- Email: [email protected]
turbuhaler in patients with moderate asthma
Comparison of efficacy and safety between flunisolide/AeroChamber and budesonide/turbuhaler in patients with moderate asthma Michael Newhouse, MD*; Allan Knight, MD†; Shanshan Wang, MD‡; Kenneth Newman, MD‡; and the AER-MD-04 Study Group (see “Appendix”)
Background: There is a limited body of evidence comparing the clinical effects of different inhaled corticosteroids in the treatment of asthma. This study compared the safety and efficacy of inhaled flunisolide and budesonide, both with unique delivery systems that may affect clinical response. Objective: This multicenter study was carried out to compare the efficacy and safety of flunisolide, administered via AeroChamber, with budesonide, administered via Turbuhaler, in the treatment of moderate asthma. Methods: Patients with moderate asthma, defined as an FEV1 of 40% to 85% of predicted, underwent a 2-week run-in period during which beclomethasone, 750 g twice daily by MDI, was administered, along with salbutamol prn. Patients (n ⫽ 176) were then randomized into two groups. One group received flunisolide administered via AeroChamber, 750 g (3 puffs), twice daily. The second group received budesonide administered via Turbuhaler, 600 g (3 puffs), twice daily. All patients took salbutamol prn. Results: At the end of the 6-week treatment period, there were no significant differences (P ⬎ .05 for all comparisons) in efficacy between the groups as evaluated by any efficacy parameter. The treatment groups also did not differ significantly in the number of adverse events or in the incidence of oropharyngeal Candida infection. Conclusion: Flunisolide administered by AeroChamber and budesonide administered via Turbuhaler demonstrate similar efficacy and safety in the treatment of moderate asthma. Ann Allergy Asthma Immunol 2000;84:313–319.
INTRODUCTION Inflammation of the lower respiratory tract (LRT) is the predominant feature of asthma, and patients consequently require long-term antiinflammatory
* Firestone Chest/Allergy Unit, St. Joseph’s Hospital/McMaster Faculty of Health Sciences, Hamilton, Ontario; Canada. † Division of Clinical Immunology, University of Toronto, Ontario; Canada. ‡ Forest Laboratories, Inc., New York, New York. The research and preparation of this article have been supported by funding from Forest Laboratories, Inc. Received for publication July 12, 1999. Accepted for publication in revised form December 18, 1999.
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prophylaxis. Systemic corticosteroids are effective but have serious side effects; inhaled corticosteroids have consequently become the first-line treatment of asthma.1–5 Inhaled delivery of medication has a number of advantages over other routes for administration of drugs to the lungs. Since the drug is delivered directly to its site of action, only a small quantity is required for an adequate therapeutic response. Systemic side effects are, therefore, greatly reduced compared with oral or intravenous administration. Several factors can affect the mass of inhaled particles reaching the lungs and their intrapulmonary distribution, including the manner of inha-
lation, aerosol characteristics, patient characteristics, and the effects of disease on airway control and the lung parenchyma. The main types of inhaler devices currently in use are metereddose inhalers (MDIs), dry powder inhalers, and nebulizers.6 Metered-dose inhalers are convenient, effective, and widely used devices for the delivery of inhaled corticosteroids; however, they have several disadvantages. Many patients find it difficult to coordinate aerosol discharge and inhalation.7,8 Even when used with optimum technique, MDIs deliver only about 15% of the drug past the oropharynx to the LRT.9 Corticosteroids deposited in the oropharynx can result in local side effects, including bad taste, candidiasis, and dysphonia.1,10 Furthermore, a portion of the drug is swallowed and absorbed in the gastrointestinal tract, with consequent systemic side effects. These may include disruption of the hypothalamic-pituitary-adrenal system, slowing of growth velocity in children (but not final height11), and decrease in bone density.2–5 The efficiency of MDIs and safety of inhaled steroids can be increased by the addition of holding chambers. These small particle size chambers provide a selective space in which the propellant evaporates, large particles are deposited, and smaller LRT targeted particles remain in suspension. This increases the proportion of inhaled smaller particles that reach the LRT. The AeroChamber is one of the most commonly used holding chambers. Frequently used with flunisolide,
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ery with the MDI. In bioavailability studies of budesonide, use of a Turbuhaler has resulted in twice the LRT drug deposition compared with its use with an MDI without a spacer.9 Both flunisolide and budesonide are widely prescribed for the treatment of asthma. Little is known, however, about how treatment with flunisolide compares with treatment with budesonide via Turbuhaler. This study tested the hypothesis that similar doses (taken in an equivalent number of inhalations) of flunisolide, administered via AeroChamber, and budesonide, administered via Turbuhaler, provide equivalent control of asthma in adults with moderate disease. A medium dose of inhaled corticosteroid, as defined by the National Institutes of Health (NIH) guidelines,14 was selected for this patient population of moderate asthmatics.
Figure 1. Study design.
it is effective, convenient, and durable and has been shown to compensate for poor user technique.8,10 Whereas oropharyngeal deposition of inhaled glucocorticoids may be 60% to 70% of the dose with an MDI alone, use of an AeroChamber has reduced this percentage to 4% to 5%.12 Although the AeroChamber removes most of the large particles, the fine particle dose is not diminished.13
The Turbuhaler is a passive drypowder inhaler that requires an inhalation technique completely different from that for a conventional MDI. It is commonly used with a dry-powder formulation of budesonide. A deep, forceful inspiration with a rapid onset is used to disaggregate the dry particles prior to inhalation. This is in contrast to the slow, coordinated inspiration required for optimal LRT aerosol deliv-
MATERIALS AND METHODS Patients Male and female patients with moderate stable asthma, aged 18 to 75, were enrolled. This illness was defined as that requiring a dose of at least 800 g/d and up to 2000 g/d of beclomethasone, fluticasone, or budesonide and the use of salbutamol. To be included in the study, patients had to have (1) a documented history of mod-
Table 1. Demographic and Baseline Characteristics of Intent-to-Treat Patients Characteristic* Sex (male/female), No. (%) Race (white/nonwhite), No. (%) Age (y) Weight (kg) Smoking history, No. (%) Current smoker Former smoker Never smoked FEV1, actual (L) FEV1 (% predicted) Salbutamol usage (puffs/d) Daily asthma symptom score Nocturnal awakenings (No./night) AM peak expiratory flow rate (L/min) PM peak expiratory flow rate (L/min)
Flunisolide With AeroChamber (n ⴝ 75)
Budesonide With Turbuhaler (n ⴝ 79)
P Values*
30/45 (40.0/60.0) 68/7 (90.7/9.3) 44.0 ⫾ 14.6† 78.8 ⫾ 20.0
34/45 (43.0/57.0) 73/6 (92.4/7.6) 42.8 ⫾ 16.2 79.2 ⫾ 19.8
.702 .698 .524 .866
4 (5.1) 30 (38.0) 45 (57.0) 2.42 ⫾ 0.69 78.5 ⫾ 15.1 2.7 ⫾ 2.5 3.8 ⫾ 3.4 0.1 ⫾ 0.3 352.1 ⫾ 94.0 357.9 ⫾ 89.6
.968
4 (5.3) 27 (36.0) 44 (58.7) 2.51 ⫾ 0.71 83.0 ⫾ 14.4 2.5 ⫾ 2.5 4.1 ⫾ 4.0 0.1 ⫾ 0.4 354.2 ⫾ 102.7 364.3 ⫾ 103.0
.434 .036 .944 .719 .701 .797 .917
* Baseline characteristics were compared using Chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables. † Values are mean ⫾ standard deviations.
