Original Article
Tolerance to the Nonbronchodilator Effects of Inhaled β2-Agonists in Asthma
N Engl J Med 1992; 327:1204-1208October 22, 1992
- Abstract
- Abstract
Background.
Tolerance to the direct bronchodilator effects of β2-agonists does not appear to occur in asthma. However, it is not known whether this is true for the nonbronchodilator effects of these agents, which protect the airways against bronchoconstrictive stimuli.
Methods.
We investigated whether tolerance develops to the protective effect of inhaled terbutaline on airway responsiveness to the bronchoconstrictors methacholine (which acts directly on airway smooth muscle) and AMP (which acts indirectly by stimulating the release of mediators from mast cells) during sustained treatment with terbutaline. In a randomized, double-blind, crossover study, 12 patients with mild asthma each inhaled a single dose of terbutaline (500 μg) or placebo before a challenge with a series of doubling doses of inhaled methacholine or AMP, before and after treatment for seven days with 500 μg of terbutaline four times daily or placebo.
Results.
Before the seven days of treatment with terbutaline, a single dose of terbutaline reduced airway responsiveness to methacholine by 2.7 doubling doses (95 percent confidence interval, 1.9 to 3.5), but it had an even greater protective effect against AMP, reducing airway responsiveness by 3.8 doubling doses (95 percent confidence interval, 2.7 to 4.9; P<0.001). After seven days of treatment with terbutaline, the protective effect of terbutaline against methacholine decreased to 2.2 doubling doses (95 percent confidence interval, 1.3 to 3.0; P = 0.04), and that against AMP decreased even more, to 1.7 doubling doses (95 percent confidence interval, 1.1 to 2.4; P<0.001). By contrast, the bronchodilator response to terbutaline was unchanged during seven days of treatment with this agent.
Conclusions.
We observed tolerance to the nonbronchodilator actions of the inhaled β2-agonist terbutaline in patients with mild asthma, an effect that may be more pronounced in mast cells than in bronchial smooth muscle. This property of β-agonists may constitute a drawback to their regular use in patients with asthma. (N Engl J Med 1992;327:1204–8.)
Media in This Article
Figure 1
Bronchodilator Effect of a Single 500-μg Inhalation of Terbutaline, Expressed as the Mean (±SEM) Percent Change from Base Line in FEV1 before (Days 0 and 1) and after (Days 7 and 8) Treatment with Terbutaline for Seven Days.Figure 2
Effect of a Single 500-μg Inhalation of Terbutaline on Airway Responsiveness to Methacholine and AMP.Article Activity
- Article
INHALED β-adrenergic agonists are the most effective of the available bronchodilator drugs used to treat asthma.1 However, recent studies have suggested that their regular use in asthma may be associated with increased morbidity and even mortality.2 , 3 The safety of β-agonists was first questioned in the late 1960s, when the availability of aerosols containing isoproterenol in the United Kingdom was linked to a sharp rise in asthma-related deaths,4 focusing attention on the development of tolerance to the airway-specific and systemic effects of β-adrenoceptor stimulants after long-term exposure.5 Although subsequent studies demonstrated subsensitization of β-adrenoceptors in the airways and peripheral-blood lymphocytes of both normal subjects and those with asthma,6 clinically important tachyphylaxis has not been observed.7
Single doses of β-agonists protect patients against a variety of bronchoconstrictive stimuli.8 9 10 This protection is independent of bronchodilation and has been attributed to functional antagonism to the contraction of smooth muscle in the airways, regardless of the provoking stimulus.11 We have recently found a greater reduction in airway responsiveness to the inhalation of the indirect bronchoconstrictor AMP than to the inhalation of either sodium metabisulfite, a presumed neural stimulus, or the direct-acting bronchoconstrictor methacholine in patients with asthma who were using a single conventional (500-μg) dose of inhaled terbutaline.10 Since AMP appears to activate mast cells in subjects with asthma,12 our observations suggest that in addition to their action on airway smooth muscle, β-agonists inhibit mast-cell function in vivo. Indeed, β-agonists are potent mast-cell stabilizers in vitro13 and inhibit the release of histamine after an allergen challenge in vivo14 —a property that may be clinically important, since the mast cell plays a key part in the pathogenesis of asthma.15
In guinea pig airways, β-adrenoceptors on mast cells exhibit greater tachyphylaxis than do those on smooth-muscle cells after prolonged exposure to β-agonists.16 To assess whether this phenomenon also occurs in patients with asthma, we examined the effect of a single dose of inhaled terbutaline on the bronchoconstrictor responses to AMP and methacholine, before and after seven days of regular treatment with inhaled terbutaline or placebo. Our hypothesis was that if tachyphylaxis was evident in response to a mast-cell stimulus, it would provide a plausible explanation for the observation that control of asthma is often poorer during regular treatment with β-agonists than when such treatment is taken only "on demand" for control of symptoms.
