Bisoprolol in Patients With Chronic Obstructive Pulmonary Disease at High Risk of Exacerbation: The BICS Randomized Clinical Trial.

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Observational studies report that ß-blocker use may be associated with reduced risk of COPD exacerbations. However, a recent trial reported that metoprolol did not reduce COPD exacerbations and increased COPD exacerbations requiring hospital admission. Objective: To test whether bisoprolol decreased COPD exacerbations in people with COPD at high risk of exacerbations. Design, Setting, and Participants: The Bisoprolol in COPD Study (BICS) was a double-blind placebo-controlled randomized clinical trial conducted in 76 UK sites (45 primary care clinics and 31 secondary clinics). Patients with COPD who had at least moderate airflow obstruction on spirometry (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity <0.7; FEV1 <80% predicted) and at least 2 COPD exacerbations treated with oral corticosteroids, antibiotics, or both in the prior 12 months were enrolled from October 17, 2018, to May 31, 2022. Follow-up concluded on April 18, 2023. Interventions: Patients were randomly assigned to bisoprolol (n = 261) or placebo (n = 258). Bisoprolol was started at 1.25 mg orally daily and was titrated as tolerated during 4 sessions to a maximum dose of 5 mg/d, using a standardized protocol. Main Outcomes and Measures: The primary clinical outcome was the number of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both during the 1-year treatment period. Safety outcomes included serious adverse events and adverse reactions. Results: Although the trial planned to enroll 1574 patients, recruitment was suspended from March 16, 2020, to July 31, 2021, due to the COVID-19 pandemic. Two patients in each group were excluded postrandomization. Among the 515 patients (mean [SD] age, 68 [7.9] years; 274 men [53%]; mean FEV1, 50.1%), primary outcome data were available for 514 patients (99.8%) and 371 (72.0%) continued taking the study drug. The primary outcome of patient-reported COPD exacerbations treated with oral corticosteroids, antibiotics, or both was 526 in the bisoprolol group, with a mean exacerbation rate of 2.03/y, vs 513 exacerbations in the placebo group, with a mean exacerbation rate of 2.01/y. The adjusted incidence rate ratio was 0.97 (95% CI, 0.84-1.13; P = .72). Serious adverse events occurred in 37 of 255 patients in the bisoprolol group (14.5%) vs 36 of 251 in the placebo group (14.3%; relative risk, 1.01; 95% CI, 0.62-1.66; P = .96). Conclusions and Relevance: Among people with COPD at high risk of exacerbation, treatment with bisoprolol did not reduce the number of self-reported COPD exacerbations requiring treatment with oral corticosteroids, antibiotics, or both. Trial Registration: isrctn.org Identifier: ISRCTN10497306.

Inhaled corticosteroid dose response in asthma: Should we measure inflammation?

BACKGROUND: Inhaled corticosteroid (ICS) titration in asthma is primarily based on symptoms and pulmonary function. ICSs may not be increased on this basis despite residual airway inflammation. OBJECTIVE: To compare the dose-response relationships of ICSs on measures of pulmonary function, symptoms, and inflammation in patients with persistent asthma. METHODS: We performed a pooled post hoc analysis of 121 patients with mild to moderate asthma from 4 randomized clinical trials that incorporated an ICS dose ramp. Dose ramps were 0 to 200, 0 to 800, and 200 to 800 µg/d (beclomethasone equivalents). Outcome measures included spirometry, fractional exhaled nitric oxide, airway hyperresponsiveness (AHR), symptoms, serum eosinophilic cationic protein, and blood eosinophils. RESULTS: We found a plateau beyond a small improvement at 0 to 200 µg for forced expiratory volume in 1 second: 3.3% (95% confidence interval [CI], 2.0%-4.7%) at 0 to 200 µg vs 0.3% (95% CI, -0.8% to 1.4%) 200 to 800 µg (P = .001). A similar plateau was seen for symptom improvement beyond 0 to 200 µg. Inflammatory and AHR outcomes revealed further room for improvement beyond low-dose ICSs. There was dose-related suppression (P < .001) for fractional exhaled nitric oxide: 40.4 ppb (95% CI, 34.7-46.9 ppb) for ICS free, 26.8 ppb (95% CI, 23.4-30.2 ppb) for 200 µg, and 20.8 ppb (95% CI, 18.8-23.1 ppb) for 800 µg. Eosinophilic cationic protein concentration was significantly reduced with both higher dose ramps. Eosinophil counts also improved across all 3 dose ramps, with dose separation of 370/µL (95% CI, 280-450/µL) for ICS free vs 250/µL (95% CI, 200-300/µL) 800 µg (P = .03). AHR improved with all 3 dose ramps, with greater improvement at lower doses for indirect vs direct challenges. CONCLUSION: ICS dose response may extend beyond low dose for inflammation and AHR but not symptoms or spirometry. Further study is required to identify whether this correlates with suboptimal longitudinal asthma control. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00667992, NCT00995657, NCT01216579, NCT01544634.

