Albuterol delivery from a metered-dose inhaler with spacer is reduced following short-duration manual ventilation in a neonatal ventilator-lung model

INTRODUCTION: Albuterol aerosol is commonly administered to mechanically ventilated neonates via metered-dose inhaler (MDI) with spacer. The spacer increases the dead space in the ventilation circuit, and some institutions limit the amount of time the spacer remains in line, to minimize carbon dioxide retention and the risk of hypercarbia. However, minimizing the amount of time the spacer remains in line might also limit albuterol delivery to the patient. OBJECTIVE: To determine whether limiting the amount of time the spacer is left in line after MDI actuation significantly reduces albuterol delivery. METHODS: We conducted a bench study with a neonatal ventilator-lung model that included a Bird VIP ventilator, in a time-cycled, pressure-limited, continuous-flow mode, with settings to simulate a 1-kg infant with moderate lung disease: peak inspiratory pressure 25 cm H2O, positive end-expiratory pressure 4 cm H2O, respiratory rate 30 breaths/min, inspiratory time 0.35 s, tidal volume approximately 7 mL. The circuit was attached to a 3.0-mm inner-diameter endotracheal tube and a neonatal test lung. We tested 5 methods of MDI albuterol administration. The first 3 methods used a spacer attached to the ETT and either 5, 15, or 30 manual breaths (flow 6 L/min, respiratory rate 30 breaths/min, peak inspiratory pressure 25 cm H2O) were delivered after each MDI actuation (2 actuations). The final 2 methods used an in-line spacer (placed between the circuit Y-piece and the endotracheal tube) with the spacer kept in line for 30 or 60 s after each actuation (2 actuations). A breathing filter was placed between the ETT and test lung to trap the aerosolized albuterol. RESULTS: Mean +/- SD albuterol delivery was 2.3 +/- 0.5%, 3.6 +/- 1.8%, and 5.1 +/- 1.3% after 5, 15, and 30 manual breaths, respectively (p < or = 0.05 for 30 breaths vs 5 and 15 breaths). Albuterol delivery was 3.7 +/- 1.3% when the spacer was left in line for 30 s, versus 3.7 +/- 0.6% when it was left in line for 60 s. CONCLUSIONS: Limiting the time that the spacer was left in line after each MDI actuation significantly reduced albuterol delivery in our neonatal ventilator-lung model.     

The efficacy of metered-dose inhalers with a spacer device in the pediatric setting

PURPOSE: To systematically review the published research and report on the efficacy of using a metered-dose inhaler with a spacer (MDI-S) device in a pediatric setting to treat acute exacerbations of asthma. DATA SOURCES: A literature search was conducted on the CINAHL, Medline, and Cochrane databases; additional searches were made by hand from the reference lists in each study retrieved from databases and from review articles written on the same topic. CONCLUSION: This critical appraisal of the research demonstrates the MDI-S is as effective as the nebulizer, faster in the delivery of medication, and cost-effective. IMPLICATIONS FOR PRACTICE: No significant difference between the MDI-S and nebulizer in delivering medication in an acute exacerbation of asthma was found in this analysis. The practitioner's choice of delivery methods should reflect the family's preference, the practice situation, and economic considerations.     

The conversion to metered-dose inhaler with valved holding chamber to administer inhaled albuterol: a pediatric hospital experience

