Publications by authors named "Mario Scuri"

23 Publications

  • Page 1 of 1

Inspiratory flow profile and usability of the NEXThaler, a multidose dry powder inhaler, in asthma and COPD.

BMC Pulm Med 2021 Feb 25;21(1):65. Epub 2021 Feb 25.

Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Inhaler selection is important when managing respiratory conditions; a patient's inhalation technique should be appropriate for the selected device, and patients should ideally be able to use a device successfully regardless of disease severity. The NEXThaler is a multidose dry-powder inhaler with a breath-actuated mechanism (BAM) and dose counter that activates only following inhalation, so effectively an 'inhalation counter'. We assessed inspiratory flow through the NEXThaler in two studies and examined whether inhalation triggered the BAM.

Methods: The two studies were open-label, single-arm, and single visit. One study recruited patients with asthma aged ≥ 18 years; the other recruited patients with chronic obstructive pulmonary disease (COPD) aged ≥ 40 years. All patients inhaled twice through a placebo NEXThaler. The inspiratory profile through the device was assessed for each inhalation using acoustic monitoring, with flow at and time to BAM firing, peak inspiratory flow (PIF), and total inhalation time assessed.

Results: A total of 40 patients were enrolled in the asthma study: 20 with controlled asthma and 20 with partly controlled/uncontrolled asthma. All patients were able to trigger the BAM, as evidenced by the inhalation counter activating on closing the device. Mean flow at BAM firing following first inhalation was 35.0 (range 16.3-52.3) L/min; mean PIF was 64.6 (35.0-123.9) L/min. A total of 72 patients were enrolled in the COPD study, with data analysed for 69 (mean forced expiratory volume in 1 s 48.7% predicted [17-92%]). As with the asthma study, all patients, regardless of airflow limitation, were able to trigger the BAM. Mean flow at BAM firing following first inhalation was 41.9 (26.6-57.1) L/min; mean PIF was 68.0 (31.5-125.4) L/min. Device usability was rated highly in both studies, with 5 min sufficient to train the patients, and a click heard shortly after inhalation in all cases (providing feedback on BAM firing).

Conclusions: Inhalation flows triggering the BAM in the NEXThaler were similar between patients with controlled and partly controlled/uncontrolled asthma, and were similar across COPD airflow limitation. All enrolled patients were able to activate the device.
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http://dx.doi.org/10.1186/s12890-021-01430-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905605PMC
February 2021

Validity and responsiveness of the Daily- and Clinical visit-PROactive Physical Activity in COPD (D-PPAC and C-PPAC) instruments.

Thorax 2021 03 21;76(3):228-238. Epub 2021 Jan 21.

Department of Respiratory Diseases, University Hospital Leuven, Leuven, Belgium.

Background: The Daily-PROactive and Clinical visit-PROactive Physical Activity (D-PPAC and C-PPAC) instruments in chronic obstructive pulmonary disease (COPD) combines questionnaire with activity monitor data to measure patients' experience of physical activity. Their amount, difficulty and total scores range from 0 (worst) to 100 (best) but require further psychometric evaluation.

Objective: To test reliability, validity and responsiveness, and to define minimal important difference (MID), of the D-PPAC and C-PPAC instruments, in a large population of patients with stable COPD from diverse severities, settings and countries.

Methods: We used data from seven randomised controlled trials to evaluate D-PPAC and C-PPAC internal consistency and construct validity by sex, age groups, COPD severity, country and language as well as responsiveness to interventions, ability to detect change and MID.

Results: We included 1324 patients (mean (SD) age 66 (8) years, forced expiratory volume in 1 s 55 (17)% predicted). Scores covered almost the full range from 0 to 100, showed strong internal consistency after stratification and correlated as a priori hypothesised with dyspnoea, health-related quality of life and exercise capacity. Difficulty scores improved after pharmacological treatment and pulmonary rehabilitation, while amount scores improved after behavioural physical activity interventions. All scores were responsive to changes in self-reported physical activity experience (both worsening and improvement) and to the occurrence of COPD exacerbations during follow-up. The MID was estimated to 6 for amount and difficulty scores and 4 for total score.