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Table 2. Primary Efficacy Parameters: Changes from Baseline During Treatment Period in Intent-to-Treat Patients
Parameter
FEV1, actual (L) FEV1 (percent predicted) Salbutamol usage (puffs/d)
Flunisolide with AeroChamber (n ⴝ 75)
Budesonide with Turbuhaler (n ⴝ 78)
Difference*
P Values*
⫺0.07 ⫾ 0.32† ⫺2.4 ⫾ 9.9 0.4 ⫾ 1.8
⫺0.02 ⫾ 0.31 ⫺0.5 ⫾ 9.9 0.1 ⫾ 1.6
⫺0.031 ⫺1.419 0.261
.544 .378 .333
* Difference of least square means of flunisolide with AeroChamber and budesonide with Turbuhaler. † Values are mean ⫾ standard deviations.
Figure 2. Mean (⫾ standard error) FEV1 in patients treated with flunisolide with AeroChamber (n ⫽ 75) and patients treated with budesonide with Turbuhaler (n ⫽ 78). Table 3. Secondary Efficacy Parameters: Changes from Baseline During Treatment Period in Intent-to-Treat Patients
Parameter
Daily asthma symptom score Nocturnal awakenings (No./night) AM peak expiratory flow rate (L/min) PM peak expiratory flow rate (L/min)
Flunisolide Budesonide With With P Difference* AeroChamber Turbuhaler Values* (n ⴝ 75) (n ⴝ 78) 0.1 ⫾ 3.5† 0.1 ⫾ 0.2 ⫺3.5 ⫾ 42.6 ⫺5.6 ⫾ 37.2
0.1 ⫾ 2.7 0.1 ⫾ 0.3 ⫺1.0 ⫾ 34.6 3.9 ⫾ 34.5
0.050 0.009 ⫺2.523 ⫺8.866
.920 .849 .692 .143
* Difference of least square means of flunisolide with AeroChamber and budesonide with Turbuhaler. † Values are mean ⫾ standard deviations.
erate asthma; (2) forced expiratory volume in 1 second (FEV1) equal to 40% to 85% of predicted; (3) a demonstrated increase in FEV1 of at least 12% after two puffs of salbutamol via
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MDI15; and (4) use of an inhaled corticosteroid for at least 30 days. Patients were excluded if they had clinically significant pulmonary disease other than asthma, significant ill-
ness that could interfere with the assessment of efficacy and safety in the study, a history of hospitalization for exacerbation of asthma in the 6 weeks before their first visit, immunotherapy other than an established maintenance program, or upper respiratory tract infection within 30 days of their first visit. Other criteria for exclusion included the use of oral or parenteral corticosteroids on two or more occasions in the preceding 3 months, unstable reversible airway obstruction, and use of long-acting 2-agonists in the preceding 2 weeks. Drugs prohibited during the study included other orally inhaled steroids, antileukotrienes, oral steroids, cromolyn/nedocromil, nasal steroids, oral -adrenergic agonists, salmeterol, ipratropium, theophylline, and formoterol. Informed consent was obtained from all patients. Investigators obtained approval for the studies from the Institutional Review Boards at their respective institutions. A final report was made to the Institutional Review Boards at the completion of the study. Study protocol This was a multicenter, randomized, parallel-group study performed at 17 sites in Canada. Patients who met the inclusion and exclusion criteria at their first visit were entered into a 2-week run-in period, during which they inhaled 750 g beclomethasone in 3 puffs administered via AeroChamber twice a day (Fig 1). They also took salbutamol (100 g/puff) prn. At the conclusion of the run-in phase, patients were randomized into two groups, provided they met the following randomization criteria: (1) their best prebronchodilator FEV1 was at least 90% of their best prebronchodilator FEV1 obtained at their first visit; and (2) their mean asthma symptom score was no greater than 8 per day, with the patient taking no more than a mean of 8 puffs (800 g) of salbutamol per day during the second week of the run-in period. Asthma symptoms were scored from 0 to 3 for cough, dyspnea, wheezing, and chest tightness and then summated.
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age during the weeks preceding week 0 and week 6. Patients recorded their salbutamol usage on diary cards. Secondary Efficacy Parameters Secondary measures of efficacy were changes in peak expiratory flow (AM and PM), clinical asthma score, and average number of nocturnal awakenings due to asthma that required salbutamol, all changes being taken from week 0 to week 6. A Mini Wright peak flow meter was used to measure morning and evening peak expiratory flow prior to administration of study medication.
Figure 3. Mean (⫾ standard error) AM peak expiratory flow in patients treated with flunisolide with AeroChamber (n ⫽ 75) and patients treated with budesonide with Turbuhaler (n ⫽ 78).