BACKGROUND: Metered-dose inhalers with valved holding chambers (MDI-VHCs) have been shown to be equivalent to small-volume nebulizers (SVNs) for the delivery of bronchodilators in children. At Seattle Children's Hospital and Regional Medical Center we sought to implement the conversion from SVN to MDI-delivered albuterol in nonintubated patients receiving intermittent treatments. METHODS: There were 4 distinct interventions used to plan and implement this conversion program: (1) literature review, (2) product selection, (3) policy and operational changes, and (4) staff training. Bronchodilator administration guidelines and clinical pathways for asthma and bronchiolitis were revised to recommend MDI-VHC use in lieu of SVNs. Computerized physician order sets were amended to indicate MDI-VHC as the preferred method of delivering inhaled albuterol in children with asthma and bronchiolitis. Data from administrative case mix files and computerized medication delivery systems were used to assess the impact of our program. RESULTS: MDI-VHC utilization increased from 25% to 77% among all non-intensive-care patients receiving albuterol, and from 10% to 79% among patients with asthma (p < 0.001). Duration of stay among patients with asthma was unchanged after conversion to MDI-VHC (p = 0.53). CONCLUSIONS: Our program was very successful at promoting the use of MDI-VHC for the administration of albuterol in our pediatric hospital. Duration of stay among patients with asthma did not change during or since the implementation of this program.     

Comparing the delivery of albuterol metered-dose inhaler via an adapter and spacer device in an in vitro infant ventilator lung model

OBJECTIVE: To compare the delivery of an albuterol metered-dose inhaler (MDI) (Ventolin) via an Aerochamber (Monaghan) with an inline adapter (Medicomp Straight Swivel) in an in vitro infant lung model. METHODS: An in vitro infant lung model was modified to compare the delivery of albuterol MDI 10 inhalations via an Aerochamber with an inline adapter. The adapter and Aerochamber were placed at the endotracheal tube. A 1000 mL intravenous bag filled with 500 mL deionized water was attached to a 3.5 mm endotracheal tube (10 cm length). An Infant Bear Cub ventilator was used at the following settings: positive inspiratory pressure 20 cm H2O, intermittent mandatory ventilation 40 breaths/min, positive end expiratory pressure 4 cm H2O, and inspiratory time 0.5 second. Each device was run at least 10 times and assayed in duplicate by HPLC. An unpaired Student's t-test was used to analyze the statistical significance of the data. RESULTS: There was significantly greater delivery of albuterol with the Aerochamber (19.49 +/- 7.23 microg; 2.17% +/- 0.8%) as compared with an inline adapter (1.0625 +/- 1.36 microg; 0.12% +/- 0.15%) (p = 0.001). CONCLUSIONS: The Aerochamber provides a greater delivery of albuterol metered-dose inhalations to the lung than the inline adapter in an in vitro infant lung model.     

Effectiveness of budesonide administered via dry-powder inhaler versus triamcinolone acetonide administered via pressurized metered-dose inhaler for adults with persistent asthma in managed care settings

BACKGROUND: Clinical studies have demonstrated the efficacy and relative safety of inhaled corticosteroids in the treatment of asthma. However, effectiveness and cost-effectiveness comparisons of available inhaled corticosteroids in real-life clinical settings are lacking. OBJECTIVE: This study compared the effectiveness and safety of budesonide administered via dry-powder inhaler versus that of triamcinolone acetonide administered via pressurized metered-dose inhaler in the treatment of adult patients with persistent asthma treated in a managed care setting. METHODS: This was a randomized, open-labe, 52-week study of adult patients (aged >or= 18 years) with persistent asthma enrolled in 25 US health plans. The primary study outcome was mean change from baseline to the end of treatment in symptom-free days. Secondary variables were changes from baseline in number of episode-free days, episode-free days at 52 weeks, forced expiratory volume in 1 second (FEV(1)), forced vital capacity, asthma symptom scores, breakthrough bronchdilator use, patient discontinuations, and health-related quality of life. Patients were issued diaries in which to record use of study medication and concomitant asthma medication use, as well as daytime and nighttime asthma symptom severity. Patients were assessed at weeks 4, 13, 26, 39, and 52. Safety was assessed based on adverse events and changes in laboratory tests, vital signs, and physical examinations. RESULTS: A total of 945 patients (344 men, 601 women; mean [SD] age, 46.8 [14] years) were enrolled; 631 received budesonide and 314 received triacinolane acetonide. Improvements in all effectiveness variables were observed with both treatments. The mean increase from baseline in the number of symptom-free days per month assessed at month 12 was 7.74 (95% CI, 6.81-8.66) for patients receiving budesonide and 3.78 (95% CI, 2.47-5.09) for patients receiving triamcinoline acetonide ( P<0.001). The estimated annual mean (SD) number symptom-free days for patients receiving budesonide was 141.1 (125.0) over the treatment phase, compared with 99.3 (112.1) for those receiving triamcinolone acetonide (P<0.001). Patients receiving budesonide demonstrated significant improvements (compared with those receiving triamcinolone acetonide) in overall quality of life, daytime and nighttime asthma symptom severity, breakthrough bronchodilator use, and FEV(1) (all P<0.001). Safety measures were similar between groups. CONCLUSION: In these managed care settings, budesonide inhalation powder administered via dry-powder inhaler was significantly more effective than triamcinolone acetonide administered via pressurized metered-dose inhaler in the treatment of adults with persistent asthma.     

