An economic assessment of inhaled formoterol dry powder versus ipratropium bromide pressurized metered dose inhaler in the treatment of chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is debilitating and costly to manage. A recent clinical trial concluded that formoterol, a long-acting beta(2)-adrenoceptor agonist, was more clinically effective than inpratropium bromide in the management of COPD. OBJECTIVE: The aim of this study was to perform an economic assessment of the management of COPD with formeterol versus ipratropium bromide. METHODS: Assessment were based on the results of a previously published 12-week, multicenter, double-masked, randomized, parallel-group, placebo-controlled clinical trial comparing inhaled formoterol dry powder 12 and 24 microg BID with ipratropium bromide 40 microg QID pressurized metered dose inhaler and with placebo in 780 COPD patients. Treatment costs for study drugs and rescue medications were estimated from resource utilization and average wholesale prices. Costs were assessed with respect to forced expiratory lung volume in 1 second (FEV(1)) and patient-reported quality of life (QOL) as assessed via the St. George's Respiratory Questionnaire. Cost-effectiveness ratios were calculated for each treatment arm and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment relative to the next best alternative. Economic efficiency frontiers were identified. Sensitivity analysis was conducted. RESULTS: Cost analysis with respect to FEV(1) revealed an economic efficiency frontier formed by placebo, ipratropium bromide 40 microg, and formoterol 12 microg at their respective FEV(1) levels, with cost-effectiveness ratios of $30.18, $53.50, and $142.04, respectively, per FEV(1). The ICER for ipratropium over placebo was $273.03; for formoterol 12 microg over ipratropium, $1611.32. Cost analysis with respect to QOL showed an economic efficiency frontier formed by placebo and formoterol 12 microg at their respective QOL outcomes, with cost-effectiveness ratios of $25.96 and $32.56, respectively, per QOL score change. The cost-effectiveness ratio for ipratropium was $69.40,which was not on the QOL economic efficiency frontier. The ICER for formoterol 12 microg over placebo was $34.51 per QOL score point. CONCLUSIONS: Formoterol 12 microg provided greater QOL outcome than ipratropium bromide at an additional cost of $554.28 per year. Further research would be necessary to assess whether the differences in outcomes, particularly QOL, observed in the short term with formoterol would lead to favorable long-term health and economic outcomes.     

A randomized,double-blind,single-dose,crossover clinical trial of the onset and duration of protection from exercise-induced bronchoconstriction by formoterol and albuterol

BACKGROUND: Inhaled short-acting beta(2)-adrenoceptor agonists are the most commonly used treatment for the prevention of exercise-induced bronchoconstriction (EIB). Formoterol, a long-acting beta(2)-adrenoceptor agonist, has been demonstrated to provide protection from EIB, although the onset and duration of this protection have not been defined. OBJECTIVE: The purpose of this study was to determine the onset and duration of the protective effect of a single dose of inhaled formoterol powder against EIB, comparing them with the effect of a single dose of placebo and albuterol administered via metered-dose inhaler (MDI). METHODS: In this double-dummy, 4-way crossover study, patients received single doses of formoterol (12 and 24 microg) via a powder inhaler, albuterol by MDI (180 microg), and placebo. Exercise challenge tests (ECTs) were conducted at 15 minutes and at 4, 8, and 12 hours postdose. Pulmonary function studies (forced expiratory volume in 1 second [FEV(1)] and peak expiratory flow rate) were performed before and after each exercise challenge. RESULTS: Twenty adolescent and adult patients (mean age, 23.8 years; range, 13-41 years; 9 male, 11 female) with asthma were enrolled in the study, and 17 completed all 4 treatment sequences. Compared with placebo, both doses of formoterol produced significantly greater inhibition of FEV(1) decreases at all time points (P < 0.01). There were no significant differences in efficacy measures between the 2 formoterol doses throughout the study. The exercise-induced decrease in FEV(1) after albuterol treatment was significantly reduced compared with placebo only at 15 minutes after dosing (P < 0.05). Formoterol and albuterol exhibited a similar rapid onset of action (<15 minutes), but formoterol continued to protect patients against EIB for at least 12 hours (P < 0.01), whereas albuterol was no longer clinically effective by the 4-hour ECT. CONCLUSIONS: Formoterol and albuterol, given as single-dose inhalations, both provided protection from EIB within 15 minutes in this group of patients. The bronchoprotection afforded by formoterol lasted up to 12 hours, whereas that of albuterol was no longer significant by 4 hours.     