Is Gly16Arg ß2 Receptor Polymorphism Related to Impulse Oscillometry in a Real-Life Asthma Clinic Setting?

PURPOSE: We evaluated whether Gly16Arg beta2-receptor genotype relates to impulse oscillometry (IOS) in a real-life clinic setting. METHODS: Patients with persistent asthma taking inhaled corticosteroid ± long-acting beta-agonist (ICS ± LABA) were evaluated. We compared genotype groups comprising either no Arg copies (i.e. GlyGly) versus one or two Arg copies (i.e. ArgArg or ArgGly). IOS outcomes included total airway resistance at 5 Hz (R5), central airway resistance at 20 Hz (R20), peripheral airway resistance (R5-R20), reactance at 5 Hz, area under reactance curve (AX) and resonant frequency (RF). In addition, we recorded ACQ-5 and salbutamol use. RESULTS: One hundred and twelve ICS-treated asthmatic patients (mean ICS dose 1238 µg/day), mean age 43 years, ACQ 2.34, FEV1 82 %, R5 177 % were identified-89 were also taking LABA. 61 patients were GlyGly, while 14 were ArgArg and 37 were ArgGly. There were no significant differences in IOS outcomes, ACQ or salbutamol use between the genotypes. The allelic risk (as odds ratio) for less well-controlled asthma (as ACQ > 1.5) was 1.1 (95 % CI 0.72-1.68) in relation to each Arg copy with a corresponding odds ratio for abnormal R5-R20 > 0.07kPA/l.s being 0.91 (95 % CI 0.57-1.44). 71 % of patients had an ACQ > 1.5 in the GlyGly group, versus 67 % in GlyArg/ArgArg group, with corresponding figures for abnormal R5-R20 > 0.07 kPa/l.s being 69 versus 73 %. CONCLUSION: In a real-life clinic setting for patients with poorly controlled persistent asthma taking ICS ± LABA, we found no evidence of any relationship of Gly16Arg to IOS, ACQ or salbutamol use.

Usefulness of impulse oscillometry for the assessment of airway hyperresponsiveness in mild-to-moderate adult asthma.

BACKGROUND: Impulse oscillometry (IOS) is a novel method of assessing airway resistance. IOS is rarely used in assessing airway resistance after bronchoprovocation in adult asthma. OBJECTIVE: To ascertain the degree of change in IOS measurements seen in patients with asthma undergoing bronchial challenge testing. METHODS: Patients 18 to 65 years old with mild to moderate asthma, forced expiratory volume in 1 second (FEV1) greater than 80% predicted, and diurnal FEV1 variation less than 30% and taking inhaled corticosteroid (≤1,000 µg/day of beclomethasone dipropionate equivalent dose) were recruited. Sequential spirometry and IOS results were measured during bronchial challenge testing to inhaled methacholine and histamine. RESULTS: The magnitude of percentage of change demonstrated in total airway resistance at 5 Hz was greater than that observed for FEV1 in the 2 bronchial challenge tests. For example, at a methacholine provocation concentration that caused a decrease in FEV1 of 20%, a 43.5% change (95% confidence interval 29.4-57.5) was seen in total airway resistance at 5 Hz as measured by IOS compared with a 23.3% change (95% confidence interval 18.7-27.9) in FEV1. The magnitude of change seen with other IOS outcomes, including peripheral airway resistance, area under the curve, and resonant frequency, also was greater compared with spirometry. CONCLUSION: The potential application of IOS in the assessment of airway hyperresponsiveness in adult asthma has been demonstrated. Further population studies are required. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01074853).

Impact of Left Ventricular Hypertrophy on Survival in Chronic Obstructive Pulmonary Disease.

PURPOSE: Left ventricular hypertrophy (LVH) is a significant cardiac risk factor, associated with increased mortality. The impact of LVH on mortality in chronic obstructive pulmonary disease (COPD) is unknown. We evaluated the impact of LVH on mortality in COPD patients by measurement of left ventricular dimensions by echocardiography. METHODS: Retrospective cohort study utilizing a NHS database of COPD patients (TARDIS), in Tayside, Scotland (2001-2010), linked with databases regarding echocardiograms, pharmacy prescription, and the General Register Office for Scotland death registry. Cox proportional hazard regression was used to determine hazard ratios for mortality and hospital admissions based upon left ventricular mass index (LVMI) and left ventricular internal diastolic diameter after correction for all available influential covariates. Increased LVIDd was defined as >5.3 cm (female) and >5.9 cm (male). LVH was defined as an LVMI of >95 g/m(2) (female) and >115 g/m(2) (male). RESULTS: 617 patients were included for analysis. Mean (SD) age at diagnosis, 70 (9); mean FEV1 % (SD), 60.6 (19.3); mean resting SaO2 % (SD), 92.7 (10). Mean follow-up 4.5 years. Increased LVIDd was not associated with increased mortality, χ (2)= 0.767, p = 0.381. Increased LVMI was associated with a significant increased risk of mortality, χ (2) = 5.447, p = 0.02 with an adjusted HR (95 % CI) of 1.542 (1.068-2.228), p = 0.021. CONCLUSIONS: The presence of LVH, demonstrated by elevated left ventricular mass index is associated with a significantly increased risk of mortality in COPD patients. Therapeutic interventions are required to address this important modifiable risk factor in COPD patients.

Thrombocytosis is associated with increased short and long term mortality after exacerbation of chronic obstructive pulmonary disease: a role for antiplatelet therapy?

INTRODUCTION: Evidence suggests that platelets play a significant role in inflammation in addition to their role in thrombosis. Systemic inflammation is linked to poor short and long term outcomes in COPD. Increased platelet activation has been reported in acute exacerbations of COPD (AECOPD). We investigated whether thrombocytosis is independently associated with poor outcomes following AECOPD. METHODS: An observational cohort study of patients hospitalised with AECOPD was performed. Patients were >40 years with spirometry confirmed COPD admitted between 2009 and 2011. Platelet count was recorded on admission. The primary outcome was 1-year all-cause mortality. Secondary outcomes included inhospital mortality and cardiovascular events. Analyses were conducted using logistic regression after adjustment for confounding variables. RESULTS: 1343 patients (49% male) were included. Median age was 72 years (IQR 63-79 years). 157 (11.7%) had thrombocytosis. Thrombocytosis was associated with both 1-year mortality and inhospital mortality; OR 1.53 (95% CI 1.03 to 2.29, p=0.030) and OR 2.37 (95% CI 1.29 to 4.34, p=0.005), respectively. Cardiovascular hospitalisation was not significantly increased (OR 1.13 (95% CI 0.73 to 1.76, p=0.600)) in patients with thrombocytosis. Aspirin or clopidogrel treatment correlated with a reduction in 1-year mortality (OR 0.63 (95% CI 0.47 to 0.85, p=0.003)) but not inhospital mortality (OR 0.69 (95% CI 0.41 to 1.11, p=0.124)). CONCLUSIONS: After adjustment for confounders thrombocytosis was associated with increased 1-year mortality after exacerbation of COPD. Antiplatelet therapy was associated with significantly lower 1-year mortality and may have a protective role to play in patients with AECOPD.

The inverse agonist propranolol confers no corticosteroid-sparing activity in mild-to-moderate persistent asthma.

The murine asthma model shows that switching off airway ß2 receptors with an inverse agonist may confer anti-inflammatory effects as well as corticosteroid-sparing activity. We have assessed for any corticosteroid-sparing effects of propranolol, an inverse agonist, added to low-dose inhaled corticosteroid (ICS) compared with higher dose ICS. A randomized double-blind placebo-controlled cross-over trial in mild-to-moderate persistent asthmatic patients was performed. After a run-in (2 weeks) on hydrofluoroalkane-beclometasone dipropionate (HFA-BDP) at 100 µg/day (HFA-BDP100), patients received randomized treatments (4 weeks) with propranolol at 80 mg/day plus HFA-BDP at 100 µg/day compared with placebo plus HFA-BDP at 400 µg/day (HFA-BDP400). Propranolol was up-titrated to 80 mg/day over the initial 2 weeks. Tiotropium was co-administered until 5 days before each histamine challenge (the primary outcome). Sixteen patients completed the study [mean age, 38 years; forced expiratory volume in 1 s (FEV1), 86.4%; histamine provocative concentration causing a 20% fall in FEV1 (PC20), 1.39 mg/ml; ICS dose, 406 µg/day]. Histamine PC20 was unchanged by adding propranolol to HFA-BDP100 compared with baseline (HFA-BDP100) {0.17 doubling dilution (dd) difference [95% confidence interval (CI): -0.58 to 0.92]}, but there was a significant improvement with HFA-BDP400 compared with both baseline [1.05 dd (95% CI: 0.43-1.66); P=0.02], and propranolol+HFA-BDP100 [0.88 dd (95% CI: 0.45-1.30); P=0.006]. Significant improvements were also observed with HFA-BDP400 for exhaled nitric oxide, blood eosinophils, serum eosinophilic cationic protein and asthma quality-of-life questionnaire symptoms compared with propranolol+HFA-BDP100. Salbutamol recovery post-challenge was partially blunted by propranolol (median prolongation 5 min; P=0.002). Domiciliary evening FEV1 also fell with propranolol+HFA-BDP100 [mean reduction from baseline 0.22 litres (95% CI: 0.10-0.34); P=0.012], whereas Asthma Control Questionnaire remained unchanged. In conclusion, the inverse agonist propranolol produced no improvements when given with low-dose ICS, whereas further significant improvements in airway hyper-responsiveness and inflammation were demonstrated with higher dose ICS. Thus, propranolol does not confer corticosteroid-sparing activity in persistent asthma.

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

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 (ß2 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.

Randomized placebo-controlled trial to evaluate chronic dosing effects of propranolol in asthma.

RATIONALE: Unblinded studies have shown improvements in airway hyperresponsiveness with chronic nadolol in steroid-naive patients with asthma. OBJECTIVES: To assess the effects of chronic nonselective ß-blockade as add-on to inhaled corticosteroids (ICS) in patients with asthma. METHODS: A double-blind randomized placebo-controlled crossover trial of propranolol in patients with mild-to-moderate asthma receiving ICS was performed. Participants underwent a 6- to 8-week dose titration of propranolol or placebo as tolerated to a maximum of 80 mg per day. Tiotropium was given for the first 4 to 6 weeks of each treatment period. MEASUREMENTS AND MAIN RESULTS: Primary outcome was methacholine challenge. Secondary outcomes included histamine challenge, pulmonary function, mini-asthma quality of life questionnaire (mini-AQLQ), and asthma control questionnaire (ACQ). Eighteen patients completed (mean [SEM]): age, 36 (4) yr; FEV1%, 93 (2); ICS, 440 (66) µg/d. No significant difference was observed in methacholine or histamine challenge after exposure to propranolol versus placebo. For methacholine challenge, the doubling dilution difference was 0.04 (95% confidence interval [CI], -0.56 to 0.63), P = 0.89. Albuterol recovery at 20 minutes after histamine challenge was partially attenuated by propranolol versus placebo: FEV1% mean difference, 5.28 (95% CI, 2.54-8.01), P = 0.001. After chronic ß-blockade there was a small worsening in FEV1 % predicted of 2.4% (95% CI, -0.1 to 4.8), P = 0.055. No difference was found for ACQ or mini-AQLQ. CONCLUSIONS: This is the first placebo-controlled study to assess the effects of chronic nonselective ß-blockade in asthma, showing no significant effect of propranolol compared with placebo on either methacholine or histamine airway hyperresponsiveness and no change in ACQ or AQLQ. Clinical trial registered with www.clinicaltrials.gov (NCT01074853).

Inhaled and systemic corticosteroid response in severe asthma assessed by alveolar nitric oxide: a randomized crossover pilot study of add-on therapy.

AIMS: Alveolar nitric oxide (CA(NO)) is a potential biomarker of small airway inflammation. We investigated effects on CA(NO) of the addition of coarse and fine particle inhaled corticosteroids to standard therapy in severe asthma. METHODS: Severe asthmatics taking ≥1600 µg day(-1) budesonide or equivalent performed a randomized open-label crossover study. Subjects with FEV(1) < 80%, gas trapping and CA(NO) ≥2 ppb entered a 6 week dose-ramp run-in of fluticasone/salmeterol(FPSM) 250/50 µg twice daily for 3 weeks, then 500/50 µg twice daily for 3 weeks. Patients then received additional HFA-beclomethasone diproprionate (BDP) 200 µg twice daily or FP 250 µg twice daily for 3 weeks in a crossover. Participants then received prednisolone(PRED) 25 mg day(-1) for 1 week. Nitric oxide, lung function, mannitol challenge, systemic inflammatory markers and urinary cortisol were measured. RESULTS: Fifteen completed per protocol: mean (SD) age 51 (12) years, FEV(1) 58 (13)% predicted, residual volume 193 (100)% predicted and mannitol(PD10) 177 (2.8) µg. There was no significant difference between FPSM and add-on therapy for CA(NO). FPSM/BDP and FPSM/PRED suppressed broncial flux (Jaw(NO)) and FE(NO) compared with FPSM alone, but there was no significant difference between FPSM/BDP and FPSM/FP. ECP, e-selectin and ICAM-1 were suppressed by FPSM/PRED compared with FPSM and FPSM/FP but not FPSM/BDP. Plasma cortisol was significantly suppressed by FPSM/PRED. CONCLUSION: In severe asthma, CA(NO) is insensitive to changes in dose and delivery of inhaled corticosteroids and is not suppressed by systemic corticosteroids. Additional inhaled HFA-BDP reduced FE(NO) and Jaw(NO) without adrenal suppression. There was a trend to reduction in FE(NO) and Jaw(NO) with additional FP but this did not reach statistical significance. PRED reduced FE(NO) and Jaw(NO) with suppression of systemic inflammatory markers and urinary cortisol.

Bisoprolol versus celiprolol on dynamic hyperinflation, cardiopulmonary exercise and domiciliary safety in COPD: a single-centre, randomised, crossover study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is frequently associated with cardiovascular disease. The utility of beta-blockers for treating patients with COPD may be beneficial, but their safety remains uncertain, including worsening of dynamic hyperinflation (DH) during exercise. We hypothesised that among cardioselective beta-blockers celiprolol, due to its partial beta-2 agonist activity, may be safer than bisoprolol on exercise DH. METHODS: We measured isotime inspiratory capacity (IC) during cycle endurance testing in eleven moderate-severe COPD subjects, alongside other non-invasive cardiopulmonary exercise, bioreactance cardiac output, pulmonary function, biomarkers and daily domiciliary measures. Participants received titrated doses of either bisoprolol (maximim 5 mg) or celiprolol (maximum 400 mg) in randomised crossover fashion, each over 4 weeks. RESULTS: Clinically relevant DH occurred between resting and exercise isotime IC but showed no significant difference with either beta-blocker compared with post-run-in pooled baseline or between treatments. There were no other significant differences observed for remaining exercise ventilatory; non-invasive cardiac output; resting pulmonary function; beta-2 receptor and cardiac biomarkers; domiciliary pulmonary function, oxygen saturation and symptom outcomes, either between treatments or compared with baseline. No significant adverse effects occurred. CONCLUSIONS: Significant DH in moderate-severe COPD subjects was no different between bisoprolol or celiprolol or versus baseline. A broad spectrum of other non-invasive cardiopulmonary and domiciliary safety outcomes was equally reassuring. Bronchoprotection with a concomitant long-acting muscarinic antagonist might be an important safety measure in this context. TRIAL REGISTRATION NUMBER: NCT02380053.

Effects of hydrocortisone on acute ß-adrenoceptor blocker and histamine induced bronchoconstriction.

AIMS: ß-adrenoceptor blockers are avoided in asthma due to concerns of bronchoconstriction. We investigated the safety of acute exposure to propranolol in asthmatics, sequentially challenged with histamine to mimic an asthma exacerbation and evaluated the role of intravenous hydrocortisone in potentiating salbutamol reversibility. METHODS: Persistent atopic asthmatics, requiring ≤ 1000 µg day(-1) budesonide, performed a randomized double-blind placebo-controlled crossover study. Following 10 mg or 20 mg of oral propranolol, patients received 400 mg intravenous hydrocortisone or placebo, followed by histamine challenge with nebulized salbutamol 5 mg and ipratropium 500 µg recovery. RESULTS: Thirteen patients completed per protocol. Hydrocortisone did not potentiate salbutamol recovery post propranolol and histamine challenge vs. placebo (mean difference in FEV(1) 0.04 ml, 95% CI -0.07, 0.15, P= 0.417). ß-adrenoceptor blocker induced bronchoconstriction was demonstrated by spirometry and impulse oscillometry. For the placebo visit, FEV(1) fell 4.7% 2 hours post propranolol (95% CI 1.8, 7.5, P= 0.008) whilst total airway resistance (R5%) increased 31.3% (95% CI 15.6, 47.0, P= 0.04). On both visits FEV(1) % and R5% returned to baseline after salbutamol post histamine. CONCLUSION: Nebulized salbutamol and ipratropium produced a full recovery after propranolol and histamine induced bronchoconstriction, independent of hydrocortisone use. Since the greatest risk of ß-adrenoceptor blockade is after first dose, our findings offer reassurance to those undertaking further evaluation of chronic ß-adrenoceptor blockade as a potential treatment for mild-to-moderate asthma.

Sensitivity of impulse oscillometry and spirometry in beta-blocker induced bronchoconstriction and beta-agonist bronchodilatation in asthma.

BACKGROUND: Impulse oscillometry (IOS) provides an alternative method of assessing pulmonary function to conventional spirometry. OBJECTIVE: To compare the sensitivities of IOS and spirometry in assessing bronchoconstriction to propranolol and bronchodilation with salbutamol. METHODS: A post-hoc analysis of a randomized placebo-controlled crossover study was performed. Patients with mild-to-moderate persistent stable asthma taking 1,000 µg/day or less beclomethasone dipropionate equivalent received 10 or 20 mg of oral propranolol followed by histamine challenge, with recovery to nebulized salbutamol (5 mg). Spirometry and IOS were measured before and 2 hours after beta-blocker, post histamine, and 20 minutes post-salbutamol. Pre versus post percent change (95%CI) values were compared, and standardized response means (SRM) were calculated to assess the "signal to noise" of each test. RESULTS: Thirteen participants (mean age, 34 years) completed the protocol. Eleven participants received 20 mg of propranolol; 2 received 10 mg, because this dose caused more than 10% decrease in forced expiratory volume in 1 second (FEV(1)) on the test-dose algorithm. All IOS indices (R5, R5-R20, AX, RF) showed significant worsening of airways resistance or reactance to propranolol. FEV(1) but not FEF25-75 showed significant deterioration after beta-blocker (mean percent change, 4.6% and 6.2%). The magnitude of change was consistently higher for parameters of IOS, with the largest change being observed with R5 and RF (mean percent change, 30.8% and 39.4%). The SRMs for IOS outcomes were better than for spirometry. All measures of lung function showed significant bronchodilator response, with the best SRMs seen in R5 and RF. CONCLUSION: IOS is a more sensitive response outcome than spirometry with respect to bronchoconstriction to oral propranolol and bronchodilatation after salbutamol in patients with mild to moderate asthma.

Effects of intranasal salmeterol and fluticasone given alone and in combination in persistent allergic rhinitis.

BACKGROUND: ß(2)-Agonists have previously been shown to be effective inhibitors of mediator release from airway mucosal mast cells. OBJECTIVE: To evaluate the effects of intranasal salmeterol and fluticasone propionate alone and in combination on the response to nasal adenosine monophosphate (AMP) challenge to assess mast cell activation. METHODS: Twenty-three patients with persistent allergic rhinitis completed a randomized, double-blind, placebo-controlled, 4-way crossover trial. They received once daily treatment with placebo, salmeterol, 50 µg, fluticasone propionate, 500 µg, or fluticasone propionate and salmeterol combination, 500/50 µg, delivered via an antistatic spacer with nasal adapter for 1 week each, with trough measurements being made 12 hours after the first and last dose. The primary outcome was the maximum percentage decrease in peak nasal inspiratory flow after nasal AMP challenge. RESULTS: For the primary outcome there was significant protection after single and long-term dosing with fluticasone alone and fluticasone-salmeterol combination, whereas salmeterol alone only afforded protection after the first dose. Fluticasone-salmeterol combination and fluticasone but not salmeterol conferred significant chronic dosing effects on secondary outcomes of nasal symptoms and disease-specific quality of life. There was no potentiation of the response to fluticasone by salmeterol on any outcomes when given in combination. CONCLUSION: Chronic dosing with fluticasone but not salmeterol confers anti-inflammatory activity against nasal AMP challenge, but there was no potentiation of fluticasone when given in combination with salmeterol. Thus, salmeterol may not be an effective treatment for use in allergic rhinitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01388595.

Effects of extra-fine inhaled and oral corticosteroids on alveolar nitric oxide in COPD.

PURPOSE: Alveolar nitric oxide (CA(NO)) has been suggested as a surrogate marker of distal airway inflammation in COPD. Coarse particle-inhaled corticosteroids (ICS) have been shown not to suppress CA(NO). We evaluated whether extra-fine particle size ICS (HFA-BDP) or systemic oral corticosteroids could suppress CA(NO) in COPD. METHODS: Chronic obstructive pulmonary disease (COPD) patients with a FEV1/FVC ratio <0.7, FEV1 <80% predicted with CA(NO) > 2 ppb underwent a double-blind randomized, controlled, crossover trial with an open-label systemic steroid comparator. After a 2 week steroid washout period, participants were randomized to 3 weeks of 100 mcg of HFA-BDP twice daily and then 3 weeks of 400 mcg of HFA-BDP twice daily, or matched placebos with subsequent crossover. All patients then received 1 week open-label, 25 mg/day of prednisolone. Exhaled nitric oxide, plasma cortisol, and lung function were recorded. CA(NO) was corrected for axial diffusion. RESULTS: In 16 participants, there were no significant differences seen with either dose of HFA-BDP compared with placebo. Oral prednisolone significantly reduced FE(NO) and J'aw(NO) but not CA(NO). Plasma cortisol was significantly suppressed by oral prednisolone only. CONCLUSIONS: Whilst CA(NO) remains a biomarker of interest in COPD, it is not suppressed by systemic or extra-fine particle ICS. CA(NO) is not a useful marker for monitoring response of small airway disease to therapies in COPD. The study was approved by the local Committee on Medical Research Ethics and registered on ClinicalTrials.Gov (NCT 00921921).

Use of the oral beta blocker bisoprolol to reduce the rate of exacerbation in people with chronic obstructive pulmonary disease (COPD): a randomised controlled trial (BICS).

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease. METHODS: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1 < 80% predicted, FEV1/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers. DISCUSSION: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally. TRIAL REGISTRATION: Current controlled trials ISRCTN10497306 . Registered on 16 August 2018.