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.     

Results of a physician and respiratory therapist collaborative effort to improve long-term metered-dose inhaler technique in a pediatric asthma clinic

BACKGROUND: Despite advances in therapy, asthma continues to be the chronic condition most responsible for school absenteeism and pediatric hospitalizations. This is especially true for inner-city children. We operate an inner-city Pediatric Asthma Compliance and Technique (PACT) clinic in which physicians and respiratory therapists collaborate to improve metered-dose inhaler (MDI) technique and outcomes among asthmatic children. OBJECTIVE: To determine the efficacy of our strategy for improving MDI technique and asthma outcomes. METHODS: Children referred to the PACT clinic underwent standardized assessment based on the Expert Panel Guidelines of the National Heart, Lung, and Blood Institute (NHLBI). Clinicians demonstrated and reinforced correct MDI technique at each visit. Using a standardized format we prospectively collected, at the patient's first visit (T1) and most recent visit (T2), data on demographics, MDI-technique scores (MDI steps done correctly; scale of 0-8), pulmonary function, and asthma severity (NHLBI classification scale: 1 = mild intermittent to 4 = severe persistent). Statistical analyses were performed using parametric and non-parametric tests. RESULTS: Of the 60 patients who attended the PACT clinic between 1999 and 2002, 15 were excluded from the study because of incomplete data recording. Mean duration from T1 to T2 was 11.8 +/- 9.5 months. At T1 and T2, respectively, the mean MDI-technique scores were 53% and 81%, the mean overall asthma severity scores were 2.6 and 2.3, and the mean overall pulmonary function severity scores were 2.4 and 2.1. MDI-technique scores significantly improved between TI and T2 (p < 0.001). The black patients had the largest improvement in MDI technique (p < 0.001), but their pulmonary function test results, overall asthma severity, and pulmonary function severity did not improve significantly. The white patients significantly improved both their MDI technique (p = 0.004) and their overall asthma severity scores (p = 0.005). CONCLUSION: In our PACT clinic asthmatic children showed sustained improvement in MDI technique, and some of the patients improved in pulmonary function and overall asthma severity score.     

Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes

OBJECTIVE: To compare the dose-response relationship following inhalation of regular insulin delivered via the Aerodose insulin inhaler with that following subcutaneously injected regular insulin in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four patients with type 2 diabetes (21 nonsmoking men, aged 36-80 years) each received two of three doses of 80, 160, or 240 units inhaled regular insulin, delivered via a clinical Aerodose insulin inhaler, and two of three corresponding doses of 8, 16, or 24 units by subcutaneous injection under isoglycemic clamp conditions on 4 separate study days in an incomplete block design study. Glucose infusion rates (GIRs) and serum insulin concentrations were monitored over the following 8 h. RESULTS: Inhaled insulin exhibited significantly shorter time-to-peak insulin levels (T(max) 77 +/- 66 vs. 193 +/- 104 min, P < 0.001) and time-to-peak metabolic effects (T(GIRmax) 240 +/- 94 vs. 353 +/- 60 min, P < 0.001) compared with subcutaneously injected insulin. Comparison of total insulin absorption (insulin area under the curve [AUC]) versus total metabolic effect (GIR-AUC) from 0 to 8 h (group means) revealed overlapping dose-response relationships for both inhaled and subcutaneous injection treatments. Comparison of slopes revealed no significant differences between the inhaled and subcutaneous injection treatment groups (P = 0.6). No significant differences in either relative bioavailability or relative biopotency were found among doses, indicating a consistent subcutaneous injection-to-inhaled dosing conversion ratio among doses. No serious adverse events or clinically relevant changes in lung function were observed. CONCLUSIONS: The overlapping dose-response curves of inhaled and subcutaneous treatments together with a consistent relative bioavailability and relative biopotency for inhaled insulin across doses suggest that the Aerodose insulin inhaler will deliver a pharmacologically predictable insulin dose to patients with diabetes similar to that observed following subcutaneous injection.     