THE DURATION OF ACTION OF INHALED FORMOTEROL DRY POWDER

SUMMARY The duration of action of formoterol inhaled as a dry powder formulation is compared with placebo and a reference treatment of salbutamol dry powder in patients with bronchial asthma. This single-centre, double-blind, cross-over study recruited 23 outpatients with clinically stable asthma. These patients were treated with 12μg formoterol, 400μg salbutamol or placebo in a randomly allocated sequence, with at least 2 days between treatments. Forced expiratory volume in 1s of expiration (FEV₁) was measured at specified time points from 15 min to 15 hours post-treatment. Formoterol produced significantly higher values of FEV₁ at the primary endpoint of 12 hours compared with placebo and salbutamol. No differences between FEV₁ values were seen for the active treatments of formoterol and salbutamol for the first 5 hours post-inhalation. Formoterol was significantly superior to placebo at all time points, whereas salbutamol was significantly superior to placebo for the first 5 hours.This study demonstrates that formoterol, when given as a dry powder inhalation, has a significantly longer duration of acute bronchodilator action than 400μg salbutamol inhaled as a dry powder. The duration of action of formoterol of at least 12 hours seen in this study is at least as long as that reported following administration from a metered dose inhaler (MDI) at the same dose level. The study also demonstrates that 12μg formoterol dry powder is well tolerated by patients.     

Formoterol 12 microg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: a multicenter,randomized, open-label,parallel-group study

BACKGROUND: Although salmeterol and formoterol are both long-acting beta(2) adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients. OBJECTIVE: The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol. METHODS: This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age >/=18 years) with suboptimally controlled asthma (mean salbutamol use, >/=2 puffs/d via pressurized metered-dose inhaler [100 microg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 microg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 microg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control.RESULTS: A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P < 0.001). Similarly, patients who were switched from on-demand salbutamol alone to formoterol plus on-demand salbutamol reported a significant increase in mean evening predose PEF compared with those who continued treatment with on-demand salbutamol alone (409.3 [105.6] vs 385.0 [105.3] L/min, respectively; P < 0.001). The results for the secondary efficacy measures mirrored the significant improvements seen in patients switched to formoterol compared with those who continued to receive on-demand salbutamol alone or salmeterol plus on-demand salbutamol. CONCLUSION: In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.     

Bronchodilator therapy with metered-dose inhaler and spacer versus nebulizer in mechanically ventilated patients: comparison of magnitude and duration of response

OBJECTIVE: Four-hour comparison of the bronchodilator response of albuterol administered via metered-dose inhaler (MDI) with spacer versus small-volume nebulizer (SVN) to mechanically ventilated patients with chronic obstructive pulmonary disease (COPD). DESIGN: Prospective randomized clinical trial. SETTING: Medical intensive care unit in a university hospital. PATIENTS: Thirteen mechanically ventilated COPD patients. INTERVENTION: Albuterol administration of 4 puffs (0.4 mg) or 10 puffs (1.0 mg) via MDI with spacer or 2.5 mg via SVN to mechanically ventilated patients in order to assess the bronchodilator response over 4 hours. MEASUREMENTS AND RESULTS: Mechanically ventilated patients were enrolled in a randomized crossover study wherein one group received 4 puffs (0.4 mg) or 2.5 mg of albuterol and another group received 10 puffs (1.0 mg) or 2.5 mg of albuterol on separate days. Respiratory mechanics measurements were obtained over 4 hours. Total airway resistance declined by 14.4 +/- 3.8% after 4 MDI puffs, 18.3 +/- 1.8% after 10 MDI puffs, or 13.7 +/- 2.6% after 2.5 mg via SVN, compared to baseline (p < 0.01). After albuterol delivery, airway resistance remained improved for 90-120 minutes (p < 0.05) and returned to baseline by 4 hours with all treatments. CONCLUSION: The airway response to albuterol administration via MDI and SVN to mechanically ventilated patients was similar in magnitude and duration, returning to baseline by 240 minutes. In stable, mechanically ventilated COPD patients, albuterol may be administered via MDI with spacer or via SVN every 4 hours.     

