Albuterol Metered-dose Inhaler Research Articles

Pretreatment with Albuterol versus Montelukast for Exercise‐Induced Bronchospasm in Children

To compare pretreatment with albuterol versus montelukast added to the current asthma regimen for protection against exercise-induced bronchospasm in children with mild-to-moderate asthma, and to determine whether cysteinyl leukotriene (Cys-LT) concentrations measured in the exhaled breath condensate correlated with response to montelukast. Prospective, randomized, double-blind, double-dummy, crossover study. Asthma clinic at a university-affiliated medical center. Eleven children aged 7-17 years with physician-diagnosed mild-to-moderate asthma for at least 6 months and with self-reported exercise-induced bronchospasm (defined as > or = 15% decrease in forced expiratory volume in 1 sec [FEV(1)] at screening and baseline visit). Patients were randomly assigned to receive 3-7 days of oral montelukast 5-10 mg/day or 2 puffs of an albuterol metered-dose inhaler just before an exercise challenge and then were crossed over to the alternate therapy for the last visit. Serial spirometry was performed before and at 0, 5, 10, 15, 30, 45, and 60 minutes after the exercise challenge at each visit. Measurement of exhaled breath condensate was performed at the screening visit and study visits 1 and 2. The primary outcome was the maximum change in FEV(1) after exercise. Secondary outcomes were the area under the curve for FEV(1) (expressed as percentage decrease from baseline) during the first 60 minutes (AUC(0-60)) after exercise and the proportion of patients in whom exercise-induced bronchospasm was prevented (defined as < 15% decrease in FEV(1) after exercise challenge). The mean +/- SD maximum decrease in FEV(1) was 27.5 +/- 7.9% at baseline. Patients receiving montelukast had an 18.3 +/- 13.7% decrease in FEV(1) compared with 0.7 +/- 1.6% in patients receiving albuterol (p=0.002, paired t test). Exercise-induced bronchospasm was prevented in 100% of the patients receiving albuterol compared with 55% receiving montelukast (p<0.05, McNemar's test). The AUC(0-60) was significantly smaller with albuterol compared with montelukast (p<0.001, Wilcoxon signed rank test). No correlations were found between Cys-LT concentration and the severity of exercise-induced bronchospasm or the response to montelukast. Pretreatment with albuterol is more effective than montelukast for prevention of exercise-induced bronchospasm in children with asthma.

Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients

Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery, particularly for COPD patients unable to use hand-held devices easily or correctly. The long-acting beta2-agonist, formoterol fumarate, is differentiated by its onset of significant bronchodilation within 5 min of administration. In a randomized, double-blind, double-dummy trial, COPD subjects (n=351, mean forced expiratory volume FEV1=1.3 L, 44% predicted) received nebulized formoterol fumarate (Perforomist inhalation solution; FFIS 20 microg) or DPI (Foradil Aerolizer; FA 12 microg), or placebo twice daily for 12 weeks. Efficacy was assessed with 12-h pulmonary function tests, and quality of life was assessed before and after treatment with the St. George's Respiratory Questionnaire (SGRQ). At the 12-week endpoint, FFIS significantly increased FEV1 AUC0-12h relative to placebo (p<0.0001). No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment. FFIS also significantly increased peak FEV1, trough FEV1, and standardized FVC AUC0-12h compared with placebo. SGRQ assessment at Week 12 demonstrated significant and clinically meaningful improvements in total score (FFIS vs placebo, -4.9, p=0.0067), symptom, and impact scores. No significant differences in efficacy were observed between the two active treatments. Drug related AEs in the FFIS arm with a frequency > or = 1% and exceeding placebo were dry mouth, nausea, and insomnia. Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated. The efficacy and safety profile of FFIS was comparable to FA DPI.

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 β 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 ≥12 years, with a diagnosis of asthma for ≥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 β 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 tlg/d or equivalent (group 1); FP 250 to 500 tlg/d or equivalent with or without LABA (group 2); and FP >500 to 1000 tlg/d or equivalent with or without LABA (group 3). Patients administered 2 inhalations BID of SFC hydrofluoroalkane at doses of 25/50 μg/actuation (group 1), 25/125 μg/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, oropharyn- geal examinations, vital signs, clinic visit lung function tests (FEV 1 and PEF), daily diary card entries of morn- ing 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 pa- tients (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.

