Systemic Corticosteriod Rapidly Reverses  Bronchodilator Subsensitivity Induced by Formoterol in Asthmatic Patients

Tan, Kia Soong; Grove, A; Mclean, A.; Gnosspelius, Yvonne; Hall, Ian P.; Lipworth, Brian J.

doi:10.1164/ajrccm.156.1.9610113

Cited by 141 publications

(67 citation statements)

References 24 publications

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“…Of importance is the observation that concomitant inhaled corticosteroid treatment did not prevent the development of tolerance. This was despite the fact that single doses of systemic corticosteroid have been shown to reverse breceptor down-regulation [17], but is in keeping with earlier findings that inhaled corticosteroids do not prevent tolerance to the bronchoprotective effects of b-agonists [18±20].…”

Section: Discussionsupporting

confidence: 85%

Respiratory impedance response to a deep inhalation in asthmatic children with spontaneous airway obstruction

Schweitzer¹,

Moreau-Colson²,

Marchal³

1999

European Respiratory Journal

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Previous reports suggest that regular use of b-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction.Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 mg, b.i.d.), both drugs or placebo in a randomized, doubleblind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 mg at 5 min intervals) was then measured. Doseresponse curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates.There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide.Significant tolerance to the bronchodilator effect of inhaled b-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled b-agonists may lead to a reduced response to emergency b-agonist treatment during asthma exacerbations. Eur Respir J 1999; 14: 283±287. b-agonists are highly effective bronchodilators and have an important role in the treatment of asthma exacerbations. However, many of the pharmacological effects of b-agonists diminish during chronic treatment, and there has been some concern that regular use of these drugs could lead to a failure to respond to treatment during severe asthma attacks. Some recent studies have shown a small reduction in bronchodilator response during treatment with long-acting b-agonists [1±3], but in general asthmatics have been found to be surprisingly resistant to the development of bronchodilator tolerance [4,5]. The reason for this is unknown. It may be because there is a high turnover of b 2 -receptors on airway smooth muscle such that receptor down-regulation has little impact on the receptor density [6]. Alternatively, it may be because maximal bronchodilation can be achieved by stimulation of a fraction of the normal receptor number.In contrast, there is increasing evidence that continuous b-agonist treatment leads to a reduction in their bronchoprotective effect for a variety of bronchoconstricting stimuli including methacholine, histamine, adenosine, exercise and allergen [7]. However, the clinical significance of these changes is uncertain in view of the apparently preserved acute bronchodilator response.This dissociation between the tendency to develop tolerance to the bronchodilator and bronchoprotective effects...

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Section: Discussionsupporting

confidence: 85%

Respiratory impedance response to a deep inhalation in asthmatic children with spontaneous airway obstruction

Schweitzer¹,

Moreau-Colson²,

Marchal³

1999

European Respiratory Journal

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“…Of the 604 current physician-diagnosed asthmatics, 37% (n5221) were homozygous for the major ADRB2 allele (Gly/ Gly), 46% (n5277) were heterozygous (Gly/Arg) and 18% (n5106) were homozygous for the minor allele (Arg/Arg). Overall, 46.5% (n5281) of asthmatics used ICSs during the previous 12 months, 27.5% (n5166) used ICSs every year during the period between the two surveys, 60.6% (n5358) used SABAs and 16.7% (n5100) used LABAs during the previous 12 months. The proportion of subjects with BHR was higher among those carrying the Arg/Arg genotype (64.1%) than among those carrying the Gly/Arg (55.6%) and Gly/Gly (45.7%) genotypes (p50.04).…”

Section: Resultsmentioning

confidence: 99%

“…Steroids have shown in experimental in vitro and in vivo studies to reverse functional desensitisation of b 2 -AR [4,23,24], increase receptor expression and density, and enhance expression of G s a, producing a dose-dependent increase in cyclic adenosine monophosphate levels [25,26]. However, in humans, loss of bronchoprotection from regularly administered b 2 -agonists seems to reverse only with acute high doses of ICS [27,28] and it is not clear that this happens with chronic use of ICS at low or medium doses [29][30][31]. Recent findings suggest that the mechanism by which ICS plus LABA therapy exerts its synergistic beneficial effects is through an increased antiinflammatory activity and an attenuation of airway remodelling [32].…”

Section: Discussionmentioning

confidence: 99%

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

Eur Respir J

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Arg/Arg homozygotes for the Gly16Arg polymorphism in the b 2 -adrenoreceptor gene (ADRB2) have a reduced response to short-acting b 2 -agonists but no effect has been associated with long-acting b 2 -agonists (LABAs).We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects.There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p50.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p50.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean¡SE decrease in decline in forced expiratory volume in 1 s of 7.7¡2.5 mL?yr -1 was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p50.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed b 2 -adrenoreceptor desensitisation.

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“…In human studies, systemic or inhaled steroids rapidly reverse desensitization of the β2-adrenergic signalling pathway [27,28]. For these reasons, it is not surprising to observe that the benefit of flexible dosing required concurrent increase of both BUD and FORM.…”

Section: Discussionmentioning

confidence: 99%

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model

Brange

Smailagic

Jansson

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Rationale: Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time.Here, we have conducted animal studies to address this issue. Objectives: 1)To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. 2) To determine whether the benefit requires adjustment of both drug components. Methods: Rats sensitized on day 0 and 7 were challenged intratracheally with ovalbumin on day 14 and 21. On days 13 through 21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis. Results: A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost. Conclusions: Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.

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Systemic Corticosteriod Rapidly Reverses Bronchodilator Subsensitivity Induced by Formoterol in Asthmatic Patients

Cited by 141 publications

References 24 publications

Respiratory impedance response to a deep inhalation in asthmatic children with spontaneous airway obstruction

Respiratory impedance response to a deep inhalation in asthmatic children with spontaneous airway obstruction

ADRB2Gly16Arg polymorphism, asthma control and lung function decline

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model

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