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.     

Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study

OBJECTIVE: This study compared the efficacy and tolerability of the combination of fluticasone propionate (FP) and salmeterol (SAL) delivered via a single hydrofluoroalkane (HFA) 134a metered-dose inhaler (MDI) with those of its 2 components alone delivered via a chlorofluorocarbon (CFC) MDI and placebo (PLA) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses (equivalent to FP 440-660 microg/d) of inhaled corticosteroids (ICSs). METHODS: This was a randomized, double-blind,placebo-controlled, parallel-group study consisting of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period. Participants had to be > or =12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study. Patients had to have used ICS therapy for > or =3 months before the study and at a consistent dose for the previous month. Lack of asthma control was defined as a forced expiratory volume in 1 second (FEV(1)) that was 40% to 85% of the predicted value. Patients could not enter the double-blind treatment period if they had 3 days when they required >12 puffs of rescue albuterol per day or >3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the randomization visit. Patients were randomized to receive one of the following treatments delivered via MDI twice daily for 12 weeks: FSC 220/42 microg HFA (2 inhalations of FSC 110/21 microg; 125 microg/21 microg ex-valve); FP 220 microg CFC (2 inhalations of FP 110 microg); SAL 42 microg CFC (2 inhalations of 21 microg); or 2 inhalations of PLA HFA. The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV(1) curve relative to the prerandomization baseline (FEV(1) AUC(bl)). The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV(1) at end point and the probability of not being withdrawn from the study due to worsening asthma. Tolerability assessments included electrocardiograms, routine clinical laboratory tests, vital signs, oropharyngeal examinations, and physical examinations. Adverse events were assessed at each clinic visit. RESULTS: Thirty-two adolescent and 333 adult patients were randomly assigned to receive double-blind treatment. The treatment groups were comparable at baseline with respect to demographic characteristics (mean age, 38-41 years; white race, 78%-88%) and pulmonary function (mean percent predicted FEV(1), 68%-69%; mean asthma symptom score, 1.6 [scale 0-5]; and mean daily albuterol use, 3.1 puffs). After 12 weeks of treatment, the mean FEV(1) AUC(bl) was significantly greater in patients who received FSC compared with those who received FP, SAL, or PLA (7.0, 3.6, 5.3, and 1.4 L-h, respectively; all comparisons, P < or = 0.020). At end point, the mean change from baseline in morning predose FEV(1) for FSC was significantly greater than that for FP, SAL, and PLA (0.41, 0.19, 0.15, and -0.12 L; all comparisons, P < or = 0.001). During 12 weeks of treatment, 7% of patients receiving FSC were withdrawn due to worsening asthma, compared with 24% of patients receiving SAL and 54% of patients receiving PLA (P < 0.001); 11% of patients receiving FP were withdrawn due to worsening asthma. Treatment with FSC resulted in significant improvements in morning and evening peak expiratory flow compared with FP, SAL, and PLA (both, P < 0.001); need for rescue albuterol compared with FP and PLA (P < or =0.005); and asthma symptom scores compared with PLA (P < 0.001). The tolerability of FSC was similar to that of FP or SAL alone. The incidence of possibly drug-related adverse events was generally similar across treatment groups, and the most common (occurring in > or= 2% of patients) were headache (1%-4%), throat irritation (1%-2%), candidiasis of the mouth/throat (0%-2%), unspecified oropharyngeal plaques (0%-2%), and palpitations (0%-2%). CONCLUSIONS: In these adolescent and adult patients whose asthma was not controlled by medium doses of an ICS, FSC delivered via HFA 134a MDI (2 inhalations of 110/21-microg strength administered BID) was more effective in improving lung function than FP or SAL monotherapy or PLA. All treatments were well tolerated.     