Conclusions: The D-PPAC and C-PPAC instruments are reliable and valid across diverse COPD populations and responsive to pharmacological and non-pharmacological interventions and changes in clinically relevant variables.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892393PMC
March 2021

Inhaled corticosteroid containing combinations and mortality in COPD.

Eur Respir J 2018 12 13;52(6). Epub 2018 Dec 13.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

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http://dx.doi.org/10.1183/13993003.01230-2018DOI Listing
December 2018

Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial.

Lancet 2018 03 9;391(10125):1076-1084. Epub 2018 Feb 9.

Division of Infection, Immunity and Respiratory Medicine and Manchester University NHS Foundation Trust, University of Manchester, Manchester, UK; Medicines Evaluation Unit, Manchester, UK.

Background: Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment.

Methods: This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850.

Findings: Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45-0·57) for BDP/FF/G and 0·59 per patient per year (0·53-0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723-0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY.

Interpretation: In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia.

Funding: Chiesi Farmaceutici.
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http://dx.doi.org/10.1016/S0140-6736(18)30206-XDOI Listing
March 2018

Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide.

Int J Chron Obstruct Pulmon Dis 2017 6;12:2917-2928. Epub 2017 Oct 6.

Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK.

The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a "step-up" therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients.
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http://dx.doi.org/10.2147/COPD.S146822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638574PMC
June 2018

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study.

Int J Chron Obstruct Pulmon Dis 2017 7;12:2001-2014. Epub 2017 Jul 7.

Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.

An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate - a "fixed triple". This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 μg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV) area under the curve (AUC) and peak FEV, with a trend toward greater efficacy with higher GB dose. All adverse events were mild-moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose-response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 μg BID, respectively (all <0.001). GB 25 and 50 μg BID were superior (<0.05) to GB 12.5 μg BID for pre-dose morning FEV on Day 8. For this endpoint, GB 25 and 50 μg BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV peak and AUC with all GB doses and placebo (all <0.001). All adverse events were mild-moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 μg BID is the optimal dose in patients with COPD.
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http://dx.doi.org/10.2147/COPD.S137659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511020PMC
April 2018

Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial.

Lancet 2017 May 3;389(10082):1919-1929. Epub 2017 Apr 3.

Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; University Hospital South Manchester NHS Foundation Trust, Manchester, UK; Medicines Evaluation Unit, Manchester, UK.

Background: Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple).

Methods: For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium, patients were randomised (2:2:1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364.

Findings: Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0·46 (95% CI 0·41-0·51) for fixed triple, 0·57 (0·52-0·63) for tiotropium, and 0·45 (0·39-0·52) for open triple; fixed triple was superior to tiotropium (rate ratio 0·80 [95% CI 0·69-0·92]; p=0·0025). For week 52 pre-dose FEV, fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p<0·0001) and non-inferior to open triple (-0·003L [-0·033 to 0·027]; p=0·85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple.

Interpretation: In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV of less than 50%, and a history of exacerbations.

Funding: Chiesi Farmaceutici SpA.
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http://dx.doi.org/10.1016/S0140-6736(17)30188-5DOI Listing
May 2017

Acute cardiovascular safety of two formulations of beclometasone dipropionate/formoterol fumarate in COPD patients: A single-dose, randomised, placebo-controlled crossover study.

Pulm Pharmacol Ther 2017 02 5;42:43-51. Epub 2017 Jan 5.

Chiesi Farmaceutici SpA, Via Palermo 26/A, 43122 Parma, Italy.

Introduction: An extrafine combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) via a pressurised metered-dose inhaler (pMDI) has been commercially available for some years for the management of asthma and chronic obstructive pulmonary disease (COPD). A dry powder inhaler (DPI) formulation of extrafine BDP/FF is now also available. This study evaluated the cardiovascular safety of BDP/FF DPI in comparison to BDP/FF pMDI and placebo.