Effect of Heliox on Albuterol Delivery by Metered-Dose Inhaler in Pediatric In Vitro Models of Mechanical Ventilation

To determine the effect of varying concentrations of heliox, a mixture of helium and oxygen, on albuterol delivery administered by metered-dose inhaler (MDI) in pediatric mechanically ventilated models. Prospective in vitro laboratory study. University-affiliated research laboratory. The lungs of a 10-kg infant and 30-kg child receiving humidified pressure-regulated volume-controlled ventilation were simulated. The infant settings were an endotracheal tube (ETT) of 4.0 mm, tidal volume of 150 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 20 breaths/minute, inspiratory time of 0.7 second; the child settings were an ETT of 6.0 mm, tidal volume of 450 ml, positive end-expiratory pressure of 2 cm H(2)O, rate of 16 breaths/minute, and inspiratory time of 0.8 second. Ten albuterol MDI canisters with chlorofluorocarbon propellants were each actuated once sequentially (total dose 1000 mug) with a commercially available aerosol holding chamber. Albuterol was collected onto a filter proximal to a lung simulator. The filter was rinsed, and concentrations were determined by high-performance liquid chromatography. In the infant model, heliox mixtures of 70:30, 60:40, and 50:50 were compared with nitrogen:oxygen (N(2):O(2)) mixtures in the same ratios. The effect of the 70:30 mixtures was also explored in a child model. Each gas mixture was tested 5 times. At all three ratios, albuterol delivery to the end of the ETT was improved with heliox compared with N(2):O(2) (approximately 7% vs 3-4%, p<0.0001, one-way analysis of variance [ANOVA] with a Bonferroni correction for multiple comparisons). No significant difference was noted in mean percentage albuterol delivery among the varying ratios of heliox studied. By two-way ANOVA, significantly greater albuterol delivery was noted with 70:30 heliox compared with 70:30 N(2):O(2) (7-8% vs 3%, p<0.0001), with no significant difference between the infant and child model (p=0.21). The gas mixture, model, and interaction of the two explained 88% of the variability in mean percentage albuterol delivery. Heliox increased albuterol delivery administered by MDI to the end of the ETT in these in vitro pediatric models of mechanical ventilation. Further studies are needed to determine if the improved albuterol delivery with heliox enhances clinical response in infants and children needing mechanical ventilation.

Regular vs Ad-lib Albuterol for Patients Hospitalized With Acute Asthma

Inhaled, short-acting beta-agonists and systemic corticosteroids form the mainstay of therapy in acute asthma exacerbation. Asthma, however, is an inflammatory disease of the airways, and its underlying pathology is not impacted by short-acting beta-agonists. While the efficacy of ad-lib beta-agonist administration in outpatient management of asthma symptoms is well established, little data exist to support this strategy in patients with acute, severe asthma. We postulate that as long as patients hospitalized with severe asthma exacerbation receive systemic corticosteroids, regular, scheduled administration of short-acting beta-agonists is unnecessary. Similar therapeutic outcomes can be achieved with the ad-lib administration of the short-acting beta-agonists. Prospective, randomized, double-blind, placebo-controlled trial. Pulmonary floor of a 600-bed municipal hospital. Sixty-two patients hospitalized for acute asthma. Patients were randomized to receive either albuterol nebulizations (regular albuterol group) or saline solution nebulizations (ad-lib group) every 4 h with management of breakthrough symptoms with albuterol metered-dose inhaler or nebulizations for both groups. All patients received systemic corticosteroids. Peak expiratory flows, asthma symptoms, and need for rescue bronchodilator were followed up on each patient until discharge. There was no significant difference in the length of hospitalization (median length, 48 h for ad-lib group vs 57.5 h for regular albuterol group, p = 0.82), rate of improvement in peak flow, or symptoms between the two groups. Ad-lib beta-agonist use compared to regular albuterol scheduled use resulted in a significant reduction in the total number of albuterol treatments administered (median, 7 treatments vs 19 treatments, p = 0.001) during hospitalization. In the management of asthma exacerbation, ad-lib administration of albuterol is therapeutically as effective as regular, scheduled administration. This method of drug administration also reduces the total dose of beta-agonists received by the hospitalized patient.