The delivery of aerosolized steroids from MDIs with nozzle extensions: Quantitative laboratory evaluation of a method to improve aerosol delivery to intubated patients

Objective Pulmonary deposition of aerosolized drug from a metered dose inhaler (MDI) is low with intubated patients. In the laboratory, extension of the MDI nozzle to the endotracheal tube tip has been shown to increase the delivered dose of albuterol. The objectives of this study were to determine the dose of aerosolized steroid (beclomethasone and triamcinolone) delivered through a MDI nozzle extension, the effect of nozzle extension length and number of actuations on the delivered dose, and particle size delivered through the nozzle extension.Design A 19-G catheter was used as the MDI nozzle extension. The nozzle extension was attached to a 60-ml syringe via the Luer-Lok connection, and the distal end was directed through a hole drilled into a 15-ml capped tube. The MDI was placed into the syringe and actuated by pressing the syringe plunger. Drug delivered through the nozzle extension into the tube was dissolved in methanol (beclomethasone) or ethanol (triamcinolone). Nozzle extension lengths of 10 cm, 20 cm and 30 cm were studied. For each nozzle extension length, delivery was assessed using one, two, three and five actuations of each drug. Drug remaining in the nozzle extension was recovered by rinsing with the appropriate solvent. Aerosol particle size leaving the nozzle extension was determined using a seven-stage cascade impactor. Beclomethasone and triamcinolone concentrations were determined by spectrophotometry at 239 nm.Setting Respiratory care laboratory of a university teaching hospital.Results For the pooled results, 70.2±14.1% of the dose was delivered through the nozzle extension, with no difference between beclomethasone and triamcinolone (p=0.838). The proportion of drug delivered through the 10-cm extension (76.7±8.4%) was greater than that from the 20-cm (66.1±16.5%) and 30-cm (67.7±13.9%) extensions (p=0.001). Less drug was delivered through the extension with one actuation (54.1±17.7%) than with two (71.2±7.7%), three (77.2±5.5%), or five actuations (78.2±4.3%) (p<0.001). There was a decrease in MMAD with increasing nozzle extension length (3.14±0.61 m for 10 cm, 2.97±0.28 m for 20 cm, 2.37±0.27 m for 30 cm;p=0.005).Conclusions A high proportion of aerosolized steroid was delivered with a MDI actuated through a nozzle extension. The proportion delivered through the nozzle extension was significantly less with longer nozzle extensions and with fewer actuations, but this may not be clinically important. Although particle sizes were smaller from longer nozzle extensions, all were within the respirable range. These results suggest that steroids can be delivered efficiently using a MDI nozzle extension.Presented in part at the 1994 International Conference, ALA/ATS, in Boston, MA, May 23, 1994Work completed in the Respiratory Care Laboratory and Henry K. Beecher Anesthesia Laboratory, Massachusetts General Hospital, Boston, MA. Supported in part by the Puritan-Bennett Corporation and the American Respiratory Care Foundation     

A Randomized, Controlled Double-blind Trial of Usual-dose versus High-dose Albuterol via Continuous Nebulization in Patients with Acute Bronchospasm