Methods: Single-dose, partially-blind, randomised, placebo-controlled, 5-period crossover study. Main inclusion criteria: aged 40-75 years; moderate to severe COPD (post-bronchodilator FEV 40-80% predicted, FEV/FVC <0.7). Patients received BDP/FF 200/12, 800/48 μg and placebo via DPI, and BDP/FF 200/12 and 800/48 μg via pMDI. In both devices, 200/12 μg is the therapeutic dose; 800/48 μg is supratherapeutic.

Primary Objective: to demonstrate non-inferiority between BDP/FF DPI and pMDI in average 4-h heart rate (HR) at each dose level. Secondary variables included: HR, HR peak and individual timepoint; QTcF interval; SBP and DBP AUC; and potassium and glucose AUC. Adverse events (AEs) were collected.

Results: Forty-nine patients were randomised; 45 (92%) received all five treatments. Non-inferiority was demonstrated between the DPI and pMDI formulations at both doses (-0.2 bpm [95% CI -1.3, 0.9] for 200/12 μg and 0.6 bpm [-0.5, 1.7] for 800/48 μg). Although there were statistically significant treatment-placebo differences at both doses and with both devices (thus confirming assay sensitivity), these differences were small and well below 5 bpm for the 200/12 μg dose. The results for the secondary parameters (QTcF, glucose and potassium) further supported the therapeutic equivalence of the two treatments. At the therapeutic dose, there were no clinically relevant treatment-placebo differences in any parameter with either formulation. There was no increase in the proportion of patients reporting AEs whilst receiving therapeutic doses of BDF/FF (either formulation) compared with placebo.

Conclusions: Overall, this study provides reassurance over the cardiovascular safety of extrafine BDP/FF, both in a DPI and a pMDI formulation.
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http://dx.doi.org/10.1016/j.pupt.2016.12.004DOI Listing
February 2017

High strength extrafine pMDI beclometasone/formoterol (200/6 μg) is effective in asthma patients not adequately controlled on medium-high dose of inhaled corticosteroids.

BMC Pulm Med 2016 12 9;16(1):180. Epub 2016 Dec 9.

Chiesi Farmaceutici, Parma, Italy.

Background: A high strength of beclomethasone/formoterol fumarate (BDP/FF) in a pressurised metered dose inhaler (pMDI), which contains extrafine BDP (200 μg/actuation) and FF (6 μg/actuation) has been developed to treat those asthmatics who are not adequately controlled on previous treatments.

Methods: A 12-week, randomized, double-blind, parallel group study was performed to compare the efficacy and safety of pMDI BDP/FF 200/6 (two actuations bid) with BDP 100 μg (four actuation bid) in a population of 376 randomized adult asthmatics not adequately controlled with high dose of inhaled corticosteroids (ICS) or medium dose of ICS plus long acting βagonists (LABA).

Results: The primary endpoint [change from baseline over the entire treatment period in average pre-dose morning peak expiratory flow (PEF)] demonstrated the superiority of BDP/FF over BDP monotherapy, with an adjusted mean difference of 19 L/min, which is above the minimal important clinical difference reported for this parameter. Overall, BDP/FF and BDP showed a similar improvement of symptom-based parameters and of the use of rescue medication after 3-month treatment. The safety profile of the two drugs was comparable, although BDP monotherapy, but not BDP/FF, slightly reduced the levels of serum cortisol.

Conclusions: The study proved that pMDI BDP/FF 200/6 μg was superior to BDP alone in improving lung function with comparable safety profiles. Therefore it may be considered as an effective treatment for adults with asthma not adequately controlled with high dose of ICS monotherapy or medium dose of ICS/LABA combinations.

Trial Registration: ClinicalTrials.gov: NCT01577082 , date 06/04/2012.
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http://dx.doi.org/10.1186/s12890-016-0335-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148913PMC
December 2016

Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial.

Lancet 2016 Sep 1;388(10048):963-73. Epub 2016 Sep 1.