Unusually persistent rhinorrhea in a patient with allergic rhinitis

History of Present Illness A 49-year-old woman who worked as an administrative assistant presented to the allergist office with symptoms of allergic rhinitis and worsening asthma. She had been diagnosed as having asthma 5 years earlier during which time her condition was well controlled with an albuterol metered-dose inhaler used as needed. However, several months before the visit, her symptoms worsened, with coughing, wheezing, and shortness of breath that required 2 emergency department visits and 4 courses of prednisone. Her rhinitis also worsened, including nasal congestion, watery nasal discharge, sneezing fits, and postnasal drip. Symptoms were perennial and subjectively worse with dust, feather pillows, animals, grass, weed, cigarettes smoke, and heat. Most notable was the copious clear, watery rhinorrhea, which initially began 4 years ago. During that time, she noted the symptoms to occur intermittently, lasting a day or two and then recurring in a few days. Symptoms initially predominated during the winter, but the rhinorrhea gradually worsened, and 2 years later, it occurred during all seasons of the year and on a daily basis. The rhinorrhea was predominantly from the left nostril, caused a sensation of postnasal drip in the supine position, and was worse when bending forward.

Response to inhaled albuterol during nocturnal asthma

During conventional daytime studies of beta(2)-agonists, 1 puff of a metered-dose inhaler often produces a near maximum bronchodilator response. Consequently, the US Food and Drug Administration-approved dose of albuterol is only 1 to 2 puffs every 4 to 6 hours. To determine whether a higher dose of albuterol is required to normalize lung function during nocturnal asthma. Fifteen subjects (age, 18-37 years) were treated with albuterol metered-dose inhalers in a randomized crossover manner at the onset of nocturnal symptoms while sleeping in the Clinical Research Center and during the day when they were asymptomatic. The dose was doubled at 15-minute intervals to 16 cumulative puffs. The mean +/- SD predose FEV(1) was lower at night than during the day (44% +/- 12% vs 68% +/- 9% predicted; P=.0001). The maximum FEV(1) achieved was also lower at night (84% +/- 15% vs 90% +/- 12%; P=.02). The nocturnal dose-response curve was shifted to the right. The median (25th, 75th percentiles) dose required to achieve 80% of the subject's personal best FEV(1) was substantially higher at night (5 [1, 19] vs 0.4 [<0.25, 2] puffs; P=.02), and the median time to achieve this endpoint was longer (47 [21, 90] vs 10 [0.2, 42] minutes; P=.005). No significant systemic effects were observed. At night, the response was slower and required a higher dose because more severe airway obstruction was present on awakening. These results suggest that studies establishing the clinical dose of a beta(2)-agonist or assessing the equivalence of different formulations should be conducted in subjects with more severe reversible airway obstruction than is present during conventional daytime studies.

Allergic rhinitis and asthma in a patient with unilateral pulmonary agenesis

History of Present Illness A 23-year-old woman presented to the allergy/immunology clinic with a previous diagnosis of allergic rhinitis and asthma. The patient reported that she had started immunotherapy (IT) 34 weeks ago, prescribed by her prior allergist, and had been receiving IT at her college health clinic. Following graduation 2 months earlier, she had been giving herself IT injections at home. She denied any reactions and had injectable epinephrine available at home. She was new to our area and was interested in restarting her IT. Her nasal symptoms included congestion, rhinorrhea, sneezing, itching, and postnasal drip. She also complained of ocular watering, itching, injection, and discharge when around cats or dogs. Chest symptoms included a daily cough and occasional wheezing that she did not notice but others had pointed out to her. She denied any nocturnal symptoms. She had an albuterol metered-dose inhaler available but had not used it in the previous 3 months.

