.1, -0.04]), cortical bone mineral density (BMDC) (beta = -0.21 [95% CI, -0.26, -0.17]), and cortical thickness (CT) (beta = -0.37 [95% CI, -0.42, -0.33]) (males and females combined, adjusted for age, height, gender, and muscle cross-sectional area). In contrast, sc fat area was positively associated with PC (beta = 0.10 [95% CI, 0.07, 0.12]), but no association was seen with BMDC or CT. To examine the role of candidate intermediary metabolic pathways, analyses were repeated after adjustment for insulin, C-reactive protein, and ß-C-telopeptides of type I collagen. Whereas similar associations were observed after adjustment for insulin and C-reactive protein, the association between muscle density and BMDC was partially attenuated by adjustment for ß-C-telopeptides of type I collagen (beta = -0.14 [95% CI, -0.20, -0.08]). CONCLUSION: Although im and sc fat were both positively associated with cortical bone mass, the nature of these relationships differed in that im fat was predominantly associated with CT and BMDC, whereas sc fat was mainly associated with PC. These relationships were largely independent of candidate metabolic pathways, such as altered bone resorption, insulin resistance, or inflammation.

Helical structures in proteins.

We examine a minimal model for helix-forming polymers. The monomer-monomer potential energy is based on the anisotropic potentials seen in proteins and is used in conjunction with a wormlike backbone. We show that the coil-helix transition involves four states. As the temperature is lowered, the first observed state is a coil state, the second a collapsed globular, the third a highly flexible helical state, and the fourth a crystalline helical state. We discuss in detail what effect the potential energy form has on these various states by systematically varying the potential from strongly anisotropic to isotropic. The data demonstrate that the foldability of a helix is strongly related to anisotropic nature of the potential. In the isotropic case, we show that the transition following a globular collapse is not first order as postulated for these systems. In the strongly anisotropic case the globular-helix transition is consistent with cooperative first-order-like behavior.

Efficacy of antileukotriene agents in asthma management.

OBJECTIVE: This article reviews information on the role of three antileukotrienes (anti-LTs), montelukast, zafirlukast, and zileuton, in the management of asthma. After reading this article, readers should have an understanding of the efficacy of anti-LTs in specific patient populations. DATA SOURCES: Relevant and appropriately controlled clinical studies on the efficacy of anti-LTs were used. Only literature in the English language was reviewed. STUDY SELECTION: Material was taken from peer-reviewed journals and published abstracts. RESULTS: The efficacy of anti-LTs has been established in numerous randomized, controlled, multicenter trials involving patients with mild-to-moderate disease. These agents reduce asthma symptoms, beta2-agonist use, and asthma exacerbations, in addition to improving pulmonary function. The anti-LTs are also effective when added to low-dose or high-dose corticosteroid regimens in symptomatic asthma patients. They have proven efficacy in patients with aspirin-sensitive asthma, and they appear able to reduce nasal congestion in asthma patients with concomitant upper airway symptoms. Some anti-LTs have been shown to be effective in pediatric asthma patients. CONCLUSIONS: In reviewing available clinical results as well as real-world experience in managing asthma patients, the Antileukotriene Working Group concludes that anti-LTs may be used in patients with mild persistent asthma as well as in combination with other asthma medications at all levels of disease severity for long-term maintenance of asthma control.

Management of asthma in children.

The prevalence of asthma in children has increased 160 percent since 1980, and the disease currently affects nearly 5 million children in the United States. The National Asthma Education and Prevention Program provides guidelines for improved asthma care. The goals of this program are to limit the frequency, severity and costliness of asthma exacerbations through extensive education of physicians, children and caregivers. The four components of asthma management include regular assessment and monitoring, control of factors that contribute to or aggravate symptoms, pharmacologic therapy and education of children and their caregivers. The guidelines recommend a stepwise approach to pharmacologic treatment, starting with aggressive therapy to achieve control and followed by a "step down" to the minimal therapy that will maintain control. Quick relief of symptoms can be achieved preferentially by the use of short-acting beta2 agonists. Medications for long-term control should be considered for use in children with persistent symptoms. Inhaled corticosteroids are the most potent long-term anti-inflammatory medications. Other options include long-acting beta2 agonists, cromolyn sodium and nedocromil, antileukotriene agents and theophylline. All have advantages and disadvantages in individual situations.

Mometasone furoate administered once daily is as effective as twice-daily administration for treatment of mild-to-moderate persistent asthma.

BACKGROUND: Despite current recommendations, many patients with persistent asthma are still treated with bronchodilators alone. OBJECTIVE: The safety and efficacy of two once daily dosing regimens (200 microg and 400 microg) of mometasone furoate (MF) administered in the morning by using a dry-powder inhaler (DPI) were compared with those of a twice daily dosing regimen (200 microg administered twice daily) in patients with mild-to-moderate persistent asthma previously taking only inhaled beta(2)-adrenergic agonists. METHODS: All patients (306 patients; age range, 12-70 years) were given a diagnosis of asthma for at least 6 months before enrollment in this 12-week, placebo-controlled, double-blind, randomized study. The primary efficacy variable was change in FEV(1) from baseline to endpoint (last evaluable visit). RESULTS: At endpoint, FEV(1) was significantly improved (P < or =.02) after MF-DPI 400 microg once daily morning treatment and MF-DPI 200 microg twice daily treatment (16.0% and 16.1%, respectively) compared with placebo (5.5%). The improvement seen with MF-DPI 200 microg once daily morning treatment (10.4%) was not significantly different from that with placebo. Secondary efficacy variables also showed significant improvement for the MF-DPI 400 microg once daily morning treatment group and the MF-DPI 200 microg twice daily treatment group compared with the placebo group. All doses of MF administered by means of a DPI were well tolerated. CONCLUSION: This is the first study to demonstrate that a total daily dose of 400 microg of MF administered by means of a DPI is an effective treatment for patients with mild-to-moderate persistent asthma previously taking only inhaled beta(2)-adrenergic agonists. This treatment was equally effective when administered either as a once daily or twice daily regimen.

Role of leukotriene receptor antagonists in pediatric asthma.

During the past decade, the inflammatory mechanisms that result in the clinical syndrome we call asthma have been emphasized in research, publications, and the various asthma management guidelines. This information clearly emphasizes the treatment of asthma with maintenance controller therapies early after the onset of symptoms in all but the very mildest of patients. Until the advent of the leukotriene receptor antagonists, nearly all of these maintenance therapies needed to be administered by inhalation through a variety of devices and spacers. Inhalation of medication was necessary to either increase the amount of drug reaching the airways or to increase the therapeutic index of drugs such as corticosteroids. Even under the best circumstances, this route of administration is difficult and expensive for many parents whose children have asthma. Now that oral controller therapies (leukotriene receptor antagonists) are available for children, their role in clinical practice needs to be examined. The latest asthma management guidelines classify asthma into four groups of severity, and base treatment recommendations on the intensity of symptoms, need for rescue medications, and pulmonary function as measured by peak expiratory flow and forced expiratory volume in 1 sec (FEV(1)). The categories of mild intermittent, mild persistent, moderate persistent, and severe asthma in children will be addressed in this presentation by reviewing the available data on the use of the leukotriene receptor antagonist montelukast in children. Mild intermittent asthma can be typified by exercise-induced asthma, a common pediatric condition. In this often troublesome condition, montelukast demonstrated effectiveness at the end of a once a day dose by blocking the effects of this naturally occurring challenge. Drug regulatory approval of a new drug also includes patients with more regular symptoms who are usually classified as having persistent or moderate asthma. In these montelukast pediatric studies, approximately 40% of patients were already taking inhaled corticosteroids. Patients had improvements in FEV(1), symptoms, and rescue medication use, clearly showing an effect with once a day dosing. Pediatric data in severe asthma patients are more limited, but in such patients a therapeutic trial of montelukast would seem preferable to using systemic corticosteroids or increasing inhaled steroids to a level where adverse effects have an increasing potential of occurring. Montelukast has been available in the United States since March 1998 and has received excellent acceptance by physicians, parents, and patients. The 5-mg chewable tablet administered once a day in the evening in children aged 6-14 years apparently fills a previously unmet need in the treatment of pediatric asthma.

Guidelines update: where do the new therapies fit in the management of asthma? NHLBI and WHO Global Initiative for Asthma.

The new leukotriene (LT) modifiers have been shown to be effective, safe and convenient 'controller' medications in patients with asthma. However, their use in asthma is recommended only in the most recent US guidelines, and then only as alternative long term controllers in patients with mild persistent asthma. In fact, as has now been shown in a number of studies, LT modifiers are effective in a variety of other asthma settings, and it is expected that expanded roles for these agents will be described in future asthma guidelines. Until then, clinicians aware of the advantages of individualising asthma therapy might consider LT modifiers for the diverse range of patients with asthma who are likely to benefit from the use of these agents.

Effect of age on response to zafirlukast in patients with asthma in the Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT).

BACKGROUND: The Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT), evaluated zafirlukast in a wide spectrum of patients from a variety of clinical practices. OBJECTIVE: To determine the effect of age on the response to zafirlukast 20 mg twice daily in 3759 patients with mild, moderate, or severe asthma. METHODS: Patients received open-label administration of zafirlukast 20 mg twice daily (bid) for 4 weeks. Pulmonary function was measured twice daily, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and beta2-agonist use were recorded daily. Trial results were analyzed to compare the efficacy of zafirlukast in 263 adolescent (12 to 17 years old), 2602 adult (18 to 65 years old), and 321 elderly (66 years old and older) patients (the evaluable population). RESULTS: After 4 weeks of zafirlukast therapy, improvements in pulmonary function decreased with age and were significant for all measures in adolescents and adults and for morning peak expiratory flow in elderly patients. Improvements in symptom response were statistically significant across age groups. Reduction in beta2-agonist rescue was similar in adolescents and adults but significantly less in elderly patients. CONCLUSIONS: Zafirlukast is an effective treatment for asthma in all patients, regardless of age. In elderly patients, improvement in asthma symptoms rather than pulmonary function may represent a primary marker for efficacy with zafirlukast.

Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction. A randomized, double-blind trial. Exercise Study Group.

BACKGROUND: Montelukast, an oral, once-daily leukotriene receptor antagonist, provides protection against exercise-induced bronchoconstriction. OBJECTIVE: To evaluate the effect of 8 weeks of therapy with salmeterol aerosol or montelukast on exercise-induced bronchoconstriction in adults with asthma. DESIGN: 8-week multicenter, randomized, double-blind study. SETTING: 17 asthma treatment centers in the United States. PATIENTS: 191 adults with asthma who had documented exercise-induced bronchoconstriction. INTERVENTION: Qualified patients were randomly assigned to double-blind treatment with montelukast (10 mg once in the evening) or salmeterol (50 microg [2 puffs] twice daily). MEASUREMENTS: Changes in pre-exercise and postexercise challenge values; percentage inhibition in the maximal percentage decrease in FEV1; the area above the FEV1-time curve; and time to recovery of FEV1 at days 1 to 3, week 4, and week 8 of treatment. RESULTS: By day 3, similar and statistically significant reductions in maximal percentage decrease in FEV1 were seen with both therapies. Sustained improvement occurred in the montelukast group at weeks 4 and 8; at these time points, the bronchoprotective effect of salmeterol decreased significantly. At week 8, the percentage inhibition in the maximal percentage decrease in FEV1 was 57.2% in the montelukast group and 33.0% in the salmeterol group (P = 0.002). By week 8, 67% of patients receiving montelukast and 46% of patients receiving salmeterol had a maximal percentage decrease in FEV1 of less than 20%. CONCLUSIONS: The bronchoprotective effect of montelukast was maintained throughout 8 weeks of study. In contrast, significant loss of bronchoprotection at weeks 4 and 8 was seen with salmeterol. Long-term administration of montelukast provided consistent inhibition of exercise-induced bronchoconstriction at the end of the 8-week dosing interval without tolerance.

Leukotriene receptor antagonists for the treatment of asthma.

Leukotriene receptor antagonists (LTRAs) are novel medications that provide symptom control in patients with persistent asthma. Current guidelines recommend the use of LTRAs as a treatment option for patients with mild-persistent asthma of at least 12 years of age. As illustrated by the results of controlled, multicenter clinical trials with zafirlukast and montelukast, as well as studies with pranlukast in Japan, LTRAs reduce daytime and night time asthma symptoms, improve pulmonary function, lower beta-adrenergic agonist use, and reduce asthma morbidity in patients with mild-intermittent to moderate-persistent asthma. Moreover, several recent clinical studies demonstrate that these agents are effective in preventing exercise-induced bronchoconstriction in children, and in improving disease control in symptomatic patients taking inhaled steroids. Based on clinical results to date, LTRAs appear to be safe and well tolerated in patients with mildto- moderate asthma. These agents represent an important addition to the drug armamentarium against asthma.

A 1-year study of salmeterol powder on pulmonary function and hyperresponsiveness to methacholine.

BACKGROUND: Long-acting beta(2)-sympathomimetic agonists such as salmeterol have been proved safe and effective for the treatment of asthma. However, controversy still exists as to the appropriateness of scheduled long-term therapy with these agents. OBJECTIVE: This study assessed the degree of bronchodilation provided by treatment with salmeterol for a period of 52 weeks and evaluated bronchial hyperresponsiveness to methacholine during and after the treatment period. METHODS: Three hundred fifty-two patients with mild to moderate asthma were assessed by 12-hour serial spirometry and serial methacholine challenge tests. RESULTS: The mean area under the FEV(1) curve above baseline over 12 hours after drug at day 1 was significantly greater with salmeterol powder compared with placebo (5.06 liter hours vs 0.77 L/h) and did not change significantly over 1 year. The mean increase in the log(2) of the provocative cumulative methacholine dose producing a 20% decrease in FEV(1) (PD(20)FEV(1)) during treatment was significantly higher in the salmeterol-treated patients than in the placebo group (1.02 doubling doses vs 0.43 doubling doses at week 4, 1.06 doubling doses vs 0.41 doubling doses at week 24). At week 52 the increase from baseline in log(2)PD(20)FEV(1) was not significantly different between salmeterol and placebo (1.08 vs 0.69 doubling doses). Seven days after treatment the log(2)PD(20)FEV(1) was -0.60 doubling doses lower than baseline for salmeterol compared with 0.10 doubling doses for placebo (P =.031). Long-term salmeterol use was not associated with a deleterious effect on asthma control during and after treatment. CONCLUSION: This study demonstrates that the bronchodilator properties of salmeterol are sustained over 52 weeks and that bronchial hyperresponsiveness to methacholine is decreased to a modest degree during treatment. Clinically significant increases in hyperresponsiveness did not develop after discontinuation of salmeterol treatment.

Study designs and challenges in clinical studies conducted in infants and children with asthma.

Because of the challenges associated with conducting clinical trials in pediatric patients, most drugs have not been adequately tested in this patient population. Insufficient testing frequently results in product labeling that fails to provide instructions for safe and effective use in pediatric patients. The most prevalent chronic disease in children is asthma; however, very few asthma medications have been evaluated in infants and young children. Budesonide inhalation suspension is an anti-inflammatory corticosteroid administered by nebulization that requires only passive inhalation and is therefore suitable for infants and young children who are unable to use currently available inhalation devices for the administration of asthma medications. The efficacy of budesonide inhalation suspension was evaluated in 3 US clinical trials. All 3 trials were randomized, controlled, double-blind, 12-week studies in children (6 months-8 years of age) with a primary diagnosis of chronic persistent asthma. Symptom assessments conducted in both the morning and evening were the primary efficacy variables. Although the children were young, secondary efficacy evaluations included spirometry and peak expiratory flow collected in both the morning and evening (in a subset of patients capable of performing these maneuvers). Patients who completed or were discontinued from the 12-week double-blind treatment phase were eligible to enter 52-week, open-label extension studies. The design of these 3 studies confirms the feasibility of the performance of placebo-controlled clinical trials of asthma medications in pediatric patients and allows for efficacy evaluations based on symptom assessments together with pulmonary function testing.

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.

Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25-75% (FEV25-75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P < 0.01) in improving FEV1 (MF DPI 5 to 7%, BDP 3%, placebo -6.6%) and all other measures of pulmonary function (FVC: MF DPI 4 to 5%, BDP 2%, placebo -4.7%; FEF25-75%: MF DPI 6 to 18%, BDP 7.5%, placebo -9.5%; PEFR (AM): MF DPI 5 to 10%, BDP 5.7%, placebo -7%). A consistent trend was observed for better improvement in patients treated with MF DPI 200 mcg b.i.d. than with MF DPI 100 mcg b.i.d., with no apparent additional benefit of MF DPI 400 mcg b.i.d. Results for the MF DPI 100 mcg b.i.d. and BDP 168 mcg b.i.d. treatment groups were similar. Patients' and physicians' subjective evaluations of symptoms found similar improvement in the MF DPI 200 and 400 mcg b.i.d. treatment groups, which were slightly better than that in the MF DPI 100 mcg b.i.d. group. Symptoms tended to worsen in the placebo group. MF DPI was well tolerated at all dose levels and the most frequently reported treatment-related adverse effects were headache, pharyngitis and oral candidiasis. No evidence of HPA-axis suppression was detected in any treatment group. In summary, all doses of MF DPI were well tolerated and significantly improved lung function and MF DPI 400 mcg (200 mcg b.i.d.) was the optimal dose in this study of patients with moderate persistent asthma.

Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness.

STUDY OBJECTIVES: To determine the effect of long-term salmeterol aerosol therapy on airway hyperresponsiveness measured by methacholine challenge. DESIGN: Randomized, double-blind, placebo-controlled, multicenter study. SETTING: Thirty-one clinical centers in the United States. PATIENTS: Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70% of predicted values. Patients were not using inhaled corticosteroids. INTERVENTIONS: Twice-daily salmeterol aerosol, 42 microg, or placebo via metered-dose inhaler for 24 weeks. Backup albuterol was available. MEASUREMENTS AND RESULTS: Pulmonary function tests were performed before, during, and after treatment. Subjects recorded asthma-related symptoms, morning and evening peak expiratory flow (PEF) levels, and use of supplemental albuterol daily on diary cards. Methacholine challenges were performed 10 to 14 h postdose at weeks 4, 12, and 24, and 3 and 7 days posttreatment. Over 24 weeks of treatment, salmeterol provided significant (p < 0.001) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection. A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy. Salmeterol treatment resulted in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo (p < 0.001). The use of salmeterol significantly reduced combined daytime asthma symptoms by 20% when compared to placebo (p = 0.005). A total of 34 and 48 exacerbations, respectively, were reported in the Salmeterol and placebo groups, and no evidence was present for a difference in the severity of asthma exacerbations between groups. Adverse event profiles were similar for the salmeterol and placebo groups. CONCLUSIONS: Regular long-term use of salmeterol aerosol resulted in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period. There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy. There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment. Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.

Zafirlukast in clinical practice: results of the Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT) in patients with asthma.

BACKGROUND: Zafirlukast is an oral leukotriene receptor antagonist used in the treatment of patients with mild to moderate asthma. To investigate its effects in a clinical practice setting, we evaluated zafirlukast in a heterogeneous group of patients who had asthma of different degrees of severity and who were receiving concomitant asthma medications. METHODS: A total of 3759 patients were enrolled at 924 sites. Patients received zafirlukast 20 mg twice a day for 4 weeks. Pulmonary function was measured twice a day, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and beta2-agonist use were recorded daily. RESULTS: In the efficacy analysis (3207 evaluable patients), all parameters showed statistically significant improvement that continued throughout the 4 weeks of the trial. A total of 71% of patients had improved pulmonary function and 72% had improved asthma symptoms. Improvement was consistent regardless of asthma severity category and regardless of concomitant asthma medication category. More than 70% of both physicians and patients indicated there was clinical improvement in pulmonary measures as well as in asthma symptoms. Common adverse events reported were headache (3.7%), nausea (1.4%), pharyngitis (1.4%), and sinusitis (1.1%). CONCLUSIONS: Zafirlukast 20 mg twice a day is well tolerated and improves pulmonary function and asthma symptoms, regardless of asthma severity category and regardless of concomitant asthma medication category.

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.

Comparative efficacy and safety of albuterol sulfate Spiros inhaler and albuterol metered-dose inhaler in asthma.

STUDY OBJECTIVE: To compare the long-term efficacy and safety of albuterol administration using a Spiros Inhalation System (Dura Pharmaceuticals; San Diego, CA) dry powder inhaler (DPI) and albuterol (Ventolin; Glaxo Wellcome; Research Triangle Park, NC) administration using a metered-dose inhaler (MDI) in patients with asthma. MATERIALS AND METHODS: This was a phase III, 12-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study of 283 adolescent and adult patients with mild to moderate asthma. The patients were randomized into one of three treatment groups: the Spiros group, who were given 108 microg/actuation of albuterol sulfate equivalent to 90 microg of albuterol base; the MDI group, who were given 90 microg/actuation of albuterol; and the placebo group. RESULTS: Over the length of the study, the Spiros and MDI groups were comparable in all FEV1 parameters. Both active treatment groups were superior to the placebo group for each FEV1 parameter at all visits. With the exception of differences at treatment week 0 for the maximum percent change in the FEV1, the duration of effect, and the area under the curve at baseline, there were no statistically significant differences between the Spiros and MDI groups for any FEV1 parameters. Using a repeated-measures analysis, the FEV1 parameters at week 0 for the Spiros group were not statistically significantly different from the parameters at weeks 4, 8, and 12. The same analysis effect at week 0 for the MDI group was greater for maximum percent change in the FEV1 from baseline (weeks 4, 8, and 12) and duration of effect. Adverse events and changes in clinical laboratory values, vital signs, ECG results, and physical examinations were reported with similar incidence in each of the three treatment groups. CONCLUSION: Both active treatments were superior to the placebo treatment. The Spiros DPI was well tolerated and was as effective as the albuterol MDI in treating patients with moderate asthma.

Therapeutic effect of zafirlukast as monotherapy in steroid-naive patients with severe persistent asthma.

STUDY OBJECTIVES: We evaluated the efficacy of the leukotriene receptor antagonist zafirlukast (Accolate), 20 mg twice daily, as monotherapy in patients with severe persistent asthma (defined by an FEV1 < 60% of predicted before treatment and frequent night-time symptoms). DESIGN: Data were analyzed from a subgroup of 261 steroid-naive patients (zafirlukast, n = 149; placebo, n = 112) from four randomized, double-blind, placebo-controlled, 13-week trials with similar experimental designs, entry criteria, and clinical assessments. PATIENTS: These patients were mostly men (57%) older than 30 years (56%) with pulmonary obstruction, ie, FEV1/FVC ratio < 0.7 (79%), and reversible airway disease demonstrated by a 15% increase in FEV1 after inhaled bronchodilator use. RESULTS: At end point, patients who received zafirlukast monotherapy had significant (p < 0.05) improvements from baseline, and compared with placebo, in FEV1, morning and evening peak expiratory flow (PEF), daytime asthma symptoms, nighttime awakenings, and beta2-agonist use. A stratified analysis based on the FEV1/FVC ratio showed an interaction between treatment and the amount of airflow obstruction for nighttime awakenings and mornings with asthma. Moreover, 37% of patients in both treatment groups had PEF variability > or = 20% (an indirect measure of airway inflammation). Zafirlukast patients with PEF variability > or = 20% had increases from baseline in the morning and evening PEF of approximately 40 and 11 L/min, respectively. For patients who take zafirlukast and who have a PEF variability of < 20%, the morning and evening PEF increased by 25 and 30 L/min, respectively. Regardless of the degree of PEF variability, zafirlukast significantly (p < 0.05) increased morning and evening PEF compared with placebo. CONCLUSION: Patients with severe persistent asthma who received zafirlukast as monotherapy had clinically significant improvements across all efficacy measures compared with placebo and significant reductions in PEF variability.