OBJECTIVE: Continuous nebulization is becoming more popular in the management of acute bronchospasm in the emergency department (ED). Controversy still exists as to the optimal dose of albuterol for such exacerbations. The present study hypothesis was that there is no difference between continuous nebulization of albuterol at 7.5 mg/hr (usual dose) and 15 mg/hr (high dose) in peak flow improvement up to three hours. METHODS: This was a randomized, controlled, double-blind trial, set in an urban county teaching ED. One hundred twenty-seven patients with acute bronchospasm and an initial peak flow (PF) less than 75% predicted were enrolled. Patients were randomized to usual-dose (UD) or high-dose (HD) groups along with a standard treatment protocol. Primary end-points were analyzed using repeated-measures analysis of variance (ANOVA), and 95% confidence intervals (95% CIs) are given for such variables. RESULTS: Sixty-seven patients were randomized to the HD albuterol group, and 63 completed the study. Sixty patients were randomized to the UD group, and 55 completed the study. Repeated-measures ANOVA found no difference in systolic blood pressure, diastolic blood pressure, pulse, respiratory rate, Borg dyspnea scale score, and peak flow over time between the groups. The mean (+/-SD) peak flow improvement at one hour was UD 51 (+/-49) L/min vs. HD 45 (+/-50) L/min, mean difference 6.8 L/min (95% CI = -11 to 24.9 L/min). Adjusting for baseline, the percentage increase in peak flow at one hour was UD 44% (+/-60%) vs. HD 30% (+/-40%), mean difference 14% (95% CI = -4.4% to 32.4%). Time to disposition showed a mean of 188 (+/-129) minutes for UD and 230 (+/-183) minutes for HD, mean difference 42 minutes (95% CI = -170 to 101 min). One patient in the HD group was intubated. Admission rate was UD 70.9% vs. HD 65%, mean difference 5.9% (95% CI = -10.9% to 22.7%). CONCLUSIONS: In treating acute, moderately-severe bronchospastic ED patients with peak flow less than 75% of predicted with albuterol by continuous nebulization, 15 mg/hr appears to offer no advantage over 7.5 mg/hr in peak flow improvement or length of stay in the ED.     

A 12-week, multicenter, randomized, partially blinded, active-controlled, parallel-group study of budesonide inhalation suspension in adolescents and adults with moderate to severe persistent asthma previously receiving inhaled corticosteroids with a metered-dose or dry powder inhaler

BACKGROUND: Nebulized budesonide inhalation suspension (BIS) is approved in the United States for children with asthma aged 1 to 8 years. OBJECTIVE: The primary objective of this study was to compare the efficacy of BIS 0.5 mg QD and 2.0 mg BID in terms of the mean change from baseline to end of treatment in predose forced expiratory volume in 1 second (FEV1). METHODS: In this 12-week, partially blinded, randomized study, subjects aged >or=12 years with moderate to severe persistent asthma previously receiving inhaled corticosteroids (ICSs) by dry powder inhaler (DPI) or metered-dose inhaler (MDI) continued therapy during a 2- to 3-week run-in period and then switched to BIS 0.5 mg QD, 1.0 mg QD, 1.0 mg BID, or 2.0 mg BID, or budesonide DPI 400 microg BID (active reference arm). Besides FEV1 (the primary variable), other outcome variables included changes in forced vital capacity (FVC) from baseline to weeks 4, 8, and 12 and to the average over the treatment period; as well as changes from baseline to the end of treatment in diary-collected daytime and nighttime asthma symptom scores, rescue medication use, nighttime awakenings due to asthma, morning and evening peak expiratory flow (PEF), percentages of symptom-free and medication-free periods, and the incidence of predefined asthma events. Adverse events were recorded by subjects. Steady-state pharmacokinetics of budesonide were assessed in all treatment arms. Efficacy analyses included data in a modified intent-to-treat approach. Differences in the change from baseline to end of treatment in FEV1 were assessed using analysis of covariance (ANCOVA). For secondary variables, changes from baseline to each visit or to the treatmentperiod average were compared among groups using an ANCOVA model. P or=65 years. There was no significant difference in mean change in predose FEV1 between BIS 0.5 mg QD and BIS 2.0 mg BID (0.02 vs 0.01 L). On average, mean values for the BIS dosage groups did not indicate any deterioration from baseline to the treatment period for variables associated with asthma control such as FEV1, FVC, daytime and nighttime asthma symptom scores, rescue medication use, nighttime awakenings, morning and evening PEF, percentages of symptom-free and rescue medication-free periods, and predefined asthma events. The BIS 1.0-mg BID treatment appeared to be closest to budesonide DPI in plasma budesonide concentrations and improvement in predose FEV1 (0.08 vs 0.12 L). All treatments were well tolerated. CONCLUSIONS: In this study, no difference in efficacy between BIS 2.0 mg BID and 0.5 mg QD was found in adolescents and adults with persistent asthma when transitioned from ICSs delivered with a DPI or MDI. Subjects taking all BIS dosages experienced similar responses for variables associated with asthma control.     

