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Impact of the Arg 16 allele of the B2AR gene on the effect of withdrawal of LABA in patients with moderate to severe asthma.
Slankard, M, Michelis, MA, Mansukhani, M, McGoey, B, Paige, A, Andrews, H, Lederer, D, Canfield, S, DiMango, E
The Journal of asthma : official journal of the Association for the Care of Asthma. 2016;(8):783-9
Abstract
INTRODUCTION Long-acting beta agonists (LABAs) are effective for controlling asthma, however questions about their safety have led to concerns over use. Genetic polymorphisms at the 16 amino acid position of the beta-2 adrenergic receptor gene (B2AR) may be associated with increased risk. METHODS A randomized, double blind study was conducted in patients with moderate to severe asthma being treated with combined inhaled corticosteroids/LABA (ICS/LABA), comparing the effect of LABA continuation versus withdrawal on asthma outcomes among patients stratified by B2AR genotype (Arg/Arg vs. Gly/Gly at the 16th amino acid position). RESULTS 67 participants (31 Arg/Arg, 36 Gly/Gly) were randomized to receive fluticasone alone (F) or continue combined fluticasone/salmeterol (F/S) after a run-in period on F/S. Among Gly/Gly subjects, those in the F/S treatment group showed improvement in AM PEFR (+ 8.4 L/s) whereas those receiving F alone experienced a reduction in AM PEFR over the study period (-14.4 L/s), (p = 0.06). There was no significant difference in morning peak expiratory flow rate (AM PEFR) in Arg/Arg participants randomized to receive F/S (-15.7L) vs F alone (-5.6 L/s) (p = 0.61). There was no significant difference in exacerbations in the Arg/Arg subjects treated with F/S compared with those treated with F (p = 0.65). CONCLUSIONS Withdrawal of LABA therapy in asthmatics with the Arg/Arg genotype at the 16th amino acid position of B2AR did not lead to significant improvement in AM PEFR. LABA withdrawal in the Gly/Gly genotype however led to a borderline significant decline in AM PEFR.
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Functional study on Boswellia phytosome as complementary intervention in asthmatic patients.
Ferrara, T, De Vincentiis, G, Di Pierro, F
European review for medical and pharmacological sciences. 2015;(19):3757-62
Abstract
OBJECTIVE The combination of inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs) is recommended for the treatment of patients with mild-to-severe persistent asthma. However, given the lack of definite and safe therapies, complementary or alternative medicines are frequently used by asthmatic patients in combination with standard treatments. PATIENTS AND METHODS A group of asthmatic subjects have been enrolled in this multicenter study; after having verified the compliance to their current medical therapy (ICS + LABAs), the subjects have been randomized to receive Casperome® 500 mg/day or no additional treatment for a period of 4 weeks. They were also asked to keep track of the number of inhalations required per day and any adverse events through a daily form. RESULTS A total of 32 subjects were enrolled in the study. Subjects receiving Casperome® 500 mg/day in addition to the standard ICS + LABAs treatment showed a decrease in the number of inhalations needed compared to patients who did not receive Casperome® therapy. The treatment was well tolerated and only mild-moderate adverse events were registered. CONCLUSIONS The use of Casperome® 500 mg/day is beneficial for asthmatic patients as it helps reduce the need for inhalation therapy with ICS + LABA.
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Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma.
Rabinovitch, N, Mauger, DT, Reisdorph, N, Covar, R, Malka, J, Lemanske, RF, Morgan, WJ, Guilbert, TW, Zeiger, RS, Bacharier, LB, et al
The Journal of allergy and clinical immunology. 2014;(2):350-6
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Abstract
BACKGROUND Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness. OBJECTIVE We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy. METHODS A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting β₂-agonist (LABA step-up therapy). RESULTS In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV₁ response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E₄ levels were marginally (P = .053) related to a differential FEV₁ response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV₁ and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses. CONCLUSION Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E₄ levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.
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A randomized, open labeled, comparative study to assess the efficacy and safety of controller medications as add on to inhaled corticosteroid and long-acting β2 agonist in the treatment of moderate-to-severe persistent asthma.
Patel, YA, Patel, P, Bavadia, H, Dave, J, Tripathi, CB
Journal of postgraduate medicine. 2010;(4):270-4
Abstract
BACKGROUND The goal of asthma therapy is to achieve clinical control and near normal lung functions. Many patients with persistent asthma fail to achieve this goal with a single controller medication add on to a inhaled corticosteroid. We have checked whether another controller medication add on to inhaled corticosteroid and long-acting β2 agonist helps in achieving the asthma goal or not. OBJECTIVES To identify the effect of controller medication add on to inhaled corticosteroid and the long-acting β2 agonist on the clinical symptom, lung function, and compliance in patients with asthma. MATERIALS AND METHODS We conducted a randomized, open-labeled, comparative trial in 50 participants with moderate-to-severe persistent asthma. The study duration was of 10 weeks. During the first two weeks of the run-in period all the participants received a dry powder inhaler drug delivery of budesonide (400 mcg/day) and formoterol (12 mcg/day) combination. At the end of the run-in period the participants were randomly allocated into three groups: group A (n = 16) received oral montelukast (10 mg/day); group B (n = 17) received oral doxophylline (400 mg/day), and group C (n = 17) received inhaled budesonide (400 mcg) as add on to the above-mentioned drugs of the run-in period. The primary outcome was improvement in forced expiratory volume at 1 second (FEV1 ). RESULTS All the participants of the three groups had significant improvement in FEV1 (P < 0.001) and asthma symptoms at the end of 10 weeks. The mean increase in FEV1 (% of predicted) from the baseline, in groups A, B, and C was: 24.6; 21.33, and 19.86%, respectively. CONCLUSIONS All add on controller medications helped, with a significant improvement of lung functions and asthma symptoms.
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Montelukast as add-on therapy with inhaled corticosteroids alone or inhaled corticosteroids and long-acting beta-2-agonists in the management of patients diagnosed with asthma and concurrent allergic rhinitis (the RADAR trial).
Keith, PK, Koch, C, Djandji, M, Bouchard, J, Psaradellis, E, Sampalis, JS, Schellenberg, RR, McIvor, RA
Canadian respiratory journal. 2009;(Suppl A):17A-31A
Abstract
OBJECTIVE To evaluate the effectiveness of montelukast as add-on therapy for patients diagnosed with asthma and concurrent allergic rhinitis who remain uncontrolled while receiving inhaled corticosteroid (ICS) monotherapy or ICS/long-acting beta-2-agonist (LABA) therapy in a community practice setting. DESIGN An eight-week, multicentre, open-label, observational study. Patients were 15 years of age or older and, while treated with an ICS or ICS/LABA, had allergic rhinitis and uncontrolled asthma symptoms by at least two criteria as per the Canadian Asthma Consensus Guidelines. The primary outcome measure was the percentage of patients with controlled asthma symptoms after eight weeks of treatment with montelukast 10 mg once daily added to ICS or ICS/LABA therapy. RESULTS In total, 1004 patients participated in the survey phase of the study. Of these patients, 319 continued in the treatment phase and 301 (94.4%) completed the eight-week assessment. At baseline, all patients had uncontrolled asthma symptoms based on the Canadian Asthma Consensus Guidelines; at the eight-week assessment, 229 patients (76.1%) achieved asthma control. According to the Asthma Control Questionnaire (as determined by scores of 0.75 or less), 164 patients (54.7%) achieved well-controlled asthma at week 8. The mean (+/- SD) Asthma Control Questionnaire score decreased from 2.03+/-0.80 to 0.92+/-0.80 (P<0.001) for all patients, representing a clinically significant improvement. A statistically and clinically significant reduction in the overall Mini Rhinitis Quality of Life Questionnaire score was achieved with a decrease from 2.57+/-1.20 to 1.12+/-1.00 (-1.45+/-1.35; P<0.001). Patient and physician satisfaction rates with montelukast add-on therapy were also significantly increased when compared with baseline treatment. CONCLUSION Montelukast add-on therapy is effective for managing asthma and allergic rhinitis symptoms in patients who were previously uncontrolled with ICS or ICS/LABA treatment.
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Effect of beta2-adrenergic receptor polymorphism on response to longacting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial.
Wechsler, ME, Kunselman, SJ, Chinchilli, VM, Bleecker, E, Boushey, HA, Calhoun, WJ, Ameredes, BT, Castro, M, Craig, TJ, Denlinger, L, et al
Lancet (London, England). 2009;(9703):1754-64
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Abstract
BACKGROUND Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid. METHODS In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967. FINDINGS After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures. INTERPRETATION In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine. FUNDING National Institutes of Health.
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Pretreatment with albuterol versus montelukast for exercise-induced bronchospasm in children.
Raissy, HH, Harkins, M, Kelly, F, Kelly, HW
Pharmacotherapy. 2008;(3):287-94
Abstract
STUDY OBJECTIVES To compare pretreatment with albuterol versus montelukast added to the current asthma regimen for protection against exercise-induced bronchospasm in children with mild-to-moderate asthma, and to determine whether cysteinyl leukotriene (Cys-LT) concentrations measured in the exhaled breath condensate correlated with response to montelukast. DESIGN Prospective, randomized, double-blind, double-dummy, crossover study. SETTING Asthma clinic at a university-affiliated medical center. PATIENTS Eleven children aged 7-17 years with physician-diagnosed mild-to-moderate asthma for at least 6 months and with self-reported exercise-induced bronchospasm (defined as > or = 15% decrease in forced expiratory volume in 1 sec [FEV(1)] at screening and baseline visit). INTERVENTION Patients were randomly assigned to receive 3-7 days of oral montelukast 5-10 mg/day or 2 puffs of an albuterol metered-dose inhaler just before an exercise challenge and then were crossed over to the alternate therapy for the last visit. MEASUREMENTS AND MAIN RESULTS Serial spirometry was performed before and at 0, 5, 10, 15, 30, 45, and 60 minutes after the exercise challenge at each visit. Measurement of exhaled breath condensate was performed at the screening visit and study visits 1 and 2. The primary outcome was the maximum change in FEV(1) after exercise. Secondary outcomes were the area under the curve for FEV(1) (expressed as percentage decrease from baseline) during the first 60 minutes (AUC(0-60)) after exercise and the proportion of patients in whom exercise-induced bronchospasm was prevented (defined as < 15% decrease in FEV(1) after exercise challenge). The mean +/- SD maximum decrease in FEV(1) was 27.5 +/- 7.9% at baseline. Patients receiving montelukast had an 18.3 +/- 13.7% decrease in FEV(1) compared with 0.7 +/- 1.6% in patients receiving albuterol (p=0.002, paired t test). Exercise-induced bronchospasm was prevented in 100% of the patients receiving albuterol compared with 55% receiving montelukast (p<0.05, McNemar's test). The AUC(0-60) was significantly smaller with albuterol compared with montelukast (p<0.001, Wilcoxon signed rank test). No correlations were found between Cys-LT concentration and the severity of exercise-induced bronchospasm or the response to montelukast. CONCLUSION Pretreatment with albuterol is more effective than montelukast for prevention of exercise-induced bronchospasm in children with asthma.
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Erdosteine enhances airway response to salbutamol in patients with mild-to-moderate COPD.
Dal Negro, R, Visconti, M, Trevisan, F, Bertacco, S, Micheletto, C, Tognella, S
Therapeutic advances in respiratory disease. 2008;(5):271-7
Abstract
BACKGROUND Oxidative stress is presumed to impair beta-adenoceptor function and airway patency. Erdosteine (E), a mucomodulatory compound, has shown important antioxidant properties. METHODS The objective was to assess the effect of antioxidant interventions on short-term airway response to salbutamol in non-reversible mild-to-moderate COPD patients. Thirty COPD patients (GOLD class 1-2), current smoker (>or=10 pack/year), randomly received E 300 mg, N-acetylcysteine (NAC) 600 mg, or placebo, twice daily for ten days. Reversibility to salbutamol 200 microg was tested in baseline, after four and ten days of each treatment. ROS and 8-isoprostane blood levels were measured on the same days. Between-treatment comparison was performed by ANOVA and t-test or Wilcoxon test, and p<0.05 assumed. E enhanced FEV1 reversibility after four and ten days significantly (+5.1% and +5.0%; both p<0.01 vs. placebo), while NAC only showed a transient effect at day 4 (+3.0%, p<0.05), but not at day 10 (+1.3%, p = ns). RESULTS E and NAC caused significant drops in ROS blood levels after four and ten days (p<0.001 and p<0.0001 vs. placebo). In contrast to NAC, E lowered 8-isoprostane levels substantially for ten days (p = 0.017 and p = 0.0004 vs. placebo, respectively). Only E restored significantly short-term reversibility in COPD patients previously unresponsive to beta(2)-adrenergics. CONCLUSIONS This effect seems more related to the peculiar protection against lipid peroxidation rather than to the scavenging activity, which proves equal to that of NAC. E provides a sort of indirect bronchodilation through 're-sensitisation' of beta( 2)-adrenoceptors. Once confirmed in further controlled studies, it may be useful in long-term treatment of COPD.