A comparative trial of granulocyte-colony-stimulating factor and dexamethasone, separately and in combination, for the mobilization of neutrophils in the peripheral blood of normal volunteers

BACKGROUND: The clinical utility of polymorphonuclear neutrophil (PMN) transfusion therapy has been compromised, in part, by the inability to obtain sufficient quantities of functional neutrophils from donors. To define the optimal conditions for mobilization of PMNs in granulocyte donors, the effects of granulocyte-colony-stimulating factor (G-CSF) and dexamethasone, separately and in combination, on PMN counts in normal volunteers were compared. STUDY DESIGN AND METHODS: Five normal subjects were randomly assigned to each of the following single-dose regimens in 5 consecutive weeks: 1) G-CSF, 300 micrograms given subcutaneously; 2) G-CSF, 600 micrograms subcutaneously: 3) dexamethasone, 8 mg given orally; 4) G-CSF, 300 micrograms subcutaneously, plus dexamethasone, 8 mg orally; and 5) G-CSF, 600 micrograms subcutaneously, plus dexamethasone 8 mg orally. Venous blood was collected at 0, 6, 12, and 24 hours after drug administration for the determination of absolute neutrophil counts (ANCs). RESULTS: Maximal ANC was achieved at 12 hours after each regimen, except dexamethasone alone (maximum, 24 hours). Dexamethasone significantly increased the maximal ANC induced by either dose of G-CSF alone (p < 0.05). The greatest mobilization of PMNs occurred after the administration of G-CSF (600 micrograms) and dexamethasone (8 mg); the ANC increased from a mean baseline value of 3,594 per microL to 43,017 per microL at 12 hours. All of the drug regimens were well tolerated. CONCLUSION: Dexamethasone significantly increases the level of neutrophilia induced in normal subjects by G-CSF. The combination of dexamethasone and G-CSF (at the dosages used in this study) is a convenient, well-tolerated regimen for the mobilization of PMNs in the peripheral blood of granulocyte donors. Moreover, the optimal quantitative yield of PMNs is likely to be achieved by leukapheresis 12 hours after drug administration.     

A survey of albuterol administration practices in intubated patients in the neonatal intensive care unit.