Table 4. Incidence of Most Frequent Adverse Events (ⱖ2% in either group) Adverse Event Headache Nausea Flu syndrome Paresthesia Monilia, nonoral Migraine Emesis Insomnia Back pain Monilia, oral
Flunisolide With AeroChamber (n ⴝ 75) No. (%)
Budesonide With Turbuhaler (n ⴝ 79) No. (%)
5 (6.7) 4 (5.3) 3 (4.0) 2 (2.7) 2 (2.7) 2 (2.7) 2 (2.7) 1 (1.3) 1 (1.3) 0 (0.0)
3 (3.8) 1 (1.3) 5 (6.3) 0 (0.0) 2 (2.5) 0 (0.0) 0 (0.0) 2 (2.5) 2 (2.5) 4 (5.1)
Group 1 received flunisolide, administered via AeroChamber, 750 g twice daily. Group 2 received budesonide, administered via Turbuhaler, 600 g twice daily. Both groups took salbutamol via inhaler prn. Study medications were administered for 6 weeks. Spirometry was performed at week 0 (baseline or start of the treatment period), at week 2 (follow-up visit), and at week 6 (end of treatment). Mouth and throat smears were obtained for culture and Candida detec-
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tion at week 0 and at week 6. Cortrosyn stimulation was performed at selected sites at week 0 and at week 6. Patients kept a diary of asthma symptoms, peak flows, salbutamol use, and adverse events. Patient compliance was monitored by diary cards. Primary Efficacy Parameters The primary measures of efficacy were (1) the change in prebronchodilator FEV1 from week 0 to week 6 and (2) the change in mean prn salbutamol us-
Safety and Tolerability Safety and tolerability were assessed by records of adverse events, a mouth and throat smear to assay for the presence of Candida, and, at selected sites, a Cortrosyn stimulation test to evaluate the effects on adrenal function. Cortrosyn 25 g was administered intramuscularly, with cortisol samples drawn before and 30 and 60 minutes after administration. The study provided 80% power to detect a 33% difference between groups in plasma cortisol levels after Cortrosyn stimulation. An adverse event was defined as any unfavorable and unintended sign, symptom, or disease temporarily associated with the use of study medication, whether or not considered related to study medication. This included all clinically relevant laboratory abnormalities of physical findings. Adverse events were judged and classified by investigators as unrelated, unlikely related, possibly related, probably related, or highly probably related to the study medication. Statistical Analysis Hypothesis tests were conducted using two-sided tests at the .05 level of significance. All efficacy variables were analyzed using analysis of covariance (ANCOVA) model with treatment and center factors and baseline efficacy measurement as a covariate in the model. Efficacy analyses were based on the intent-to-treat population, ie, all randomized patients who had at least one follow-up visit. Missing values for
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Table 5. Change in the Incidence of Oropharyngeal Candida During Treatment Period Change Baseline No yeast cells present Yeast cells present End of treatment No yeast cells present Yeast cells present
Flunisolide With AeroChamber (n ⴝ 75) No. (%)
Budesonide With Turbuhaler (n ⴝ 79) No. (%)
41 (54.7) 34 (45.3)
46 (58.2) 33 (41.8)
.656
46 (64.8) 25 (35.2)
46 (58.2) 33 (41.8)
.410
efficacy variables at the final visit were imputed by last observation carried forward (LOCF). Safety analysis was based on all randomized patients who received at least one dose of study medication. RESULTS Patient Characteristics The demographic characteristics and clinical parameters of the patients randomized to the two treatment arms were comparable (Table 1). There were no statistically significant differences between the groups at baseline except for a small but statistically significant difference (P ⫽ .04) in percent predicted FEV1. A total of 154 patients were randomized, 75 in the flunisolide/ AeroChamber arm and 79 in the budesonide/Turbuhaler arm. All but one of these was available for inclusion in the intent-to-treat analysis. The number of patients withdrawn from the study for all reasons (adverse event/ intercurrent illness; protocol violation; administrative reasons; withdrawal of consent; lost to follow-up; screening failure; did not meet randomization criteria; and insufficient efficacy) was
P Values
11 in the flunisolide group and 3 in the budesonide group. Primary Efficacy Parameters There were no statistically significant differences between the two treatment groups in the changes in FEV1 or salbutamol usage during the 6-week treatment period (Table 2). There was little change from baseline in FEV1 in either treatment group as measured either by actual FEV1 (Fig 2) or by percent predicted FEV1, and the difference between groups was not significant in either case. Salbutamol usage did not change significantly from baseline in either group. To determine whether the baseline imbalance between the two treatment groups could bias the treatment group comparison, a treatment-only baseline percent-predicted FEV1 interaction was added to the ANCOVA model. The results showed that the difference in baseline FEV1 values did not affect the comparison between groups. Secondary Efficacy Parameters There were no statistically significant differences between the two treatment groups in the change in peak expira-
tory flow (AM and PM), asthma symptom score, and nocturnal awakenings (number/night) during the treatment period (Table 3, Fig 3). Safety and Tolerability Both treatments were well tolerated. Overall, there were no significant differences between the groups in the frequency of adverse events (Table 4). Adverse events were reported by 48.0% of patients who received flunisolide and by 54.4% of patients who received budesonide. The majority of adverse events were mild or moderate in severity. There were no significant changes in blood pressure or other vital signs during the course of the study, nor were there any differences between the treatment groups. Mouth and throat smears were taken and cultured to assay for the presence of Candida (Table 5). The change in the incidence of oropharyngeal Candida colonization did not differ significantly between the treatment groups (P ⫽ .809). Pre-Cortrosyn plasma cortisol levels at baseline and after 6 weeks of treatment were comparable in the flunisolide and budesonide groups. The response at 30 minutes to intramuscular injection of Cortrosyn was greater in the flunisolide group than in the budesonide group, both at baseline and after 6 weeks of treatment. The response at 60 minutes was comparable between the two groups (Table 6).
* Between treatment groups.
DISCUSSION Few studies have undertaken direct comparison of the efficacy and safety of the various inhaled steroid medications now available for the treatment of asthma. Such comparisons must take into account the delivery system, the dosage, and the characteristics of the patients treated. The study reported here compared the efficacy and safety of flunisolide, 1500 g/d, administered via AeroChamber with budesonide, 1200 g/d, administered via Turbuhaler in the treatment of patients with moderate asthma.
