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Original Research: ASTHMA |

Population Pharmacodynamic Model of Bronchodilator Response to Inhaled Albuterol in Children and Adults With Asthma FREE TO VIEW

Kathryn Blake, PharmD; Rajanikanth Madabushi, PhD; Hartmut Derendorf, PhD; John Lima, PharmD
Author and Funding Information

*From the Center for Clinical Pediatric Pharmacology Research (Drs. Blake and Lima), Nemours Children's Clinic, Jacksonville; and Department of Pharmaceutics (Drs. Madabushi and Derendorf), College of Pharmacy, University of Florida, Gainesville, FL.

Correspondence to: Kathryn Blake, PharmD, Center for Clinical Pediatric Pharmacology Research, Nemours Children's Clinic, 807 Childrens Way, Jacksonville, FL 32207; e-mail: kblake@nemours.org


All work was performed in the Center for Clinical Pediatric Pharmacology Research, Nemours Children's Clinic, Jacksonville, FL.

The authors have no conflicts of interest to report.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2008;134(5):981-989. doi:10.1378/chest.07-2991
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Background:  Because interpatient variability in bronchodilation from inhaled albuterol is large and clinically important, we characterized the albuterol dose/response relationship by pharmacodynamic modeling and quantified variability.

Methods:  Eighty-one patients with asthma (24% African American [AA]; 8 to 65 years old; baseline FEV1, 40 to 80% of predicted) received 180 μg of albuterol from a metered-dose inhaler (MDI), and then 90 μg every 15 min until maximum improvement or 540 μg was administered; all then received 2.5 mg of nebulized albuterol. FEV1 was measured 15 min after each dose. The population cumulative dose/response data were fitted with a sigmoid maximum effect of albuterol (Emax) [maximum percentage of predicted FEV1 effect] model by nonlinear mixed-effects modeling. The influence of covariates on maximum percentage of predicted FEV1 reached after albuterol administration (Rmax) and cumulative dose of albuterol required to bring about 50% of maximum effect of albuterol (ED50) and differences between AA and white patients were explored.

Results:  ED50 was 141 μg, and Emax was 24.0%. Coefficients of variation for ED50 and Emax were 40% and 56%, respectively. Ethnicity was a statistically significant covariate (p < 0.05). AA and white patients reached 82.4% and 91.9% of predicted FEV1, respectively (p = 0.0004); and absolute improvement in percentage of predicted FEV1 was 16.6% in AA patients vs 26.7% in white patients (p < 0.0003). There were no baseline characteristic differences between AA and white patients. Nebulized albuterol increased FEV1 ≥ 200 mL in 21% of participants. Heart rate and BP were unchanged from baseline after maximal albuterol doses.

Conclusions:  Our model predicts that 180 μg of albuterol by MDI produces a 14.4% increase in percentage of predicted FEV1 over baseline (11.7% in AA patients, and 17.5% in white patients). Emax varies widely between asthmatic patients. AA patients are less responsive to maximal doses of inhaled albuterol than white patients.

Figures in this Article

Inhaled short-acting β2-agonists (SABAs) are the most potent bronchodilators used today to treat acute symptoms of asthma1; and albuterol, a partial β2-agonist, is the most frequently prescribed asthma medication in the United States.2 Although universally used for acute asthma symptoms, SABAs have been associated with significant interpatient variability in response.39 Many studies312 have characterized the SABA dose to bronchodilator response relationship under controlled conditions. However, few studies have explored the magnitude and sources of bronchodilator response variability, and no studies have characterized the dose to bronchodilator response relationship using population pharmacokinetic/pharmacodynamic (PPK/PD) modeling.

In a patient-care setting, the purpose of PPK/PD modeling is to gain a better understanding of the quantitative guidelines for dosage individualization and optimization. Additionally, PPK/PD modeling allows one to identify and quantify fixed and random sources of variability that characterize the dose (or concentration) vs response relationship in the target population to be treated with the drug.13

American Thoracic Society guidelines state that an increase in FEV1 of 12 to 15% above baseline measured 15 min following inhalation of 100 to 400 μg of a SABA, such as albuterol, by metered-dose inhaler (MDI) “suggest a significant bronchodilatation.”14 Additionally, this measurement is a criterion used to diagnose asthma.1 However, it is not clear if these dosing recommendations will achieve maximal bronchodilator response in patients.

In the present study, we characterized the albuterol dose to bronchodilator response relationship in 81 children and adults with moderate-to-severe persistent asthma using a population pharmacodynamic approach. The purpose was to obtain estimates of the pharmacodynamic parameters that characterize the albuterol dose/bronchodilator response curve, quantify and identify sources of interpatient pharmacodynamic variability, and determine the additional bronchodilator effect of a single dose of nebulized albuterol after maximal dosing from an MDI.

Participants

Participants of any ethnicity 8 to 65 years old with a well-defined history of physician-diagnosed asthma; a baseline prebronchodilator FEV1 of 40% to 80% predicted for age, height, and gender15,16; who denied oral corticosteroid use, emergency department visits, or hospitalizations within the previous 3 months; who were nonsmokers or had < 5–pack-year history with no smoking in the previous year; and who had a normal physical examination and no confounding diseases were selected. Participants had to withhold inhaled SABAs or inhaled anticholinergic drugs for 8 h, oral antihistamines for 5 days, theophylline for 24 h, and cromolyn, nedocromil, and inhaled corticosteroids (ICS) for 2 h prior to the study. Inhaled salmeterol and formoterol and leukotriene modifiers were not available in the United States when this study was conducted. Participants were recruited from our asthma research clinic database or newspaper advertisements. The study was approved by our local Institutional Review Board, and written informed consent was obtained.

Study Design and Drug Administration

This was an open-label study conducted over 1 to 2 h for each participant on a single day. After we obtained baseline spirometry, heart rate, and BP measurements, participants received two inhalations of albuterol (90 μg per inhalation) from an MDI attached to a holding chamber (InspirEase; Schering-Plough Corporation; Kenilworth, NJ). Additional inhalations of 90 μg through the holding chamber were administered every 15 min, with spirometry, heart rate, and BP measured immediately prior to each dose. When there was no further improvement in FEV1 (< 100 mL change from the highest FEV1 obtained after the previous dose), each participant received a single 2.5-mg dose of nebulized albuterol. Final spirometry, heart rate, and BP measurements were obtained 15 min after nebulized albuterol. The cumulative doses of albuterol administered from the MDI were 180 μg, 270 μg, 360 μg, 450 μg, 540 μg; and the cumulative doses from the MDI plus nebulizer were 270 μg MDI plus 2,500 μg nebulized (2,770 μg); 360 μg MDI plus 2,500 μg nebulized (2,860 μg); 450 μg MDI plus 2,500 μg nebulized (2,950 μg); and 540 μg MDI plus 2,500 μg nebulized (3,040 μg). The number of participants receiving each dose and the cumulative administered doses (MDI and MDI plus nebulized) are shown in Figure 1. These doses represent the amount of drug administered to the patient from each device.