Implications of persistent cough in a 3-year-old female

HISTORY OF PRESENTING ILLNESS A 3-year-old female was seen by a family physician for daily, persistent nonproductive cough for the past 6 months. Vigorous activity or upper respiratory infections did not provoke the cough; seasonal changes did not alter its frequency. It did occasionally worsen at night. Although there was no complaint of wheezing or dyspnea, use of an albuterol inhaler helped somewhat, but not always. The patient did not complain of any nasal symptoms. The mother did not recall any past choking episodes to suggest ingestion of a foreign body. A diagnosis of mild persistent asthma based on clinical presentation was made and she was empirically started on albuterol metered-dose inhaler as needed, and beclomethasone dipropionate 42 g, three puffs, twice daily. She had never received oral or intravenous steroids, nor had she been hospitalized. Other medications included cetirizine syrup 2.5 mg nightly and mometasone nasal inhaler one spray each nostril nightly. Further questioning revealed occasional episodes of a “fast heartbeat,” excessive sweating, and persistent hoarseness.

A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered-dose inhalers

Background: With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation. Objective: In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED50, the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations. Methods: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 μg by using specially manufactured MDI canisters. FEV1 was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV1 was measured after each methacholine dose until a 20 % decrease in FEV1 (PD20) was achieved. Results: Mean PD20 values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD20 values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 μg) of albuterol MDI were within the sensitive region of the dose-response curve. The mean estimated ED50 value on the basis of nonlinear mixed effect modeling was 119.2 μg (range, 33.3-337.1 μg), with an intersubject percentage coefficient of variation of 69.0 %. Conclusions: The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products. (J Allergy Clin Immunol 2002;110:713-20.)

Effect of beta2-agonist treatment and spirometry on exhaled nitric oxide in healthy children and children with asthma.

We set out to determine the effect of spirometry and bronchodilator therapy on exhaled nitric oxide (FE(NO)) values in children. We hypothesized that there will be no difference on FE(NO) values pre- and postspirometry and following bronchodilator therapy. Sixteen children [(mean = 14.4 +/- 1.2 years; range, 12-18 years; healthy controls (n = 6); asthmatics on inhaled steroids (n = 5); and asthmatics on no steroids (n = 5)] had exhaled nitric oxide (FE(NO)) measurements on 4 consecutive days as follows: pre- and postspirometry (day 1); pre- and postalbuterol metered dose inhaler (MDI) therapy (day 2); pre- and postspirometry and albuterol MDI therapy (day 3); and pre- and postspirometry and placebo MDI (day 4). FE(NO) was measured with a chemiluminescence analyzer, using the single vital capacity exhalation technique at an exhalation flow of 50 mL/sec. There were no statistically significant differences in FE(NO) values pre- and poststudy maneuvers under all experimental conditions in healthy children. However, in healthy children, clinically relevant (>10%) differences from baseline were observed on day 1 (3-18 min) and day 4 at 18 min. In children with asthma, FE(NO) values increased significantly by 11-19% from pretreatment levels at 8 and 18 min, postbronchodilator on day 2, and 12-17% at 8 and 18 min post bronchodilator and spirometry on day 3. Spirometry and treatment with a placebo (day 4) resulted in a decrease in FE(NO) values by 11% at 3 min postbaseline in patients on inhaled steroids. The changes observed were similar in children on vs. off inhaled steroids, and also in well-controlled vs. poorly controlled asthma. We conclude that FE(NO) values should be obtained consistently either pre- and at a specific time postalbuterol treatment or spirometry. Alternatively, changes in FE(NO) values should be interpreted in relationship to the timing of these maneuvers.

The Effects of Inhaled Albuterol and Salmeterol in 2- to 5-Year-Old Asthmatic Children as Measured by Impulse Oscillometry*

