β 2-Adrenoceptor polymorphism and bronchoprotective sensitivity with regular short- and long-acting β2-agonist therapy

1999 ◽  
Vol 96 (3) ◽  
pp. 253-259 ◽  
Author(s):  
B. J. LIPWORTH ◽  
I. P. HALL ◽  
I. AZIZ ◽  
K. S. TAN ◽  
A. WHEATLEY
Keyword(s):  
Inhaled Corticosteroids ◽  
Forced Expiratory Volume ◽  
Double Blind ◽  
Geometric Means ◽  
Once Daily ◽  
Regular Treatment ◽  
Parallel Group ◽  
Long Acting ◽  
To Receive ◽  
Β2 Agonist

The aim of the present study was to investigate bronchoprotective sensitivity in patients receiving regular treatment with short- and long-acting β2-agonists and to evaluate any possible association with genetic polymorphism. Thirty-eight patients with stable mild to moderate asthma and receiving inhaled corticosteroids were randomized in a parallel group, double-blind, double-dummy fashion to receive 2 weeks of treatment with either formoterol (12μg once daily, 6μg twice daily or 24μg twice daily) or terbutaline (500μg four times daily). Bronchoprotection against methacholine challenge (as a provocative dose to produce a 20% fall in forced expiratory volume in 1.0 ;s: PD20) was measured at baseline (unprotected) after an initial 1 week run-in without β2-agonist, and at 1 ;h after the first and last doses of each treatment. The PD20 values were log-transformed and calculated as change from baseline. Percentage desensitization of log PD20 for first- versus last-dose bronchoprotection was calculated and analysed according to effects of treatment and β2-adrenoceptor polymorphism at codon 16 or 27. The mean degree of desensitization for bronchoprotection was comparable with all four treatments and there were no significant differences in absolute PD20 values after 2 weeks of chronic dosing. The PD20 values were (as μg of methacholine, geometric means±S.E.M.): formoterol, 12μg once daily, 99±42μg; formoterol, 6μg twice daily, 107±44μg; formoterol, 24μg twice daily, 108±45μg; terbutaline, 500μg four times daily, 88±37μg. All patients receiving formoterol, 24μg twice daily, exhibited a loss of protection greater than 30% which was unrelated to polymorphism at codon 16 or 27. For codon 16, the use of lower doses of formoterol (12μg once daily or 6μg twice daily) showed wider variability in the propensity for protection loss in patients who were heterozygous, in contrast to a more uniform protection loss seen with homozygous glycine patients. The amount of protection loss was not significantly related to polymorphism at codon 16 or 27, expressed as values (mean±S.E.M.) for percentage desensitization according to each genotype (pooled treatments): Gly-16, 66±11%; Het-16, 53±8%; Arg-16, 69±18%; Glu-27, 68±12%; Het-27, 58±8%; Gln-27, 52±12%. The results of this preliminary study showed that bronchoprotective desensitization occurred readily in response to short- or long-acting β2-agonist exposure irrespective of β2-adrenoceptor polymorphism at codon 16 or 27. Further studies with larger patient numbers are required to further evaluate the effects of polymorphisms with lower doses of regular formoterol.

A Parallel-Group Comparison of Astemizole and Loratadine for the Treatment of Perennial Allergic Rhinitis

1997 ◽  
Vol 25 (4) ◽  
pp. 175-181 ◽  
Author(s):  
H Al-Muhaimeed
Keyword(s):  
Allergic Rhinitis ◽  
Statistical Significance ◽  
Double Blind Study ◽  
Perennial Allergic Rhinitis ◽  
Double Blind ◽  
Once Daily ◽  
Runny Nose ◽  
Parallel Group ◽  
The Mean ◽  
To Receive

The efficacy and safety of the two antihistamines, astemizole and loratadine, were compared in a double-blind study of 84 patients with perennial allergic rhinitis. Patients were randomized to receive orally either astemizole 10 mg once daily ( n = 40) or loratadine 10 mg once daily ( n = 44) for 1 week. No other antirhinitis medication was allowed during the study. By day 7 the mean daily symptom scores, recorded on diary cards, were lower in patients receiving astemizole than in those receiving loratadine for runny nose, itchy nose and sneezing, although not for blocked nose, and treatment differences only reached statistical significance for runny nose. After 7 days, 53.75% of patients on astemizole and 38.6% on loratadine were free of symptoms, and 87% of patients on astemizole described the treatment as good or excellent compared with 62% on loratadine. The present results suggest that astemizole may be more effective than loratadine in controlling symptoms of perennial allergic rhinitis.

scholarly journals Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
François Maltais ◽  
Leif Bjermer ◽  
Edward M. Kerwin ◽  
Paul W. Jones ◽  
Michael L. Watkins ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Inhaled Corticosteroids ◽  
Randomised Trial ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Short Term ◽  
Double Blind ◽  
Once Daily ◽  
Clinically Important Deterioration ◽  
Exacerbation Risk

Abstract Background Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids. Methods The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions. Results Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16–25% [p < 0.01]) and salmeterol (by 26–41% [p < 0.001]). Safety profiles were similar between treatments. Conclusions Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

scholarly journals Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD)

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
James F. Donohue ◽  
Edward Kerwin ◽  
Sanjay Sethi ◽  
Brett Haumann ◽  
Srikanth Pendyala ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Health Outcomes ◽  
Pulmonary Disease ◽  
Inhaled Corticosteroids ◽  
Forced Expiratory Volume ◽  
Chronic Obstructive ◽  
Open Label ◽  
Double Blind ◽  
Obstructive Pulmonary Disease ◽  
Long Acting

Abstract Background Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 μg or 88 μg daily during the 52-week trial. Methods In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 μg or 88 μg in a double-blind manner, or open-label active control tiotropium. Results Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV1). The trough FEV1 profile (least squares mean change from baseline) for revefenacin 175 μg ranged from 52.3–124.3 mL and the trough FEV1 profile for tiotropium ranged from 79.7–112.8 mL. In subgroup comparisons, the effect of revefenacin on trough FEV1 was comparable in patients taking concomitant long-acting β-agonists, with or without inhaled corticosteroids, with patients who were not taking these medications. There were statistically significant (p < 0.05) improvements in all measured health status outcomes (evaluated using St. George’s Respiratory Questionnaire, COPD Assessment Test, Clinical COPD Questionnaire and Baseline and Transition Dyspnea Index) from 3 months onward, in all treatment arms. Conclusions Significant sustained improvements from baseline in trough FEV1 and respiratory health outcomes were demonstrated for 175-μg revefenacin over 52 weeks, further supporting its use as a once-daily bronchodilator for the nebulized treatment of patients with COPD. Trial registration NCT02518139; Registered 5 August 2015.

scholarly journals Formoterol Thrice Weekly Does Not Result in the Development of Tolerance to Bronchoprotection

2003 ◽  
Vol 10 (1) ◽  
pp. 23-26 ◽  
Author(s):  
Beth E Davis ◽  
John K Reid ◽  
Donald W Cockcroft
Keyword(s):  
Crossover Trial ◽  
Positive Control ◽  
Forced Expiratory Volume ◽  
Weekly Administration ◽  
Double Blind ◽  
Once Daily ◽  
Regular Treatment ◽  
Significant Difference ◽  
Direct Acting ◽  
Development Of Tolerance

BACKGROUND: Loss of bronchoprotection routinely follows regular treatment with beta2-agonists. There are no data on the effects on bronchoprotection for thrice weekly use of a beta2-agonist.METHODS: A double-blind, randomized, placebo controlled crossover trial was conducted to investigate the effects of thrice weekly administration of 12 μg of formoterol versus placebo on bronchoprotection against methacholine. As an expected positive control, formoterol 12 μg once daily was also evaluated.RESULTS: There was no significant difference versus placebo in the bronchoprotective effects of 12 μg of formoterol administered on day 8, following daily treatment for seven days or treatment every other day (analysis of variance P=0.34). However, a nonsignificant trend towards lower concentration of methacholine that caused a 20% fall in forced expiratory volume in 1 s developed only following the daily formoterol dosing.CONCLUSIONS: Thrice weekly dosing does not result in the development of tolerance to bronchoprotection against the direct acting stimulus methacholine.

scholarly journals Lung function, pharmacokinetics, and tolerability of inhaled indacaterol maleate and acetate in asthma patients

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
David Miller ◽  
Soniya Vaidya ◽  
Juergen Jauernig ◽  
Brian Ethell ◽  
Kristina Wagner ◽  
...  
Keyword(s):  
Lung Function ◽  
Systemic Exposure ◽  
Forced Expiratory Volume ◽  
Fixed Dose ◽  
Chronic Obstructive ◽  
Electronic Diary ◽  
Double Blind ◽  
Once Daily ◽  
Long Acting ◽  
Salt Forms

Abstract Background Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting β2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 μg once daily (o.d.) and indacaterol acetate 150 μg o.d. in comparison with placebo. Methods This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 μg o.d., indacaterol acetate 150 μg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study. Results Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%). Conclusions In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. Trial registration ClinicalTrials.gov NCT03257995 June 06, 2017

scholarly journals Tailored second-line therapy in asthmatic children with the Arg16 genotype

2013 ◽  
Vol 124 (8) ◽  
pp. 521-528 ◽  
Author(s):  
Brian J. Lipworth ◽  
Kaninika Basu ◽  
Helen P. Donald ◽  
Roger Tavendale ◽  
Donald F. Macgregor ◽  
...  
Keyword(s):  
Forced Expiratory Volume ◽  
Second Line ◽  
Once Daily ◽  
Asthmatic Children ◽  
Long Acting ◽  
To Receive ◽  
Β2 Agonists ◽  
Genotype A ◽  
Increased Susceptibility

The Arg16 β2 receptor genotype confers increased susceptibility to exacerbations in asthmatic children taking regular LABA (long-acting β2 agonists). We therefore evaluated using montelukast as an alternative to salmeterol as tailored second-line asthma controller therapy in children expressing this susceptible genotype. A total of 62 persistent asthmatic children with the homozygous Arg16 genotype were randomized to receive salmeterol (50 μg, b.i.d.) or montelukast (5 or 10 mg, once daily) as an add-on to inhaled fluticasone for 1 year. School absences (the primary outcome) were reduced with montelukast compared with salmeterol {difference in score=−0.40 [95% CI (confidence interval), −0.22 to −0.58]; P=0.005}. Salbutamol use was also reduced with montelukast compared with salmeterol [difference in score=−0.47 (95% CI, −0.16 to −0.79); P<0.0001]. Greater improvements occurred in both symptom and quality of life scores with montelukast against salmeterol, whereas there was no difference in FEV1 (forced expiratory volume in 1 s). In conclusion, montelukast may be suitable as tailored second-line controller therapy instead of salmeterol in asthmatic children expressing the susceptible Arg16 genotype, a move towards a personalized medicine approach to management.

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