Figure Jump LinkFigure 1 Number of participants who received each cumulative dose of albuterol. After baseline spirometry, participants received 180 μg of albuterol and then 90 μg every 15 min until maximum improvement or 540 μg was administered; all then received 2.5 mg of nebulized albuterolGrahic Jump Location

Prior to the first dose of study drug, two actuations from the albuterol MDI were discharged into the holding chamber to prime the MDI and to neutralize the electrostatic charge present in the plastic holding chamber.17,18 The holding chamber was collapsed and expanded several times in a location away from the participant to remove any aerosolized albuterol from the interior chamber of the InspirEase. For each single inhalation of albuterol from the MDI, including the initial two inhalations, participants were instructed to actuate the inhaler to release one dose (90 μg) of albuterol into the holding chamber, breathe in slowly through the mouthpiece without sounding the reed (inhalation rate of 0.3 L/s is not exceeded), and breath hold for 5 s. Participants were instructed to exhale into the chamber and inhale a second time followed by a 5-s breath hold.19

Albuterol for nebulization (inhalation solution 0.5%) was diluted with saline solution to a final volume of 3.5 mL. The dose was administered by tidal breathing to nebulizer sputtering after repeated tamping of the nebulizer bowl using an open system consisting of a nebulizer (Puritan-Bennett; Overland Park, KS) connected to a mouthpiece by a T joint and driven by an air compressor (Medi-mist; Mountain Medical Equipment; Littleton, CO).

Spirometry (MultiSpiro; Irvine, CA) was performed with the participant standing and wearing a nose clip, and up to eight efforts were recorded after each dose to obtain the two highest FEV1 measurements within 100 mL of each other; the highest FEV1 was recorded. Polgar reference equations were used for determining predicted FEV1 values in girls and boys < 19 years of age; Knudson reference equations were used for men and women ≥ 19 years of age.15,16 BP and heart rate were measured with the participant seated (Dinamap BP monitor; Critikon, GE Healthcare; Bucks, UK).

Population Pharmacodynamic Analysis

Population analysis was performed on the cumulative albuterol dose/response data.13 A sigmoid maximum effect of albuterol (Emax) model was used to describe the relationship between albuterol dose and bronchodilator response as determined by the change in percentage of predicted FEV1 from baseline (R0).20

where D is cumulative albuterol dose, Rmax is the maximum percentage of predicted FEV1 reached after albuterol administration, γ is the Hill coefficient that describes the steepness of the dose/response relation, and ED50 is the cumulative dose of albuterol required to bring about 50% of Emax.

Mean and between subject coefficient of variation values for population parameters were obtained by nonlinear mixed-effects modeling (NONMEM Project Group; San Francisco, CA). The between-participant variability was assumed to follow a log-normal distribution, while an additive error model was used to explain the random residual error. The method of estimation was first-order conditional estimation, which uses conditional estimates of the random interindividual variability while estimating the population parameters.21,22 The first-order conditional estimation method is applicable for nonlinear data and as the amount of data per individual increases.23

Gender, ethnicity, age, years diagnosed with asthma, and current ICS use (yes/no) were incorporated into the model as covariates. A power function was used to test the influence of continuous covariates normalized to their median values for numerical stability on the model parameters. Categorical covariates that take numerical values were tested using a linear model.

Two-sample t tests (two-tailed, unequal variance) were used to test for significant differences in baseline pulmonary function (R0), Rmax, baseline percentage of predicted FEV1 between users and nonusers of ICS, duration of asthma between users and nonusers of ICS, absolute improvement in percentage of predicted FEV1 between whites and African Americans, and duration of asthma between whites and African Americans. The proportion of whites vs African Americans who used ICS, the proportion of whites vs African Americans who used regularly scheduled inhaled albuterol for daily asthma management, and the proportion of ICS users vs nonusers who reported regularly scheduled inhaled albuterol therapy for daily asthma management were compared by χ2 analysis. Paired t tests (two-tailed) were used to test for differences in BP and heart rate after maximal albuterol doses compared with baseline. A p value < 0.05 was considered significant.

Participant Characteristics

Of 107 asthmatics screened, 81 patients met the inclusion criteria. Participant characteristics are presented in Table 1. Race and ethnicity were determined by self-report from the adults and by parental report for children < 18 years old. Thirty-seven percent of participants were < 20 years old, 40% were 20 to 45 years old, and 23% were 46 to 65 years old. Baseline FEV1 was from 60 to 80% of predicted in 68% of participants, classifying them as having moderate persistent asthma.1 By patient report on the day of the study visit, 26 patients (8 African Americans) stated that they used two inhalations of albuterol on a regular schedule either once daily (n = 5), twice daily (n = 5), three times daily (n = 8), or four times daily (n = 8) [African Americans vs whites, p = 0.40]. All other patients reported using albuterol at two inhalations on an as-needed basis. Quantification of SABA use during the week immediately prior to the study day was not obtained. Forty percent of participants were using low-dose ICS, 14% were using medium-dose ICS, and 2% were using high-dose ICS; one pediatric patient was treated with prednisone every other day.1 All participants had been using ICS for at least 3 months, but the majority had used ICS for ≤ 2 years. Clinical characteristics were similar between users and nonusers of ICS (baseline FEV1 percentage of predicted [p = 0.89]; duration of asthma [p = 0.89]; and frequency of SABA use [p = 0.48]). Thirty-two patients were using a theophylline product, and 1 patient was using cromolyn sodium. Of these 32 patients, 21 patients were also using an ICS. All participants had long-standing asthma with an asthma diagnosis for 64%, 63%, and 56% of their lives in the age groups < 20 years, 20 to 45 years, and 46 to 65 years, respectively.

Table Graphic Jump Location
Table 1 Participant Characteristics*

*Data are presented as mean ± SD or No. (%) unless otherwise indicated. FEF25–75 = forced expiratory flow, midexpiratory phase.