INTRODUCTION: Aerosolized albuterol is commonly used in the treatment of neonatal respiratory illnesses. Clinical and in vitro studies have identified numerous factors that affect aerosol drug delivery during neonatal mechanical ventilation, including the choice of metered-dose inhaler (MDI) or nebulizer, the use of a holding chamber, time between actuations, the volume of nebulized solution, and the position and placement of the nebulizer or MDI. Because there is no consensus on the optimal method of administration, there is probably substantial variability among institutions in how aerosolized albuterol is administered to mechanically ventilated infants in the neonatal intensive care unit (NICU). OBJECTIVE: Survey academic medical centers in the United States regarding their practices of administering aerosolized albuterol to intubated newborns in the NICU. METHODS: A survey instrument was developed that queried 18 aspects of albuterol administration in mechanically ventilated infants, including the frequency of MDI and nebulizer use, the average and maximum dose, the time between MDI actuations and following the final actuation, the use of a holding chamber, and the placement location of the holding chamber or nebulizer. Respiratory therapists and respiratory therapy managers having direct knowledge of neonatal clinical practices in their neonatal fellowship program NICUs were surveyed via telephone. Those who did not respond via telephone were surveyed via fax. RESULTS: Eighty institutions were surveyed and there were 68 respondents (85% response rate). Responders averaged 35 +/- 13 NICU beds and 11 +/- 5 ventilators/d. Nineteen percent of the respondents reported administering albuterol via MDI 100% of the time; 22% use MDIs 75-99% of the time; 9% use MDIs 50-74% of the time; 4% use MDIs 25-49% of the time; and 43% never use MDIs to deliver albuterol. The average dose via MDI was: 1 puff: 30%; 2 puffs: 65%; and 4 puffs: 5%. The maximum dose via MDI was: 2 puffs: 30%; 3 puffs: 14%; 4 puffs: 36%; 6 puffs: 11%; and 8 puffs: 6%. Thirty-one percent of the respondents place the holding chamber in-line with the ventilator circuit, 56% administer the aerosol via manual ventilation, and 13% use both methods. Fifty-six percent place the in-line holding chamber between the endotracheal tube and ventilator circuit, and the other 44% place the in-line holding chamber in the inspiratory limb. The time between MDI actuations depended on whether the holding chamber was placed in-line or the aerosol was administered via manual ventilation (MV): < or = 0.5 min: 18% in-line and 28% MV; 1 min: 47% in-line and 43% MV; 2 min: 6% in-line and 4% MV; 3 min: 6% in-line and 0% MV. Eighty-three percent of respondents indicated that dead space introduced by a holding chamber/spacer was not a concern. Forty-three percent use nebulizers exclusively to administer albuterol to mechanically ventilated patients. Seventy-four percent of centers that nebulize albuterol use a dose of 1.25-2.5 mg. Eighty-eight percent of the surveyed institutions place nebulizers in-line with the ventilator circuit, and the other 12% use manual ventilation to administer the nebulized aerosol. Of those that use in-line nebulization, 95% place the nebulizer in the inspiratory limb of the circuit, and the other 5% place the nebulizer between the endotracheal tube and circuit Y-piece. Among centers that place the nebulizer in the inspiratory limb, 52% place it adjacent to the circuit Y-piece, 36% place it midway upstream in the inspiratory limb, and 12% place it near the humidifier. CONCLUSION: There is substantial variability among NICUs in albuterol administration to mechanically ventilated infants, with the majority of institutions now administering albuterol via MDI.     

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.     

Twelve-week, randomized, placebo-controlled, multicenter study of the efficacy and tolerability of budesonide and formoterol in one metered-dose inhaler compared with budesonide alone and formoterol alone in adolescents and adults with asthma

BACKGROUND: The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo. METHODS: This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients aged > or =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) for > or =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) of > or =60% to < or =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call. RESULTS: A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P<0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P < 0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P < 0.001) or withdrew because of (7.3%; P < or = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups. CONCLUSIONS: In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated.     

Efficacy and tolerability of formoterol Turbuhaler in children

A randomised, double-blind trial was undertaken to investigate the efficacy and tolerability of formoterol Turbuhaler in children with mild to moderate asthma. After a two-week run-in, 248 children aged 6-17 years were randomised to receive formoterol 4.5 and 9 pmicro b.i.d. or placebo for 12 weeks. Morning PEF (primary variable), was significantly improved versus placebo only in the formoterol 9 pmicro b.i.d. group (13 l/min, 95% CCI 1.9, 24.2%; p = 0 .02). Both formoterol 4.5 and 9 pmicro significantly increased the pre-bronchodilator FEV1 by 5.2-6.7% (p < 0 .05) and reduced use of daytime relief medication versus placebo (p < 0 .05). Formoterol 9 pmicro significantly reduced night-time reliever use and awakenings due to asthma versus placebo (p < 0.05). Both doses of formoterol were as well tolerated as placebo. In conclusion, formoterol 4.5 and 9 micro b.i.d. is effective and well tolerated as maintenance therapy in children with mild to moderate asthma.     

The volume of gas emitted from five metered dose inhalers at three levels of fullness

We conducted this study to determine the volume of gas emitted from five commonly used metered dose inhalers (MDIs). MATERIALS & METHODS: We used the following MDIs: Alupent (Boehringer Ingelheim), Atrovent (Boehringer Ingelheim), Beclovent (Allen & Hanburys), Intal (Fisons), and Ventolin (Allen & Hanburys). The test system consisted of plastic bag, MDI adapter, 4-way stopcock, and 60-mL calibrated syringe. This system was glued together, and absence of leaks was confirmed by underwater testing. Each evaluation consisted of 10 puffs from the MDI into the bag, after which the volume in the bag was determined using the syringe, and the volume/puff was calculated by dividing by 10. Each MDI was evaluated at 3 levels of fullness: nearly full, partially empty, and nearly empty. Five measurements were made with each MDI brand, using a new MDI for each set of measurements. RESULTS: Although there was a significant difference in the volumes emitted between MDI (p less than 0.001) and the levels of fullness (p = 0.001), the volume of gas emitted from these MDIs was small (approximately 15-20 mL). A significant interaction existed between MDI brand and level of fullness (p = 0.001). CONCLUSIONS: Based on prior studies of propellant toxicity coupled with our findings on the volumes of gas emitted from MDIs, we conclude that the volumes of gas emitted are too small to be clinically important in the care of adult patients. The volume of gas emitted from an MDI is only potentially important if MDIs are used with very small tidal volumes in a closed system (eg. infants).     

Duration of salmeterol-induced bronchodilation in mechanically ventilated chronic obstructive pulmonary disease patients: a prospective clinical study

Introduction

Delivery of bronchodilators with a metered-dose inhaler (MDI) and a spacer device in mechanically ventilated patients has become a widespread practice. However, except for the short-acting β2-agonist salbutamol, the duration of action of other bronchodilators, including long-acting β2-agonists, delivered with this technique is not well established. The purpose of this study was to examine the duration of bronchodilation induced by the long-acting β2-agonist salmeterol administered with an MDI and a spacer in a group of mechanically ventilated patients with exacerbation of chronic obstructive pulmonary disease (COPD).

Methods

Ten mechanically ventilated patients with acute exacerbation of COPD received four puffs of salmeterol (25 μg/puff). Salmeterol was administered with an MDI adapted to the inspiratory limb of the ventilator circuit using an aerosol cloud enhance spacer. Static and dynamic airway pressures, minimum (R_int) and maximum (Rrs) inspiratory resistance, and the difference between Rrs and R_int (ΔR) were measured before and at 15, 30, and 60 minutes as well as at 2, 3, 4, 6, 8, 10, and 12 hours after salmeterol administration. The overall effects of salmeterol on respiratory system mechanics and heart rate during the 12-hour study period were analyzed by nonparametric Wilcoxon signed rank test.

Results

Salmeterol caused a significant decrease in dynamic and static airway pressures, R_int, and Rrs. These changes were evident at 30 minutes and remained significant for 8 hours after salmeterol administration. The duration of bronchodilation varied significantly among patients, lasting in some patients more than 10 hours and wearing off in others in less than 6 hours.

Conclusions

It is concluded that four puffs of salmeterol delivered with an MDI and a spacer device induces significant bronchodilation in mechanically ventilated patients with COPD exacerbation, the duration of which is highly variable, precluding definite conclusions in regard to optimum dosing schedules.     

Systemic absorption of inhaled epinephrine

To determine the systemic absorption of epinephrine when it is given by inhalation, six normal volunteers were given 15 puffs, followed by 30 puffs, of epinephrine from a pressurized aerosol (160 micrograms epinephrine/puff). The peak mean (+/- SE) plasma epinephrine levels were 1.50 (+/- 0.61) and 4.22 (+/- 1.93) nmol/L 1 minute after each dose, respectively. The effect on physiologic finger tremor correlated with the plasma epinephrine level and returned to baseline 20 minutes after taking the higher dose. There was a small fall in mean plasma potassium levels of 0.45 mmol/L and a small rise in plasma glucose levels of 0.81 mmol/L. On a separate occasion an injection of 0.3 ml of 1/1000 (300 micrograms) epinephrine was given subcutaneously to the same individuals. This caused a peak plasma epinephrine level of 2.43 (+/- 0.47) nmol/L at 10 minutes, and this was still raised at 2.05 (+/- 0.41) nmol/L after 40 minutes. The maximum fall in the mean plasma potassium level was 0.43 mmol/L after the injection.     

Efficacy, tolerability, and effect on asthma-related quality of life of formoterol bid via multidose dry powder inhaler and albuterol QID via metered dose inhaler in patients with persistent asthma: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study

BACKGROUND: Inhaled beta(2)-agonists are widely used in asthma treatment. The design limitations of pressurized metered dose inhalers (pMDIs) have prompted the development of dry powder inhalers (DPIs) for the delivery of asthma medications. OBJECTIVE: The goal of this study was to evaluate the efficacy, tolerability, and effect on asthma-related quality of life (QOL) of a long-acting beta(2)-adrenoreceptor agonist, formoterol, delivered via multidose DPI, compared with albuterol delivered via pMDI or placebo in adolescents and adults with persistent asthma. METHODS: This multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study was conducted in outpatient clinics at 18 US centers. Adolescents and adults with persistent asthma received formoterol 10 pg BID via multidose DPI, albuterol 180 microg QID via pMDI, or placebo for 12 weeks. The primary efficacy variable was the 12-hour AUC of forced expiratory volume in 1 second (FEV(1)) after 12 weeks treatment. Secondary efficacy variables included asthma-related QOL, asthma symptom scores, rescue medication use, and other pulmonary function measures. RESULTS: A total of 239 patients (147 females, 92 males; age range, 13-85 years) with persistent asthma were enrolled (formoterol, n = 80; albuterol, n = 79; placebo, n = 80). Formoterol delivered via the multidose DPI resulted in clinically relevant and statistically significant increases in 12-hour AUC of FEV(1) after 12 weeks of treatment compared with albuterol pMDI and placebo (P < 0.019 and P < 0.001, respectively). Asthma-related QOL (total score) was significantly improved with formoterol treatment compared with placebo (P < 0.015). Nocturnal asthma symptom scores significantly improved with formoterol compared with albuterol and placebo (P < 0.001 and P < 0.003, respectively) and rescue medication use was significantly less with formoterol compared with albuterol and placebo (P < 0.004 and P < 0.002, respectively). Treatment with formoterol was well tolerated. CONCLUSIONS: In this study of adolescents and adults with persistent asthma, 12 weeks of treatment with formoterol 10 microg BID delivered via a multidose DPI provided significantly greater 24-hour bronchodilation compared with albuterol and placebo and resulted in significant improvements in asthma-related QOL compared with placebo. Formoterol was well tolerated in these patients.     

Protection by ipratropium bromide and metaproterenol against methacholine and histamine bronchoconstriction

To establish relative protection against methacholine and histamine, 40 micrograms of ipratropium bromide, an anticholinergic compound, 1.3 mg of metaproterenol or placebo aerosols were administered by metered-dose inhaler prior to inhalation challenge with methacholine or histamine in nine asthmatic subjects. Double-blind, randomized challenges were performed. Subjects required a mean methacholine dose of 1.72 +/- 0.73 and 2.46 +/- 0.72 (Ln inhalation units), and mean histamine dose of 2.16 +/- 0.65 and 2.68 +/- 0.49, to cause a drop of 20% and 35% respectively in the FEV1 following the placebo. In the methacholine challenges, both ipratropium bromide and metaproterenol had significant protection as compared to placebo (P less than 0.001). There was no statistical difference in the degree of protection against methacholine between ipratropium bromide and metaproterenol. In histamine challenges, metaproterenol had significant protection as compared to the placebo, while ipratropium bromide did not protect against histamine.     