The functional assessment of the response to bronchodilators in 2- to 5-year-old asthmatic children is technically difficult. For this reason, there have been no reports on the effects of long-acting bronchodilators, such as salmeterol, in this age group. Of the several techniques available for measuring resistance to airflow, forced oscillation remains the most adaptable to young children and the most practical for research and clinical use. In this study we used the Jaeger MasterScreen Impulse Oscillometry System to assess the response of 2 to 5 year-old asthmatic children to an inhaled long-acting bronchodilator, salmeterol, by comparing it to the effect of a standard dose of the short-acting bronchodilator, albuterol. We performed a placebo-controlled, randomized, crossover study in 10 children aged 2 to 5 years who had a history of physician-diagnosed asthma and who were not on regular controller therapy. At weekly intervals after baseline measurements of reversibility, each child received two inhalations from an albuterol metered-dose inhaler (MDI) with a spacer (200 µg), or placebo MDI with spacer, or two inhalations from a salmeterol MDI (50 µg), or 50 µg from a salmeterol Diskus®. Measurements were obtained at 5, 30, 60, 360, and 540 min, the last time interval only on the salmeterol days. Based on previous studies, total respiratory system reactance at 5 Hz (X5), calculated by the MasterScreen computer from mouth pressure and flow data, was used as the primary efficacy variable. The mean intra-individual variability in X5 was 10.5% (range 3.6% to 17.9%). The mean (SE) changes from baseline X5 at each time point were as follows: for placebo, 9.6 (3.0), 10.1 (2.6), 5.1 (2.9), 6.1 (3.5), p=0.36 vs. baseline; after treatment with albuterol, 32.7 (3.8), 53.9 (1.2), 47.3 (5.4), 18.1 (5.8), p<0.01 vs. baseline at all time points; after salmeterol MDI, 16 (6.4), 28.9 (5.2), 32.7 (3.9), 34.6 (4.4), 31.2 (4.8), p<0.05 at 60, 360, and 540 min; and after salmeterol Diskus®, 16.4 (4.0), 16.9 (6.6), 27.8 (5.9), 28.6 (5.6), 33.8 (4.0), p<0.05 at 540 min. No significant adverse events or electrocardiographic changes were noted at any time. Impulse oscillometry is an acceptable method of assessing airway responses to bronchoactive drugs in this age group. Compared to albuterol and to its effect in older children and adults, the response to salmeterol Diskus® appears to be somewhat blunted in this age group. The MasterScreen system is well suited for pharmacodynamic studies and clinical investigations in pre-school-aged children.

A randomized, 12-week, double-blind, placebo-controlled study comparing formoterol dry powder inhaler with albuterol metered-dose inhaler

Formoterol is a beta2-adrenergic agent which, when inhaled, produces rapid and long-lasting bronchodilatation. The aim of this study was to compare the efficacy, safety, and tolerability of formoterol powder for inhalation delivered via the Aerolizer device with placebo and with albuterol delivered via metered-dose inhaler in patients with mild to moderate persistent asthma. In a multicenter, double-blind, parallel-group study, 541 patients were randomized at 26 trial sites to receive either formoterol, 12 microg twice daily; formoterol, 24 microg twice daily; albuterol, 180 microg four times daily; or a placebo for 12 weeks. The effects of each treatment on lung function, asthma symptoms, and frequency of rescue albuterol use were evaluated. Adverse effects and clinical laboratory parameters were also evaluated. The bronchodilatory effects of formoterol were rapid in onset and persisted for 12 hours. Both formoterol doses were more effective than placebo and albuterol for objective measures of lung function. Morning and evening peak expiratory flow rates were more improved with formoterol, and formoterol provided significantly greater improvements in asthma symptom scores compared with both albuterol and placebo. Overall, patients taking formoterol used significantly less rescue medication than did those taking albuterol or placebo. Nocturnal awakenings occurred less often with formoterol than with placebo or albuterol. The therapeutic effects of formoterol were maintained over the entire 12 weeks of treatment. Adverse events were similar for all treatment groups, and clinical laboratory data were unremarkable. Rapid-onset, long-acting formoterol, administered via the Aerolizer inhaler, is an effective and safe treatment for patients with mild to moderate persistent asthma.

Laryngospasm and Paradoxical Bronchoconstriction After Repeated Doses of β 2- Agonists Containing Edetate Disodium

A 22-year-old woman with mild intermittent asthma, who had no previous history of an adverse reaction to an albuterol metered-dose inhaler, developed paradoxical bronchoconstriction after inhalation of the fourth dose of an albuterol nebulizer solution. She experienced the same symptoms and laryngospasm with repeated inhalations of albuterol and metaproterenol nebulizer solutions that contained edetate disodium. Each episode responded to racemic and subcutaneously administered epinephrine. To our knowledge, this is the first report of paradoxical bronchoconstriction and laryngospasm due to repeated doses of beta 2-agonist solutions with edetate disodium.

