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Background: Primatene ® MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. Method: A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Results: Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The C max in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Conclusion: Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. Clinical trial registration number: NCT04207840.

Patients with early-stage COPD were assigned to usual care plus tiotropium or placebo. Tiotropium resulted in better FEV 1 values. The annual decline in the prebronchodilator FEV 1 was similar in the two groups, but a benefit from tiotropium was seen in postbronchodilator FEV 1 .

In this trial, patients with mild asthma used albuterol alone as needed, inhaled budesonide maintenance therapy plus albuterol as needed, or an inhaler containing both budesonide and formoterol as needed for asthma symptoms. There were fewer exacerbations in both groups in which treatment included budesonide.

In this large, randomized trial, the investigators compared outcomes in patients with chronic obstructive pulmonary disease (COPD) treated with once-daily inhalation of tiotropium or placebo. There was no benefit of treatment on the rate of loss of lung function over time, although benefits were observed in some secondary end points. These investigators compared outcomes in patients with chronic obstructive pulmonary disease treated with once-daily inhalation of tiotropium or placebo. There was no benefit of treatment on the rate of loss of lung function over time, although benefits were observed in some secondary end points. Prospective studies testing effects on the progression of chronic obstructive pulmonary disease (COPD) through the evaluation of the slope of the forced expiratory volume in 1 second (FEV 1 ) have not shown that inhaled short-acting anticholinergic drugs, inhaled corticosteroids, or N -acetylcysteine alter this marker of disease progression. 1 – 7 To date, only smoking cessation has prospectively been shown to alter the rate of decline of FEV 1 in patients with COPD. 2 Tiotropium is a once-daily, inhaled anticholinergic drug that provides at least 24-hour improvements in airflow and hyperinflation in patients with COPD. 8 – 10 Clinical trials lasting 6 weeks to . . .

In patients with mild asthma, inhaled glucocorticoid and β-agonist in a single inhaler, used as needed, was compared with maintenance glucocorticoid or as-needed β-agonist for asthma control. The combination was superior to β-agonist but less effective than maintenance therapy. Two articles report comparisons of glucocorticoid plus β-agonist in a single inhaler with maintenance glucocorticoid or as-needed β-agonist in patients with mild asthma. Combination therapy was superior to β-agonist for symptoms but was less effective than maintenance therapy. Combination therapy and maintenance therapy were effective for asthma control and were superior to β-agonist.

The frequency of COPD exacerbations during treatment with a triple inhaler — delivering a long-acting beta-agonist (LABA), a long-acting muscarinic antagonist (LAMA), and an inhaled glucocorticoid — was compared with that with a LABA–LAMA or LABA–inhaled glucocorticoid.

Inhaled glucocorticoid plus β-agonist in a single inhaler was compared with maintenance inhaled glucocorticoid for exacerbation risk among patients with mild asthma. Combination therapy was noninferior to maintenance therapy. Two articles report comparisons of glucocorticoid plus β-agonist in a single inhaler with maintenance glucocorticoid or as-needed β-agonist in patients with mild asthma. Combination therapy was superior to β-agonist for symptoms but was less effective than maintenance therapy. Combination therapy and maintenance therapy were effective for asthma control and were superior to β-agonist.

In two trials, the addition of tiotropium to the treatment of patients whose asthma was not controlled by inhaled glucocorticoids and long-acting beta-agonists led to a modest improvement in lung function and a decrease in severe asthma exacerbations over 48 weeks. A substantial proportion of patients with asthma have poorly controlled disease, with recurring symptoms and exacerbations despite the use of preferred controller drugs (i.e., inhaled glucocorticoids with or without inhaled long-acting beta-agonists [LABAs]). For these patients, alternative treatment options may have substantial limitations, including marginal efficacy, cumbersome routes of administration, side effects, and high cost. 1 , 2 The option of adding a second long-acting inhaled bronchodilator in patients with uncontrolled asthma has been supported by results from recent studies that examined the efficacy of tiotropium, a long-acting anticholinergic bronchodilator approved for the treatment of chronic obstructive pulmonary disease (COPD) but not . . .