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Table 6. Plasma Cortisol Levels (g/L) in Cortrosyn Stimulation Test Time Relative to Cortrosyn Injection Baseline Pre-Cortrosyn Change at 30 minutes Change at 60 minutes Week 6 Pre-Cortrosyn Change at 30 minutes Change at 60 minutes
Flunisolide With AeroChamber
Budesonide With Turbuhaler
(n ⫽ 31) 13.4 ⫾ 5.5 9.4 ⫾ 3.7 12.6 ⫾ 4.6 (n ⫽ 29) 14.9 ⫾ 6.6 9.2 ⫾ 3.7 12.5 ⫾ 36
(n ⫽ 32) 14.7 ⫾ 7.7 7.3 ⫾ 2.9 10.4 ⫾ 3.7 (n ⫽ 30) 14.7 ⫾ 5.9 6.9 ⫾ 2.7 10.5 ⫾ 4.1
P Values* .558 .026 .077 .697 .017 .053
After the 2-week run-in period, during which patients received beclomethasone and salbutamol, patients were randomized to receive one of the two treatments for 6 weeks. At the end of this treatment period, there were no statistically significant differences between the two treatment groups in the primary efficacy parameters— changes from baseline in FEV1 and salbutamol usage. There were also no statistically significant differences between the two treatment groups in the secondary efficacy parameters— changes in peak expiratory flow rate (AM and PM), asthma symptom score, and nocturnal awakenings (number/night) during the treatment period. Both treatments were effective in the continued control of moderate asthma; there was little change from baseline parameters, which were taken after the 2-week run-in period of 1500 g/d beclomethasone and salbutamol prn. It can be concluded that flunisolide administered via AeroChamber provided equivalent outcomes as a similar dose of budesonide administered via Turbuhaler in relieving asthma. Safety and tolerability were comparable between the two treatments. Both were well tolerated, and the frequency of adverse events was similar in the two treatment groups. There was no difference in the incidence of oropharyngeal Candida colonization. Oropharyngeal candidiasis can be a problem in some patients, particularly the elderly and those taking high doses of glucocorticoids.1 Deposition of inhaled glucocorticoids in the oropharynx is reduced by 90% to 95% by the AeroChamber, thus reducing the likelihood of Candida infection.10,12 In a study of asthma patients treated with inhaled beclomethasone dipropionate, the addition of an AeroChamber was shown to significantly reduce the incidence of oropharyngeal Candida infection and colonization compared with patients treated with an MDI alone.10 The small changes from baseline in nearly all the primary and secondary efficacy parameters tend to confirm previous reports that budesonide and beclomethasone are of approximately equivalent potency.16 This study sug-
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gests that flunisolide is at least as potent, microgram for microgram, as beclomethasone. Corticosteroids differ in anti-inflammatory potency when measured by in vitro methods, such as receptor binding affinity or binding halflife.14 There is however, no evidence that any of the inhaled corticosteroids has greater efficacy in patients when compared using identical doses,17 with the possible exception of fluticasone. There is in vitro evidence that the optimum inhalation delivery system may differ with the drug formulation administered.13 The available data also suggest that, when administered in equipotent doses with a MDI plus spacer or by dry-powder inhaler as opposed to MDI alone, the currently available inhaled corticosteroids have less risk of systemic effects than when administered without a spacer or inhaler.17 When corticosteroid MDIs, such as flunisolide (Aerobid) are used with an AeroChamber valved holding chamber, this not only helps to overcome problems of hand-breath coordination, but also greatly reduces oropharyngeal and systemic side effects. This considerably improves the therapeutic ratio compared with MDI alone or passive dry powder inhaler, such as the budesonide Turbuhaler. It is for this reason that the NIH asthma guidelines have recommended that for treating asthma, cortisol MDIs should generally be used with aerosol holding chambers, particularly in the pediatric age group.14 It is worth stressing that, since it is not possible to reduce the upper respiratory tract dose of corticosteroid in a similar fashion with the current dry powder inhalers, their therapeutic ratio at equivalent doses is likely to be lower. In summary, we conclude that flunisolide administered with an AeroChamber and budesonide administered with a Turbuhaler have similar efficacy, safety, and tolerability in the treatment of patients with moderate asthma.
3.
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12.
REFERENCES 1. Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995;332: 868 – 875. 2. Goldberg S, Algur N, Levi M, et al.
13.
Adrenal suppression among asthmatic children receiving chronic therapy with inhaled corticosteroid with and without spacer device. Ann Allergy Asthma Immunol 1996;76:234 –238. Hanania NA, Chapman KR, Sturtridge WC, et al. Dose-related decrease in bone density among asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol 1995;96: 571–579. Kiviranta K, Turpeinen M. Effect of eight months of inhaled beclomethasone dipropionate and budesonide on carbohydrate metabolism in adults with asthma. Thorax 1993;48: 974 –978. Nicolaizik WH, Marchant JL, Preece MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Crit Care Med 1994;150:624 – 628. Pavia D. Efficacy and safety of inhalation therapy in chronic obstructive pulmonary disease and asthma. Respirology 1997;2(Suppl 1):S5–S10. Conner WT, Dolovich MB, Frame RA, Newhouse MT. Reliable salbutamol administration in 6- to 36-month-old children by means of a metered dose inhaler and Aerochamber with mask. Pediatr Pulmonol 1989;6:263–267. Dolovich M, Ruffin R, Corr D, Newhouse MT. Clinical evaluation of a simple demand inhalation MDI aerosol delivery device. Chest 1983;84:36 – 41. Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler PMDI. Eur Respir J 1994;7:1839 –1844. Salzman GA, Pyszczynski DR. Oropharyngeal candidiasis in patients treated with beclomethasone dipropionate delivered by metered-dose inhaler alone and with Aerochamber. J Allergy Clin Immunol 1988;81:424 – 428. Shapiro G, Bronsky EA, LaForce CF, et al. Dose-related efficacy of budesonide administered via a dry powder inhaler in the treatment of children with moderate to severe persistent asthma. J Pediatr 1998;132:976 –982. Chua HL, Chambers CB, Newhouse MT. Upper respiratory tract salbutamol deposition following MDI and AeroChamber: effect of mouth rinsing on oropharyngeal clearance. J Aerosol Med 1995;8:83. Ahrens R, Lux C, Bahl T, Han SH. Choosing the metered-dose inhaler
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spacer or holding chamber that matches the patient’s need: evidence that the specific drug being delivered is an important consideration. J Allergy Clin Immunol 1995;96:288 –294. National Asthma Education and Prevention Program. Clinical Practice Guidelines. Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health; April 1997. Publication 974051. American Thoracic Society. Lung function testing: selection of reference values and interpretive strategies. Am Rev Respir Dis 1991;144:1202–1218. Ebden P, Jenkins A, Houston G, Davies BH. Comparison of two high dose corticosteroid aerosol treatments, beclomethasone dipropionate (155 micrograms/day) and budesonide (1600 micrograms/day), for chronic asthma. Thorax 1986;41: 869–874. Kelly HW. Comparison of inhaled corticosteroids. Ann Pharmacother 1998; 32:220 –232.
APPENDIX AER-MD-04 Study Group 1. Michael Alexander, MD Niagara Falls, Ontario
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2. William Arkinstall, MD Kelowna Allergy and Respiratory Health Clinic, Kelowna, British Columbia 3. Meyer Balter, MD Mount Sinai Hospital, Toronto, Ontario 4. Andre´ Cartier, MD Sacre´ Coeur Hospital, Montre´al, Que´bec 5. Anthony D’Urzo, MD Primary Care Asthma Clinic, Toronto, Ontario 6. David Thomson, MD Montre´al General Hospital, Montre´al, Que´bec 7. Jacques He´bert, MD CRAAQ, St. Foy, Que´bec 8. Victor Hoffstein, MD St. Michael’s Hospital, Toronto, Ontario 9. Allan Knight, MD University of Toronto, Toronto, Ontario 10. Jorge Mazza, MD London Health Sciences, London, Ontario 11. Andrew McIvor, MD
12. 13. 14. 15. 16. 17.
The Toronto Hospital, Toronto, Ontario Peter Small, MD SMBD Jewish General Hospital, Montre´al, Que´bec William Yang, MD Ottawa Allergy Research Center, Ottawa, Ontario Robert Cowie, MD Calgary Asthma Program, Calgary, Alberta G. Fred MacDonald, MD The Grey Nuns Hospital, Edmonton, Alberta Michael Newhouse, MD Barnett Medical Aerosol, Hamilton, Ontario Paul Keith, MD McMaster University, Hamilton, Ontario
Request for reprints should be addressed to: Kenneth Newman Newhouse, MD Forest Laboratories, Inc 909 Third Ave New York, NY 10022
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Background: There is a limited body of evidence comparing the clinical effects of different inhaled corticosteroids in the treatment of asthma. This study compared the safety and efficacy of inhaled flunisolide and budesonide, both with unique delivery systems that may affect clinical response. Objective: This multicenter study was carried out to compare the efficacy and safety of flunisolide, administered via AeroChamber, with budesonide, administered via Turbuhaler, in the treatment of moderate asthma. Methods: Patients with moderate asthma, defined as an FEV1 of 40% to 85% of predicted, underwent a 2-week run-in period during which beclomethasone, 750 g twice daily by MDI, was administered, along with salbutamol prn. Patients (n ⫽ 176) were then randomized into two groups. One group received flunisolide administered via AeroChamber, 750 g (3 puffs), twice daily. The second group received budesonide administered via Turbuhaler, 600 g (3 puffs), twice daily. All patients took salbutamol prn. Results: At the end of the 6-week treatment period, there were no significant differences (P ⬎ .05 for all comparisons) in efficacy between the groups as evaluated by any efficacy parameter. The treatment groups also did not differ significantly in the number of adverse events or in the incidence of oropharyngeal Candida infection. Conclusion: Flunisolide administered by AeroChamber and budesonide administered via Turbuhaler demonstrate similar efficacy and safety in the treatment of moderate asthma. Ann Allergy Asthma Immunol 2000;84:313–319.
INTRODUCTION Inflammation of the lower respiratory tract (LRT) is the predominant feature of asthma, and patients consequently require long-term antiinflammatory
* Firestone Chest/Allergy Unit, St. Joseph’s Hospital/McMaster Faculty of Health Sciences, Hamilton, Ontario; Canada. † Division of Clinical Immunology, University of Toronto, Ontario; Canada. ‡ Forest Laboratories, Inc., New York, New York. The research and preparation of this article have been supported by funding from Forest Laboratories, Inc. Received for publication July 12, 1999. Accepted for publication in revised form December 18, 1999.
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prophylaxis. Systemic corticosteroids are effective but have serious side effects; inhaled corticosteroids have consequently become the first-line treatment of asthma.1–5 Inhaled delivery of medication has a number of advantages over other routes for administration of drugs to the lungs. Since the drug is delivered directly to its site of action, only a small quantity is required for an adequate therapeutic response. Systemic side effects are, therefore, greatly reduced compared with oral or intravenous administration. Several factors can affect the mass of inhaled particles reaching the lungs and their intrapulmonary distribution, including the manner of inha-
lation, aerosol characteristics, patient characteristics, and the effects of disease on airway control and the lung parenchyma. The main types of inhaler devices currently in use are metereddose inhalers (MDIs), dry powder inhalers, and nebulizers.6 Metered-dose inhalers are convenient, effective, and widely used devices for the delivery of inhaled corticosteroids; however, they have several disadvantages. Many patients find it difficult to coordinate aerosol discharge and inhalation.7,8 Even when used with optimum technique, MDIs deliver only about 15% of the drug past the oropharynx to the LRT.9 Corticosteroids deposited in the oropharynx can result in local side effects, including bad taste, candidiasis, and dysphonia.1,10 Furthermore, a portion of the drug is swallowed and absorbed in the gastrointestinal tract, with consequent systemic side effects. These may include disruption of the hypothalamic-pituitary-adrenal system, slowing of growth velocity in children (but not final height11), and decrease in bone density.2–5 The efficiency of MDIs and safety of inhaled steroids can be increased by the addition of holding chambers. These small particle size chambers provide a selective space in which the propellant evaporates, large particles are deposited, and smaller LRT targeted particles remain in suspension. This increases the proportion of inhaled smaller particles that reach the LRT. The AeroChamber is one of the most commonly used holding chambers. Frequently used with flunisolide,
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ery with the MDI. In bioavailability studies of budesonide, use of a Turbuhaler has resulted in twice the LRT drug deposition compared with its use with an MDI without a spacer.9 Both flunisolide and budesonide are widely prescribed for the treatment of asthma. Little is known, however, about how treatment with flunisolide compares with treatment with budesonide via Turbuhaler. This study tested the hypothesis that similar doses (taken in an equivalent number of inhalations) of flunisolide, administered via AeroChamber, and budesonide, administered via Turbuhaler, provide equivalent control of asthma in adults with moderate disease. A medium dose of inhaled corticosteroid, as defined by the National Institutes of Health (NIH) guidelines,14 was selected for this patient population of moderate asthmatics.
Figure 1. Study design.
it is effective, convenient, and durable and has been shown to compensate for poor user technique.8,10 Whereas oropharyngeal deposition of inhaled glucocorticoids may be 60% to 70% of the dose with an MDI alone, use of an AeroChamber has reduced this percentage to 4% to 5%.12 Although the AeroChamber removes most of the large particles, the fine particle dose is not diminished.13
The Turbuhaler is a passive drypowder inhaler that requires an inhalation technique completely different from that for a conventional MDI. It is commonly used with a dry-powder formulation of budesonide. A deep, forceful inspiration with a rapid onset is used to disaggregate the dry particles prior to inhalation. This is in contrast to the slow, coordinated inspiration required for optimal LRT aerosol deliv-
MATERIALS AND METHODS Patients Male and female patients with moderate stable asthma, aged 18 to 75, were enrolled. This illness was defined as that requiring a dose of at least 800 g/d and up to 2000 g/d of beclomethasone, fluticasone, or budesonide and the use of salbutamol. To be included in the study, patients had to have (1) a documented history of mod-
Table 1. Demographic and Baseline Characteristics of Intent-to-Treat Patients Characteristic* Sex (male/female), No. (%) Race (white/nonwhite), No. (%) Age (y) Weight (kg) Smoking history, No. (%) Current smoker Former smoker Never smoked FEV1, actual (L) FEV1 (% predicted) Salbutamol usage (puffs/d) Daily asthma symptom score Nocturnal awakenings (No./night) AM peak expiratory flow rate (L/min) PM peak expiratory flow rate (L/min)
Flunisolide With AeroChamber (n ⴝ 75)
Budesonide With Turbuhaler (n ⴝ 79)
P Values*
30/45 (40.0/60.0) 68/7 (90.7/9.3) 44.0 ⫾ 14.6† 78.8 ⫾ 20.0
34/45 (43.0/57.0) 73/6 (92.4/7.6) 42.8 ⫾ 16.2 79.2 ⫾ 19.8
.702 .698 .524 .866
4 (5.1) 30 (38.0) 45 (57.0) 2.42 ⫾ 0.69 78.5 ⫾ 15.1 2.7 ⫾ 2.5 3.8 ⫾ 3.4 0.1 ⫾ 0.3 352.1 ⫾ 94.0 357.9 ⫾ 89.6
.968
4 (5.3) 27 (36.0) 44 (58.7) 2.51 ⫾ 0.71 83.0 ⫾ 14.4 2.5 ⫾ 2.5 4.1 ⫾ 4.0 0.1 ⫾ 0.4 354.2 ⫾ 102.7 364.3 ⫾ 103.0
.434 .036 .944 .719 .701 .797 .917
* Baseline characteristics were compared using Chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables. † Values are mean ⫾ standard deviations.