Tolerability of a salmeterol xinafoate/fluticasone propionate hydrofluoroalkane metered-dose inhaler in adolescent and adult patients with persistent asthma: a 52-week, open-label, stratified, parallel-group, multicenter study

BACKGROUND: Many patients with asthma require an inhaled long-acting beta(2)-agonist (LABA) in addition to an inhaled corticosteroid to adequately control their disease. OBJECTIVE: The purpose of this study was to assess the long-term tolerability of a salmeterol xinafoate/ fluticasone propionate (SFC) hydrofluoroalkane metered-dose inhaler (MDI) at 3 different doses BID. METHODS: This 52-week, open-label, stratified, parallel-group study assessed SFC in patients with persistent asthma. Patients, aged > or = 12 years, with a diagnosis of asthma for > or = 6 months, and a percent predicted forced expiratory volume in 1 second (FEV(1)) or peak expiratory flow (PEF) between 40% and 90% were enrolled between January 1999 and June 1999. The last patient completed the 12-month study in June 2000. Patients were allowed to continue their current asthma treatment during run-in, with the exception that short-acting beta(2)-agonists (SABAs), LABAs, and oral bronchodilators were not to be used 6, 12, and 24 hours, respectively, prior to the randomization visit. During the open-label randomized treatment period, patients were instructed to discontinue all other asthma medications with the exception of the albuterol MDI to use on an as-needed basis. Patients were assigned to treatment based on their existing asthma regimen: SABA monotherapy or LABA with or without fluticasone propionate (FP) <250 microg/d or equivalent (group 1); FP 250 to 500 microg/d or equivalent with or without LABA (group 2); and FP >500 to 1000 microg/d or equivalent with or without LABA (group 3). Patients administered 2 inhalations BID of SFC hydrofluoroalkane at doses of 25/50 microg/actuation (group 1), 25/125 microg/actuation (group 2), or 25/250 pg/actuation (group 3). The primary end point was tolerability as assessed by adverse events (AEs). AEs were determined via diary cards and investigator inquiry at visits. Serious AEs were defined as death, any life-threatening event, hospitalization, disability, congenital anomaly in the patient's offspring, or other important medical events judged by the investigator to be serious. Other outcomes included clinical laboratory tests (hematology, chemistry, electrolytes), 24-hour urinary-free cortisol excretion, 12-lead electrocardiograms, oropharyngeal examinations, vital signs, clinic visit lung function tests (FEV(1) and PEF), daily diary card entries of morning PEF, and rescue medication usage. RESULTS: Of the 372 patients assessed for eligibility, 325 from 22 centers across Canada were enrolled and randomized to treatment. Group 1 consisted of 98 patients (55% women; 86% white; mean age, 37 years; mean [SD] weight, 79 [20] kg). Group 2 consisted of 109 patients (46% women; 94% white; mean age, 44 years; mean [SD] weight, 80 [17] kg). Group 3 consisted of 118 patients (47% women; 90% white; mean age, 45 years; mean [SD] weight, 80 [18] kg). A total of 15 adolescents (aged 12-17 years) comprised 11%, 2%, and 2% of groups 1, 2, and 3, respectively. Treatments were well tolerated, and 274 (84%) of the 325 patients enrolled completed the study. Upper respiratory tract infection was the most common AE reported: 52%, 37%, and 49% of patients in groups 1, 2, and 3, respectively. Twenty (6%) patients withdrew because of an AE, with worsening asthma being the most frequent reason (n = 9). None of the serious AEs (11 [3 %]) were considered drug related by the investigators. Improvements in FEV(1) and PEF and re- duction in symptomatic albuterol use occurred during the first 4 weeks and were maintained in all groups throughout the 52-week study. CONCLUSIONS: BID doses of SFC hydrofluoroalkane 50/100 pg, 50/250 pg, and 50/500 pg administered via MDI for 52 weeks were well tolerated in this population of adolescents and adults with persistent asthma.     