Proof of concept study to evaluate step-down therapy with inhaled corticosteroid alone or additive therapy on surrogate inflammatory markers in asthma.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Much of the focus of inflammatory surrogates and airway challenges in asthma has been directed towards success of therapy and diagnosis. Few have considered them in the context of guiding dose reduction once sufficient control has been achieved. WHAT THIS STUDY ADDS: Adenosine monophosphate (AMP) as an indirect bronchial airway challenge, together with non invasive inflammatory surrogate measures were not found to be clinically useful when guiding therapy in a group of asthmatic patients through step 3-4 in British Thoracic Society asthma guidelines. However, they may still play a role in predicting failure of individual step-down. AIM: The aim of the study was to evaluate the usefulness of inflammatory surrogates in determining step-down therapy in asthma. METHODS: AMP challenge, serum eosinophil cationic protein (ECP), exhaled nitric oxide (eNO) and pulmonary function tests were recorded. Subjects were divided into two groups following high dose inhaled corticosteroids (ICS): Group A fixed dose ICS vs. Group B ICS alone and in combination with add on therapies. RESULTS: No differences were seen in inflammatory measures between fixed dose ICS and reduced dose ICS alone or with combination therapies. CONCLUSIONS: AMP challenge conferred no additional benefit in guiding step-down therapy. The role of inflammatory surrogates may still play a role in predicting failed step-down on an individual basis.

Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers.

PURPOSE: This study compares the in vivo relative lung bioavailability of Hydrofluoroalkane (HFA) Seretide delivered via unprimed and unwashed Aerochamber Plus (AP) or Volumatic (VM) spacers, a integrated breath-actuated vortex Synchro-Breathe (SB) device and an Evohaler pMDI (EH) device using adrenal suppression and early fall in serum potassium (K) as surrogates for respirable dose. METHODS: Seventeen healthy volunteers completed this randomised double-blind, double-dummy crossover study. Single doses of placebo/Seretide 250 (total dose ex valve fluticasone 2000 mcg/salmeterol 200 mcg) were administered via the devices. Overnight urinary cortisol/creatinine (OUCC) and serum K were measured at baseline and after each dose. RESULTS: Significant suppression of OUCC and K occurred from baseline with the SB, AP and VM but not with the EH devices. The geometric mean fold suppression (95% confidence interval, p) was: EH, 1.59 (0.80-3.14, p=0.40); AP, 4.26 (3.01-6.02, p<0.001); VM, 3.11 (1.99-4.78, p<0. 001); SB, 3.29 (2.04-5.24, p<0.001). For K, the arithmetic mean fall (mmol/l) (95% confidence interval; p) was: EH, -0.10 (-0.25-0.05, p=0.18); AP, -0.23 (-0.41 to -0.04, p=0.02); VM, -0.22 (-0.44 to -0.01, p=0.04); SB, -0.28 (-0.42 to -0.13, p=0.001). CONCLUSIONS: The breath-actuated SB device was comparable to 'out of the box' small and large volume spacers and produced similar improvements in relative systemic lung bioavailability for fluticasone and salmeterol.

Single wall carbon nanotubes enter cells by endocytosis and not membrane penetration.

BACKGROUND: Carbon nanotubes are increasingly being tested for use in cellular applications. Determining the mode of entry is essential to control and regulate specific interactions with cells, to understand toxicological effects of nanotubes, and to develop nanotube-based cellular technologies. We investigated cellular uptake of Pluronic copolymer-stabilized, purified ~145 nm long single wall carbon nanotubes (SWCNTs) through a series of complementary cellular, cell-mimetic, and in vitro model membrane experiments. RESULTS: SWCNTs localized within fluorescently labeled endosomes, and confocal Raman spectroscopy showed a dramatic reduction in SWCNT uptake into cells at 4°C compared with 37°C. These data suggest energy-dependent endocytosis, as shown previously. We also examined the possibility for non-specific physical penetration of SWCNTs through the plasma membrane. Electrochemical impedance spectroscopy and Langmuir monolayer film balance measurements showed that Pluronic-stabilized SWCNTs associated with membranes but did not possess sufficient insertion energy to penetrate through the membrane. SWCNTs associated with vesicles made from plasma membranes but did not rupture the vesicles. CONCLUSIONS: These measurements, combined, demonstrate that Pluronic-stabilized SWCNTs only enter cells via energy-dependent endocytosis, and association of SWCNTs to membrane likely increases uptake.