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Table 2. Primary Efficacy Parameters: Changes from Baseline During Treatment Period in Intent-to-Treat Patients
Parameter
FEV1, actual (L) FEV1 (percent predicted) Salbutamol usage (puffs/d)
Flunisolide with AeroChamber (n ⴝ 75)
Budesonide with Turbuhaler (n ⴝ 78)
Difference*
P Values*
⫺0.07 ⫾ 0.32† ⫺2.4 ⫾ 9.9 0.4 ⫾ 1.8
⫺0.02 ⫾ 0.31 ⫺0.5 ⫾ 9.9 0.1 ⫾ 1.6
⫺0.031 ⫺1.419 0.261
.544 .378 .333
* Difference of least square means of flunisolide with AeroChamber and budesonide with Turbuhaler. † Values are mean ⫾ standard deviations.
Figure 2. Mean (⫾ standard error) FEV1 in patients treated with flunisolide with AeroChamber (n ⫽ 75) and patients treated with budesonide with Turbuhaler (n ⫽ 78). Table 3. Secondary Efficacy Parameters: Changes from Baseline During Treatment Period in Intent-to-Treat Patients
Parameter
Daily asthma symptom score Nocturnal awakenings (No./night) AM peak expiratory flow rate (L/min) PM peak expiratory flow rate (L/min)
Flunisolide Budesonide With With P Difference* AeroChamber Turbuhaler Values* (n ⴝ 75) (n ⴝ 78) 0.1 ⫾ 3.5† 0.1 ⫾ 0.2 ⫺3.5 ⫾ 42.6 ⫺5.6 ⫾ 37.2
0.1 ⫾ 2.7 0.1 ⫾ 0.3 ⫺1.0 ⫾ 34.6 3.9 ⫾ 34.5
0.050 0.009 ⫺2.523 ⫺8.866
.920 .849 .692 .143
* Difference of least square means of flunisolide with AeroChamber and budesonide with Turbuhaler. † Values are mean ⫾ standard deviations.
erate asthma; (2) forced expiratory volume in 1 second (FEV1) equal to 40% to 85% of predicted; (3) a demonstrated increase in FEV1 of at least 12% after two puffs of salbutamol via
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MDI15; and (4) use of an inhaled corticosteroid for at least 30 days. Patients were excluded if they had clinically significant pulmonary disease other than asthma, significant ill-
ness that could interfere with the assessment of efficacy and safety in the study, a history of hospitalization for exacerbation of asthma in the 6 weeks before their first visit, immunotherapy other than an established maintenance program, or upper respiratory tract infection within 30 days of their first visit. Other criteria for exclusion included the use of oral or parenteral corticosteroids on two or more occasions in the preceding 3 months, unstable reversible airway obstruction, and use of long-acting 2-agonists in the preceding 2 weeks. Drugs prohibited during the study included other orally inhaled steroids, antileukotrienes, oral steroids, cromolyn/nedocromil, nasal steroids, oral -adrenergic agonists, salmeterol, ipratropium, theophylline, and formoterol. Informed consent was obtained from all patients. Investigators obtained approval for the studies from the Institutional Review Boards at their respective institutions. A final report was made to the Institutional Review Boards at the completion of the study. Study protocol This was a multicenter, randomized, parallel-group study performed at 17 sites in Canada. Patients who met the inclusion and exclusion criteria at their first visit were entered into a 2-week run-in period, during which they inhaled 750 g beclomethasone in 3 puffs administered via AeroChamber twice a day (Fig 1). They also took salbutamol (100 g/puff) prn. At the conclusion of the run-in phase, patients were randomized into two groups, provided they met the following randomization criteria: (1) their best prebronchodilator FEV1 was at least 90% of their best prebronchodilator FEV1 obtained at their first visit; and (2) their mean asthma symptom score was no greater than 8 per day, with the patient taking no more than a mean of 8 puffs (800 g) of salbutamol per day during the second week of the run-in period. Asthma symptoms were scored from 0 to 3 for cough, dyspnea, wheezing, and chest tightness and then summated.
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age during the weeks preceding week 0 and week 6. Patients recorded their salbutamol usage on diary cards. Secondary Efficacy Parameters Secondary measures of efficacy were changes in peak expiratory flow (AM and PM), clinical asthma score, and average number of nocturnal awakenings due to asthma that required salbutamol, all changes being taken from week 0 to week 6. A Mini Wright peak flow meter was used to measure morning and evening peak expiratory flow prior to administration of study medication.
Figure 3. Mean (⫾ standard error) AM peak expiratory flow in patients treated with flunisolide with AeroChamber (n ⫽ 75) and patients treated with budesonide with Turbuhaler (n ⫽ 78).
Table 4. Incidence of Most Frequent Adverse Events (ⱖ2% in either group) Adverse Event Headache Nausea Flu syndrome Paresthesia Monilia, nonoral Migraine Emesis Insomnia Back pain Monilia, oral
Flunisolide With AeroChamber (n ⴝ 75) No. (%)
Budesonide With Turbuhaler (n ⴝ 79) No. (%)
5 (6.7) 4 (5.3) 3 (4.0) 2 (2.7) 2 (2.7) 2 (2.7) 2 (2.7) 1 (1.3) 1 (1.3) 0 (0.0)
3 (3.8) 1 (1.3) 5 (6.3) 0 (0.0) 2 (2.5) 0 (0.0) 0 (0.0) 2 (2.5) 2 (2.5) 4 (5.1)
Group 1 received flunisolide, administered via AeroChamber, 750 g twice daily. Group 2 received budesonide, administered via Turbuhaler, 600 g twice daily. Both groups took salbutamol via inhaler prn. Study medications were administered for 6 weeks. Spirometry was performed at week 0 (baseline or start of the treatment period), at week 2 (follow-up visit), and at week 6 (end of treatment). Mouth and throat smears were obtained for culture and Candida detec-
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tion at week 0 and at week 6. Cortrosyn stimulation was performed at selected sites at week 0 and at week 6. Patients kept a diary of asthma symptoms, peak flows, salbutamol use, and adverse events. Patient compliance was monitored by diary cards. Primary Efficacy Parameters The primary measures of efficacy were (1) the change in prebronchodilator FEV1 from week 0 to week 6 and (2) the change in mean prn salbutamol us-
Safety and Tolerability Safety and tolerability were assessed by records of adverse events, a mouth and throat smear to assay for the presence of Candida, and, at selected sites, a Cortrosyn stimulation test to evaluate the effects on adrenal function. Cortrosyn 25 g was administered intramuscularly, with cortisol samples drawn before and 30 and 60 minutes after administration. The study provided 80% power to detect a 33% difference between groups in plasma cortisol levels after Cortrosyn stimulation. An adverse event was defined as any unfavorable and unintended sign, symptom, or disease temporarily associated with the use of study medication, whether or not considered related to study medication. This included all clinically relevant laboratory abnormalities of physical findings. Adverse events were judged and classified by investigators as unrelated, unlikely related, possibly related, probably related, or highly probably related to the study medication. Statistical Analysis Hypothesis tests were conducted using two-sided tests at the .05 level of significance. All efficacy variables were analyzed using analysis of covariance (ANCOVA) model with treatment and center factors and baseline efficacy measurement as a covariate in the model. Efficacy analyses were based on the intent-to-treat population, ie, all randomized patients who had at least one follow-up visit. Missing values for
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Table 5. Change in the Incidence of Oropharyngeal Candida During Treatment Period Change Baseline No yeast cells present Yeast cells present End of treatment No yeast cells present Yeast cells present
Flunisolide With AeroChamber (n ⴝ 75) No. (%)
Budesonide With Turbuhaler (n ⴝ 79) No. (%)
41 (54.7) 34 (45.3)
46 (58.2) 33 (41.8)
.656
46 (64.8) 25 (35.2)
46 (58.2) 33 (41.8)
.410
efficacy variables at the final visit were imputed by last observation carried forward (LOCF). Safety analysis was based on all randomized patients who received at least one dose of study medication. RESULTS Patient Characteristics The demographic characteristics and clinical parameters of the patients randomized to the two treatment arms were comparable (Table 1). There were no statistically significant differences between the groups at baseline except for a small but statistically significant difference (P ⫽ .04) in percent predicted FEV1. A total of 154 patients were randomized, 75 in the flunisolide/ AeroChamber arm and 79 in the budesonide/Turbuhaler arm. All but one of these was available for inclusion in the intent-to-treat analysis. The number of patients withdrawn from the study for all reasons (adverse event/ intercurrent illness; protocol violation; administrative reasons; withdrawal of consent; lost to follow-up; screening failure; did not meet randomization criteria; and insufficient efficacy) was
P Values
11 in the flunisolide group and 3 in the budesonide group. Primary Efficacy Parameters There were no statistically significant differences between the two treatment groups in the changes in FEV1 or salbutamol usage during the 6-week treatment period (Table 2). There was little change from baseline in FEV1 in either treatment group as measured either by actual FEV1 (Fig 2) or by percent predicted FEV1, and the difference between groups was not significant in either case. Salbutamol usage did not change significantly from baseline in either group. To determine whether the baseline imbalance between the two treatment groups could bias the treatment group comparison, a treatment-only baseline percent-predicted FEV1 interaction was added to the ANCOVA model. The results showed that the difference in baseline FEV1 values did not affect the comparison between groups. Secondary Efficacy Parameters There were no statistically significant differences between the two treatment groups in the change in peak expira-
tory flow (AM and PM), asthma symptom score, and nocturnal awakenings (number/night) during the treatment period (Table 3, Fig 3). Safety and Tolerability Both treatments were well tolerated. Overall, there were no significant differences between the groups in the frequency of adverse events (Table 4). Adverse events were reported by 48.0% of patients who received flunisolide and by 54.4% of patients who received budesonide. The majority of adverse events were mild or moderate in severity. There were no significant changes in blood pressure or other vital signs during the course of the study, nor were there any differences between the treatment groups. Mouth and throat smears were taken and cultured to assay for the presence of Candida (Table 5). The change in the incidence of oropharyngeal Candida colonization did not differ significantly between the treatment groups (P ⫽ .809). Pre-Cortrosyn plasma cortisol levels at baseline and after 6 weeks of treatment were comparable in the flunisolide and budesonide groups. The response at 30 minutes to intramuscular injection of Cortrosyn was greater in the flunisolide group than in the budesonide group, both at baseline and after 6 weeks of treatment. The response at 60 minutes was comparable between the two groups (Table 6).
* Between treatment groups.
DISCUSSION Few studies have undertaken direct comparison of the efficacy and safety of the various inhaled steroid medications now available for the treatment of asthma. Such comparisons must take into account the delivery system, the dosage, and the characteristics of the patients treated. The study reported here compared the efficacy and safety of flunisolide, 1500 g/d, administered via AeroChamber with budesonide, 1200 g/d, administered via Turbuhaler in the treatment of patients with moderate asthma.
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Table 6. Plasma Cortisol Levels (g/L) in Cortrosyn Stimulation Test Time Relative to Cortrosyn Injection Baseline Pre-Cortrosyn Change at 30 minutes Change at 60 minutes Week 6 Pre-Cortrosyn Change at 30 minutes Change at 60 minutes
Flunisolide With AeroChamber
Budesonide With Turbuhaler
(n ⫽ 31) 13.4 ⫾ 5.5 9.4 ⫾ 3.7 12.6 ⫾ 4.6 (n ⫽ 29) 14.9 ⫾ 6.6 9.2 ⫾ 3.7 12.5 ⫾ 36
(n ⫽ 32) 14.7 ⫾ 7.7 7.3 ⫾ 2.9 10.4 ⫾ 3.7 (n ⫽ 30) 14.7 ⫾ 5.9 6.9 ⫾ 2.7 10.5 ⫾ 4.1
P Values* .558 .026 .077 .697 .017 .053