Methods
Patients
Twelve nonsmoking subjects with mild asthma (five men and seven women, 22 to 47 years old) (Table 1Table 1
Characteristics of the Patients, Base-Line FEV1, and Responsiveness to Methacholine and AMP.*) with documented sensitivity to inhaled methacholine and AMP gave written informed consent to participate in the study, which was approved by the Royal Brompton and National Heart Hospitals Ethics Committee. All were atopic, as defined by positive skin tests in response to common airborne allergens (Dermatophagoides pteronyssinus, mixed-grass pollen, cat fur, and dog hair). None had had either an exacerbation of wheezing or a respiratory infection in the preceding six weeks. Each subject had only occasional symptoms, which were controlled by therapy with inhaled β2-adrenoceptor agonists alone, and had a base-line forced expiratory volume in one second (FEV1) greater than 80 percent of the predicted value. Four of the subjects were moderately responsive to methacholine and AMP before entry into the study, with a provocative concentration that causes a 20 percent fall in FEV1 (PC20) of less than 0.5 mg per milliliter and 12.5 mg per milliliter, respectively (mildly responsive range for methacholine, 0.5 to 8 mg per milliliter; for AMP, 12.5 to 100 mg). Geometric mean values for the group were 0.73 mg per milliliter for methacholine and 14.6 mg per milliliter for AMP (Table 1).Study Design
The study had a randomized, double-blind, crossover design and was divided into four phases: two seven-day treatment periods (500 μg of terbutaline four times daily or placebo), each of which was preceded by a seven-day run-in or washout period. The subjects were asked to use an inhaler containing ipratropium bromide rather than their usual β-agonist for relief of symptoms throughout all four periods. Terbutaline and a matched placebo were administered by a multidose, dry-powder delivery system (Turbuhaler, Astra Draco, Lund, Sweden) in 500-μg doses. The total daily dose was 2000 μg, delivered as four inhalations per day of 500 μg each and taken at 9 a.m., 1 p.m., 5 p.m., and 9 p.m.
The subjects were studied in the laboratory at 8:30 a.m. on eight occasions: two consecutive mornings before (days 0 and 1 ) and after (days 7 and 8) each treatment period, in order to receive a single dose of the treatment assigned for that period before separate challenges with methacholine and AMP. After a base-line FEV1 measurement at 9 a.m., 500 μg of terbutaline or placebo was administered 20 minutes before the challenge. The sequence of the inhalation challenges was randomized, but it remained identical for each subject throughout the study. Treatment was begun immediately after the completion of the challenge on day 1, and it continued up to and including the dose given at 9 a.m. on day 8. The study was designed to allow an interval of 12 hours between the preceding dose of terbutaline, given at 9 a.m., and the dose given at 9 a.m. immediately before the challenge on days 7 and 8. Inhaled ipratropium bromide and caffeinated beverages were also withheld for at least 12 hours before each challenge.
Bronchial Provocation and Measurement of Pulmonary Function
On each day of an inhalation challenge, fresh solutions of methacholine and AMP (Sigma, Poole, United Kingdom) were made up in 0.9 percent saline in a range of concentrations, from 0.125 to 128 mg per milliliter for methacholine and from 0.39 to 1600 mg per milliliter for AMP. Each solution was administered from a nebulizer attached to a breath-activated dosimeter (Mefar, Brescia, Italy). The nebulizer delivered particles with an aerodynamic-mass median diameter of 3.5 to 4 μm at an output of 9 μl per breath.
Pulmonary function was assessed by measurement of FEV1 with a dry wedge spirometer (Vitalograph, Buckingham, United Kingdom). A standard challenge protocol was used for all provocation tests. On arrival in the laboratory, each subject rested quietly for 15 minutes. Three measurements of FEV1 were then taken at one-minute intervals, the best of which was taken as the base line. The subjects then inhaled a series of five breaths of saline as control, followed by a series of five breaths of doubling doses of methacholine or AMP at three-minute intervals (i.e., during each sequential inhalation, the amount of methacholine or AMP administered was doubled). FEV1 was measured two minutes after each inhalation. The challenges were terminated when a 20 percent decrease in FEV1 from the post-saline value was recorded. A log dose–response curve was constructed for each agonist, and the PC20 was calculated by linear interpolation.
Statistical Analysis
The PC20 values for methacholine and AMP after a single inhalation of terbutaline and placebo on each study day (days 0, 1, 7, and 8) were log10-transformed for analysis, and the log values are reported here. These values were compared by a multifactor analysis of variance that took into account the variation in values for individual patients over time, in addition to testing for possible effects of treatment.17 A standard computerized statistical package, Statsgraphics, version 2.6 (Statistical Graphics System, Statistical Graphics, Rockville, Md.), was used for the analysis. Multiple comparisons were made by the technique of multiple-range tests, using 95 percent confidence intervals. All tests of significance were two-tailed.
The PC20 values for methacholine and AMP before and after seven days of treatment with terbutaline were individually compared with the corresponding values after the administration of placebo. The effect on these values of treatment with terbutaline or placebo was assessed by comparing the change in PC20 on the challenge days before and after treatment. In addition, the short-term effects of terbutaline and placebo on the magnitude of the responses to both agonists were compared at each time point. FEV1 measurements before and after treatment were compared in a similar manner.
The effect of treatment on responses to provocation on each challenge day was calculated by comparing the difference in PC20 after the administration of terbutaline and placebo in each subject; this effect was expressed in terms of doubling doses, as means and 95 percent confidence intervals, using the formula
(log PC20 after terbutaline — log PC20 after placebo) ÷ log 2.
The values for PC20 obtained before and after each treatment period are expressed as means ±SEM. Geometric mean concentrations were calculated by taking the antilog of the average PC20 values and are expressed as milligrams per milliliter.
Results
Terbutaline and Airway Caliber
The base-line FEV1 was 97±2 percent of the predicted FEV1, a value that did not change through both treatment periods (Table 2Table 2
Changes in Airway Caliber, Measured as the FEV1 before and after a Single Inhalation of Terbutaline or Placebo on Each Study Day.*). Terbutaline caused a small but substantial degree of bronchodilation on days 0, 1, and 7, increasing FEV1 from base line by 5.0, 6.1, and 6.2 percent, respectively; the increase in FEV1 of 3.9 percent on day 8 was not statistically significant (P = 0.07) (Fig. 1Figure 1Bronchodilator Effect of a Single 500-μg Inhalation of Terbutaline, Expressed as the Mean (±SEM) Percent Change from Base Line in FEV1 before (Days 0 and 1) and after (Days 7 and 8) Treatment with Terbutaline for Seven Days.). No patients required ipratropium bromide during the run-in or washout periods. Two subjects (Subjects 5 and 8) took 120 μg (six puffs) or less of ipratropium while taking placebo, whereas Subject 12 took 40 μg during treatment with terbutaline.The Effect of Terbutaline on Methacholine Challenge
Before seven days of treatment with terbutaline, the log PC20 for methacholine after placebo was -0.07±0.10 (geometric mean, 0.85 mg per milliliter), increasing to 0.74±0.13 (geometric mean, 5.5 mg per milliliter) after a single dose of terbutaline. Thus, the protective effect of a single inhalation of terbutaline was 2.7 doubling doses (95 percent confidence interval, 1.93 to 3.46; P<0.001) (Table 3Table 3
Effect of a Single Inhalation of Placebo or Terbutaline on Individual Responses to Methacholine and AMP, Expressed as Log PC20 (in Milligrams per Milliliter) before and after Each Treatment Period. and Fig. 2Figure 2Effect of a Single 500-μg Inhalation of Terbutaline on Airway Responsiveness to Methacholine and AMP.). After seven days of treatment with terbutaline, the log PC20 after placebo was -0.29±0.09 (geometric mean, 0.51 mg per milliliter), increasing to 0.36±0.14 (geometric mean, 2.3 mg per milliliter) after terbutaline (Table 3). Thus, the short-term protective effect of terbutaline after seven days of treatment was reduced to 2.2 doubling doses (95 percent confidence interval, 1.3 to 3.0) as compared with the pretreatment value (Fig. 2). The change in the protective effect measured in doubling doses for patients receiving terbutaline was significantly greater than that for patients receiving placebo (P = 0.04) (Table 3).The Effect of Terbutaline on AMP Challenge
Before treatment with terbutaline, the log PC20 for AMP after placebo was 1.17±0.14 (geometric mean, 14.8 mg per milliliter), increasing to 2.31±0.18 (geometric mean, 204 mg per milliliter) after a single dose of terbutaline (Table 3). Thus, the protective effect of a single inhalation of terbutaline was 3.8 doubling doses (95 percent confidence interval, 2.6 to 4.9; P<0.001) (Fig. 2). This protection against AMP was significantly greater than the corresponding protection against methacholine (P<0.001).
After seven days of treatment with terbutaline, the short-term protective effect of terbutaline was significantly reduced to 1.7 doubling doses (95 percent confidence interval, 1.1 to 2.4; P<0.001) as compared with the pretreatment values, with a log PC20 of 1.54±0.14 (geometric mean, 34.7 mg per milliliter) after terbutaline and of 1.02±0.10 (geometric mean, 10.5 mg per milliliter) after placebo (Table 3 and Fig. 2). There was no difference between this short-term protection against AMP and the corresponding protection against methacholine at the end of seven days of treatment with terbutaline. The reduction protection against AMP, a decrease of 2.0 doubling doses, was significantly greater than that against methacholine, a decrease of 0.5 doubling doses (P<0.01).
Discussion
A single inhaled dose of terbutaline reduced airway responsiveness to methacholine by 2.7 doubling doses but caused a significantly greater reduction (by 3.8 doubling doses) in airway responsiveness to AMP, confirming our previous findings.10 (The higher the number of doubling doses needed to provoke bronchoconstriction, the less responsive are the airways.) After seven days of treatment with inhaled terbutaline, however, the protection against methacholine-induced bronchoconstriction was reduced to 2.2 doubling doses, whereas the additional protection against AMP was abolished, since the inhibitory effect of terbutaline (1.7 doubling doses) was similar to that with methacholine challenge. The FEV1 at base line was unchanged by treatment with terbutaline, and there was no significant diminution in the bronchodilator response to a single dose of terbutaline after seven days of treatment.
The short-term effect of a single dose of terbutaline (500 μg) on the response to methacholine challenge is compatible with previous data obtained when equivalent doses of β-agonists were used to protect against the effects of inhaled methacholine,10 another direct-acting bronchoconstrictor, histamine,8 and the indirect bronchoconstrictor sodium metabisulfite.10 The additional and greater protective effect against AMP cannot be explained by functional antagonism alone and is likely to be due to a non—smooth muscle action of terbutaline. Because β-agonists are potent mast-cell stabilizers in vitro13 and inhibit the release of histamine after an allergen challenge in vivo,14 it is likely that this action is mediated through airway mast cells. AMP induces bronchoconstriction indirectly in patients with asthma, probably by activating airway mast cells to release bronchospastic mediators.12 , 18 Further evidence that AMP acts primarily on mast cells is provided by the recent observation that the contractile effect of adenosine, the active metabolite of AMP, on isolated bronchi from patients with asthma is blocked by specific leukotriene-receptor and histamine-receptor antagonists.19 In addition, adenosine is a potent stimulus of mediator release from mast cells in vitro.13
We have demonstrated an impaired response to the protective action of terbutaline against both methacholine and AMP challenge after sustained treatment with terbutaline. In contrast, the base-line airway caliber and the bronchodilator effects of terbutaline were not affected by sustained treatment. Tolerance to the effects of terbutaline on responsiveness to methacholine has been observed by some investigators8 , 20 , 21 but not all.6 , 22 Possible reasons for the inconsistent findings of tolerance to the smooth-muscle effects of β-agonists include the lack of a placebo group, small numbers of subjects, an inadequate period of withdrawal from β-agonists, the performance of the studies in patients with moderate to severe asthma, and the use of concomitant therapy such as inhaled corticosteroids. We endeavored to overcome these potential drawbacks by studying subjects with mild asthma and a minimal requirement for treatment. Thus, our subjects were not exposed to the long-term exogenous β-adrenergic stimulation seen in more severe disease. Moreover, our study design included run-in and washout periods of seven days without β-agonists. Consequently, our subjects were unlikely to have substantial desensitization of β-receptors on airway smooth muscle, which may explain the decreased protection. This is supported by previous findings that tolerance to the airway effects of β-agonists develops in normal subjects but not in subjects with asthma.7
In asthma, a change of at least one doubling dose in airway responsiveness to a bronchoconstrictor stimulus is considered to be clinically important in the evaluation of disease progression or response to treatment.1 In this study, regular treatment with terbutaline resulted in a loss of short-term protection against inhaled methacholine of only 0.5 doubling doses, an effect that was statistically significant but not clinically important. Although it did not occur in our study, clinically important loss of functional antagonism could conceivably develop after more prolonged treatment with longer-acting inhaled β-agonists.
In contrast, the marked reduction, by 2.0 doubling doses, in short-term protection against airway responsiveness to AMP after seven days of treatment with terbutaline was significantly greater than the corresponding reduction in protection against methacholine. This suggests that tolerance to the mast-cell—stabilizing effects of β-agonists may occur. The additional short-term protection against the effects of AMP (3.8 doubling doses, as compared with 2.7 for methacholine) after a single dose of terbutaline was completely abolished. Although AMP primarily activates mast cells, it may act partly through neural pathways.23 It is possible, therefore, that these effects of terbutaline may be neurally mediated.10 Indeed, the impaired short-term protection conferred by terbutaline against AMP cannot be due solely to an effect on mast cells. The loss of functional antagonism against methacholine indicates that a component of the response to AMP must also involve an effect on airway smooth muscle.
In a clinical context, the results of this study suggest that the regular use of inhaled β-agonists in patients with asthma may result in a blunted protective effect of short-term therapy with β-agonists against bronchoconstrictor stimuli, despite well-maintained bronchodilation. In the presence of a potent mast-cell bronchoconstrictor stimulus, such as an allergen, this short-term protective effect may be impaired even more. We propose that tolerance to the nonbronchodilator effects of β-agonists on airway function may explain why regular treatment with such agonists could lead to a deterioration in the control of asthma.
Supported by a grant (HL 45947) from the National Institutes of Health and by grants from Astra Draco (Lund, Sweden) to Dr. O'Connor and Ms. Aikman.
Source Information
From the Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse St., London SW3 6LY, United Kingdom, where reprint requests should be addressed to Dr. Barnes.
- References
References
1
Barnes
Full Text | Web of Science | Medline2
Spitzer
Full Text | Web of Science | Medline3
Sears
CrossRef | Web of Science | Medline4
Speizer
CrossRef | Web of Science | Medline5
Conolly
Web of Science | Medline6
Tashkin
Web of Science | Medline7
Tattersfield
Medline8
Vathenen
CrossRef | Web of Science | Medline9
Cockcroft
CrossRef | Web of Science | Medline10
O'Connor 11
Britton
CrossRef | Web of Science | Medline12
Cushley
CrossRef | Web of Science | Medline13
Church
Web of Science | Medline14
Howarth
Web of Science | Medline15
Kaliner
CrossRef | Web of Science | Medline16
van der Heijden
Medline17
Armitage P, Berry G. Statistical methods in medical research. 2nd ed. London: Blackwell Scientific, 1987.
18
Phillips
CrossRef | Web of Science | Medline19
Bjorck
CrossRef | Web of Science | Medline20
Kraan
CrossRef | Web of Science | Medline21
Kerrebijn
CrossRef | Web of Science | Medline22
Peel
Web of Science | Medline23
Phillips
Web of Science | Medline
- Citing Articles (104)
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1
Mark A. Giembycz. 2011. Development of Phosphodiesterase 4 Inhibitors for Allergic and Nonallergic Inflammatory Diseases of the Airways. .
CrossRef2
Brian J. Lipworth, Philip Short, Patricia Burns, Arun Nair. (2011) Effects of intranasal salmeterol and fluticasone given alone and in combination in persistent allergic rhinitis. Annals of Allergy, Asthma & Immunology
CrossRef3
Nobuyuki Hizawa. (2011) Pharmacogenetics of β2-Agonists. Allergology International 60:3, 239-246
CrossRef4
John M. Weiler, Sandra D. Anderson, Christopher Randolph, Sergio Bonini, Timothy J. Craig, David S. Pearlman, Kenneth W. Rundell, William S. Silvers, William W. Storms, David I. Bernstein, Joann Blessing-Moore, Linda Cox, David A. Khan, David M. Lang, Richard A. Nicklas, John Oppenheimer, Jay M. Portnoy, Diane E. Schuller, Sheldon L. Spector, Stephen A. Tilles, Dana Wallace, William Henderson, Lawrence Schwartz, David Kaufman, Talal Nsouli, Lawrence Schieken, Nelson Rosario. (2010) Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter. Annals of Allergy, Asthma & Immunology 105:6, S1-S47
CrossRef5
N. Hizawa. (2009) Beta-2 adrenergic receptor genetic polymorphisms and asthma. Journal of Clinical Pharmacy and Therapeutics 34:6, 631-643
CrossRef6
Kaninika Basu, Colin N.A. Palmer, Roger Tavendale, Brian J. Lipworth, Somnath Mukhopadhyay. (2009) Adrenergic β2-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol. Journal of Allergy and Clinical Immunology 124:6, 1188-1194.e3
CrossRef7
Anne-Marie Scola, Matthew Loxham, Steven J Charlton, Peter T Peachell. (2009) The long-acting β-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cells. British Journal of Pharmacology 158:1, 267-276
CrossRef8
Elin T.G. Kersten, Jean M.M. Driessen, Julianne D. van der Berg, Bernard J. Thio. (2009) Mannitol and exercise challenge tests in asthmatic children. Pediatric Pulmonology 44:7, 655-661
CrossRef9
Ian P. Hall. 2009. β2-Adrenoceptor Agonists. , 609-614.
CrossRef10
Nathan D. Allen, Beth E. Davis, Donald W. Cockcroft. (2008) Correlation between airway inflammation and loss of deep-inhalation bronchoprotection in asthma. Annals of Allergy, Asthma & Immunology 101:4, 413-418
CrossRef11
Richard A. Bond, Domenico Spina, Sergio Parra, Clive P. Page. (2007) Getting to the heart of asthma: Can “β blockers” be useful to treat asthma?. Pharmacology & Therapeutics 115:3, 360-374
CrossRef12
Alain Boussuges, Pascal Rossi, Marion Gouitaa, Eric Nussbaum. (2007) Alterations in the peripheral circulation in COPD patients. Clinical Physiology and Functional Imaging 27:5, 284-290
CrossRef13
P.L. Paggiaro, D. Giannini, A. Di Franco, E. Bacci, F.L. Dente, B. Vagaggini, M. Tonelli, M. Zingoni. (2006) Minimal tolerance to the bronchoprotective effect of inhaled salmeterol/fluticasone combination on allergene challenge. Pulmonary Pharmacology & Therapeutics 19:6, 425-429
CrossRef14
Juan Jose Tellería, Alfredo Blanco-Quirós, Sandra Muntión, Jose Antonio Garrote, Eduardo Arranz, Alicia Armentia, Ignacio Díez, Jesús Castro. (2006) Tachyphylaxis to β2-agonists in Spanish asthmatic patients could be modulated by β2-adrenoceptor gene polymorphisms. Respiratory Medicine 100:6, 1072-1078
CrossRef15
Kenneth J. Broadley. (2006) β-Adrenoceptor responses of the airways: For better or worse?. European Journal of Pharmacology 533:1-3, 15-27
CrossRef16
Luis Prieto, Valentina Gutiérrez, Carmen Pérez-Francés, Carlos Badiola, Amparo Lanuza, Laura Bruno, Anna Ferrer. (2005) Effect of fluticasone propionate–salmeterol therapy on seasonal changes in airway responsiveness and exhaled nitric oxide levels in patients with pollen-induced asthma. Annals of Allergy, Asthma & Immunology 95:5, 452-461
CrossRef17
G. W. Volcheck, P. Kelkar, K. R. Bartemes, G. J. Gleich, H. Kita. (2005) Effects of (R)- and (S)-isomers of beta-adrenergic agonists on eosinophil response to interleukin-5. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 35:10, 1341-1346
CrossRef18
Frank Kanniess, Rudolf A. Jörres, Helgo Magnussen. (2005) Effect of reproterol either alone or combined with disodium cromoglycate on airway responsiveness to methacholine. Pulmonary Pharmacology & Therapeutics 18:5, 315-320
CrossRef19
Heather S. Tomlinson, Sarah A. Corlett, Martin B. Allen, Henry Chrystyn. (2005) Assessment of different methods of inhalation from salbutamol metered dose inhalers by urinary drug excretion and methacholine challenge. British Journal of Clinical Pharmacology 0:0, 050913044129006
CrossRef20
Nicolas Roche, Hugues Morel, Philippe Martel, Philippe Godard. (2005) Clinical practice guidelines: Medical follow-up of patients with asthma—Adults and adolescents. Respiratory Medicine 99:7, 793-815
CrossRef21
(2005) Suivi de la tolérance des traitements. Revue des Maladies Respiratoires 22:2, 52-57
CrossRef22
Donald W Cockcroft. (2005) As-Needed Inhaled ??2-Adrenoceptor Agonists in??Moderate-to-Severe Asthma. Treatments in Respiratory Medicine 4:3, 169-174
CrossRef23
Anne-Marie Scola, Lee K Chong, Russell Chess-Williams, Peter T Peachell. (2004) Influence of agonist intrinsic activity on the desensitisation of β 2 -adrenoceptor-mediated responses in mast cells. British Journal of Pharmacology 143:1, 71-80
CrossRef24
F.L. Dente, E. Bacci, M.L. Bartoli, S. Cianchetti, A. Di Franco, D. Giannini, M. Taccola, B. Vagaggini, P.L. Paggiaro. (2004) One week treatment with salmeterol does not prevent early and late asthmatic responses and Sputum eosinophilia induced by allergen challenge in asthmatics. Pulmonary Pharmacology & Therapeutics 17:3, 147-153
CrossRef25
Alexandra Goldkorn, Patricia Diotto, Carl Burgess, Mark Weatherall, Shaun Holt, Richard Beasley, Robert Siebers. (2004) The pulmonary and extra-pulmonary effects of high-dose formoterol in COPD: A comparison with salbutamol. Respirology 9:1, 102-108
CrossRef26
Anne-Marie Scola, Lee K Chong, S Kim Suvarna, Russell Chess-Williams, Peter T Peachell. (2004) Desensitisation of mast cell β 2 -adrenoceptor-mediated responses by salmeterol and formoterol. British Journal of Pharmacology 141:1, 163-171
CrossRef27
Ian P Hall. (2004) The β-agonist controversy revisited. The Lancet 363:9404, 183-184
CrossRef28
Daniele Giannini, Antonella Di Franco, Elena Bacci, Federico Lorenzo Dente, Barbara Vagaggini, Mauro Taccola, Monica Tonelli, Margherita Zingoni, Pierluigi Paggiaro. (2003) Tolerance to the protective effect of salmeterol in mild untreated asthmatics. Pulmonary Pharmacology & Therapeutics 16:6, 355-360
CrossRef29
J.F Donohue, S Menjoge, S Kesten. (2003) Tolerance to bronchodilating effects of salmeterol in COPD. Respiratory Medicine 97:9, 1014-1020
CrossRef30
Dennis W. McGraw, Khalid F. Almoosa, Richard J. Paul, Brian K. Kobilka, Stephen B. Liggett. (2003) Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway β-agonist paradox. Journal of Clinical Investigation 112:4, 619-626
CrossRef31
D. K. C. Lee, R. D. Gray, B. J. Lipworth. (2003) Adenosine monophosphate bronchial provocation and the actions of asthma therapy. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 33:3, 287-294
CrossRef32
Lee K Chong, Kim Suvarna, Russell Chess-Williams, Peter T Peachell. (2003) Desensitization of β 2 -adrenoceptor-mediated responses by short-acting β 2 -adrenoceptor agonists in human lung mast cells. British Journal of Pharmacology 138:3, 512-520
CrossRef33
E. Haydn Walters, Julia AE Walters, Peter G Gibson, Paul Jones, E. Haydn Walters. 2003. Inhaled short acting beta2-agonist use in chronic asthma: regular versus as needed treatment. .
CrossRef34
EH Walters, JAE Walters, MDP Gibson, E. Haydn Walters. 2003. .
CrossRef35
Kerstin Naidu Sjosward, Martin Josefsson, Johan Ahlner, Birgitta Schmekel. (2003) Preserved bronchial dilatation after salbutamol does not guarantee protection against bronchial hyperresponsiveness. Clinical Physiology and Functional Imaging 23:1, 14-20
CrossRef36
Y. Tohda, M. Fujimura, H. Taniguchi, K. Takagi, T. Igarashi, H. Yasuhara, K. Takahashi, S. Nakajima. (2002) Leukotriene receptor antagonist, montelukast, can reduce the need for inhaled steroid while maintaining the clinical stability of asthmatic patients. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 32:8, 1180-1186
CrossRef37
A.S. YURDAKUL, H.C. ÇALIŞIR, B. TUNÇTAN, M. Ö Ǧ. (2002) Comparison of second controller medications in addition to inhaled corticosteroid in patients with moderate asthma. Respiratory Medicine 96:5, 322-329
CrossRef38
C.P. VAN SCHAYCK, S.G.M. CLOOSTERMAN, I.D. BIJL-HOFLAND, H. VAN DEN HOOGEN, H.Th.M. FOLGERING, C. VAN WEEL. (2002) Is the increase in bronchial responsiveness or FEV1 shortly after cessation ofβ2 -agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting β2-agonists. Respiratory Medicine 96:3, 155-162
CrossRef39
L. BJERMER. (2001) History and future perspectives of treating asthma as a systemic and small airways disease. Respiratory Medicine 95:9, 703-719
CrossRef40
O. Selroos. (2001) Formoterol used as needed—clinical effectiveness. Respiratory Medicine 95, S17-S20
CrossRef41
J. VILSVIK, J. ANKERST, M. PALMQVIST, G. PERSSON, J. SCHAANNING, G. SCHWABE, Å. JOHANSSON. (2001) Protection against cold air and exercise-induced bronchoconstriction while on regular treatment with Oxis®. Respiratory Medicine 95:6, 484-490
CrossRef42
Tuomas Jartti. (2001) Asthma, asthma medication and autonomic nervous system dysfunction. Clinical Physiology 21:2, 260-269
CrossRef43
M. Johnson. (2001) Beta2-adrenoceptors: mechanisms of action of beta2-agonists. Paediatric Respiratory Reviews 2:1, 57-62
CrossRef44
E S Silverman, S B Liggett, E W Gelfand, L J Rosenwasser, R M Baron, S Bolk, S T Weiss, J M Drazen. (2001) The pharmacogenetics of asthma: a candidate gene approach. The Pharmacogenomics Journal 1:1, 27-37
CrossRef45
Margaret J Leckie, Anneke ten Brinke, Jamey Khan, Zuzana Diamant, Brian J O'Connor, Christine M Walls, Ashwini K Mathur, Hugh C Cowley, K Fan Chung, Ratko Djukanovic, Trevor T Hansel, Stephen T Holgate, Peter J Sterk, Peter J Barnes. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsìveness, and the late asthmatic response. The Lancet 356:9248, 2144-2148
CrossRef46
Veronica A. Swystun, John R. Gordon, E.Beth Davis, Xiaobei Zhang, Donald W. Cockcroft. (2000) Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. Journal of Allergy and Clinical Immunology 106:1, 57-64
CrossRef47
Paul A. Finney, Maria G. Belvisi, Louise E. Donnelly, Tsu-Tshen Chuang, Judith C.W. Mak, Carol Scorer, Peter J. Barnes, Ian M. Adcock, Mark A. Giembycz. (2000) Albuterol-induced downregulation of Gsα accounts for pulmonary β2-adrenoceptor desensitization in vivo. Journal of Clinical Investigation 106:1, 125-135
CrossRef48
Todd Horiuchi, Mario Castro. (2000) THE PATHOBIOLOGIC IMPLICATIONS FOR TREATMENT. Clinics in Chest Medicine 21:2, 381-395
CrossRef49
L. BJERMER, H. BISGAARD, J. BOUSQUET, L.M. FABBRI, A. GREENING, T. HAAHTELA, S.T. HOLGATE, C. PICADO, J.A. LEFF. (2000) Montelukast or salmeterol combined with an inhaled steroid in adult asthma: design and rationale of a randomized, double-blind comparative study (the IMPACT Investigation of Montelukast as a Partner Agent for Complementary Therapy-trial). Respiratory Medicine 94:6, 612-621
CrossRef50
Peter Konig. (2000) Risks and benefits of asthma therapies. Allergology International 49:1, 1-6
CrossRef51
Hans Bisgaard. (2000) Long-acting ?2-agonists in management of childhood asthma: A critical review of the literature. Pediatric Pulmonology 29:3, 221-234
CrossRef52
James R. Loss, Raymond F. Orzechowski, Rick S. Hock. (2000) Measurement of albuterol in guinea pig serum by high performance liquid chromatography with fluorescence detection. Biomedical Chromatography 14:1, 1-5
CrossRef53
Steven G. Kelsen, Mark O. Aksoy, Kathleen Brennan, David Ciccolella, Bernard Borbely. (2000) Chronic Effects of Inhaled Albuterol on β-Adrenoceptor System Function in Human Respiratory Cells. Journal of Asthma 37:4, 361-370
CrossRef54
D. R. Taylor, R. J. Hancox, W. McRae, J. O. Cowan, E. M. Flannery, C. R. McLachlan, G. P. Herbison. (2000) The Influence of Polymorphism at Position 16 of the β 2 -Adrenoceptor on the Development of Tolerance to β-Agonist. Journal of Asthma 37:8, 691-700
CrossRef55
K. J. Broadley. (1999) Review of mechanisms involved in the apparent differential desensitization of β 1 - and β 2 -adrenoceptor-mediated functional responses. Journal of Autonomic Pharmacology 19:6, 335-345
CrossRef56
Horvath, Barnes. (1999) Exhaled monoxides in asymptomatic atopic subjects. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 29:9, 1276-1280
CrossRef57
S. T. Holgate. (1999) Experimental models in asthma. Clinical & Experimental Allergy 29:S3, 82-86
CrossRef58
Lee K. Chong, Peter T. Peachell. (1999) β-Adrenoceptor reserve in human lung: a comparison between airway smooth muscle and mast cells. European Journal of Pharmacology 378:1, 115-122
CrossRef59
Donald W. Cockcroft, Beth E. Davis, Veronica A. Swystun, Darcy D. Marciniuk. (1999) Tolerance to the bronchoprotective effect of β2 -agonists: Comparison of the enantiomers of salbutamol with racemic salbutamol and placebo. Journal of Allergy and Clinical Immunology 103:6, 1049-1053
CrossRef60
J.Mark FitzGerald, Kenneth R. Chapman, Giovanni Della Cioppa, David Stubbing, Mary Sue Fairbarn, M.Denise Till, Reto Brambilla. (1999) Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. Journal of Allergy and Clinical Immunology 103:3, 427-435
CrossRef61
S W Martin, Kenneth J Broadley. (1999) Relative resistance of functional β 2 -adrenoceptor-mediated smooth muscle responses to in vitro desensitization. Canadian Journal of Physiology and Pharmacology 77:3, 156-165
CrossRef62
Brian J O’Connor, Simon D Crowther, John F Costello, John Morley. (1999) Selective airway responsiveness in asthma. Trends in Pharmacological Sciences 20:1, 9-11
CrossRef63
Nelson, Jo Ann, Strauss, Louise, Skowronski, Mary, Ciufo, Russell, Novak, Ronald, McFadden, E.R. Jr., . (1998) Effect of Long-Term Salmeterol Treatment on Exercise-Induced Asthma. New England Journal of Medicine 339:3, 141-146
Full Text64
Gunver Fuglsang, Jennifer Vikre-Jørgensen, Lone Agertoft, Søren Pedersen. (1998) Effect of salmeterol treatment on nitric oxide level in exhaled air and dose–response to terbutaline in children with mild asthma. Pediatric Pulmonology 25:5, 314-321
CrossRef65
Ian P. Hall, Anne E. Tattersfield. 1998. ß-Adrenoceptor Agonists. , 651-676.
CrossRef66
D. A. Handley, J. R. McCullough, S. D. Crowther, J. Morley. (1998) Sympathomimetic enantiomers and asthma. Chirality 10:3, 262-272
CrossRef67
Robert A Nathan. (1998) Is the Tolerance to the Bronchoprotective Effect of Salmeterol Clinically Relevant?. Annals of Allergy, Asthma & Immunology 80:1, 1-3
CrossRef68
Dawn E Drotar, E Elizabeth Davis, Donald W Cockcroft. (1998) Tolerance to the Bronchoprotective Effect of Salmeterol 12 Hours After Starting Twice Daily Treatment. Annals of Allergy, Asthma & Immunology 80:1, 31-34
CrossRef69
Pauwels, Romain A., Löfdahl, Claes-Göran, Postma, Dirkje S., Tattersfield, Anne E., O'Byrne, Paul, Barnes, Peter J., Ullman, Anders, . (1997) Effect of Inhaled Formoterol and Budesonide on Exacerbations of Asthma. New England Journal of Medicine 337:20, 1405-1411
Full Text70
V. J. Tormey, J. Faul, C. Leonard, A. Lennon, C. M. Burke. (1997) A comparison of regular with intermittent bronchodilators in asthma patients on inhaled steroids. Irish Journal of Medical Science 166:4, 249-252
CrossRef71
S. D. CROWTHER, I. D. CHAPMAN, J. MORLEY. (1997) Heterogeneity of airway hyperresponsiveness. Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy 27:6, 606-616
CrossRef72
Lee K. Chong, Duncan E. J. Drury, Jack F. Dummer, Parviz Ghahramani, Robert P. Schleimer, Peter T. Peachell. (1997) Protection by dexamethasone of the functional desensitization to β 2 -adrenoceptor-mediated responses in human lung mast cells. British Journal of Pharmacology 121:4, 717-722
CrossRef73
Stephan F. Lanes, Brenda Birmann, Drusilla Raiford, Alexander M. Walker. (1997) International trends in sales of inhaled fenoterol, all inhaled β-agonists, and asthma mortality, 1970–1992. Journal of Clinical Epidemiology 50:3, 321-328
CrossRef74
(1997) COMPONENT 3: PHARMACOLOGIC THERAPY. Pediatric Asthma, Allergy & Immunology 11:3, 57-79
CrossRef75
Eric K. Baker, Sandra K. Willsie, Jacqueline S. Marinac, Gary A. Salzman. (1997) Continuously Nebulized Albuterol in Severe Exacerbations of Asthma in Adults: A Case-Controlled Study. Journal of Asthma 34:6, 521-530
CrossRef76
Ruth Hildebrandt, Hans-Karl Weitzel, Ursula Gundert-Remy. (1997) Hypokalaemia in pregnant women treated with the β 2 -mimetic drug fenoterol — a concentration and time dependent effect. Journal of Perinatal Medicine 25:2, 173-179
CrossRef77
NAZAN TOMAÇ, AYFER TUNCER, YILDIZ SARAÇLAR, GÖNÜL ADALIOǦLU. (1996) Efficacy of salmeterol in the treatment of childhood asthma. Pediatrics International 38:5, 489-494
CrossRef78
Mark A. Giembycz. (1996) Phosphodiesterase 4 and tolerance to β2-adrenoceptor agonists in asthma. Trends in Pharmacological Sciences 17:9, 331-336
CrossRef79
JM Planquois, Y. Ruffin-Morin, V. Lagente, AN Payne, SG Dahl. (1996) Salbutamol potentiates the relaxant effects of selective phosphodiesterase inhibitors on guinea pig isolated trachea. Fundamental & Clinical Pharmacology 10:4, 356-367
CrossRef80
D. Robin Taylor, Malcolm R. Sears, Donald W. Cockcroft. (1996) THE BETA-AGONIST CONTROVERSY. Medical Clinics of North America 80:4, 719-748
CrossRef81
B. Lebel, B. Arnoux, P. Chanez, Y.-H. Bougeard, J. P. Daures, J. Bousquet, A. M. Campbell. (1996) Ex vivo pharmacologic modulation of basophil histamine release in asthmatic patients. Allergy 51:6, 394-400
CrossRef82
Gunnar Aberg, John Costello. (1996) Concerns regarding the current use of β-agonists in the therapy of asthma. Clinical Reviews in Allergy & Immunology 14:1, 3-6
CrossRef83
Max Perrin-Fayolle, Paul S. Blum, John Morley, Martine Grosclaude, Marie-Thérèse Chambe. (1996) Differential responses of asthmatic airways to enantiomers of albuterol. Clinical Reviews in Allergy & Immunology 14:1, 139-147
CrossRef84
John Morley. (1996) Anomalous effects of albuterol and other sympathomimetics in the guinea pig. Clinical Reviews in Allergy & Immunology 14:1, 65-89
CrossRef85
PETER J. BARNES. (1996) Asthma Therapy with Aerosols: Clinical Relevance for the Next Decade. Journal of Aerosol Medicine 9:1, 131-141
CrossRef86
Rajesh Bhagat, Veronica A. Swystun, Donald W. Cockcroft. (1996) Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: Dose response. Journal of Allergy and Clinical Immunology 97:1, 47-52
CrossRef87
Nils Svedmyr, Claes-Göran Löfdahl. (1996) The Use of β 2 -Adrenoceptor Agonists in the Treatment of Bronchial Asthma. Pharmacology & Toxicology 78:1, 3-11
CrossRef88
D.W. Cockcroft, R. Bhagat, S. Kalra, V.A. Swystun. (1995) Inhaled β2-agonists and allergen-induced airway responses. Journal of Allergy and Clinical Immunology 96:6, 1013-1014
CrossRef89
Karl-Heinz Buchheit, Alfred Hofmann, John R. Fozard. (1995) Salbutamol-induced airway hyperreactivity in guinea pigs is not due to a loss of its bronchodilator effect. European Journal of Pharmacology 287:1, 85-88
CrossRef90
Anders Ullman. (1995) β-Adrenoceptor Agonists in Future Asthma Theraphy. Pharmacology & Toxicology 77, 36-39
CrossRef91
Wood, Alastair J.J., , Nelson, Harold S., . (1995) β-Adrenergic Bronchodilators. New England Journal of Medicine 333:8, 499-507
Full Text92
JOHN WILSON, CHRISTINE JENKINS, COLIN ROBERTSON. (1995) Beta-2 agonists in asthma*. Australian and New Zealand Journal of Medicine 25:4, 358-361
CrossRef93
Mauro M. Teixeira, Timothy J. Williams, Paul G. Hellewell. (1995) Anti-inflammatory effects of a short-acting and a long-acting β2-adrenoceptor agonist in guinea pig skin. European Journal of Pharmacology 272:2-3, 185-193
CrossRef94
Kr Chapman, S. Kesten, J.P. Szalai. (1994) Regular vs as-needed inhaled salbutamol in asthma control. The Lancet 343:8910, 1379-1382
CrossRef95
L. Ramage, B.J. Lipworth, C.G. Ingram, I.A. Cree, D.P. Dhillon. (1994) Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol. Respiratory Medicine 88:5, 363-368
CrossRef96
M Aubier. (1994) Stratégies bronchodilatatrices actuelles du traitement de l'asthme. La Revue de Médecine Interne 15, 240s-244s
CrossRef97
D. Cockcroft, Va Swystun, R. Bhagat. (1994) β-agonists and asthma. The Lancet 343:8889, 122
CrossRef98
Jan Lötvall, Nils Svedmyr. (1993) Salmeterol: An inhaled /β2-agonist with prolonged duration of action. Lung 171:5, 249-264
CrossRef99
Weinberger, Steven E.. (1993) Recent Advances in Pulmonary Medicine. New England Journal of Medicine 328:19, 1389-1397
Full Text100
(1993) Sympathomimetic Agents and Airway Hyperreactivity. New England Journal of Medicine 328:9, 665-666
Full Text101
A.A.P.H. Verberne, K.F. Kerrebijn. (1993) Effects of β2-receptor agonists on airway responsiveness. Life Sciences 52:26, 2181-2191
CrossRef102
P.J. Barnes. (1993) β-adrenoceptors on smooth muscle, nerves and inflammatory cells. Life Sciences 52:26, 2101-2109
CrossRef103
McFadden, E.R. Jr., Gilbert, Ileen A., . (1992) Asthma. New England Journal of Medicine 327:27, 1928-1937
Full Text104
&NA;. (1992) Terbutaline. Reactions Weekly &NA;:425, 12
CrossRef