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, 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.     

Pharmacoscintigraphic comparison of HMR 1031, a VLA-4 antagonist, in healthy volunteers following delivery via a nebulizer and a dry powder inhaler

A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day. Scintigraphic images were acquired immediately after dosing to estimate the percentage of the dose delivered to the lungs and oropharynx. Serial plasma samples were collected up to 12 hours post-dose on each occasion and analyzed for HMR 1031 by a LC/MS/MS method with a lower limit of quantitation of 10 pg/mL (0.01 ng/mL). Pharmacokinetic parameters were calculated for HMR 1031 using noncompartmental methods. No serious adverse events were reported. The systemic absorption of HMR 1031 following inhalation administration was relatively rapid, with median T(max) values of 0.5 hours and 1.0 hours post-dose after administration via Ultrahaler and nebulizer, respectively. The mean plasma AUC(0-12) (Ultrahaler, 15.8 ng*h/mL; nebulizer, 11.1 ng*h/mL) and C(max) (Ultrahaler, 4.96 ng/mL; nebulizer, 2.28 ng/mL) values were approximately 42% and 118% higher for the Ultrahaler compared with the nebulizer. The mean terminal half-life of HMR 1031 was similar after administration from both devices (2.91 and 3.18 hours). Based on the scintigraphic data, the lung deposition of HMR 1031 after administration by Ultrahaler (24.6% of the administered dose) was approximately 37% higher compared with the lung deposition from the nebulizer (18.0% of the administered dose). This observation was in agreement with the relative difference in the plasma AUC values achieved after administration of the two formulations. The in vivo results based on the scintigraphic data were also comparable with those from in vitro studies for the Ultrahaler. Based on the ratio of the dose delivered by both the formulations, the required doses for the future Ultrahaler formulation can be predicted.     

Induction of IgG3 to LPS via Toll-Like Receptor 4 Co-Stimulation

B-cells integrate antigen-specific signals transduced via the B-cell receptor (BCR) and antigen non-specific co-stimulatory signals provided by cytokines and CD40 ligation in order to produce IgG antibodies. Toll-like receptors (TLRs) also provide co-stimulation, but the requirement for TLRs to generate T-cell independent and T-cell dependent antigen specific antibody responses is debated. Little is known about the role of B-cell expressed TLRs in inducing antigen-specific antibodies to antigens that also activate TLR signaling. We found that mice lacking functional TLR4 or its adaptor molecule MyD88 harbored significantly less IgG3 natural antibodies to LPS, and required higher amounts of LPS to induce anti-LPS IgG3. In vitro, BCR and TLR4 signaling synergized, lowering the threshold for production of T-cell independent IgG3 and IL-10. Moreover, BCR and TLR4 directly associate through the transmembrane domain of TLR4. Thus, in vivo, BCR/TLR synergism could facilitate the induction of IgG3 antibodies against microbial antigens that engage both innate and adaptive B-cell receptors. Vaccines might exploit BCR/TLR synergism to rapidly induce antigen-specific antibodies before significant T-cell responses arise.