scholarly journals Salmeterol and Airway Response to Allergen

1997 ◽  
Vol 4 (1) ◽  
pp. 37-40 ◽  
Author(s):  
Donald W Cockcroft ◽  
Veronica A Swystun ◽  
Rajesh Bhagat ◽  
Sanjay Kalra
Keyword(s):  
Inhaled Corticosteroids ◽  
Day Treatment ◽  
Tertiary Care ◽  
Forced Expiratory Volume ◽  
Airway Responsiveness ◽  
Double Blind ◽  
Regular Treatment ◽  
Beta Agonists ◽  
Randomized Crossover Trial ◽  
Airway Response

BACKGROUND: Regular treatment with inhaled salbutamol (seven to 14 days) increases airway responsiveness to allergen.OBJECTIVE: To assess the effect of salmeterol 50 µg twice daily for six days on the early asthmatic response to allergen (PC15).DESIGN: Double-blind, randomized, crossover trial comparing salmeterol with placebo (twice daily over six days) with one week or more washout. Forced expiratory volume in 1 s (FEV1) and allergen PC15were measured 36 h after each treatment was discontinued.SETTING: Tertiary care out-patient bronchoprovocation laboratory.SUBJECTS: Fourteen atopic asthmatics well controlled with (n=5) or without (n=9) inhaled corticosteroids. Subjects did not use inhaled beta-agonists for at least two weeks before and during the trial.RESULTS: FEV1was slightly but significantly lower 36 h after the last dose of salmeterol versus placebo (3.28±0.83 versus 3.40±0.88 L, P=0.032). Airway responsiveness to allergen increased by about half a doubling concentration (log10PC152.71±0.61 versus 2.85±0.61, P=0.047).CONCLUSION: A six-day treatment course of salmeterol 50 μg twice daily resulted in a slight decline in FEV1and a modest increase in airway response to allergen at 36 h.

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.

scholarly journals Effect of a Single Dose Montelukast Sodium on Methacholine Chloride PC20

2005 ◽  
Vol 12 (1) ◽  
pp. 26-28 ◽  
Author(s):  
Beth E Davis ◽  
Donald W Cockcroft
Keyword(s):  
Single Dose ◽  
Crossover Trial ◽  
Chloride Concentration ◽  
Forced Expiratory Volume ◽  
Tidal Breathing ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Randomized Crossover Trial ◽  
Montelukast Sodium ◽  
Airway Response

BACKGROUND: It is currently recommended that leukotriene modifiers (receptor antagonists and synthesis inhibitors) be withheld for a minimum of 24 h before direct bronchoprovocation testing, but there is little evidence to support this recommendation.OBJECTIVE: To examine the effect of a single oral dose of montelukast sodium 10 mg on airway response to methacholine chloride-induced bronchoconstriction.METHODS: A double-blind, placebo-controlled, randomized crossover trial was performed in 12 subjects with asthma whose methacholine chloride concentration causing a 20% decrease in the forced expiratory volume during the first second of exhalation (PC20) was 8 mg/mL or lower and a baseline forced expiratory volume during the first second of exhalation of 70% predicted or greater. Two-minute tidal breathing methacholine chloride inhalation challenges were performed 1 h and 25 h after both 10 mg montelukast sodium and identical-appearing placebo.RESULTS: There were no significant differences in the methacholine chloride PC20between active treatment and placebo at 1 h post-10 mg montelukast sodium (1.0 mg/mL versus 1.3 mg/mL; n=12; P=0.17, respectively) or at 25 h post-10 mg montelukast sodium (1.4 mg/mL versus 1.9 mg/mL; n=11; P=0.15, respectively).CONCLUSION: A single dose of montelukast sodium did not affect methacholine chloride-induced bronchoconstriction measured after 1 h and 25 h.

scholarly journals Dose-response Protective Effect of Salbutamol on Methacholine Airway Responsiveness using Pressurized Metered Dose Inhalers and Turbuhalers

1998 ◽  
Vol 5 (2) ◽  
pp. 119-123 ◽  
Author(s):  
Albert G Wong ◽  
Paul M O'Byrne ◽  
Christer Lindbladh ◽  
Mark D Inman ◽  
Elisabeth Ståhl ◽  
...  
Keyword(s):  
Protective Effect ◽  
Forced Expiratory Volume ◽  
Airway Responsiveness ◽  
Dose Inhaler ◽  
Metered Dose Inhalers ◽  
Double Blind ◽  
Beta Agonists ◽  
Metered Dose ◽  
Dose Dependent Fashion ◽  
Dose Dependent