†There was one Hispanic patient in each age group and one other ethnicity in the 20-to 45-year age group.

‡ICS included beclomethasone, flunisolide, and triamcinolone.

§Low-, medium-, and high-dose levels as specified in National Asthma Education and Prevention Program.1

Modeled Data

Population modeling of the albuterol dose/response relationship is shown in Figure 2. A Hill coefficient (γ) of 2 was found to best fit the data and had lowest objective function value. In preliminary studies, several pharmacodynamic models were fitted to the albuterol dose vs FEV1 relationship. The sigmoid Emax model with γ = 2 provided the best fit to the data. Subsequent analyses setting γ as a parameter resulted in unreasonable pharmacodynamic and variability estimates suggesting that fitting the sigmoid Emax model with four parameters resulted in overparameterization. Therefore, we set γ = 2 and fit the model with thee parameters. The modeled parameters, ED50 of 141 μg and Emax of 24.0%, predict that the standard of administering two inhalations of albuterol (180 μg) is sufficient to produce a 14.4% increase in percentage of predicted FEV1 from baseline and to reach 60.0% of Emax (Table 2. There were 40% and 56% variabilities associated with ED50 and Emax, respectively.

Figure Jump LinkFigure 2 Fitted dose/response after cumulative doses of albuterol (solid line). Open circles represent individual patient responses. Response is percentage of predicted FEV1. The cumulative doses of albuterol administered from the MDI were 180 μg, 270 μg, 360 μg, 450 μg, and 540 μg; and the cumulative doses from the MDI plus nebulizer were 2,770 μg (270 μg MDI plus 2,500 μg nebulized); 2,860 μg (360 μg MDI plus 2,500 μg nebulized); 2,950 μg (450 μg MDI plus 2,500 μg nebulized); and 3,040 μg (540 μg MDI plus 2,500 μg nebulized).Grahic Jump Location
Table Graphic Jump Location
Table 2 Population Modeling of Albuterol Dose/Response Relationship

Incorporating gender, age, years diagnosed with asthma, and current ICS use (yes/no) as covariates for R0, Rmax, and ED50 did not account for significant between-participant variability. Including ethnicity as a covariate on Emax decreased the interpatient variability by 1% (p < 0.05). Modeled data for whites and African Americans demonstrated no difference in ED50, but Rmax was 91.9% of predicted FEV1 in whites and 82.4% of predicted in African Americans (p = 0.0004) [Fig 3]. Consistent with our modeled data of difference in Rmax between ethnic groups, whites had an absolute improvement in percentage of predicted FEV1 of 26.7% from baseline after receiving maximum albuterol doses compared with 16.6% in African Americans (p < 0.0003). Using the modeled parameters, two inhalations of albuterol (180 μg) would increase percentage of predicted FEV1 by 11.7% in African Americans vs 17.5% in whites. Baseline percentage of predicted FEV1 was not different between whites and African Americans (65.2 ± 11.4% vs 65.8 ± 8.3%, respectively; p = 0.81), nor was duration of asthma (p = 0.31) nor the proportion using ICS (p = 0.61).

Figure Jump LinkFigure 3 Fitted dose/response after cumulative doses of albuterol in African Americans (solid line) and whites (dotted line). Open triangles are individual patient responses for African Americans. Open circles are individual patient responses for whites. Response is percentage of predicted FEV1. The cumulative doses of albuterol administered from the MDI were 180 μg, 270 μg, 360 μg, 450 μg, and 540 μg; and the cumulative doses from the MDI plus nebulizer were 2,770 μg (270 μg MDI plus 2,500 μg nebulized); 2,860 μg (360 μg MDI plus 2,500 μg nebulized); 2,950 μg (450 μg MDI plus 2,500 μg nebulized); and 3,040 μg (540 μg MDI plus 2,500 μg nebulized).Grahic Jump Location
Effect of Nebulized Albuterol After Maximum Doses From the MDI

All participants reached maximum improvement in FEV1 (< 100 mL change from highest FEV1 obtained after previous dose) after six inhalations or less of albuterol from the MDI (Fig 2). The population-modeled data in Figure 2 demonstrate that addition of nebulized albuterol to maximal doses from an MDI (from 2,770 to 3,040 μg) does not further increase bronchodilator response. However, nebulized albuterol provided additional bronchodilation (≥ 200 mL)14 in 11 participants (21%) [mean ± SD improvement, 366.5 ± 126.1 mL; range, 200 to 610 mL]. After receiving nebulized albuterol, six participants had a fall in FEV1 > 100 mL (range, 3.3 to 25%).

Adverse Effects

There was no change from baseline in BP or heart rate after maximal albuterol doses (Table 3). There were no complaints of tremor.

Table Graphic Jump Location
Table 3 BP and Heart Rate at Baseline and After Maximal Albuterol Doses*

*Data are presented as mean ± SD.

†p = 0.53.

‡p = 0.06.

§p = 0.13.

Inhaled albuterol is the most extensively used medication for patients with asthma. Bronchodilator response to SABAs has been observed to be highly variable between patients.39 The results of the present study support these findings and extend them to include quantification of the variability in bronchodilator response using a pharmacodynamic population model. This is the first study to our knowledge to use population pharmacodynamic modeling to characterize the dose/response relationship and variability associated with bronchodilator response after inhaled albuterol in physician-diagnosed asthmatic patients with moderate-to-severe persistent disease. With an Emax of 24% of predicted FEV1 (absolute change in percentage of predicted FEV1 over baseline) and an ED50 of 141 μg (dose of albuterol that produced half-maximal bronchodilation, ie, 12% [0.5 × 24%]), these modeled data predict that two inhalations of albuterol (180 μg) would increase the percentage of predicted FEV1 by 14.4%. The results of this study cannot be applied to the management of acute exacerbations of asthma, which may have a predominantly inflammatory component. Inflammation is known to impair the response to inhaled β2-agonists, which would result in different β2-agonist pharmacodynamic characteristics.24

Patients were considered stable and enrolled in the study if they had not had an asthma exacerbation requiring treatment with oral steroids, emergency department care, or hospitalization in the past 3 months and were not having an acute worsening of their symptoms (albuterol use for acute symptom control was unchanged over previous days). It is likely that some patients would be considered as having poorly controlled but stable asthma based on their baseline pulmonary function, lack of antiinflammatory therapy, and regularly scheduled use of inhaled albuterol. Questionnaires currently used to assess asthma stability such as the Asthma Control Test, the Childhood Asthma Control Test, the Asthma Control Questionnaire, and the Asthma Therapy Assessment Questionnaire control index1 were not available at the time this study was conducted.