Centre for Respiratory Medicine and Allergy, University of Manchester, Manchester, UK.

Background: Few data are available for the efficacy of "triple therapy" with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We designed this study to assess efficacy of single-inhaler combination of an extra fine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB) in COPD compared with beclometasone dipropionate and formoterol fumarate (BDP/FF) treatment.

Methods: TRILOGY was a randomised, parallel group, double-blind, active-controlled study done in 159 sites across 14 countries. The sites were a mixture of primary, secondary, and tertiary care providers, and specialist investigation units. Eligible patients with COPD had post-bronchodilator forced expiratory volume in 1 s (FEV1) of lower than 50%, one or more moderate-to-severe COPD exacerbation in the previous 12 months, COPD Assessment Test total score of 10 or more, and a Baseline Dyspnea Index focal score of 10 or less. Patients who met the inclusion and exclusion criteria at screening entered a 2-week open-label run-in period where they received beclometasone dipropionate (100 μg) and formoterol fumarate (6 μg) in two actuations twice daily. Patients were then randomly assigned (1:1) with an interactive response technology system to either continue BDP (100 μg) and FF (6 μg) or step-up to BDP (100 μg), FF (6 μg), and GB (12·5 μg) in two actuations twice daily for 52 weeks via pressurised metered-dose inhaler. The three co-primary endpoints were pre-dose FEV1, 2-h post-dose FEV1, and Transition Dyspnea Index (TDI) focal score, all measured at week 26 in the intention-to-treat population (all patients who were randomly assigned and received at least one dose of study drug and had at least one post-baseline efficacy assessment). Safety outcomes were measured in the safety population (all patients who were randomly assigned and received at least one dose of study drug). Secondary endpoints included moderate-to-severe COPD exacerbation rate over 52 weeks. This study is registered with ClinicalTrials.gov number NCT01917331.

Findings: Between March 21, 2014, and Jan 14, 2016, 1368 patients received either BDP/FF/GB (n=687) or BDP/FF (n=681). At week 26, BDP/FF/GB improved pre-dose FEV1 by 0·081 L (95% CI 0·052-0·109; p<0·001) and 2-h post-dose FEV1 by 0·117 L (0·086-0·147; p<0·001) compared with BDP/FF. Mean TDI focal scores at week 26 were 1·71 for BDP/FF/GB and 1·50 for BDP/FF, with a difference of 0·21 (95% CI -0·08 to 0·51; p=0·160). Adjusted annual moderate-to-severe exacerbation frequencies were 0·41 for BDP/FF/GB and 0·53 for BDP/FF (rate ratio 0·77 [95% CI 0·65-0·92]; p=0·005), corresponding to a 23% reduction in exacerbations with BDP/FF/GB compared with BDP/FF. Adverse events were reported by 368 (54%) patients with BDP/FF/GB and 379 (56%) with BDP/FF. One serious treatment-related adverse event occurred (atrial fibrillation) in a patient in the BDP/FF/GB group.

Interpretation: We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β2-agonist combination treatment to triple therapy using a single inhaler.

Funding: Chiesi Farmaceutici SpA.
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http://dx.doi.org/10.1016/S0140-6736(16)31354-XDOI Listing
September 2016

Inhaled beclometasone dipropionate/formoterol fumarate extrafine fixed combination for the treatment of asthma.

Expert Rev Respir Med 2016 16;10(5):481-90. Epub 2016 Mar 16.

a Department of Clinical and Experimental Medicine, Respiratory Disease and Lung Function Unit , University of Parma , Parma , Italy.