The purpose of this study was to estimate the relative dose potency of salbutamol Turbuhaler compared with salbutamol pressurized metered dose inhaler (pMDI) with respect to the protective effect against methacholine bronchoconstriction. Twenty-three asthmatic subjects with stable asthma participated in the study. Baseline forced expiratory volume in 1 s (FEV1) was 70% or more of predicted, and baseline methacholine provocative concentration causing a 20% fall in FEV1(PC20) was 4 mg/mL or less. The design was randomized, double-blind, double-dummy, crossover and placebo controlled and was conducted over seven study days. On each study day, the subjects inhaled 50 µg or 100 µg of salbutamol via Turbuhaler, 100 µg, 200 µg, 400 µg or 800 µg of salbutamol via pMDI, or placebo in randomized order. PC20was determined 30 mins after inhalation. Increasing doses of salbutamol pMDI increased the PC20in a dose-dependent fashion from 3.9 mg/mL after placebo to 13.3 mg/mL after pMDI 100 µg, 19.0 mg/mL after 200 µg, 32.6 mg/mL after 400 µg, and 35.1 mg/mL after 800 µg. The half-maximum response dose for pMDI (ED50) was 104 µg. Salbutamol Turbuhaler 50 µg increased the PC20to 10.0 mg/mL and 100 µg to 12.6 mg/mL. Salbutamol pMDI 200 µg provided significantly greater protection to methacholine than pMDI 100 µg or Turbuhaler 100 µg and significantly less protection than pMDI 400 µg (P<0.05). This study demonstrates that the relative protective dose potency of inhaled beta-agonists can be determined by comparing their effects on methacholine airway responsiveness. The estimated relative protective dose potency for salbutamol Turbuhaler in comparison with pMDI was 1.38 (95% CI 0.67 to 2.87) at 50 µg and was 0.96 (95% CI 0.56 to 1.64) at 100 µg.

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.

Bronchiolitis als mögliche unerwünschte Wirkung von Immuncheckpoint-Inhibitoren

2020 ◽  
Vol 8 (3) ◽  
pp. 152-153
Author(s):  
Nicolas Carlos Kahn
Keyword(s):  
Inhaled Corticosteroids ◽  
Respiratory Infections ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Airway Disease ◽  
Forced Expiratory Volume ◽  
Functional Improvement ◽  
High Dose ◽  
Double Blind ◽  
Dose Prednisone

Immune checkpoint inhibitors (ICIs) have been shown to improve overall and progression-free survival in various cancers but have been associated with various immune-related adverse events (IRAEs), including interstitial lung disease, especially organizing pneumonia. We report 2 cases of isolated severe airway disease attributable to ICIs, a rarely reported pattern of lung toxicity. The first patient received nivolumab with or without ipilimumab in a randomized double-blind trial for locoregional metastatic melanoma. The second patient was treated with nivolumab for lung adenocarcinoma. An IRAE was suspected in both cases due to a temporal relationship between ICI initiation and symptom onset. ICIs were stopped, and high-dose prednisone, inhaled corticosteroids, and bronchodilators were administered, allowing a rapid clinical and functional improvement in Patient 1. In Patient 2, despite prolonged high-dose prednisone, only a stabilization of forced expiratory volume in 1 s could be achieved, and the disease course was complicated by respiratory infections resulting in further loss of lung function. The patient died 1 year later due to progression of metastatic disease. These 2 cases suggest that pulmonary IRAEs secondary to ICIs may present as isolated bronchitis or bronchiolitis, with variable outcomes following ICI withdrawal and systemic corticosteroids.

Does baseline airway caliber affect measurements of airway responsiveness to histamine

1993 ◽  
Vol 74 (6) ◽  
pp. 3034-3039 ◽  
Author(s):  
O. P. Twentyman ◽  
S. V. Hood ◽  
S. T. Holgate
Keyword(s):  
Time Course ◽  
Geometric Mean ◽  
Forced Expiratory Volume ◽  
Airway Responsiveness ◽  
Bronchial Responsiveness ◽  
Subsequent Response ◽  
Airway Caliber ◽  
Before And After ◽  
Airway Response ◽  
Considerable Controversy

Considerable controversy exists over the influence of baseline airway caliber on indexes of bronchial responsiveness in asthma. To directly investigate this, we used inhaled methacholine to alter baseline airway caliber to determine whether this altered the airway response to subsequent bronchoprovocation with inhaled histamine. Seventeen stable asthmatic subjects were studied; their median age was 22 yr, baseline forced expiratory volume in 1 s (FEV1) was 101.5 +/- 3.7% (SE) predicted, and geometric mean provocative concentration of inhaled methacholine causing a 20% fall in FEV1 (PC20) was 0.87 mg/ml. Initially the time course of bronchoconstriction to inhaled methacholine was determined. Subsequently the airway response to inhaled histamine administered as a single concentration was determined, both before and after reductions in baseline FEV1 by saline or methacholine of 0, 15, 25, and 35%, on 4 separate days. Altering baseline airway caliber had no effect on the subsequent response of the airways to inhaled histamine when calculated as percent fall from the new baseline. The power of the study to detect an effect of altering baseline FEV1 on the measured PC20 histamine of 0.5 doubling dilutions was > 55%, and the power to detect an effect of 1.0 doubling dilutions was > 98%.