After the 2-week run-in period, during which patients received beclomethasone and salbutamol, patients were randomized to receive one of the two treatments for 6 weeks. At the end of this treatment period, there were no statistically significant differences between the two treatment groups in the primary efficacy parameters— changes from baseline in FEV1 and salbutamol usage. There were also no statistically significant differences between the two treatment groups in the secondary efficacy parameters— changes in peak expiratory flow rate (AM and PM), asthma symptom score, and nocturnal awakenings (number/night) during the treatment period. Both treatments were effective in the continued control of moderate asthma; there was little change from baseline parameters, which were taken after the 2-week run-in period of 1500 g/d beclomethasone and salbutamol prn. It can be concluded that flunisolide administered via AeroChamber provided equivalent outcomes as a similar dose of budesonide administered via Turbuhaler in relieving asthma. Safety and tolerability were comparable between the two treatments. Both were well tolerated, and the frequency of adverse events was similar in the two treatment groups. There was no difference in the incidence of oropharyngeal Candida colonization. Oropharyngeal candidiasis can be a problem in some patients, particularly the elderly and those taking high doses of glucocorticoids.1 Deposition of inhaled glucocorticoids in the oropharynx is reduced by 90% to 95% by the AeroChamber, thus reducing the likelihood of Candida infection.10,12 In a study of asthma patients treated with inhaled beclomethasone dipropionate, the addition of an AeroChamber was shown to significantly reduce the incidence of oropharyngeal Candida infection and colonization compared with patients treated with an MDI alone.10 The small changes from baseline in nearly all the primary and secondary efficacy parameters tend to confirm previous reports that budesonide and beclomethasone are of approximately equivalent potency.16 This study sug-
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gests that flunisolide is at least as potent, microgram for microgram, as beclomethasone. Corticosteroids differ in anti-inflammatory potency when measured by in vitro methods, such as receptor binding affinity or binding halflife.14 There is however, no evidence that any of the inhaled corticosteroids has greater efficacy in patients when compared using identical doses,17 with the possible exception of fluticasone. There is in vitro evidence that the optimum inhalation delivery system may differ with the drug formulation administered.13 The available data also suggest that, when administered in equipotent doses with a MDI plus spacer or by dry-powder inhaler as opposed to MDI alone, the currently available inhaled corticosteroids have less risk of systemic effects than when administered without a spacer or inhaler.17 When corticosteroid MDIs, such as flunisolide (Aerobid) are used with an AeroChamber valved holding chamber, this not only helps to overcome problems of hand-breath coordination, but also greatly reduces oropharyngeal and systemic side effects. This considerably improves the therapeutic ratio compared with MDI alone or passive dry powder inhaler, such as the budesonide Turbuhaler. It is for this reason that the NIH asthma guidelines have recommended that for treating asthma, cortisol MDIs should generally be used with aerosol holding chambers, particularly in the pediatric age group.14 It is worth stressing that, since it is not possible to reduce the upper respiratory tract dose of corticosteroid in a similar fashion with the current dry powder inhalers, their therapeutic ratio at equivalent doses is likely to be lower. In summary, we conclude that flunisolide administered with an AeroChamber and budesonide administered with a Turbuhaler have similar efficacy, safety, and tolerability in the treatment of patients with moderate asthma.
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REFERENCES 1. Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med 1995;332: 868 – 875. 2. Goldberg S, Algur N, Levi M, et al.
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Adrenal suppression among asthmatic children receiving chronic therapy with inhaled corticosteroid with and without spacer device. Ann Allergy Asthma Immunol 1996;76:234 –238. Hanania NA, Chapman KR, Sturtridge WC, et al. Dose-related decrease in bone density among asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol 1995;96: 571–579. Kiviranta K, Turpeinen M. Effect of eight months of inhaled beclomethasone dipropionate and budesonide on carbohydrate metabolism in adults with asthma. Thorax 1993;48: 974 –978. Nicolaizik WH, Marchant JL, Preece MA, Warner JO. Endocrine and lung function in asthmatic children on inhaled corticosteroids. Am J Respir Crit Care Med 1994;150:624 – 628. Pavia D. Efficacy and safety of inhalation therapy in chronic obstructive pulmonary disease and asthma. Respirology 1997;2(Suppl 1):S5–S10. Conner WT, Dolovich MB, Frame RA, Newhouse MT. Reliable salbutamol administration in 6- to 36-month-old children by means of a metered dose inhaler and Aerochamber with mask. Pediatr Pulmonol 1989;6:263–267. Dolovich M, Ruffin R, Corr D, Newhouse MT. Clinical evaluation of a simple demand inhalation MDI aerosol delivery device. Chest 1983;84:36 – 41. Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler PMDI. Eur Respir J 1994;7:1839 –1844. Salzman GA, Pyszczynski DR. Oropharyngeal candidiasis in patients treated with beclomethasone dipropionate delivered by metered-dose inhaler alone and with Aerochamber. J Allergy Clin Immunol 1988;81:424 – 428. Shapiro G, Bronsky EA, LaForce CF, et al. Dose-related efficacy of budesonide administered via a dry powder inhaler in the treatment of children with moderate to severe persistent asthma. J Pediatr 1998;132:976 –982. Chua HL, Chambers CB, Newhouse MT. Upper respiratory tract salbutamol deposition following MDI and AeroChamber: effect of mouth rinsing on oropharyngeal clearance. J Aerosol Med 1995;8:83. Ahrens R, Lux C, Bahl T, Han SH. Choosing the metered-dose inhaler
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spacer or holding chamber that matches the patient’s need: evidence that the specific drug being delivered is an important consideration. J Allergy Clin Immunol 1995;96:288 –294. National Asthma Education and Prevention Program. Clinical Practice Guidelines. Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. National Institutes of Health; April 1997. Publication 974051. American Thoracic Society. Lung function testing: selection of reference values and interpretive strategies. Am Rev Respir Dis 1991;144:1202–1218. Ebden P, Jenkins A, Houston G, Davies BH. Comparison of two high dose corticosteroid aerosol treatments, beclomethasone dipropionate (155 micrograms/day) and budesonide (1600 micrograms/day), for chronic asthma. Thorax 1986;41: 869–874. Kelly HW. Comparison of inhaled corticosteroids. Ann Pharmacother 1998; 32:220 –232.
APPENDIX AER-MD-04 Study Group 1. Michael Alexander, MD Niagara Falls, Ontario
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2. William Arkinstall, MD Kelowna Allergy and Respiratory Health Clinic, Kelowna, British Columbia 3. Meyer Balter, MD Mount Sinai Hospital, Toronto, Ontario 4. Andre´ Cartier, MD Sacre´ Coeur Hospital, Montre´al, Que´bec 5. Anthony D’Urzo, MD Primary Care Asthma Clinic, Toronto, Ontario 6. David Thomson, MD Montre´al General Hospital, Montre´al, Que´bec 7. Jacques He´bert, MD CRAAQ, St. Foy, Que´bec 8. Victor Hoffstein, MD St. Michael’s Hospital, Toronto, Ontario 9. Allan Knight, MD University of Toronto, Toronto, Ontario 10. Jorge Mazza, MD London Health Sciences, London, Ontario 11. Andrew McIvor, MD
12. 13. 14. 15. 16. 17.
The Toronto Hospital, Toronto, Ontario Peter Small, MD SMBD Jewish General Hospital, Montre´al, Que´bec William Yang, MD Ottawa Allergy Research Center, Ottawa, Ontario Robert Cowie, MD Calgary Asthma Program, Calgary, Alberta G. Fred MacDonald, MD The Grey Nuns Hospital, Edmonton, Alberta Michael Newhouse, MD Barnett Medical Aerosol, Hamilton, Ontario Paul Keith, MD McMaster University, Hamilton, Ontario
Request for reprints should be addressed to: Kenneth Newman Newhouse, MD Forest Laboratories, Inc 909 Third Ave New York, NY 10022
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