Bronchodilator response in the present study was extremely variable (Fig 2). Nevertheless, the results of our study clearly show the typical pharmacologic pattern for the bronchodilator response to albuterol (steep increase in response at low doses followed by flattening of the response curve at high doses). The between-subject coefficient of variation for R0 and Rmax was approximately 16%, and for Emax was 56.2% (Table 2). The similar coefficient of variation for R0 and Rmax compared with the large variability in Emax suggests that variability associated with Emax is due to R0, ED50, and Rmax, and that the change from baseline (Emax) between individuals is highly variable. Thus, the Emax 56.2% coefficient of variation predicts that certain asthmatics may be particularly responsive to the bronchodilator effects of albuterol and may experience relief of symptoms with relatively low doses of inhaled albuterol. This individual variation in bronchodilator responsiveness is clearly evident in Figure 2. However, the variability in the ED50, although high (41%), is not clear from the graph and indicates that the relationship between the dose of inhaled albuterol to achieve a targeted reversibility is highly variable.

The actual doses of albuterol delivered to the lungs of the study participants would be lower than the doses we used in the pharmacodynamic model for the MDI (90 μg) and nebulizer (2,500 μg). Of the 100 μg present in the valve of an albuterol MDI (90 μg delivered from the mouthpiece of the actuator), only 25 to 40 μg is delivered to the patient in an in vitro model when the MDI is attached to a holding chamber.2527 Likewise, only 400 to 500 μg of a 2,500-μg dose of albuterol inhalation solution placed in the nebulizer used in this study is available for inhalation.28 As we did not measure the amount of drug available to the patient from the devices, we chose to use the MDI and nebulizer doses most commonly recognized by practitioners.

Patients in this study had a wide range of baseline FEV1 values (40 to 80% of predicted FEV1). Baseline FEV1 influences the bronchodilator response to inhaled β2-agonists such that larger doses are required in patients with lower baseline values to reach maximum bronchodilation compared with patients who have higher baseline values.29 Reasons for this phenomenon could include the presence of endogenous functional antagonists acting at the β2-receptor, or desensitization of the β2-receptor due to either the action of inflammatory mediators at the receptor or from excessive exposure (due to overuse) to β2-agonist drugs.24,30,31 Baseline FEV1 was not included as a covariate in our analysis because it is included as a parameter in the pharmacodynamic model.20,3234

Other studies5,7,8,35 have also noted significant interpatient variability in response. In the present study, the covariates of gender, ethnicity, age, years diagnosed with asthma, and current ICS use (yes/no) did not further explain the variability observed. We were surprised that ICS use did not influence our findings because corticosteroids increase β-adrenergic expression and could affect ED50 and Emax.36 However, only a little over half of patients were using ICS, and 73% were using a low dose. There were no significant differences between ICS users (including the pediatric patient on prednisone) and nonusers for baseline FEV1 percentage of predicted nor duration of asthma. In addition, a similar proportion of ICS users and nonusers reported albuterol use on a regular schedule (two inhalations once to four times daily). Thus, there were not any obvious clinical differences between ICS users and nonusers that would be expected to influence the ED50 or Emax findings. It is possible that inclusion of participants with differing genotypes or haplotypes for genes in the β2-receptor pathway could have contributed to variability.3743 However, a limitation of our study is that we did not collect DNA.

Additionally, we do not know the extent of prior inhaled SABA usage in the week immediately prior to the study day. Twenty-six patients reported regular use of albuterol one to four times daily as part of their asthma self-management. Frequent use of inhaled SABAs and long-acting β2-agonists can induce β2-receptor desensitization, causing patients to become less bronchodilator responsive to additional SABA doses.4446 In addition, frequent use is considered a marker of airways inflammation and inflammatory mediators impair β2-receptor activation by β2-agonists.24,31 Thus, the variability in bronchodilator response observed in this study could reflect dysfunction of the β2-receptor induced by overuse of albuterol and the presence of underlying airway inflammation in some patients.

While patients included in our study had been nonsmokers for at least the previous year, patients with < 5–pack-year history were allowed to participate. Smoking is known to increase responsiveness to albuterol and methacholine, and even former smoking increases the risk of having poorly controlled asthma.4749 It is possible that the inclusion of a mix of former and never-smokers in our study could have contributed to the variability in bronchodilator response.

Our data demonstrate an ethnic difference in bronchodilator reversibility in white vs African-American patients with moderate-to-severe, stable asthma. Ethnicity as a covariate accounted for only 1% of the variability in Emax (p < 0.05), but when bronchodilator response was stratified by ethnicity, differences became clinically important. White patients achieved a 9.5% higher maximum percentage of predicted FEV1 than African-American patients (91.9% vs 82.4%, p = 0.0004), and the pharmacodynamic model predicts that African-American patients would increase percentage of predicted FEV1 by 11.7%, compared with 17.5% for white patients after a standard dose of albuterol (two inhalations of 90 μg from an MDI). There was no difference in baseline FEV1 nor duration of asthma to explain this finding, and 50% of the African Americans were receiving ICS therapy. It is possible that there were genetic differences between white and Africans-American patients in our study population that influenced response.41 Our data could have important clinical implications for β2-agonist treatment in African Americans, in which higher doses of albuterol or additional or alternative drugs such as anticholinergics may be required for sufficient bronchodilation.

Three previous studies34,50,51 compared bronchodilator response to albuterol between white and African-American asthmatics. Our data are consistent with Hardie et al,50 who found that maximum bronchodilation in mild asthmatics was lower in African-American compared to white patients after multiple doses of albuterol by MDI following methacholine-induced bronchoconstriction. Of the other two studies,34,51 one was underpowered to detect a difference between ethnic groups, and the other was conducted in emergency department patients (whose clinical features differ from stable asthmatics), and patients were not dosed with albuterol to maximal bronchodilation. Differences in response between other ethnic groups have been observed.52,53

The finding from our modeled data that 180 μg of albuterol is sufficient to increase percentage of predicted FEV1 14.4% from baseline and to reach 60.0% of Emax is supported by results from other studies5,8,11 in which four inhalations (90 μg per inhalation) or less achieve near-maximal bronchodilation. Studies that found that larger doses were required to reach a maximum bronchodilator response included patients with severe bronchoconstriction, which is known to shift the albuterol dose/response curve to the right54 (larger doses needed to achieve the same effect), or demonstrated relatively small incremental increases (< 100 mL) in FEV1 at higher doses.7,9,11

Nebulizer treatment is often used in patients with insufficient response to multiple inhalations of albuterol from an MDI. Our modeled population data predict that nebulized albuterol does not add to the bronchodilator effects from maximal albuterol dosing from an MDI as shown by the flat dose/response curve for all cumulative doses, which include the 2.5-mg nebulized albuterol dose (2,770 μg, 2,860 μg, 2,950 μg, 3,040 μg) [Fig 1, 2]. These data are consistent with a study in hospitalized asthmatics in which approximately seven inhalations of albuterol produced maximal bronchodilation and the addition of a single 5.0-mg dose of nebulized albuterol increased FEV1 by only 44 ± 8.7 mL.55 Examination of individual responses indicates that there are asthmatics who benefit with treatment by nebulizer following maximal MDI dosing (Fig 2). Further research is needed to identify which patients would require additional dosing by nebulization.

Both the asthma and COPD diagnosis and management guidelines recommend up to a 400-μg dose of a short-acting inhaled bronchodilator to assess the degree of bronchodilator response as an indicator of disease severity.1,56 Our findings do not alter this recommendation for asthmatics because we found that two to four inhalations of albuterol (as predicted by the ED50 of 141 μg) could increase FEV1 percentage of predicted by 12% in patients with moderate-to-severe persistent disease. However, after maximal bronchodilation was achieved by dosing with the MDI, 21% of our study patients had further clinically relevant increases in FEV1 with a 2.5-mg nebulized dose of albuterol. Therefore, our results suggest that if adequate bronchodilation is not achieved with the MDI, administration of a nebulized dose may be warranted. Nebulized albuterol is known to cause palpitations, sinus tachycardia, anxiety, tremor, and increased BP.

A small number of participants had bronchoconstriction after nebulized albuterol. The formulation of albuterol solution used at the time this study was conducted contained 50 μg of benzalkonium chloride per 2.5-mg dose. Inhaled benzalkonium chloride administered in the absence of an SABA is known to induce bronchospasm in asthmatics.57,58 However, aside from case reports, there are no controlled studies to indicate that the dose of benzalkonium chloride used in albuterol solutions for nebulization approved by the Food and Drug Administration cause clinically relevant bronchoconstriction.5861

Our pharmacodynamic population model of albuterol bronchodilator response data is important to the practicing clinician because we found that the majority of stable asthmatics with moderate-to-severe asthma having symptoms will achieve a 12% increase in percentage of predicted FEV1 with two to four inhalations of albuterol from their MDI. However, the maximum percentage of predicted FEV1 will vary widely between patients with additional doses. Importantly, the reduced bronchodilator response to albuterol in African-American asthmatics compared to whites suggests that African Americans may require more aggressive treatment than whites to ensure the bronchodilator and dose used will be effective in relieving bronchoconstriction.

ED50

cumulative dose of albuterol required to bring about 50% of maximum effect of albuterol

Emax

maximum effect of albuterol

γ

Hill coefficient that describes the steepness of the dose/response relation

ICS

inhaled corticosteroids

MDI

metered-dose inhaler

PPK/PD

population pharmacokinetic/pharmacodynamic

R0

baseline percentage of predicted FEV1

Rmax

maximum percentage of predicted FEV1 reached after albuterol administration

SABA

short-acting β2-agonist

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Fishwick D, Bradshaw L, Macdonald C, et al. Cumulative and single-dose design to assess the bronchodilator effects of β2-agonists in individuals with asthma. Am J Respir Crit Care Med. 2001;163:474-477. [PubMed]
 
Lotvall J, Palmqvist M, Arvidsson P, et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol. 2001;108:726-731. [PubMed]
 
Blake KV, Hoppe M, Harman E, et al. Relative amount of albuterol delivered to lung receptors from a metered-dose inhaler and nebulizer solution: bioassay by histamine bronchoprovocation. Chest. 1992;101:309-315. [PubMed]
 
Ette EI, Williams PJ. Population pharmacokinetics: I Background, concepts, and models. Ann Pharmacother. 2004;38:1702-1706. [PubMed]
 
Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-968. [PubMed]
 
Polgar G, Promadhat V. Standard values: pulmonary function testing in children; techniques and standards. 1971; Philadelphia, PA WB Saunders:87-212
 
Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127:725-734. [PubMed]
 
Blake KV, Harman E, Hendeles L. Evaluation of a generic albuterol metered-dose inhaler: importance of priming the MDI. Ann Allergy. 1992;68:169-174. [PubMed]
 
Kenyon CJ, Thorsson L, Borgstrom L, et al. The effects of static charge in spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients. Eur Respir J. 1998;11:606-610. [PubMed]
 
InspirEase prescribing information [package insert]. 2007; Kenilworth, NJ Schering-Plough Corporation
 
Gabrielsson J, Weiner D. Pharmacodynamic concepts: pharmacokinetic and pharmacodynamic data analysis; concepts and applications. 1997; Stockholm, Sweden Swedish Pharmaceutical Press:172-250
 
Jonsson EN, Wade JR, Karlsson MO. Nonlinearity detection: advantages of nonlinear mixed-effects modeling. AAPS PharmSci. 2000;2:E32. [PubMed]
 
NONMEM users guide, NONMEM Project GroupBeal SL, Scheiner LB. 1989; San Francisco, CA University of California at San Francisco
 
Beal SL, Scheiner LB. NONMEM users guide. Part VII: Conditional estimation methods. 1992; San Francisco, CA University of California at San Francisco
 
Shore SA, Moore PE. Regulation of β-adrenergic responses in airway smooth muscle. Respir Physiol Neurobiol. 2003;137:179-195. [PubMed]
 
Barry PW, O'Callaghan C. Inhalational drug delivery from seven different spacer devices. Thorax. 1996;51:835-840. [PubMed]
 
Wilkes W, Fink J, Dhand R. Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler. J Aerosol Med. 2001;14:351-360. [PubMed]
 
Proventil prescribing information [package insert]. 2007; Kenilworth, NJ Schering-Plough Corporation
 
Hess D, Fisher D, Williams P, et al. Medication nebulizer performance: effects of diluent volume, nebulizer flow, and nebulizer brand. Chest. 1996;110:498-505. [PubMed]
 
Barnes PJ, Pride NB. Dose-response curves to inhaled β-adrenoceptor agonists in normal and asthmatic subjects. Br J Clin Pharmacol. 1983;15:677-682. [PubMed]
 
Lemoine H, Overlack C, Kohl A, et al. Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: comparison of relaxation with receptor binding. Lung. 1992;170:163-180. [PubMed]
 
Nijkamp FP, Engels F, Henricks PA, et al. Mechanisms of β-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev. 1992;72:323-367. [PubMed]
 
Lima JJ, Krukemyer JJ, Boudoulas H. Drug- or hormone-induced adaptation: model of adrenergic hypersensitivity. J Pharmacokinet Biopharm. 1989;17:347-364. [PubMed]
 
Lalonde RL, Straka RJ, Pieper JA, et al. Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers. J Pharmacokinet Biopharm. 1987;15:569-582. [PubMed]
 
Lima JJ, Mohamed MH, Self TH, et al. Importance of β(2)adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics. Pulm Pharmacol Ther. 2000;13:127-134. [PubMed]
 
Tinkelman DG, Avner SE, Cooper DM. Assessing bronchodilator responsiveness. J Allergy Clin Immunol. 1977;59:109-114. [PubMed]
 
Barnes PJ. β-Adrenergic receptors and their regulation. Am J Respir Crit Care Med. 1995;152:838-860. [PubMed]
 
Martinez FD, Graves PE, Baldini M, et al. Association between genetic polymorphisms of the β2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest. 1997;100:3184-3188. [PubMed]
 
Lima JJ, Thomason DB, Mohamed MH, et al. Impact of genetic polymorphisms of the β2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther. 1999;65:519-525. [PubMed]
 
Small KM, Brown KM, Theiss CT, et al. An Ile to Met polymorphism in the catalytic domain of adenylyl cyclase type 9 confers reduced β2-adrenergic receptor stimulation. Pharmacogenetics. 2003;13:535-541. [PubMed]
 
Tantisira KG, Small KM, Litonjua AA, et al. Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways. Hum Mol Genet. 2005;14:1671-1677. [PubMed]
 
Hawkins GA, Tantisira K, Meyers DA, et al. Sequence, haplotype, and association analysis of ADRβ2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med. 2006;174:1101-1109. [PubMed]
 
Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predictin vivoresponsiveness. Proc Natl Acad Sci U S A. 2000;97:10483-10488. [PubMed]
 
Silverman EK, Kwiatkowski DJ, Sylvia JS, et al. Family-based association analysis of β2-adrenergic receptor polymorphisms in the Childhood Asthma Management Program. J Allergy Clin Immunol. 2003;112:870-876. [PubMed]
 
Hancox RJ, Aldridge RE, Cowan JO, et al. Tolerance to β-agonists during acute bronchoconstriction. Eur Respir J. 1999;14:283-287. [PubMed]
 
Haney S, Hancox RJ. Tolerance to bronchodilation during treatment with long-acting β-agonists: a randomised controlled trial. Respir Res. 2005;6:107. [PubMed]
 
van der Woude HJ, Winter TH, Aalbers R. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists. Thorax. 2001;56:529-535. [PubMed]
 
Boskabady MH, Farhadi H. Relation of airway responsiveness to salbutamol and to methacholine in smokers. Med Sci Monit. 2005;11:CR344-CR350. [PubMed]
 
Pedersen SE, Bateman ED, Bousquet J, et al. Determinants of response to fluticasone propionate and salmeterol/fluticasone propionate combination in the Gaining Optimal Asthma Control study. J Allergy Clin Immunol. 2007;120:1036-1042. [PubMed]
 
Boulet LP, Lemiere C, Archambault F, et al. Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation. Chest. 2006;129:661-668. [PubMed]
 
Hardie GE, Brown JK, Gold WM. Adrenergic responsiveness: FEV(1) and symptom differences in whites and African Americans with mild asthma. J Asthma. 2007;44:621-628. [PubMed]
 
El Ekiaby A, Brianas L, Skowronski ME, et al. Impact of race on the severity of acute episodes of asthma and adrenergic responsiveness. Am J Respir Crit Care Med. 2006;174:508-513. [PubMed]
 
Choudhry S, Ung N, Avila PC, et al. Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am J Respir Crit Care Med. 2005;171:563-570. [PubMed]
 
Naqvi M, Thyne S, Choudhry S, et al. Ethnic-specific differences in bronchodilator responsiveness among African Americans, Puerto Ricans, and Mexicans with asthma. J Asthma. 2007;44:639-648. [PubMed]
 
Kelly HW, Murphy S. β-Adrenergic agonists for acute, severe asthma. Ann Pharmacother. 1992;26:81-91. [PubMed]
 
Tarala RA, Madsen BW, Paterson JW. Comparative efficacy of salbutamol by pressurized aerosol and wet nebulizer in acute asthma. Br J Clin Pharmacol. 1980;10:393-397. [PubMed]
 
Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2007; Bethesda, MD National Institutes of Health, National Heart, Lung, and Blood Institute, and the World Heath Organization
 
Asmus MJ, Sherman J, Hendeles L. Bronchoconstrictor additives in bronchodilator solutions. J Allergy Clin Immunol. 1999;104:S53-S60. [PubMed]
 
Beasley R, Fishwick D, Miles JF, et al. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy. 1998;18:130-139. [PubMed]
 
Ponder RD, Wray BB. A case report: sensitivity to benzalkonium chloride. J Asthma. 1993;30:229-231. [PubMed]
 
Spooner LM, Olin JL. Paradoxical bronchoconstriction with albuterol administered by metered-dose inhaler and nebulizer solution. Ann Pharmacother. 2005;39:1924-1927. [PubMed]
 
Boucher M, Roy MT, Henderson J. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann Pharmacother. 1992;26:772-774. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Number of participants who received each cumulative dose of albuterol. After baseline spirometry, participants received 180 μg of albuterol and then 90 μg every 15 min until maximum improvement or 540 μg was administered; all then received 2.5 mg of nebulized albuterolGrahic Jump Location
Figure Jump LinkFigure 2 Fitted dose/response after cumulative doses of albuterol (solid line). Open circles represent individual patient responses. Response is percentage of predicted FEV1. The cumulative doses of albuterol administered from the MDI were 180 μg, 270 μg, 360 μg, 450 μg, and 540 μg; and the cumulative doses from the MDI plus nebulizer were 2,770 μg (270 μg MDI plus 2,500 μg nebulized); 2,860 μg (360 μg MDI plus 2,500 μg nebulized); 2,950 μg (450 μg MDI plus 2,500 μg nebulized); and 3,040 μg (540 μg MDI plus 2,500 μg nebulized).Grahic Jump Location
Figure Jump LinkFigure 3 Fitted dose/response after cumulative doses of albuterol in African Americans (solid line) and whites (dotted line). Open triangles are individual patient responses for African Americans. Open circles are individual patient responses for whites. Response is percentage of predicted FEV1. The cumulative doses of albuterol administered from the MDI were 180 μg, 270 μg, 360 μg, 450 μg, and 540 μg; and the cumulative doses from the MDI plus nebulizer were 2,770 μg (270 μg MDI plus 2,500 μg nebulized); 2,860 μg (360 μg MDI plus 2,500 μg nebulized); 2,950 μg (450 μg MDI plus 2,500 μg nebulized); and 3,040 μg (540 μg MDI plus 2,500 μg nebulized).Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Participant Characteristics*

*Data are presented as mean ± SD or No. (%) unless otherwise indicated. FEF25–75 = forced expiratory flow, midexpiratory phase.

†There was one Hispanic patient in each age group and one other ethnicity in the 20-to 45-year age group.

‡ICS included beclomethasone, flunisolide, and triamcinolone.

§Low-, medium-, and high-dose levels as specified in National Asthma Education and Prevention Program.1

Table Graphic Jump Location
Table 2 Population Modeling of Albuterol Dose/Response Relationship
Table Graphic Jump Location
Table 3 BP and Heart Rate at Baseline and After Maximal Albuterol Doses*

*Data are presented as mean ± SD.

†p = 0.53.

‡p = 0.06.

§p = 0.13.

References

National Asthma Education and Prevention Program Expert panel report 3: guidelines for the diagnosis and management of asthma. 2007; Bethesda, MD U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute publication 08–4051.
 
Top 200 generic drugs by units 2005. Drug Topics Magazine. 2006;
 
Lehmann S, Bakke PS, Eide GE, et al. Bronchodilator reversibility testing in an adult general population; the importance of smoking and anthropometrical variables on the response to a β2-agonist. Pulm Pharmacol Ther. 2006;19:272-280. [PubMed] [CrossRef]
 
Dales RE, Spitzer WO, Tousignant P, et al. Clinical interpretation of airway response to a bronchodilator: epidemiologic considerations. Am Rev Respir Dis. 1988;138:317-320. [PubMed]
 
Kradjan WA, Driesner NK, Abuan TH, et al. Effect of age on bronchodilator response. Chest. 1992;101:1545-1551. [PubMed]
 
Turner DJ, Landau LI, LeSouef PN. The effect of age on bronchodilator responsiveness. Pediatr Pulmonol. 1993;15:98-104. [PubMed]
 
Chaieb J, Belcher N, Rees PJ. Maximum achievable bronchodilatation in asthma. Respir Med. 1989;83:497-502. [PubMed]
 
Hendeles L, Beaty R, Ahrens R, et al. Response to inhaled albuterol during nocturnal asthma. J Allergy Clin Immunol. 2004;113:1058-1062. [PubMed]
 
Lipworth BJ, Clark RA, Dhillon DP, et al. β-Adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma. Br J Clin Pharmacol. 1988;26:527-533. [PubMed]
 
Fishwick D, Bradshaw L, Macdonald C, et al. Cumulative and single-dose design to assess the bronchodilator effects of β2-agonists in individuals with asthma. Am J Respir Crit Care Med. 2001;163:474-477. [PubMed]
 
Lotvall J, Palmqvist M, Arvidsson P, et al. The therapeutic ratio of R-albuterol is comparable with that of RS-albuterol in asthmatic patients. J Allergy Clin Immunol. 2001;108:726-731. [PubMed]
 
Blake KV, Hoppe M, Harman E, et al. Relative amount of albuterol delivered to lung receptors from a metered-dose inhaler and nebulizer solution: bioassay by histamine bronchoprovocation. Chest. 1992;101:309-315. [PubMed]
 
Ette EI, Williams PJ. Population pharmacokinetics: I Background, concepts, and models. Ann Pharmacother. 2004;38:1702-1706. [PubMed]
 
Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948-968. [PubMed]
 
Polgar G, Promadhat V. Standard values: pulmonary function testing in children; techniques and standards. 1971; Philadelphia, PA WB Saunders:87-212
 
Knudson RJ, Lebowitz MD, Holberg CJ, et al. Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 1983;127:725-734. [PubMed]
 
Blake KV, Harman E, Hendeles L. Evaluation of a generic albuterol metered-dose inhaler: importance of priming the MDI. Ann Allergy. 1992;68:169-174. [PubMed]
 
Kenyon CJ, Thorsson L, Borgstrom L, et al. The effects of static charge in spacer devices on glucocorticosteroid aerosol deposition in asthmatic patients. Eur Respir J. 1998;11:606-610. [PubMed]
 
InspirEase prescribing information [package insert]. 2007; Kenilworth, NJ Schering-Plough Corporation
 
Gabrielsson J, Weiner D. Pharmacodynamic concepts: pharmacokinetic and pharmacodynamic data analysis; concepts and applications. 1997; Stockholm, Sweden Swedish Pharmaceutical Press:172-250
 
Jonsson EN, Wade JR, Karlsson MO. Nonlinearity detection: advantages of nonlinear mixed-effects modeling. AAPS PharmSci. 2000;2:E32. [PubMed]
 
NONMEM users guide, NONMEM Project GroupBeal SL, Scheiner LB. 1989; San Francisco, CA University of California at San Francisco
 
Beal SL, Scheiner LB. NONMEM users guide. Part VII: Conditional estimation methods. 1992; San Francisco, CA University of California at San Francisco
 
Shore SA, Moore PE. Regulation of β-adrenergic responses in airway smooth muscle. Respir Physiol Neurobiol. 2003;137:179-195. [PubMed]
 
Barry PW, O'Callaghan C. Inhalational drug delivery from seven different spacer devices. Thorax. 1996;51:835-840. [PubMed]
 
Wilkes W, Fink J, Dhand R. Selecting an accessory device with a metered-dose inhaler: variable influence of accessory devices on fine particle dose, throat deposition, and drug delivery with asynchronous actuation from a metered-dose inhaler. J Aerosol Med. 2001;14:351-360. [PubMed]
 
Proventil prescribing information [package insert]. 2007; Kenilworth, NJ Schering-Plough Corporation
 
