Is there a problem with inhaled long-acting β-adrenergic agonists?

Nelson, Harold S.

doi:10.1016/j.jaci.2005.10.013

Cited by 67 publications

(33 citation statements)

References 107 publications

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“…The finding that the degree of protection against EIB is Indeed, several studies highlighted that the extent of protection on EIB diminishes with the regular use both for shortacting and long-acting b 2 -agonists [22]. Furthermore, in a placebo-controlled study of EIB in children, 12-week treatment with inhaled beclomethasone induced tolerance to the bronchoprotective effect [23].…”

Section: Discussionmentioning

confidence: 99%

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children

Benedictis

Giudice²,

Forenza³

et al. 2006

Eur Respir J

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The effect over time of regular treatment with montelukast (MNT) in inhibiting exercise-induced bronchoconstriction (EIB) has never been evaluated in children. The aim of the present study was to examine the preventive effect of MNT against EIB in children at different time-points over a 4-week treatment period.Thirty-two asthmatic children (aged 6-12 yrs) were enrolled in a double-blinded, randomised, parallel group design to receive a 4-week treatment with MNT (5 mg chewable tablets administered once daily in the evening) or placebo. Exercise challenge was performed at baseline and after 3, 7 and 28 days of treatment, 20-24 h after dosing.MNT was significantly more protective than placebo against EIB at each time. The mean percentage drop of forced expiratory volume in one second (FEV1) was 24.6, 13.6, 12.0 and 11.6 for MNT, and 24.4, 22.4, 21.8 and 21.0 for placebo, at baseline and after 3, 7 and 28 days, respectively. For each drug, no significant difference in the percentage drop of FEV1 was found between different days.Regular treatment with montelukast provided significant protection against exercise-induced bronchoconstriction in asthmatic children over a 4-week period with no tolerance to the bronchoprotective effect.KEYWORDS: Exercise-induced bronchoconstriction, montelukast, tolerance E xercise-induced bronchoconstriction (EIB) is a common manifestation of asthma in children and can interfere in their daily activities. The pathogenetic mechanism of EIB is not completely clear, but the release of inflammatory mediators from airway mast cells appears likely [1]. Although leukotrienes (LTs) have been inconstantly recovered from urine after exercise [2], the evidence for the role of these mediators in EIB derives from the bronchoprotective effect of anti-LT drugs [3].Montelukast (MNT), a specific antagonist of cysteinyl-leukotriene (Cys-LT) receptors, showed a consistent effect against EIB in children when administered either as a single dose [4,5] or as regular treatment [6]. In adults, a 12-week treatment with MNT attenuated the fall in pulmonary function following exercise with no tolerance to the bronchoprotective effect [7]. No study has evaluated the effect over time of regular treatment with MNT in inhibiting EIB in children. The present authors therefore examined the effect of once-daily MNT on EIB at several time-points during a 4-week treatment period. PATIENTS AND METHODS SubjectsA total of 32 children aged 6-12 yrs with mild-tomoderate asthma [8] were enrolled into the current study. Patients were recruited from the Depts of Paediatrics, at the University of Perugia and the University of Naples, Italy. The study protocol was approved by the institutional review boards of the two participating centres. Informed consent was obtained from patients and their parents.At screening, all patients had a forced expiratory volume in one second (FEV1) of at least 75% of predicted and a decrease in FEV1 of at least 12% from the baseline after a standardised exercise challenge. Patients were not e...

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Section: Discussionmentioning

confidence: 99%

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children

Benedictis

Giudice²,

Forenza³

et al. 2006

Eur Respir J

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“…There is also some evidence to suggest that during regular LABA therapy there might be a reduced response to SABA, although some of the studies in this area are difficult to interpret. 115,130 Effect of LABAs on life-threatening asthma attacks and asthma-related deaths Concerns have been raised in the literature regarding the association between treatment with a LABA and an increased risk of death due to asthma. This association, however, has remained uncertain, since it can be suggested that a high level of beta 2 agonist use is probably correlated with severity of asthma, and that those with more severe asthma are at greater risk of death.…”

Section: Tolerancementioning

confidence: 99%

Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in adults and children aged 12 years and over

Shepherd¹,

Rogers²,

Anderson³

et al. 2008

Health Technol Assess

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“…However, these studies include only ten or tens of patients per study and are thus significantly underpowered to detect a ~20% increase in eosinophil counts. The survival-prolonging action of β 2 -agonists on eosinophils may be also affected by the findings that, excessive use of β 2 -adrenoceptor agonists is associated with increased risk of death or near death from asthma [10]. Furthermore, regular treatment of chronic asthma with a long-acting β 2 -agonist salmeterol in patients most of whom were not on inhaled glucocorticoids, resulted in increased morbidity and mortality due to asthma [11].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

“…However, excessive use of β 2 -adrenoceptor agonists has been associated with increased risk of death or near death from asthma [10,11]. One possible mechanism contributing to this detrimental activity could be the prevention of eosinophil clearance by inhibition of apoptosis resulting in more severe inflammatory response and asthma symptoms.…”

Section: Introductionmentioning

confidence: 99%

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

Kankaanranta¹,

Parkkonen²,

Ilmarinen³

et al. 2011

Pulmonary Pharmacology & Therapeutics

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Eosinophils play a major role in asthma. One described mechanism leading to the impaired clearance of these cells from the lung is the delay in their programmed cell death (apoptosis). β 2 -adrenoceptor agonists have been shown to prolong survival and delay apoptosis of eosinophils. The aim of the present study was to evaluate the mechanisms, especially the role of cAMP pathway, in the prolongation of human eosinophil survival by a selective β 2 -agonist salbutamol.Isolated human peripheral blood eosinophils were cultured in the absence or presence of a β 2 -agonist salbutamol and the indicated antagonists/inhibitors under sterile conditions. Apoptosis was measured by using the relative DNA fragmentation assay and Annexin-V binding.Salbutamol prolonged survival of human eosinophils and it was inhibited by a β-receptor antagonist propranolol and mimicked by cell-permeant cAMP analogues dibutyryl-and 8-bromo-cAMP. Pharmacological inhibitors of adenylyl cyclase (SQ-22,536) and protein kinase A (Rp-8-CPT-cAMPS) antagonized the effects of salbutamol. The survival-prolonging action of salbutamol was potentiated by a phosphodiesterase inhibitor rolipram (EC 50 for the salbutamol effect was 13.6 ± 4.0 and 8.1 ± 3.1 nM in the absence and presence of rolipram, respectively; P=0.0142, n=10).In contrast, inhibition of Ca 2+ -activated K + -channels by apamin, charybdotoxin, iberiotoxin or paxilline did not affect the ability of salbutamol to prolong eosinophil survival.Taken together, the present results suggest that salbutamol at clinically relevant concentrations decreases apoptosis in human eosinophils by activating the cannonical β 2 -receptor-adenylyl cyclase-cAMP-protein kinase A pathway.

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Is there a problem with inhaled long-acting β-adrenergic agonists?

Cited by 67 publications

References 107 publications

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children

Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in adults and children aged 12 years and over

Salbutamol delays human eosinophil apoptosis via a cAMP-dependent mechanism

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