Loss Of Bronchoprotection Research Articles

Evaluation of salivary alpha-amylase as a potential biomarker of inhaled β2-agonist response

In individuals with asthma, chronic use of short (SABAs) and long-acting beta-2 agonists (LABAs) can lead to loss of bronchoprotection (LOBP) from direct and indirect stimuli.1-3 It is hypothesized that LOBP is the result of beta-2 receptor down-regulation, reduced production or internalization of receptors, and uncoupling from secondary messengers leading to desensitization of beta-2 receptors.4 Assessment of beta-2 receptor activation is a laborious process.5 Therefore, a biomarker that serves as an indirect method of measuring beta-2 receptor activation would facilitate clinical studies on beta-2 agonist-induced LOBP and beta-2 receptor desensitization.

Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics

IntroductionLoss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. MethodsWe performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. ResultsThe average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). ConclusionLAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.

Regular use effect of inhaled ipratropium bromide and methacholine responsiveness in well-controlled asthma

RATIONALE: Short-acting β2-agonists provide significant bronchoprotection to inhaled methacholine in individuals with asthma. Regular use of β2-agonists results in the development of tolerance to the bronchoprotective effect. A relatively minimal amount is known regarding the development of tolerance following regular use of short-acting muscarinic antagonists. OBJECTIVES The current study was undertaken to assess bronchoprotection after regular use of inhaled ipratropium bromide (“ipratropium”) and after treatment withdrawal. METHODS Twelve adult participants with mild asthma were assigned to treatment in this double-blind randomized placebo-controlled crossover study. Ipratropium, 40 µg thrice daily, and matching placebo were administered for 1 week (22 doses). Methacholine challenges were performed at baseline, 30-min post first and last dose and 24-h after the final dose. A minimum 7-day washout period separated the treatments. MEASUREMENTS AND MAIN RESULTS: Significant bronchoprotection, measured as an increase in methacholine PD20 of 4.3 doubling doses (95% CI 3.62–5.06), occurred following the first dose of ipratropium. Bronchoprotection increased slightly to 4.5 doubling doses (95% CI 3.80–5.27) following regular use. Dose shifts following placebo were significantly lower at 0.23 (95% CI −0.30–0.75) and 0.11 (95%CI −0.63–0.85) after the first and last dose respectively (p < 0.001 vs. ipratropium for both). Changes from baseline methacholine PD20 24-h after treatment withdrawal were not significant between treatments (p = 0.19). CONCLUSIONS Our data provide evidence that regular use of inhaled ipratropium does not result in loss of bronchoprotection or lead to rebound hyperresponsiveness following treatment withdrawal. Muscarinic antagonists appear to have a superior safety profile over β2-agonist use in the treatment of asthma.

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate

Loss of bronchoprotection (LOBP) with a regularly used long-acting β2-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β2-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients. We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250μg of fluticasone twice daily for 2weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC20 value. The mean doubling dose reduction in SPMCh PC20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P=.62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P=.81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P=.86) and 0.8 for placebo (P=.15; P=.31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P=.43) and 1.02 for placebo (P=.84; P=.44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP. This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.

Loss of bronchoprotection to Salbutamol during sputum induction with hypertonic saline: implications for asthma therapy

BackgroundSputum induction with hypertonic saline in obstructive airway diseases is generally safe. However, saline induces bronchoconstriction in some patients despite pre-medication with Salbutamol. Our objectives were to investigate the predictors of failure of Salbutamol to protect against saline-induced-bronchoconstriction in patients with asthma and COPD and to evaluate implications for asthma therapy.MethodsRetrospective survey on a database of 3565 patients with obstructive airway diseases who had sputum induced with hypertonic saline. The effect of baseline FEV1, bronchitis and concomitant medication on saline-induced-bronchoconstriction (≥ 15% drop in FEV1) were examined by logistic regression analysis. A subgroup had this re-examined 8–12 weeks after decreasing long-acting-beta-2-agonist dose or after adding Montelukast, which included an assessment of mast cell activity in sputum.Results222 (6.2%) patients had saline-induced-bronchoconstriction despite pre-treatment with inhaled Salbutamol. Baseline airflow obstruction (FEV1% predicted < 60% OR 3.29, p < 0.001) and long-acting-beta-agonist use (OR 2.02, p = 0.001), but not bronchitis, were predictors of saline-induced-bronchoconstriction, which decreased when long-acting-beta-agonist dose was decreased. Refractoriness to subsequent bronchodilation was associated with mast cell activity and was attenuated by Montelukast.ConclusionSputum induction with saline provides information on bronchitis and additional physiological data on tolerance to beta-agonists and mast cell activity that may have implications for clinical therapy.

Long-Acting β2-Agonists in Asthma: Enantioselective Safety Studies are Needed.

Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without ICS. LABAs clearly demonstrate effective bronchodilatation and steroid-sparing activity, but long-term treatment can lead to tolerance of their bronchodilator effects. There are also concerns with regard to the effects of LABAs on bronchial hyperresponsiveness (BHR), where long-term use is associated with increased BHR and loss of bronchoprotection. A complicating factor is that formoterol and salmeterol are both chiral compounds, usually administered as 50:50 racemic (rac-) mixtures of two enantiomers. The chiral nature of these compounds has been largely forgotten in the debate regarding LABA safety and effects on BHR, particularly that (S)-enantiomers of β2-agonists may be deleterious to asthma control. LABAs display enantioselective pharmacokinetics and pharmacodynamics. Biological plausibility of the deleterious effects of β2-agonists (S)-enantiomers is provided by in vitro and in vivo studies from the short-acting β2-agonist (SABA) salbutamol. Supportive clinical findings include the fact that patients in emergency departments who demonstrate a blunted response to salbutamol are more likely to benefit from (R)-salbutamol than rac-salbutamol, and resistance to salbutamol appears to be a contributory mechanism in rapid asthma deaths. More effort should therefore be applied to investigating potential enantiospecific effects of LABAs on safety, specifically bronchoprotection. Safety studies directly assessing the effects of LABA (S)-enantiomers on BHR are long overdue.

Impaired Bronchoprotection Is Not Induced by Increased Smooth Muscle Mass in Chronic Treatment In Vivo with Formoterol in Asthmatic Mouse Model.

Inhaling β2-adrenoceptor agonist is first-line asthma treatment, which is used for both acute relief of and prevention of bronchoconstriction. However, chronic use of β-agonists results in impaired bronchoprotection and increasing occurrences of severe asthma exacerbation, even death in clinical practice. The mechanism of β-adrenoceptor hyposensitivity has not been thoroughly elucidated thus far. Bronchial smooth muscle contraction induces airway narrowing and also mediates airway inflammation. Moreover, bronchial smooth muscle mass significantly increases in asthmatics. We aim to establish an asthmatic model that demonstrated that formoterol induced impaired bronchoprotection and to see whether increased smooth muscle mass play a role in it. We combined routine allergen challenging (seven weeks) with repeated application of formoterol, formoterol plus budesonide or physiological saline in allergen-sensitized BALB/c mouse. The bronchoprotection mediated by β-agonist was measured in five consecutive weeks. Smooth muscle mass was shown by morphometric analysis, and α-actin expression was detected by western blot. The trend of bronchoprotection was wavy in drug interventional groups, which initially increased and then decreased. Chronic treatment with formoterol significantly impaired bronchoprotection. According to the morphometric analysis and α-actin expression, no significant difference was detected in smooth muscle mass in all groups. This experiment successfully established that a chronic asthmatic mouse model, which manifested typical features of asthmatic patients, when treated chronically with formoterol, resulted in a loss of bronchoprotection. No significant difference was detected in smooth muscle mass in all groups, which implied some subcellular signalling changes may be the key points.

Loss of Salmeterol Bronchoprotection against Exercise in Relation to ADRB2 Arg16Gly Polymorphism and Exhaled Nitric Oxide

β2-Agonists are the treatment of choice for exercise-induced bronchoconstriction (EIB) and act through specific receptors (ADRB2). Arg16Gly polymorphisms have been shown to affect responses to regular use of β2-agonists. To evaluate the influence of the Arg16Gly receptor polymorphism on salmeterol bronchoprotection in EIB and assess predictors of bronchoprotection. A prospective, genotype-blinded, randomized trial was performed in 26 subjects (12 Arg16Arg and 14 Gly16Gly) with EIB who were not on controller therapy. Subjects were administered salmeterol, 50 μg twice a day for 2 weeks, and underwent an exercise challenge 9 hours after the first and last drug dose. In addition to genotype, FEV1, response to salmeterol, degree of EIB, and exhaled nitric oxide (FE(NO)) at baseline were examined for their association with loss of bronchoprotection (LOB). The maximum exercise-induced FEV1 fall was 27.9 ± 1.4% during the run-in period, 8.1 ± 1.2% (70.3 ± 4.1% bronchoprotection) after the first salmeterol dose, and 22.8 ± 3.2% (18.9 ± 11.5% bronchoprotection) after 2 weeks of salmeterol (P = 0.0001). The Arg16Gly polymorphisms were not associated with the LOB in response to salmeterol. FeNO values at baseline were significantly related to the LOB (r = 0.47; P = 0.01). Mean change was a 74 ± 13% LOB in subjects with FE(NO) levels greater than 50 ppb and a 7 ± 16% gain in bronchoprotection in those with FE(NO) levels less than 25 ppb (P = 0.01). The LOB that occurs with chronic long-acting β2-agonists use is not affected by ADRB2 Arg16Gly polymorphisms. High FE(NO) was associated with marked LOB. Use of long-acting β2-agonists before achieving a reduction in FeNO may need to be avoided. Clinical trial registered with www.clinicaltrials.gov (NCT 00595361).

Effect of reproterol either alone or combined with disodium cromoglycate on airway responsiveness to methacholine

Regular use of inhaled β 2-agonists might lead to tolerance as reflected in a loss of bronchoprotection. In vitro-data suggest that this might be prevented by disodium cromoglycate (DSCG). Therefore, we studied the effect of the β 2-agonist reproterol in combination with DSCG. In a cross-over design, 19 subjects with airway hyperresponsiveness inhaled either placebo, 1 mg reproterol, 2 mg DSCG, or 1 mg reproterol plus 2 mg DSCG 4× daily over 2 weeks. Treatment periods were separated by ≥7 days. Before and at the end of periods, lung function and methacholine responsiveness were determined in the morning, and 6 h later the bronchodilator effect and the protection against methacholine-induced bronchoconstriction. Reproterol or DSCG or their combination did not exert detrimental effects on lung function, airway responsiveness, or bronchodilator capacity. However, bronchoprotection was significantly reduced ( p<0.05) after treatment with placebo, reproterol or reproterol plus DSCG, the respective changes being 0.59, 0.96 and 1.37 doubling concentrations. All changes were small as compared to intraindividual variability. In this model all treatments except with DSCG caused a significant but small loss of protection against methacholine-induced bronchoconstriction. Thus, tolerance was not prevented by 2 weeks of additional treatment with DSCG, in contrast to in vitro findings.

The role of lung inflation in airway hyperresponsiveness and in asthma

Airway hyperresponsiveness (AHR) is a fundamental phenomenon in asthma that can explain many aspects of the clinical manifestations of the disease. Several theories on the mechanisms of AHR have been proposed, but the true nature of this problem is yet to be defined. During the past decade, the role of lung inflation in airway physiology and its relationship to AHR have attracted major attention. Deep inspirations are known to exert strong beneficial effects on the airways of healthy humans. These effects appear to be of dual nature: bronchoprotective and bronchodilatory. The bronchoprotective effect of deep inspiration is lost in asthma, even in mild disease. It is also lost in individuals with rhinitis and AHR, but no asthma. Therefore, the loss of bronchoprotection is related to AHR. The bronchodilatory effect of deep inspiration is somewhat reduced in mild asthma and is only lost in severe disease, in the presence of significant airway obstruction. Current research is focused on the elucidation of the physiologic mechanisms behind lung inflation-induced bronchoprotection and bronchodilation and on the causes of their loss. This information could open new horizons in asthma therapy and prevention.

Absence of deep inspiration-induced bronchoprotection against inhaled allergen.

Deep inspiration-induced bronchoprotection appears to be a major mechanism through which airway obstruction by spasmogens is avoided. Loss of bronchoprotection is associated with airway hyper-responsiveness. Individuals with allergic rhinitis and no airway hyperresponsiveness develop obstruction after allergen inhalation. To test the hypothesis that deep inspiration-induced bronchoprotection is not active against allergic reactions, we performed four single-dose bronchial challenges, two with methacholine and two with allergen, on 10 subjects with allergic rhinitis. Without deep inspirations, the methacholine-induced reduction in FEV1 from baseline was 36.9 +/- 3.6% (mean +/- SEM); this was attenuated to 15.0 +/- 2.0 when five deep inspirations preceded methacholine inhalation (p = 0.0001). When allergen was inhaled, the reduction in FEV1 was 24.7 +/- 2.9% and 28.8 +/- 6.4% without and with deep inspirations, respectively. We conclude that bronchoprotection by deep inspirations is absent against allergic reactions. Understanding the cause of this phenomenon may shed light into the pathogenesis of airway hyperresponsiveness in allergic asthma.

Effect of Long-term Salmeterol Therapy Compared With As-Needed Albuterol Use on Airway Hyperresponsiveness

To determine the effect of long-term salmeterol aerosol therapy on airway hyperresponsiveness measured by methacholine challenge. Randomized, double-blind, placebo-controlled, multicenter study. Thirty-one clinical centers in the United States. Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70% of predicted values. Patients were not using inhaled corticosteroids. Twice-daily salmeterol aerosol, 42 microg, or placebo via metered-dose inhaler for 24 weeks. Backup albuterol was available. Pulmonary function tests were performed before, during, and after treatment. Subjects recorded asthma-related symptoms, morning and evening peak expiratory flow (PEF) levels, and use of supplemental albuterol daily on diary cards. Methacholine challenges were performed 10 to 14 h postdose at weeks 4, 12, and 24, and 3 and 7 days posttreatment. Over 24 weeks of treatment, salmeterol provided significant (p < 0.001) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection. A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy. Salmeterol treatment resulted in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo (p < 0.001). The use of salmeterol significantly reduced combined daytime asthma symptoms by 20% when compared to placebo (p = 0.005). A total of 34 and 48 exacerbations, respectively, were reported in the Salmeterol and placebo groups, and no evidence was present for a difference in the severity of asthma exacerbations between groups. Adverse event profiles were similar for the salmeterol and placebo groups. Regular long-term use of salmeterol aerosol resulted in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period. There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy. There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment. Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks.

Loss of Bronchoprotection With Salmeterol-To the Editor

Loss of Bronchoprotection With Salmeterol-To the Editor