Demonstration of In Vivo Bioequivalence of a Generic Albuterol Metered-Dose Inhaler to Ventolin

To use histamine bronchoprovocation and bioassay statistical procedures to evaluate the in vivo bioequivalence of a generic albuterol metered-dose inhaler (MDI). A randomized, double-blind, balanced, crossover design was used to determine the potency of each generic albuterol MDI actuation relative to Ventolin (Glaxo Wellcome; Research Triangle Park, NC) administration. One treatment was administered on each of 4 study days. A histamine bronchoprovocation procedure was initiated 1.25 h before and 15 min after administration of the study treatment. Twenty-four nonsmoking subjects with mild-to-moderate asthma were studied (18 to 65 years of age; FEV(1), > 60% of predicted; and provocative concentration of histamine causing a 20% fall in FEV(1) [PC(20)], < or = 8 mg/mL at screening). One and four actuations (90 and 360 microg, respectively) of the generic MDI and of Ventolin MDI. Placebo inhalers were used to maintain blinding of inhaler and doses. The primary outcome variable was histamine PC(20) measured after study treatment administration. A significant dose-effect relationship was present (p < 0.0001). Deviation from parallelism of the generic and Ventolin dose-response curves (p = 0.95) and differences in overall mean response between the two formulations (p = 0.68) were not significant. Using Finney 2 x 2 bioassay statistical procedures, we estimated that one actuation of the generic albuterol MDI was equivalent to 1.01 puffs of Ventolin (90% confidence interval, 0.69 to 1.50). The generic albuterol MDI delivers a quantity of albuterol to the beta(2)-receptor site in the lung that is the bioequivalent to Ventolin. Further, this study reinforces the validity of this statistical methodology for determining in vivo bioequivalence.

Controlled Trial of Two Formulations of Cromolyn Sodium in the Treatment of Asthmatic Patients ≥ 12 Years of Age

This multicenter, randomized, double-blind, placebo-controlled, parallel study compared the efficacy and safety of the hydrofluoroalkane (HFA) formulation of cromolyn sodium metered-dose inhaler (MDI) with the chlorofluorocarbon (CFC) formulation in asthmatic patients > or = 12 years old over a 12-week period. Stable asthmatics using only currently marketed cromolyn sodium and as-needed inhaled beta2-agonists were randomly assigned to treatment with HFA cromolyn sodium, CFC cromolyn sodium, or placebo, administered as two inhalations (2 mg) qid for 12 weeks. Prior to randomization, all patients were required to meet minimum symptom and/or pulmonary function test criteria after discontinuation of cromolyn sodium. Efficacy was assessed by changes in daily symptom scores, albuterol use, peak expiratory flow, pulmonary function measurements, and overall opinions of effectiveness. A total of 280 patients in 29 centers were randomly assigned to treatment with HFA cromolyn sodium (n = 94), CFC cromolyn sodium (n = 91), or placebo (n = 95). Patients treated with the HFA formulation of cromolyn sodium demonstrated a 28 to 33% improvement over placebo for all symptom scores (p < 0.05) and a 35% improvement over placebo in the use of albuterol MDI (p < 0.05). The patients' opinions of overall effectiveness favored HFA cromolyn sodium (p = 0.011) and CFC cromolyn sodium (p = 0.006) over placebo. The investigators' opinions indicated a statistically significant difference favoring CFC cromolyn sodium compared with both placebo (p < 0.001) and HFA cromolyn sodium (p = 0.042). No statistically significant differences existed among groups in the incidence of treatment-related adverse events. The HFA formulation of cromolyn sodium MDI is a well-tolerated and effective treatment for asthma patients > or = 12 years old. The safety and efficacy profile of the HFA formulation is comparable to that of the CFC formulation.

Comparative Efficacy and Safety of Albuterol Sulfate Spiros Inhaler and Albuterol Metered-Dose Inhaler in Asthma

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

Emergency Treatment of Acute Asthma With Albuterol Metered-Dose Inhaler Plus Holding Chamber: How Often Should Treatments Be Administered?