Inhaled therapy is often considered the cornerstone of asthma management and international guidelines recommend combination therapy of inhaled corticosteroids (ICS) and long-acting-beta2-agonists (LABA) in a large proportion of asthmatic patients. The effectiveness of ICS/LABA is dependent on the correct choice of device and proper inhalation technique, this influences drug delivery and distribution along the bronchial tree, including the most peripheral airways. The fixed combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) is the only extrafine formulation available in pressurized metered dose inhaler (pMDI) and in dry powder inhaler (DPI). Here, we focus on the recent significant advances regarding BDP/FF fixed combination for the treatment of asthma.
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http://dx.doi.org/10.1586/17476348.2016.1161508DOI Listing
January 2017

Pharmacokinetics and pharmacodynamics of an extrafine fixed pMDI combination of beclometasone dipropionate/formoterol fumarate in adolescent asthma.

Br J Clin Pharmacol 2015 Sep 1;80(3):569-80. Epub 2015 Jun 1.

Department of Pediatrics and Allergy, Medical University of Lodz, Poland.

Aim: The aim was to investigate the pharmacokinetics and pharmacodynamics of an extrafine pressurized metered-dose inhaler (pMDI) fixed combination of beclometasone dipropionate (BDP)/formoterol fumarate (FF) in adolescent and adult asthma.

Methods: This was a three-way crossover study, on 30 asthmatic adolescents receiving BDP/FF pMDI with or without a valved holding chamber (VHC) or a free licenced combination of BDP pMDI and FF pMDI plus a parallel arm of 30 asthmatic adults receiving BDP/FF pMDI. All patients received a single dose of BDP and FF of 400 µg and 24 µg, for each treatment, respectively. Assessments were performed over 8 hours.

Results: In adolescents, the 90% confidence intervals (CIs) for the systemic exposure (AUC(0,t)) geometric mean ratio of the fixed combination with or without VHC vs. the free combination were within the bioequivalence range 0.80-1.25, both for beclometasone-17-monopropionate (B17MP, the active metabolite of BDP) and formoterol. Pharmacodynamic variables for plasma potassium and glucose, pulse rate and pulmonary function in adolescents were equivalent between treatments, 95% CI within 0.9, 1.09. The upper level of 90% CIs for AUC(0,t) geometric mean ratio adolescents : adults of B17MP and formoterol after treatment with BDP/FF pMDI was lower than 1.25, 90% CI 0.78, 1.04 and 0.86, 1.17, respectively.

Conclusions: In adolescents the pharmacodynamics and the overall systemic exposure to the active ingredients of an extrafine fixed combination of BDP/FF pMDI with or without a VHC was equivalent to that of a free licenced combination of pMDIs of established safety and efficacy profiles. The systemic exposure in adolescents was not higher than in adults. These results support the indication for use of inhaled corticosteroid/long acting β2 -adrenoceptor agonist pMDIs in adolescents at the same dosage as in adults.
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http://dx.doi.org/10.1111/bcp.12640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574841PMC
September 2015

Extrafine beclomethasone/formoterol combination via a dry powder inhaler (NEXThaler(®)) or pMDI and beclomethasone monotherapy for maintenance of asthma control in adult patients: A randomised, double-blind trial.

Pulm Pharmacol Ther 2015 Feb 1;30:121-7. Epub 2014 Aug 1.

Chiesi Farmaceutici S.p.A., Parma, Italy.

Background: The fixed combination of extrafine beclomethasone dipropionate and formoterol fumarate (BDP/FF) pMDI (Foster(®)) is approved for treatment of adult asthmatic patients. In order to provide an alternative drug delivery system for BDP/FF to physicians and patients, a dry powder inhaler (NEXThaler(®)) has been developed, capable to deliver extrafine particles to the lungs and therefore improve the dosing of the drugs, especially in patients with poor hand-breath coordination.

Objective: This trial was performed to compare efficacy and safety of extrafine BDP/FF NEXThaler(®) with extrafine BDP/FF pMDI or non-extrafine BDP DPI alone in adult patients with controlled asthma.

Methods: In this 8-week randomised, double-blind, parallel-group trial, patients were randomized to receive either extrafine BDP/FF NEXThaler(®) 100/6 μg bid, extrafine BDP/FF 100/6 μg pMDI bid or non-extrafine BDP DPI 100 μg bid. The primary efficacy variable was change from baseline to the entire 8-week randomised treatment period in average pre-dose morning PEF.