In adults with mild asthma, a combination of an inhaled corticosteroid with a fast-onset long-acting β-agonist (LABA) used as reliever monotherapy reduces severe exacerbations compared with short-acting β-agonist (SABA) reliever therapy. We investigated the efficacy of combination budesonide–formoterol reliever therapy compared with maintenance budesonide plus as-needed terbutaline. We did a 52-week, open-label, parallel-group, multicentre, superiority, randomised controlled trial at 15 primary care or hospital-based clinical trials units and primary care practices in New Zealand. Participants were adults aged 18–75 years with a self-reported doctor's diagnosis of asthma who were using SABA for symptom relief with or without maintenance low to moderate doses of inhaled corticosteroids in the previous 12 weeks. We randomly assigned participants (1:1) to either reliever therapy with budesonide 200 μg–formoterol 6 μg Turbuhaler (one inhalation as needed for relief of symptoms) or maintenance budesonide 200 μg Turbuhaler (one inhalation twice daily) plus terbutaline 250 μg Turbuhaler (two inhalations as needed). Participants and investigators were not masked to group assignment; the statistician was masked for analysis of the primary outcome. Six study visits were scheduled: randomisation, and weeks 4, 16, 28, 40, and 52. The primary outcome was the number of severe exacerbations per patient per year analysed by intention to treat (severe exacerbations defined as use of systemic corticosteroids for at least 3 days because of asthma, or admission to hospital or an emergency department visit because of asthma requiring systemic corticosteroids). Safety analyses included all participants who had received at least one dose of study treatment. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12616000377437. Between May 4, 2016, and Dec 22, 2017, we assigned 890 participants to treatment and included 885 eligible participants in the analysis: 437 assigned to budesonide–formoterol as needed and 448 to budesonide maintenance plus terbutaline as needed. Severe exacerbations per patient per year were lower with as-needed budesonide–formoterol than with maintenance budesonide plus terbutaline as needed (absolute rate per patient per year 0·119 vs 0·172; relative rate 0·69, 95% CI 0·48–1·00; p=0·049). Nasopharyngitis was the most common adverse event in both groups, occurring in 154 (35%) of 440 patients receiving as-needed budesonide–formoterol and 144 (32%) of 448 receiving maintenance budesonide plus terbutaline as needed. In adults with mild to moderate asthma, budesonide–formoterol used as needed for symptom relief was more effective at preventing severe exacerbations than maintenance low-dose budesonide plus as-needed terbutaline. The findings support the 2019 Global Initiative for Asthma recommendation that inhaled corticosteroid–formoterol reliever therapy is an alternative regimen to daily low-dose inhaled corticosteroid for patients with mild asthma. Health Research Council of New Zealand.

Preliminary evidence is equivocal about the role of exhaled nitric oxide (NO) in clinical asthma management. We aimed to assess whether measurement of exhaled NO, as a biomarker of airway inflammation, could increase the effectiveness of asthma treatment, when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults. We did a randomised, double-blind, parallel-group trial at ten centres in the USA. We screened 780 inner-city patients, aged 12–20 years, who had persistent asthma. All patients completed a run-in period of 3 weeks on a regimen based on standard treatment. 546 eligible participants who adhered to treatment during this run-in period were then randomly assigned to 46 weeks of either standard treatment, based on the guidelines of the National Asthma Education and Prevention Program (NAEPP), or standard treatment modified on the basis of measurements of fraction of exhaled NO. The primary outcome was the number of days with asthma symptoms. We analysed patients on an intention-to-treat basis. This trial is registered with clinicaltrials.gov, number NCT00114413. During the 46-week treatment period, the mean number of days with asthma symptoms did not differ between the treatment groups (1·93 [95% CI 1·74 to 2·11] in the NO monitoring group vs 1·89 [1·71 to 2·07] in the control group; difference 0·04 [−0·22 to 0·29], p=0·780). Other symptoms, pulmonary function, and asthma exacerbations did not differ between groups. Patients in the NO monitoring group received higher doses of inhaled corticosteroids (difference 119 μg per day, 95% CI 49 to 189, p=0·001) than controls. Adverse events did not differ between treatment groups (p>0·1 for all adverse events). Conventional asthma management resulted in good control of symptoms in most participants. The addition of fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids, without clinically important improvements in symptomatic asthma control. US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.