Hess D, Fisher D, Williams P, et al. Medication nebulizer performance: effects of diluent volume, nebulizer flow, and nebulizer brand. Chest. 1996;110:498-505. [PubMed]
 
Barnes PJ, Pride NB. Dose-response curves to inhaled β-adrenoceptor agonists in normal and asthmatic subjects. Br J Clin Pharmacol. 1983;15:677-682. [PubMed]
 
Lemoine H, Overlack C, Kohl A, et al. Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: comparison of relaxation with receptor binding. Lung. 1992;170:163-180. [PubMed]
 
Nijkamp FP, Engels F, Henricks PA, et al. Mechanisms of β-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev. 1992;72:323-367. [PubMed]
 
Lima JJ, Krukemyer JJ, Boudoulas H. Drug- or hormone-induced adaptation: model of adrenergic hypersensitivity. J Pharmacokinet Biopharm. 1989;17:347-364. [PubMed]
 
Lalonde RL, Straka RJ, Pieper JA, et al. Propranolol pharmacodynamic modeling using unbound and total concentrations in healthy volunteers. J Pharmacokinet Biopharm. 1987;15:569-582. [PubMed]
 
Lima JJ, Mohamed MH, Self TH, et al. Importance of β(2)adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics. Pulm Pharmacol Ther. 2000;13:127-134. [PubMed]
 
Tinkelman DG, Avner SE, Cooper DM. Assessing bronchodilator responsiveness. J Allergy Clin Immunol. 1977;59:109-114. [PubMed]
 
Barnes PJ. β-Adrenergic receptors and their regulation. Am J Respir Crit Care Med. 1995;152:838-860. [PubMed]
 
Martinez FD, Graves PE, Baldini M, et al. Association between genetic polymorphisms of the β2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest. 1997;100:3184-3188. [PubMed]
 
Lima JJ, Thomason DB, Mohamed MH, et al. Impact of genetic polymorphisms of the β2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther. 1999;65:519-525. [PubMed]
 
Small KM, Brown KM, Theiss CT, et al. An Ile to Met polymorphism in the catalytic domain of adenylyl cyclase type 9 confers reduced β2-adrenergic receptor stimulation. Pharmacogenetics. 2003;13:535-541. [PubMed]
 
Tantisira KG, Small KM, Litonjua AA, et al. Molecular properties and pharmacogenetics of a polymorphism of adenylyl cyclase type 9 in asthma: interaction between beta-agonist and corticosteroid pathways. Hum Mol Genet. 2005;14:1671-1677. [PubMed]
 
Hawkins GA, Tantisira K, Meyers DA, et al. Sequence, haplotype, and association analysis of ADRβ2 in a multiethnic asthma case-control study. Am J Respir Crit Care Med. 2006;174:1101-1109. [PubMed]
 
Drysdale CM, McGraw DW, Stack CB, et al. Complex promoter and coding region β2-adrenergic receptor haplotypes alter receptor expression and predictin vivoresponsiveness. Proc Natl Acad Sci U S A. 2000;97:10483-10488. [PubMed]
 
Silverman EK, Kwiatkowski DJ, Sylvia JS, et al. Family-based association analysis of β2-adrenergic receptor polymorphisms in the Childhood Asthma Management Program. J Allergy Clin Immunol. 2003;112:870-876. [PubMed]
 
Hancox RJ, Aldridge RE, Cowan JO, et al. Tolerance to β-agonists during acute bronchoconstriction. Eur Respir J. 1999;14:283-287. [PubMed]
 
Haney S, Hancox RJ. Tolerance to bronchodilation during treatment with long-acting β-agonists: a randomised controlled trial. Respir Res. 2005;6:107. [PubMed]
 
van der Woude HJ, Winter TH, Aalbers R. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting β2 agonists. Thorax. 2001;56:529-535. [PubMed]
 
Boskabady MH, Farhadi H. Relation of airway responsiveness to salbutamol and to methacholine in smokers. Med Sci Monit. 2005;11:CR344-CR350. [PubMed]
 
Pedersen SE, Bateman ED, Bousquet J, et al. Determinants of response to fluticasone propionate and salmeterol/fluticasone propionate combination in the Gaining Optimal Asthma Control study. J Allergy Clin Immunol. 2007;120:1036-1042. [PubMed]
 
Boulet LP, Lemiere C, Archambault F, et al. Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation. Chest. 2006;129:661-668. [PubMed]
 
Hardie GE, Brown JK, Gold WM. Adrenergic responsiveness: FEV(1) and symptom differences in whites and African Americans with mild asthma. J Asthma. 2007;44:621-628. [PubMed]
 
El Ekiaby A, Brianas L, Skowronski ME, et al. Impact of race on the severity of acute episodes of asthma and adrenergic responsiveness. Am J Respir Crit Care Med. 2006;174:508-513. [PubMed]
 
Choudhry S, Ung N, Avila PC, et al. Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma. Am J Respir Crit Care Med. 2005;171:563-570. [PubMed]
 
Naqvi M, Thyne S, Choudhry S, et al. Ethnic-specific differences in bronchodilator responsiveness among African Americans, Puerto Ricans, and Mexicans with asthma. J Asthma. 2007;44:639-648. [PubMed]
 
Kelly HW, Murphy S. β-Adrenergic agonists for acute, severe asthma. Ann Pharmacother. 1992;26:81-91. [PubMed]
 
Tarala RA, Madsen BW, Paterson JW. Comparative efficacy of salbutamol by pressurized aerosol and wet nebulizer in acute asthma. Br J Clin Pharmacol. 1980;10:393-397. [PubMed]
 
Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2007; Bethesda, MD National Institutes of Health, National Heart, Lung, and Blood Institute, and the World Heath Organization
 
Asmus MJ, Sherman J, Hendeles L. Bronchoconstrictor additives in bronchodilator solutions. J Allergy Clin Immunol. 1999;104:S53-S60. [PubMed]
 
Beasley R, Fishwick D, Miles JF, et al. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy. 1998;18:130-139. [PubMed]
 
Ponder RD, Wray BB. A case report: sensitivity to benzalkonium chloride. J Asthma. 1993;30:229-231. [PubMed]
 
Spooner LM, Olin JL. Paradoxical bronchoconstriction with albuterol administered by metered-dose inhaler and nebulizer solution. Ann Pharmacother. 2005;39:1924-1927. [PubMed]
 
Boucher M, Roy MT, Henderson J. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann Pharmacother. 1992;26:772-774. [PubMed]
 
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