To determine the optimal treatment interval for administering albuterol metered-dose inhaler (MDI) with a holding chamber to patients presenting to the emergency department (ED) with acute asthma. Prospective, randomized, double-blind study. EDs of two affiliated teaching hospitals in the Bronx, NY. One hundred adult patients with acute asthma and FEV1 <60% predicted of normal. At entry (T=0 min), eligible patients all openly received inhaled albuterol (six puffs) via MDI with a spacer. Subsequently, in a double-blind fashion, they received six puffs of albuterol or placebo with new MDIs and spacers at 30, 60, and 90 min such that group 1 (n=34) received albuterol every 30 min, group 2 (n=33) every 60 min, and group 3 (n=33) at 120 min only. FEV1 and vital signs were measured at T=0 and at 15, 30, 60, 90, and 120 min following initial treatment. Potassium levels were measured at T=0 and 120 min. Adverse events, the use of additional inhaled beta-agonists or systemic corticosteroids, and hospitalization rates were recorded. At T=0, the groups did not differ in age, FEV1, or prescribed asthma medications. All groups showed significant improvement in FEV1 (p<0.05; T=120 vs 0 min). The conditions of groups 1 and 2 improved significantly more than those of group 3, but did not differ compared to each other. The mean+/-SEM change in FEV1 (T=120 vs 0 min) was 0.993+/-0.108, 0.858+/-0.135, and 0.321+/-0.056 L, respectively, for the three groups. Separate analysis for patients with FEV1% <40% or >40% predicted showed similar results. However, patients who initially were low responders to albuterol treatment (<15 percentage point increase at 15 min) improved significantly with 30-min treatments compared to the other two treatment regimens. Patients who initially responded with >15 percentage point increase in FEV1 at 15 min following initial albuterol inhalation benefited equally from 30- or 60-min treatments compared to 120 min. Potassium levels did not change significantly during the study. Adverse events and hospitalization rates were equivalent. After the conclusion of the study, group 3 patients required a greater number of beta-agonist treatments prior to eventual discharge from the ED. For acute asthma, albuterol MDI with a holding chamber can be given optimally at 60-min intervals with minimal adverse effects for the majority of patients. However, patients who initially demonstrate a low or poor bronchodilator response to albuterol should be given subsequent treatments at 30-min intervals. This will optimize care and conserve resources for patients who will benefit the most.

A One-Week Dose-Ranging Study of Inhaled Salmeterol in Children with Asthma

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 μg and 42 μg administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral β-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vita signs, electrocardiogram (ECC), and 24-hr ECG (Holter) monitoring. Both the 21 -μg and 42-μg doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV1) (p ≤ 0.02) and PEFR (p ≤ 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-μg dosage producing consistently higher serial FEV1and PEFR than did the 21 -μg dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p ≤ 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECCs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 μg or 42 μg twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 μg twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 μg.

Cardiovascular Safety of High Doses of Inhaled Fenoterol and Albuterol in Acute Severe Asthma

It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma. Asthmatic patients presenting to the ED with acute severe asthma (FEV1 less than 50% of predicted) were enrolled in a multicenter, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 micrograms per puff, or albuterol, 100 micrograms per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled beta 2-agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV1 plateau (i.e., < 10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV1 were assessed after each dose. 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV1 160 mL more than albuterol. The mean (SEM) FEV1 increase from baseline was 0.75 +/- 0.06 L in the fenoterol group and 0.59 +/- 0.06 L in the albuterol group (p < 0.03). Both beta 2-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23 +/- 0.04 mmol/L) than in the salbutamol (0.06 +/- 0.03 mmol/L) group (p = 0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011 +/- 0.003 s compared with 0.003 +/- 0.003 s in the albuterol group (p < 0.05). Differences in hypokalemia and Q-Tc prolongation associated with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group. In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 micrograms per puff by MDI valved holding chamber and mask, to a total dose of 3,200 micrograms and salbutamol (100 micrograms per puff) to a total dose of 1,600 micrograms over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV1 significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia.