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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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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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Toxin-induced cardiovascular failure.
Jang, DH, Spyres, MB, Fox, L, Manini, AF
Emergency medicine clinics of North America. 2014;(1):79-102
Abstract
Adverse cardiovascular events comprise a large portion of the morbidity and mortality in drug overdose emergencies. Adverse cardiovascular events encountered by emergency physicians treating poisoned patients include myocardial injury, hemodynamic compromise with shock, tachydysrhythmias, and cardiac arrest. Early signs of toxin-induced cardiovascular failure include bradycardia, tachycardia, and specific ECG findings. Treatment of toxicologic tachycardia relies on rapid supportive care along with proper use of benzodiazepines for sedation. Treatment of toxicologic bradycardia consists of the use of isotonic fluids, atropine, calcium salts, and glucagon. High-dose insulin euglycemia should be used early in the course of suspected severe poisoning and intravenous lipid emulsion given to patients who suffer cardiac arrest.
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Inhaled magnesium sulfate in the treatment of acute asthma.
Powell, C, Dwan, K, Milan, SJ, Beasley, R, Hughes, R, Knopp-Sihota, JA, Rowe, BH
The Cochrane database of systematic reviews. 2012;:CD003898
Abstract
BACKGROUND Asthma exacerbations can be frequent and range in severity from relatively mild to status asthmaticus. The use of magnesium sulfate (MgSO(4)) is one of numerous treatment options available during acute exacerbations. While the efficacy of intravenous MgSO(4) has been demonstrated, little is known of the role of inhaled MgSO(4). OBJECTIVES To determine the efficacy of inhaled MgSO(4) administered in acute asthma on pulmonary functions and admission rates. SPECIFIC AIMS To quantify the effects of inhaled MgSO(4) i) in addition to inhaled β(2)-agonist, ii) in comparison to inhaled β(2)-agonist alone or iii) in addition to combination treatment with inhaled β(2) -agonist and ipratropium bromide. SEARCH METHODS Randomised controlled trials were identified from the Cochrane Airways Group register of trials in September 2012. These trials were supplemented with trials found in the reference list of published studies, studies found using extensive electronic search techniques, as well as a review of the grey literature and conference proceedings. SELECTION CRITERIA Randomised (or pseudo-randomised) controlled trials including adults or children with acute asthma were eligible for inclusion in the review. Studies were included if patients were treated with nebulised MgSO(4) alone or in combination with β(2)-agonist and/or ipratropium bromide and were compared with β(2)-agonist alone or inactive control. DATA COLLECTION AND ANALYSIS Trial selection, data extraction and risk of bias were assessed independently by two review authors. Efforts were made to collect missing data from authors. Results are presented as standardised mean differences (SMD) for pulmonary function and risk ratios (RR) for hospital admission; both are displayed with their 95% confidence intervals (CI). MAIN RESULTS Sixteen trials (21 references) of unclear and high risk of bias were eligible and included 896 patients who were randomised (838 patients completed). Seven of the 16 included studies involved adults exclusively, three included adults and paediatric patients, four studies enrolled paediatric patients and in the remaining two studies the age of participants was not stated.The design, definitions, intervention and outcomes were different in all 16 studies; this heterogeneity made direct comparisons difficult (see additional tables 1-3).The overall risk of bias among the included studies was variable and this is reflected in the 'Summary of findings' table with most outcomes being judged as only moderate or less.Inhaled magnesium sulfate in addition to inhaled β(2)-agonistThere was no statistically significant improvement in pulmonary function when inhaled MgSO(4) and β(2)-agonist was compared with β(2)-agonist alone (SMD 0.23; 95% CI -0.27 to 0.74; three studies, n = 188); however, there was considerable between study heterogeneity. There was no clear advantage in terms of hospital admissions (RR 0.76 95% CI 0.49, 1.16; four studies, n = 249), and there were no serious adverse events reported.Inhaled magnesium sulfate versus inhaled β(2)-agonistThe results of pulmonary function in three studies that compared inhaled MgSO(4) versus β(2)-agonist were too heterogeneous to combine; however, two of the studies found poorer lung function on MgSO(4). There was no significant difference in terms of hospital admissions in a single small study when MgSO(4) was compared to β(2)-agonist (RR 0.53 95% CI 0.05, 5.31; one study, n = 33), and there were no serious adverse events reported.Inhaled magnesium sulfate in addition to inhaled β(2)-agonist and ipratropiumA further comparison has been included in the 2012 update of this review of MgSO(4) given in addition to inhaled ipratropium and β(2)-agonist therapy (as recommended by the GINA guidelines). However, there is not yet enough data for this outcome to come to any definite conclusions, but both small studies in adults with severe asthma exacerbation found improvements in pulmonary function with additional inhaled MgSO(4). AUTHORS' CONCLUSIONS There is currently no good evidence that inhaled MgSO(4) can be used as a substitute for inhaled β(2)-agonists. When used in addition to inhaled β(2)-agonists (with or without inhaled ipratropium), there is currently no overall clear evidence of improved pulmonary function or reduced hospital admissions. However, individual study results from three trials suggest possible improved pulmonary function in those with severe asthma exacerbations (FEV1 less than 50% predicted). Heterogeneity among trials included in this review precludes a more definitive conclusion. Further studies should focus on inhaled MgSO(4) in addition to the current guideline treatment for acute asthma (inhaled β(2) -agonist and ipratropium bromide). As the evidence suggests that the most effective role of nebulised MgSO(4) may be in those with severe acute features and this is where future research should be focused. A set of core outcomes needs to be agreed upon both in adult and paediatric studies to allow improved study comparison in future.
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Clinical trials and tribulations: the MASCOT study.
Lenney, W, Perry, S, Price, D
Thorax. 2011;(6):457-8
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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
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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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Exercise-induced bronchoconstriction and asthma.
Dryden, DM, Spooner, CH, Stickland, MK, Vandermeer, B, Tjosvold, L, Bialy, L, Wong, K, Rowe, BH
Evidence report/technology assessment. 2010;(189):1-154, v-vi
Abstract
OBJECTIVES The objectives are: (1) To assess diagnostic test characteristics of six alternative index tests compared with the selected reference standard-a standardized exercise challenge test (ECT) in patients with suspected exercise-induced bronchoconstriction or asthma (EIB/EIA); (2) to determine the efficacy of a single prophylactic dose of four pharmacologic and one nonpharmacologic interventions vs. placebo to attenuate EIB/EIA in patients with diagnosed EIB/EIA; and (3) to determine if regular daily treatment with short-acting or long-acting beta-agonists (SABA or LABA) causes patients with EIA to develop tachyphylaxis when additional prophylactic doses are used pre-exercise. DATA SOURCES A systematic and comprehensive literature search was conducted in 14 electronic databases (Diagnosis) and the Cochrane Airways Register (Therapy). REVIEW METHODS Study selection, quality assessment, and data extraction were conducted independently by two reviewers. The primary outcome was the maximum percent fall in the post-exercise forced expiratory volume in 1 second (percent fall FEV1). The diagnostic threshold for a positive ECT was a percent fall FEV1 of 10% or more. Sensitivity (SN) and specificity (SP) were calculated. For therapy, mean differences (MD) in the percent fall FEV1 and 95% confidence intervals (CI) (random effects model) were calculated. A positive MD indicates the intervention works better than the control. RESULTS For the diagnostic reviews, 5,318 citations yielded 28 relevant studies; for the therapy reviews, 1,634 citations yielded 109 relevant RCTs. Diagnostic test results versus ECT: self-reported history (2 studies) SN=36-8 percent; SP=85-86 percent; sport specific challenges (5 studies) SN=0-100 percent, SP=0-100 percent; eucapnic voluntary hyperpnea (7 studies) SN=25-90 percent, SP=0-71 percent; free running asthma screening test (3 studies) SN=60-67 percent, SP=47-67 percent; mannitol (3 studies) SN=58-96 percent, SP=65-78 percent. All SN and SP calculations indicated substantial heterogeneity that could not be explained by sensitivity or subgroup analyses. Therapy results: SABA offered greater protection than mast cell stabilizers (MCS) (12 studies); MD=6.8 (95 percent CI: 4.5, 9.2) but combining them offered no additional benefit; SABA versus MCS plus SABA (5 studies) MD=1.3 (95 percent CI: -6.3, 8.9). Leukotriene receptor antagonists (LTRA), MCS, ipratropium bromide, and interval warmup routines provided statistically significant attenuation of EIA when compared with placebo; inhaled corticosteroids (ICS) and other warmup routines did not. Single-dose intervention versus placebo results are: LTRA (9 studies) MD=8.9 (95 percent CI: 6.9, 11.0); MCS (nedocromil sodium) (17 studies) MD=15.6 (95 percent CI: 13.2, 18.2); interval warmup versus no warmup (4 studies) MD=10.6 (95 percent CI: 6.5, 14.7); ICS (4 studies) MD=5.0 (95 percent CI: 0.0, 9.9); continuous low intensity warmup versus no warmup (3 studies) MD=12.6 (95 percent CI: -1.5, 26.7); continuous high intensity warmup versus no warmup (2 studies) MD=9.8 (95 percent CI: -6.4, 26.0). After daily LABA (salmeterol) use for 3 to 4 weeks (4 studies), the percent fall FEV1 following an ECT at 2 and 4 weeks was greater than at day 1 in the LABA arm indicating that tachyphylaxis to prophylactic LABA use occurred. Daily SABA use for 1 week (1 study) also indicated development of tachyphylaxis. However, both LABA and SABA continued to have an attenuating effect on EIA. CONCLUSIONS Given the small number of studies comparing EIB/EIA diagnostic tests, the heterogeneity of the study populations, and the varied study methodologies, there is no clear evidence that any of the index tests are a suitable replacement for a standardized ECT to diagnose EIB/EIA in the general population. All bronchodilator agents and most anti-inflammatory agents when used as pretreatment are somewhat effective in attenuating the percent fall FEV1 associated with EIA.
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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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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.