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Comparison of bronchodilator responses of levosalbutamol and salbutamol given via a pressurized metered dose inhaler: a randomized, double blind, single-dose, crossover study.
Jantikar, A, Brashier, B, Maganji, M, Raghupathy, A, Mahadik, P, Gokhale, P, Gogtay, J, Salvi, S
Respiratory medicine. 2007;(4):845-9
Abstract
BACKGROUND Salbutamol, the most widely used short-acting beta(2)-agonist, consists of a racemic mixture of equal amounts of two enantiomers, (R)-salbutamol and (S)-salbutamol. The bronchodilator effects of salbutamol are attributed entirely to (R)-salbutamol (levosalbutamol), while (S)-salbutamol has been shown to possess bronchospastic and pro-inflammatory effects both in vitro and in vivo studies. Levosalbutamol, the (R)-enantiomer of salbutamol is currently available only in a liquid formulation for use via a nebulizer. Recently, levosalbutamol to be administered via a pressurized metered dose inhaler (pMDI) has been developed. AIMS To compare the time-dependent bronchodilator responses of single doses of 100mcg levosalbutamol and 200 mcg racemic salbutamol administered via a pMDI in subjects with stable mild-to-moderate bronchial asthma over a period of 6h. METHODS Single doses of 100 mcg levosalbutamol, 200 mcg salbutamol and placebo were administered with a pMDI in 30 stable asthmatic subjects in a randomized, double-blind, placebo-controlled, three-way cross over study. Forced expiratory volume in 1s (FEV(1)) and forced vital capacity (FVC) were measured at baseline, and over 6h post-study drug administration. RESULTS Levosalbutamol and salbutamol produced significantly better bronchodilator responses than placebo. Both the drugs showed equivalent time-dependent bronchodilator responses as measured by area under curve for percent change in FEV(1) and FVC over 6h. The time to onset of action, mean maximum bronchodilator response and duration of bronchodilator response were similar between levosalbutamol and salbutamol. CONCLUSION A single dose of 100 mcg levosalbutamol administered by a pMDI produced a similar bronchodilator response as salbutamol when measured over 6h in subjects with stable, mild-to-moderate bronchial asthma.
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Montelukast as add-on therapy to beta-agonists and late airway response.
Rosewich, M, Rose, MA, Eickmeier, O, Travaci, M, Kitz, R, Zielen, S
The European respiratory journal. 2007;(1):56-61
Abstract
The present study investigated whether single-dose oral leukotriene receptor antagonists as add-on therapy to short-acting beta-agonists, immediately after allergen challenge, block the late-phase airway response. In total, 35 mild asthmatics (mean age 24 yrs, 19 males) sensitised for house dust mites underwent two courses of bronchial allergen challenge. After the early allergic response (EAR), subjects received salbutamol once and were randomly assigned to either 10 mg of montelukast or placebo (double-blind crossover). To identify a late allergic response, forced expiratory volume in one second (FEV(1)) was monitored over the following 8 h. Baseline exhaled nitric oxide (NO) was determined ahead of each allergen challenge. Baseline NO levels differed significantly depending on the reaction to allergen challenge. In total, 12 subjects showed no significant response, 11 only showed an EAR, and 12 had a dual response and underwent further analysis. The area under the FEV(1) time-response curve 3-8 h after bronchial allergen challenge was -0.77+/-1.68 from the pre-challenge values on montelukast compared with -2.47+/-1.32 on placebo. The baseline exhaled NO fraction of subjects without an EAR was significantly lower than of those presenting a dual response. The results of the present study demonstrate that single-dose leukotriene receptor antagonists given orally right after the early allergic response can significantly inhibit the late allergic response after bronchial allergen challenge.