Randomized trial to assess the efficacy and safety of beclomethasone dipropionate breath-actuated inhaler in patients with asthma.

BACKGROUND: Breath-actuated inhalers (BAI) eliminate the need for the hand-breath coordination required with standard metered-dose inhalers (MDI). OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate (BDP) administered via BAI. METHODS: This 6-week, phase III, double-blind study included patients aged ≥12 years with persistent asthma. During the single-blind run-in, patients discontinued asthma medications and received twice-daily placebo BAI or MDI. At randomization, BAI patients received BDP BAI 320 µg/day, BDP BAI 640 µg/day, or placebo BAI, and MDI patients received BDP MDI 320 µg/day or placebo MDI. Assessments included standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from 0 to 6 weeks (AUEC[0-6 wk]) (obtained by clinic-based spirometry; the primary end point), morning peak expiratory flow (PEF), trough daily morning FEV1 (obtained by handheld spirometry), withdrawals, and tolerability. RESULTS: Of 425 patients randomized, most were white (81%) and female (61%). BDP BAI 320 and 640 µg/day significantly improved FEV1 AUEC(0-6 wk) versus placebo (p < 0.001). The BDP BAI treatment groups exhibited significantly improved morning PEF and daily morning FEV1 versus placebo (p < 0.001). Similar treatment effects were demonstrated for BDP MDI (p < 0.001). Fewer patients withdrew due to worsening asthma while taking BDP BAI 320 µg/day (n = 1), BDP BAI 640 µg/day (n = 0), and BDP MDI 320 µg/day (n = 1) versus placebo (n = 10). BDP BAI was well tolerated. CONCLUSION: BDP BAI demonstrated significant improvements in pulmonary function versus placebo, with results similar to BDP MDI. The safety profile of BDP BAI was comparable to BDP MDI, with no new safety signals.The study was registered on ClinicalTrials.gov (NCT02513160), www.clinicaltrials.gov.

Advancing Alternative Analysis: Integration of Decision Science.

BACKGROUND: Decision analysis-a systematic approach to solving complex problems-offers tools and frameworks to support decision making that are increasingly being applied to environmental challenges. Alternatives analysis is a method used in regulation and product design to identify, compare, and evaluate the safety and viability of potential substitutes for hazardous chemicals. OBJECTIVES: We assessed whether decision science may assist the alternatives analysis decision maker in comparing alternatives across a range of metrics. METHODS: A workshop was convened that included representatives from government, academia, business, and civil society and included experts in toxicology, decision science, alternatives assessment, engineering, and law and policy. Participants were divided into two groups and were prompted with targeted questions. Throughout the workshop, the groups periodically came together in plenary sessions to reflect on other groups' findings. RESULTS: We concluded that the further incorporation of decision science into alternatives analysis would advance the ability of companies and regulators to select alternatives to harmful ingredients and would also advance the science of decision analysis. CONCLUSIONS: We advance four recommendations: a) engaging the systematic development and evaluation of decision approaches and tools; b) using case studies to advance the integration of decision analysis into alternatives analysis; c) supporting transdisciplinary research; and d) supporting education and outreach efforts. https://doi.org/10.1289/EHP483.

Novel albuterol multidose dry powder inhaler in patients with exercise-induced bronchoconstriction: A single-dose, double-blind, randomized, 2-way crossover study.

BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) was developed that eliminates the need to coordinate device actuation with inhalation as is required with conventional metered-dose inhalers. OBJECTIVE: To evaluate albuterol MDPI efficacy and safety in patients with exercise-induced bronchoconstriction (EIB). METHODS: This single-dose, double-blind, 2-way crossover study randomized adolescents and adults with EIB (≥20% fall from pre-exercise challenge FEV(1)) to treatment sequences of albuterol MDPI (180 µg [2 inhalations of 90 µg each])/placebo MDPI (n = 19) or the reverse sequence (n = 19). FEV(1) was measured 30 and 5 min predose, 30 min postdose (ie, 5 min before treadmill exercise challenge; baseline) and 5, 10, 15, 30, and 60 min after exercise challenge. The primary efficacy endpoint was maximum percentage fall from baseline in FEV(1) up to 60 min post-exercise challenge. RESULTS: Mean maximum percentage fall in FEV(1) within 60 min post-exercise challenge was 6.2 ± 1.4% for albuterol MDPI versus 22.4 ± 1.4% for placebo MDPI (between-treatment difference: -16.2%; 95% CI: -20.2% to -12.1%; P < 0.0001). A significantly higher percentage of albuterol MDPI-treated patients were protected against EIB (<10% maximum FEV(1) fall post-exercise challenge) versus placebo MDPI (84.2% vs 15.8%; P < 0.0001). Protection with albuterol MDPI was evident within 5 min and maintained through 30 min; recovery was complete for both groups at 60 min. Treatment with a single dose of albuterol MDPI was generally well tolerated. CONCLUSIONS: Albuterol MDPI provides clinically significant protection from EIB in adolescents and adults with EIB; no new safety issues were observed with short-term albuterol MDPI use. ClinicalTrials.gov identifier NCT01791972.

The history and progression of treatments for allergic rhinitis.

This article intends to place new treatments in the context of allergic rhinitis (AR) treatment history. The medical literature was searched for significant advances and changes in AR treatment. Historical data on AR treatment options and management were selected. Reviews of AR management published throughout the 20th century were included to provide context for treatment advances. Modern AR treatment began in the early 20th century with immunotherapy and was soon followed by the emergence of antihistamine therapy in the 1930s. Numerous treatments for AR have been used over the ensuing decades, including decongestants, mast cell stabilizers, and leukotriene receptor antagonists. Topical corticosteroid options were developed the 1950s, and, added to baseline antihistamine therapy, became the foundation of AR treatment. Treatment options were significantly impacted after the 1987 Montreal Protocol, which phased out the use of chlorofluorocarbon propellant aerosols because of environmental concerns. From the mid-1990s until recently, this left only aqueous solution options for intranasal corticosteroids (INSs). The approval of the first hydrofluoroalkane propellant aerosol INSs for AR in 2012 restored a "dry" aerosol treatment option. The first combination intranasal antihistamine/INSs was also approved in 2012, providing a novel treatment option for AR. Treatment of AR has progressed with new therapeutic options now available. This should continue to move forward with agents to alter the allergic mechanism itself and impact the disease burden that has a significant impact on patient outcomes.

Recommendations for the pharmacologic management of allergic rhinitis.

Allergic rhinitis (AR) affects at least 60 million people in the United States each year, resulting in a major impact on patient quality of life, productivity, and direct and indirect costs. As new therapies, data, and literature emerge in the management of AR, there is a need to communicate and disseminate important information to health care professionals to advance the practice of medicine and lessen the disease burden from AR. Treatment recommendations for AR have not been updated since the 2012 Food and Drug Administration approval of nonaqueous intranasal aerosol agents using hydrofluoroalkane propellants and the first aqueous intranasal combination product. Here, we present an updated algorithm for the pharmacologic treatment of AR that includes these new treatment options. Treatment recommendations are categorized by disease severity (mild versus moderate/severe) and duration of symptoms (episodic versus nonepisodic, with episodic defined as <3 days/wk or for <3 weeks). Preferred treatments are suggested, as well as alternative options for consideration by clinicians in the context of individual patient needs. This recommendation article also outlines the importance of treatment monitoring, which can be conducted using the recently developed Rhinitis Control Assessment Test. Successful therapeutic outcomes depend on multiple factors, including use of the most effective pharmacologic agents as well as patient adherence to therapy. Therefore, it is imperative that rhinitis patients not only receive the most effective therapeutic options, but that they also understand and are able to adhere to the comprehensive treatment regimen. Successful treatment, with all of these considerations in mind, results in better disease outcomes, improved quality of life for patients, and greater economic productivity in the home and workplace.

Exercise-induced bronchospasm, asthma control, and obesity.

Exercise-induced bronchospasm (EIB) commonly affects patients with asthma. However, the relationship between EIB and asthma control remains unclear. Exercise limitation due to asthma might lead to reduced physical activity, but little information is available regarding obesity and EIB in asthma. A recent survey evaluated the frequency of EIB and exercise-related respiratory symptoms in a large number of patients with asthma. The survey results were reanalyzed to address any relationship between EIB and asthma control and obesity. A nationwide random sample of children aged 4-12 years (n = 250), adolescents aged 13-17 years (n = 266), and adults aged ≥18 years (n = 1001) with asthma were interviewed by telephone. Questions in the survey addressed asthma symptoms in general, medication use, and height and weight. Asthma control was categorized using established methods in the Expert Panel Report 3. Body mass index (BMI) was calculated using standard nomograms and obesity was defined as a BMI ≥ 30 kg/m(2). Most children (77.6%), adolescents (71.1%), and adults (83.1%) had either "not well" or "very poorly" controlled asthma. Children with "not well" controlled asthma reported a history of EIB significantly more often than those with "well" controlled" asthma. Asthma patients of all ages who had "not well" and "very poorly" controlled asthma described multiple (four or more) exercise-related respiratory symptoms significantly more often than those with "well-controlled" asthma. Obesity was significantly more common in adolescents with "not well" and "very poorly" controlled asthma and adults with "very poorly" controlled asthma. Children, adolescents, and adults with asthma infrequently have well-controlled disease. A history of EIB and exercise-related respiratory symptoms occur more commonly in patients with not well and very poorly controlled asthma. Obesity was found more often in adolescents and adults, but not children, with asthma, which was not well and very poorly controlled.

The CHOICE survey: high rates of persistent and uncontrolled asthma in the United States.

BACKGROUND: Surveys have consistently shown that many patients with asthma do not have their disease well controlled. OBJECTIVES: The CHOICE (Comprehensive Survey of Healthcare Professionals and Asthma Patients Offering Insight on Current Treatment Gaps and Emerging Device Options) survey was designed to evaluate the current status of inhalation devices used in asthma treatment, but questions also were included about asthma severity and control. METHODS: A total of 1,000 patients with asthma were interviewed about their use of inhalation devices and asthma-related burden, medication use, and hospital/emergency care. Based on the responses to these questions, asthma severity and control were categorized using methods established in the Expert Panel Report III (EPR 3). RESULTS: Almost half (490) of the patients with asthma participating in the CHOICE survey were not using controller medications. Most of those not using controllers (79%) had persistent asthma; 47% had either mild or moderate persistent asthma. Of those on controllers (510), only 14.3% were well controlled. Acute care utilization was greater for patients with persistent asthma than those with intermittent asthma and for patients with not well and poorly controlled asthma than those with well-controlled asthma. CONCLUSION: The CHOICE survey is particularly pertinent clinically, because it demonstrates for the first time, using EPR 3 methods, the current extent of poor asthma control in the United States. This situation falls far short of national asthma management targets.

Exercise-induced bronchospasm: a case study in a nonasthmatic patient.

PURPOSE: To provide an overview of the clinical presentation, diagnosis, and management of exercise-induced bronchospasm (EIB) without underlying asthma. DATA SOURCES: Case presentation and review of the EIB Landmark Survey. CONCLUSIONS: EIB is a common and well-described occurrence in patients with asthma, as well as in patients with no overt respiratory condition. Treatment with a short-acting beta-agonist before starting exercise is effective, yet this treatment approach is underutilized in the majority of patients with asthma. IMPLICATIONS FOR PRACTICE: This case highlights the implications of undermanaged EIB and the disconnect between healthcare provider recommendations and the beliefs and behaviors in patients with EIB. Inhaled short-acting beta-agonists can attenuate EIB in 80%-95% of patients and are effective during 2-3 h of exercise. Patients with a compromised level of physical activity because of EIB who do not respond to conventional treatment strategies should be referred to a respiratory specialist for diagnostic evaluation and confirmation of underlying asthma. Nurse practitioners should remain vigilant to identify untreated EIB and ensure that affected patients understand the condition and appropriate treatment options.

Exercise-induced bronchospasm: implications for patients with or without asthma in primary care practice.

Exercise-induced bronchospasm (EIB) can represent a substantial barrier to physical activity. We present the cases of two patients with EIB, one with asthma, and one without asthma, who were evaluated at our primary care practice. The first case was a 44-year-old man with a history of seasonal allergic rhinitis but no asthma, who reported difficulty breathing when playing tennis. The second case was a 45-year-old woman who presented with persistent, generally well-controlled asthma, who was now experiencing bouts of coughing and wheezing during exercise. In both cases, an exercise challenge was used to diagnose EIB, and patients were prescribed a short-acting beta agonist to be used immediately before initiating exercise. EIB is a frequently encountered problem among patients presenting to primary care specialists. Affected patients should be made aware of the importance of proactive treatment with a short-acting beta agonist before initiating any exercise.

Exercise-induced bronchospasm in children with asthma in the United States: results from the Exercise-Induced Bronchospasm Landmark Survey.

Despite the availability of effective therapies, uncontrolled asthma remains a common problem. Previous large surveys suggest that exercise-related respiratory symptoms may be a significant element of uncontrolled asthma. The Exercise-Induced Bronchospasm (EIB) Landmark Survey is the first comprehensive, national survey evaluating EIB awareness and impact among the general public, asthma patients, and health care providers. This study was designed to evaluate the prevalence and impact of exercise-related respiratory symptoms in children (aged 4-17 years) with asthma. A national survey was conducted with parents of 516 children diagnosed with asthma or taking medications for asthma in the prior year. The majority of parents reported that their child experienced one or more exercise-related respiratory symptom and almost one-half (47.4%) experienced four or more symptoms. Most commonly reported symptoms were coughing, shortness of breath, and wheezing. Respondents reported that asthma limited their child's ability to participate either "a lot" or "some" in sports (30%), other outdoor activities (26.3%), and normal physical exertion (20.9%). Only 23.1% of children with exercise-related respiratory symptoms were reported to take short-acting beta-agonists such as albuterol "always" or "most of the time" before exercising. Exercise-related respiratory symptoms among pediatric asthma patients are common and substantially limit the ability of children to participate normally and perform optimally in physical activities. Such symptoms may reflect uncontrolled underlying asthma that should be evaluated and treated with appropriate controller medications. Despite the availability of preventative therapy, many children do not use short-acting bronchodilators before exercise as recommended in national guidelines.

Impact of exercise-related respiratory symptoms in adults with asthma: Exercise-Induced Bronchospasm Landmark National Survey.

An estimated 5-20% of the general population and up to 90% of people with asthma experience exercise-induced bronchospasm (EIB). The EIB Landmark Survey is the first comprehensive study on exercise-related respiratory symptoms in the United States. Two surveys were conducted: the first surveyed adults (≥18 years) in the general public and the second surveyed adults with asthma or taking medications for asthma in the prior year. Parameters assessed included exercise-related respiratory symptoms, activity levels, and short-acting beta-antagonist (SABA) use. In the general public survey (n = 1085), 8% were currently diagnosed with asthma. However, 29% reported experiencing one or more of six respiratory-related symptoms during or immediately after exercising. In the EIB in adult asthma survey (n = 1001), although >80% of adults experienced one or more of six exercise-related respiratory symptoms, only 30.6% reported a diagnosis of EIB. Almost one-half (45.6%) of adults with asthma reported that they avoid physical activities because of symptoms. Despite symptoms, only 22.2% of respondents took SABAs before exercise "always" or "most of the time"; 36.3% took rescue medications after or during exercise. Exercise-related respiratory symptoms limit physical activities and negatively impact daily lives. However, adults in the United States lack awareness of EIB. Although many subjects stated that their asthma symptoms limit their physical activity, few adhered to treatment guidelines by using SABAs appropriately before exercising. Findings from this survey support the need for better communication about the proper evaluation and management of EIB in the community and in asthma patients.

The Childhood Asthma Control Test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma.

BACKGROUND: The Childhood Asthma Control Test (C-ACT) has demonstrated validity in classifying children aged 4 to 11 years as having either "well-controlled" or "not well-controlled" asthma. However, new asthma management guidelines distinguish 3 levels of asthma control. OBJECTIVE: We sought to determine a second cut point on the C-ACT to identify children with "very poorly controlled" asthma. METHODS: Binomial logistic regression was performed on data from 671 children. The specialist's rating of control was the criterion measure. Specialists' severity ratings, specialists' assessment of therapy, and FEV(1) percent predicted were used to assess the clinical validity of the cut point. RESULTS: A cut point of 12 was selected because it correctly classified the highest percentage of participants (66.3%) as having "very poorly controlled" (vs "not well controlled") asthma and demonstrated high specificity (89.8%) and moderate positive predictive value (69.1%). Children scoring 12 or less versus 13 to 19 had lower mean FEV(1) percent predicted (79.8% vs 92.6%, P = .0002) and were more frequently stepped up in therapy (72.9% vs 53.6%, P = .0131) and rated as having severe asthma (13.6% vs 4.5%, P = .0005). One month later, significant differences in C-ACT scores and lung function between these 2 groups persisted. The mean C-ACT score of participants classified as "very poorly controlled" was significantly lower than that of participants classified as "not well-controlled" (17.2 vs 20.3, respectively; P = .0001). CONCLUSION: A second cut point of 12 or less on the C-ACT identifies children with the lowest level of control, who are at risk for poorer outcomes, and is conceptually consistent with the classification of "very poorly controlled" asthma adopted by asthma management guidelines.

Adding montelukast to fluticasone propionate/salmeterol for control of asthma and seasonal allergic rhinitis.

Limited information exists comparing fluticasone propionate/salmeterol combination (FSC) versus montelukast (MON) in patients with coexistent asthma and allergic rhinitis. The purpose of this study was to compare the addition of MON to patients receiving FSC on asthma control while experiencing asthma and allergy symptoms. Additionally, the effect of fluticasone propionate aqueous nasal spray (FPANS) and MON were assessed in allergic rhinitis control. Symptomatic patients (n = 1385) with asthma and seasonal allergic rhinitis were randomized to receive FSC, 100/50 micrograms twice daily; FSC twice daily + FPANS, 200 micrograms once daily; FSC twice daily + MON, 10 mg once daily; or MON once daily for 4 weeks during the allergy pollen season. Patients recorded peak expiratory flow, rescue albuterol use, and asthma and rhinitis symptoms. No additional improvements in overall asthma control were seen when MON was added to FSC. Treatment with FSC produced significant (p < 0.001) improvements in all clinical and patient-reported measures versus MON. FSC + FPANS was superior to FSC + MON (p < or = 0.001) in improving daytime and nighttime total nasal symptom scores. Adverse events were similar. In patients with asthma and allergic rhinitis, adding MON to FSC provided no additional benefit in asthma control. FSC resulted in superior improvement in asthma control compared with MON. FPANS also provided superior nasal symptom control versus MON in allergic patients treated with FSC for asthma. Optimal disease control in patients with asthma and allergic rhinitis should be achieved by the most effective therapy directed toward each disease component.

Ciclesonide improves health-related quality of life in adults and adolescents with mild-to-moderate persistent asthma.

Health-related quality of life (HRQOL) provides information on patients' everyday physical, emotional, and social difficulties that traditional measurements of asthma severity (pulmonary function assessments and asthma symptom scores) may not reflect. Our objective is to evaluate the effect of ciclesonide (CIC) on HRQOL in a combined analysis of two identical, 12-week, multicenter, double-blind, parallel-group, placebo-controlled trials. Patients (N=1015) with mild-to-moderate asthma (aged >or=12 years; forced expiratory volume in 1 s 60-85% predicted at randomization after administration of single-blind placebo during baseline [5-28 days]) were randomized to receive placebo or CIC 80, 160, or 320 microg (ex-actuator) once daily. HRQOL was assessed using the Juniper Asthma Quality-of-Life Questionnaire (AQLQ). The overall AQLQ score and individual domain scores (activity limitation, symptoms, emotional function, and exposure to environmental stimuli) were recorded at baseline, week 4 and week 12. Statistically significant improvements (p<0.0001) in overall AQLQ scores were observed for all CIC groups versus placebo (CIC80, 0.50; CIC160, 0.61; CIC320, 0.69; placebo, 0.14) from baseline to week 12. Similar significant improvements were observed for all CIC groups in the four individual domain scores, except the CIC80 environmental stimuli domain score. A greater proportion of CIC-treated patients achieved a minimally important difference in overall AQLQ score (>or=0.5 improvement) by week 4, which was sustained through to week 12, compared with placebo (week 12: CIC80, 47.1%; CIC160, 50%; CIC320, 50.6%; placebo, 31%). In this combined analysis, once-daily CIC significantly improved HRQOL compared with placebo, in adults/adolescents with mild-to-moderate persistent asthma.

Women with asthma: a review of potential variables and preferred medical management.

OBJECTIVES: To summarize the potential variables that contribute to the increased risk of asthma in women, outline therapeutic strategies that address these variables, and review current treatment recommendations for both pregnant and nonpregnant women with asthma. DATA SOURCES: Literature searches (MEDLINE and cross-references) were performed using the keywords asthma and women in combination with the terms compliance, depression, emergency department, hormones, menstruation, mortality, National Asthma Education and Prevention Program, osteoporosis, pregnancy, prevalence, smoking, and treatment. Searches were limited to human studies with data published before 2005. STUDY SELECTION: The author selected relevant articles for inclusion in this review. RESULTS: Fluctuations in sex hormones, menstruation, pregnancy, obesity, depression, medication nonadherence, and smoking may contribute to increased asthma symptoms or severity in women. Asthma control may be improved if physicians address conditions and behaviors associated with asthma variability and severity in women. Notably, asthma must be managed aggressively in pregnant women, because uncontrolled asthma can lead to perinatal complications. Asthma treatment in women is optimized through patient and physician adherence to national guideline recommendations, including provision of patient education and asthma action plans. CONCLUSIONS: Multiple variables throughout the female life cycle may influence asthma control. Successful asthma management requires an ongoing partnership between the patient and her physician to address physiologic (eg, sex hormones, pregnancy, obesity, depression) and nonphysiologic (eg, smoking, medication nonadherence) factors that may contribute to decreased asthma control.

Comparative efficacy and safety of low-dose fluticasone propionate and montelukast in children with persistent asthma.

OBJECTIVE: To evaluate efficacy, safety, health outcomes, and cost-effectiveness of fluticasone propionate (FP) versus montelukast (MON) in 342 children (6 to 12 years of age) with persistent asthma. STUDY DESIGN: Randomized, double-blind, 12-week study of treatment with FP inhalation powder 50 mug twice daily or MON chewable 5 mg once daily for 12 weeks. RESULTS: Compared with MON, FP significantly increased mean percent change from baseline FEV1 (forced expiratory volume in 1 second) (P=.002), morning PEF (peak expiratory flow) (P=.004), evening PEF (P=.020), and percent rescue-free days (P=.002) at end point, and it significantly reduced nighttime symptom scores (P <.001) and mean total (P=.018), and nighttime (P <.001) albuterol use. Withdrawals from the study were more frequent with MON (21%) than with FP (13%). Adverse events (69% vs 71%) and mean end point to baseline 12-hour urinary cortisol excretion ratios were similar. Parents and physicians were more satisfied with FP treatment than with MON (P=.006 and P=.016, respectively, at Week 12). Mean total daily asthma-related cost per patient in the FP group was approximately one-third of that in the MON group ($1.25 vs $3.49). CONCLUSION: FP was significantly more effective than MON in improving pulmonary function, asthma symptoms, and rescue albuterol use. Both therapies had similar safety profiles. Parent- and physician-reported satisfaction ratings were higher with FP treatment, and asthma-related costs were lower.

Tolerability of short-term, high-dose formoterol in healthy volunteers and patients with asthma.

BACKGROUND: Formoterol is a long-acting (>or=12 hours) beta(2)-receptor agonist with a rapid onset of action (1-3 minutes). It is approved in the United States, delivered via a single-dose dry-powder inhaler (DPI), for use in combination with anti-inflammatory therapy for the maintenance treatment of asthma and for the prevention of exercise-induced bronchospasm. Potential exposure of patients to higher doses than are currently approved is an important consideration in assessing the safety profile of formoterol. OBJECTIVE: This article reviews data from clinical trials investigating the effects of short-term use (4-48 hours) of high doses of formoterol (maximum, 228 microg). METHODS: Comparative and noncomparative studies of the effects of short-term, high-dose formoterol, inhaled via metered-dose inhaler (MDI) or single-dose DPI, were identified through searches of the literature indexed on MEDLINE, EMBASE, Current Contents, and Science Citation Index from their inception through August 15, 2003. RESULTS: This review included 1 open-label noncomparative study of high-dose formoterol in 12 healthy volunteers (mean age, 29 years), 1 placebo-controlled dose-escalation study of formoterol in 20 patients with asthma (mean age, 30 years), and 3 comparative studies of formoterol and short-acting beta(2)-agonists. The latter included a dose-escalation study in 13 patients with asthma (mean age, 47.2 years), a high-dose study in 12 healthy volunteers (mean age, 27 years), and a dose-escalation study in 9 children with asthma (mean age, 10 years). In the study in healthy volunteers, the metabolic and cardiovascular effects of high single doses of formoterol (maximum, 120 microg) were small and had no clinical consequences. In the placebo-controlled dose-escalation study in patients with asthma, however, the metabolic effects of formoterol at doses from 24 to 96 microg and the cardiovascular effects of formoterol at doses from 48 to 96 microg differed significantly from those of placebo (P < 0.05 to P <0.001) but were unlikely to result in clinically significant adverse effects. In the studies comparing formoterol with short-acting beta(2)-agonists in patients with stable asthma, the cardiovascular and metabolic effects of short-term, high-dose formoterol (cumulative dose, up to 228 microg) were comparable to those of high-dose albuterol (salbutamol) (cumulative dose, up to 3800 microg). Studies of high-dose formoterol delivered via multidose DPI (not available in the United States) have reported a safety profile similar to those of high-dose terbutaline and albuterol. CONCLUSION: In studies of the short-term use of high-dose formoterol delivered via an MDI or single-dose DPI, this agent had a safety profile comparable to that of short-acting beta(2)-agonists.