Proof-of-concept evaluation of trough airway hyper-responsiveness following regular racemic or levosalbutamol in genotype-stratified steroid-treated persistent asthmatic patients

2013 ◽  
Vol 126 (1) ◽  
pp. 75-83 ◽  
Author(s):  
William J. Anderson ◽  
Philip M. Short ◽  
Peter A. Williamson ◽  
Ashley E. Morrison ◽  
Colin Palmer ◽  
...  
Keyword(s):  
Primary Outcome ◽  
Inhaled Corticosteroids ◽  
Forced Expiratory Volume ◽  
Proof Of Concept ◽  
Post Dose ◽  
Double Blind ◽  
Asthmatic Patients ◽  
On Demand ◽  
Concept Evaluation ◽  
Doubling Dilution

Asthmatic patients receiving ICSs (inhaled corticosteroids) may take frequent add-on therapy with salbutamol despite on-demand prescription. Frequent salbutamol use can be detrimental in asthma. The isomeric formulation of salbutamol and the B2ADR (β2 adrenoceptor) 16 genotype may also influence this phenomenon. We performed a randomized, double-blind, placebo-controlled, triple crossover, proof of concept trial comparing 2 weeks of regular therapy with inhaled racemic salbutamol [200 μg q.i.d. (four times daily)], levosalbutamol (100 μg q.i.d.) or placebo on trough methacholine PC20 [provocative concentration causing 20% fall in FEV1 (forced expiratory volume in 1 s)] 6 h post-dose (the primary outcome) in 30 persistent asthmatic patients (15 who were Arg16 homozygous and 15 who were Gly16 homozygous) all receiving ICSs. There was no worsening of AHR (airway hyper-responsiveness) at trough to methacholine after 2 weeks regular exposure to either racemic (P=0.53) or levosalbutamol (P=0.84) compared with placebo, nor between genotypes–as dd (doubling dilution) difference in methacholine PC20 from placebo [salbutamol/Arg16=0.36 dd [95% CI (confidence interval), −0.43, 1.15]; salbutamol/Gly16=0.01 dd (95% CI, −0.47, 0.49); levosalbutamol/Arg16=−0.01 dd (95% CI, −0.89, 0.87); and levosalbutamol/Gly16=0.28 dd (95% CI, −0.22, 0.77)]. Both active treatments improved morning PEF (peak expiratory flow) in Gly16 (P=0.04 overall) but not Arg16 (P=0.50 overall) patients, whereas evening PEF improved in both Gly16 (P<0.001 overall) and Arg16 (P=0.006 overall) patients. In conclusion, the regular exposure to either racemic or levosalbutamol for 2 weeks added to ICSs did not cause worsening of AHR at trough compared with placebo; with no difference seen between B2ADR 16 genotypes.

Role of neutral endopeptidase in exercise-induced bronchoconstriction in asthmatic subjects

1996 ◽  
Vol 81 (2) ◽  
pp. 673-678 ◽  
Author(s):  
H. W. de Gouw ◽  
Z. Diamant ◽  
E. A. Kuijpers ◽  
J. K. Sont ◽  
P. J. Sterk
Keyword(s):  
Recovery Period ◽  
Neutral Endopeptidase ◽  
Bicycle Ergometer ◽  
Forced Expiratory Volume ◽  
Double Blind ◽  
Airway Response ◽  
Membrane Bound ◽  
Exercise Induced ◽  
Response To Exercise

The membrane-bound metalloproteinase, neutral endopeptidase (NEP), is a degrading enzyme of both bronchoconstrictor and bronchodilator peptides within the airways. To examine the role of NEP in exercise-induced bronchoconstriction (EIB) in asthmatic subjects, we used inhaled thiorphan, a NEP inhibitor, as pretreatment to a 6-min standardized exercise challenge. Thirteen clinically stable asthmatic subjects participated in this double-blind, placebo-controlled, crossover study that was performed on 2 days separated by 48 h. Thiorphan was administered by two inhalations of 0.5 ml containing 1.25 mg/ml. Subsequently, exercise was performed on a bicycle ergometer at 40–50% of predicted maximal voluntary ventilation while inhaling dry air (20 degrees C, relative humidity 6%). The airway response to exercise was measured by forced expiratory volume in 1 s (FEV1) every 3 min, up to 30 min postexercise challenge, and was expressed both as the maximal percent fall in FEV1 from baseline and as the area under the time-response curve (AUC) (0–30 min). The acute effects of both pretreatments on baseline FEV1 were not different (P > 0.2), neither was there any difference in maximal percent fall in FEV1 between thiorphan and placebo (P > 0.7). However, compared with placebo, thiorphan reduced the AUC by, on average, 26% [AUC (0–30 min, +/-SE): 213.6 +/- 47.7 (thiorphan) and 288.6 +/- 46.0%fall.h (placebo); P = 0.047]. These data indicate that NEP inhibition by thiorphan reduces EIB during the recovery period. This suggests that bronchodilator NEP substrates, such as vasoactive intestinal polypeptide or atrial natriuretic peptide, modulate EIB in patients with asthma.

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