Budesonide/formoterol in a single inhaler (Symbicort) reduces healthcare costs compared with separate inhalers in the treatment of asthma over 12 months

This open, multinational, randomised, parallel-group, six-month extension conducted in the Swedish centres of a previous six-month study compared the costs of a total of 12 months of treatment with budesonide/formoterol in a single inhaler with budesonide plus formoterol separate inhalers in 320 adults with asthma. Patients received budesonide/formoterol (Symbicort Turbuhaler) 160/4.5 mg delivered doses, two inhalations b.i.d., or corresponding doses of budesonide (Pulmicort Turbuhaler) plus formoterol (Oxis Turbuhaler). Direct costs and indirect costs were estimated. Budesonide/formoterol treatment was associated with reduced healthcare service utilisation and statistically significant reductions in direct (SEK1595, p=0.0004) and total costs (SEK1884, p=0.043) per person per year compared with budesonide plus formoterol. Budesonide/formoterol reduced the average annual emergency room admission cost per person by SEK489.7 (31% of direct cost reduction) and physician costs by SEK235.4 (15%).The direct cost of study, relief and other medication was reduced by SEK893.8 (47% of total reduction). There were no statistically significant differences in efficacy and safety parameters following treatment with budesonide/formoterol from single or separate inhalers, other than a significantly lower proportion of withdrawals with the single inhaler (9.2% vs 19.4%, p=0.008). In summary, budesonide/formoterol treatment from a single inhaler reduced 12-month treatment costs compared with separate inhalers, while maintaining at least as good control of asthma.     

A double-blind, randomized, crossover assessment of blood pressure following administration of avitriptan, sumatriptan, or placebo to patients with mild to moderate hypertension

We examined the effects of avitriptan, a 5-hydroxytryptamine 1-like (5HT1) receptor agonist for the treatment of migraine, in patients with medicated, controlled, mild to moderate hypertension relative to placebo and sumatriptan. The study was randomized, double-blinded, placebo-controlled, and 4-way crossover in design. Twenty patients (12M, 8F) participated. As required by protocol, all were stable on medications for mild to moderate hypertension, with a supine diastolic blood pressure of < 95 mmHg. Qualified subjects were randomized to receive oral administration of either 75 or 150 mg of avitriptan, 100 mg sumatriptan or placebo during the four treatment visits. Supine blood pressure and pulse rates were recorded up to 24 h after drug administration. Avitriptan 150 mg significantly increased peak diastolic and systolic blood pressure, and mean arterial pressure compared to placebo and sumatriptan 100 mg (p < 0.05). Only those hypertensive patients receiving medication for hypertension should receive anti-migraine medications, such as avitriptan, which are 5HT1-like receptor agonists.     

Effect of inspiratory flow rate on β2-agonist induced bronchodilation in mechanically ventilated COPD patients

OBJECTIVES: To test the effect of two different inspiratory flow rates on the bronchodilation induced by beta2-agonists administered by metered dose inhaler (MDI). PATIENTS: Ten patients with acute exacerbation of chronic obstructive pulmonary disease and receiving mechanical ventilation with constant inspiratory flow (V'I). DESIGN: Patients received four puffs of salbutamol (100 microg/puff) with either low V'I (0.6 l/s) or high V'I (1.2 l/s) administered with an MDI adapted to inspiratory limb of the ventilator circuit using an aerosol cloud enhance spacer. After a 6-h washout patients were crossed-over to receive the drug by the alternative mode of administration. MEASUREMENTS AND RESULTS: Static and dynamic airway pressures, intrinsic positive end-expiratory pressure, and minimum and maximum inspiratory resistance values showed a significant decrease after salbutamol. These changes were not affected by the inspiratory flow rate and were evident 15, 30, and 60 min after administration. Heart rate, static end-inspiratory respiratory system compliance, and the difference between minimum and maximum inspiratory resistance were unchanged after salbutamol. CONCLUSIONS: Salbutamol delivered by MDI and spacer device induces significant bronchodilation in mechanically ventilated patients with chronic obstructive pulmonary disease, but the magnitude of the effect is not affected by the inspiratory flow rate. These results do not support flow rate manipulations when bronchodilators are administered during controlled mechanical ventilation.     

Efficacy and safety of salmeterol/fluticasone propionate delivered via a hydrofluoroalkane metered dose inhaler in Chinese patients with moderate asthma poorly controlled with inhaled corticosteroids

A randomised, open-label, multicentre study compared the efficacy and tolerability of salmeterol 25 microg/fluticasone propionate 125 microg (two puffs, twice daily) delivered via a hydrofluoroalkane metered-dose inhaler (HFA-MDI) and salmeterol 50microg/fluticasone propionate 250 microg (one puff, twice daily) delivered via a Diskus inhaler in Chinese patients with moderate asthma uncontrolled with inhaled corticosteroids (ICSs). Morning peak expiratory flow (PEF) was the primary efficacy endpoint. Secondary endpoints included evening PEF, forced expiratory volume in 1 s, day and night symptom scores, rescue medication and patient self-evaluation of efficacy. Safety was assessed according to adverse events recorded. Both treatments were equipotent and significantly improved morning PEF (HFA-MDI 40 l/min; Diskus 42 l/min; p < 0.05) and all secondary endpoints (p < 0.05) from baseline, over 1-4 weeks. Similarly, both treatments were well tolerated. Salmeterol/fluticasone propionate delivered via an HFA-MDI or Diskus inhaler provides a choice of efficacious delivery systems in Chinese patients whose asthma is poorly controlled on ICSs alone.     

Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations

This randomised, double-blind, 6-month study compared budesonide/formoterol for maintenance and relief with salmeterol/fluticasone and a fixed maintenance dose of budesonide/formoterol, both with terbutaline for relief. Following a 2-week run-in, 3335 symptomatic adults and adolescents (mean FEV1 73% predicted, mean inhaled corticosteroid dose 745 microg/day) received budesonide/formoterol 160/4.5 microg one inhalation bid plus additional inhalations as needed, salmeterol/fluticasone 25/125 microg two inhalations bid plus as-needed terbutaline or budesonide/formoterol 320/9 microg one inhalation bid plus as-needed terbutaline. Budesonide/formoterol for maintenance and relief prolonged the time to first severe exacerbation requiring hospitalisation, emergency room treatment or oral steroids (primary variable) vs. fixed-dose salmeterol/fluticasone and budesonide/formoterol (p=0.0034 and p=0.023 respectively; log-rank test). Exacerbation rates were 19, 16 and 12 events/100 patients/6 months for salmeterol/fluticasone, fixed-dose budesonide/formoterol and budesonide/formoterol for maintenance and relief, respectively, [rate reduction vs. fixed-dose salmeterol/fluticasone (0.61; 95% CI 0.49-0.76, p<0.001) and vs. fixed-dose budesonide/formoterol (0.72; 95% CI 0.57-0.90, p=0.0048)]. Budesonide/formoterol maintenance and relief patients used less inhaled corticosteroid vs. salmeterol/fluticasone and fixed-dose budesonide/formoterol patients. All treatments provided similar marked improvements in lung function, asthma control days and asthma-related quality of life. Budesonide/formoterol for maintenance and relief reduces asthma exacerbations and maintains similar daily asthma control at a lower overall drug load compared with fixed-dose salmeterol/fluticasone and budesonide/formoterol.