Results: The ITT population comprised 754 patients. Extrafine BDP/FF NEXThaler(®) was non-inferior (pre-defined margin: -15 L/min) relative to extrafine BDP/FF pMDI (mean difference: -1.84; 95% CI: -6.73, 3.05) in terms of the primary efficacy variable, change from baseline in average pre-dose morning PEF. Statistical superiority of both extrafine BDP/FF formulations over non-extrafine BDP DPI was demonstrated for the primary efficacy variable (providing evidence of assays sensitivity of the trial), ACQ score and percentage of rescue medication use-free days. No significant safety signals were observed.

Conclusion: NEXThaler(®) is an effective and well-tolerated delivery device for treatment of patients with asthma who need a regular treatment.
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http://dx.doi.org/10.1016/j.pupt.2014.07.006DOI Listing
February 2015

Comparing usability of NEXThaler(®) with other inhaled corticosteroid/long-acting β2-agonist fixed combination dry powder inhalers in asthma patients.

J Aerosol Med Pulm Drug Deliv 2014 Oct 3;27(5):363-70. Epub 2013 Dec 3.

1 Krankenhaus Bethanien Moers, Moers, Germany .

Background: Inhaler mishandling is a common issue among patients suffering from asthma and is associated with poor clinical outcomes and greater consumption of health-care resources. Ease of use can improve inhaler technique and, possibly, patients' preference for their inhaler device, which in turn may lead to better adherence to therapy.

Methods: This study investigated usability characteristics of NEXThaler(®) versus two other dry powder inhalers (DPIs; Diskus(®) and Turbuhaler(®)). Sixty-six adult patients with asthma (mean age 42.9±17.7 years) and with no previous experience of using a DPI were included in a randomized crossover comparison of the three devices. The main measures of usability were the number of steps failed for each device and the number of people who were able to use the device successfully (effectiveness), the time it took patients to set up the device and the time to read the instructions for use (IFU; efficiency), and patient preferences (satisfaction). Inhaler technique was evaluated after the IFU leaflet was read.

Results: NEXThaler was found to be superior to the other two DPIs in terms of the number of device use failures (p<0.001), time to set up (p<0.001), and time to read IFU (p<0.001). Additionally, the proportion of participants who completed a successful inhalation without any errors at all was significantly higher for NEXThaler than for Diskus and Turbuhaler (p<0.001). Patients rated NEXThaler as the easiest to use and most preferred inhaler to own (p<0.001).

Conclusions: NEXThaler displayed better usability compared with Diskus and Turbuhaler. The improved usability and higher satisfaction with the device may contribute to increased patient adherence to asthma treatment.
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http://dx.doi.org/10.1089/jamp.2013.1086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175427PMC
October 2014

Effects of titanium dioxide nanoparticle exposure on neuroimmune responses in rat airways.

J Toxicol Environ Health A 2010 ;73(20):1353-69

Department of Pediatrics, West Virginia University School of Medicine, Morgantown, West Virginia 26506, USA.

Exposure to ambient nanoparticles (defined as particulate matter [PM] having one dimension <100 nm) is associated with increased risk of childhood and adult asthma. Nanomaterials feature a smaller aerodynamic diameter and a higher surface area per unit mass ratio compared to fine or coarse-sized particles, resulting in greater lung deposition efficiency and an increased potential for biological interaction. The neurotrophins nerve growth factor and brain-derived neurotrophic factor are key regulatory elements of neuronal development and responsiveness of airway sensory neurons. Changes in their expression are associated with bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The neurogenic-mediated control of airway responses is a key pathophysiological mechanism of childhood asthma. However, the effects of nanoparticle exposure on neurotrophin-driven airway responses and their potential role as a predisposing factor for developing asthma have not been clearly elucidated. In this study, in vivo inhalation exposure to titanium dioxide nanoparticles (12 mg/m(3); 5.6 h/d for 3 d) produced upregulation of lung neurotrophins in weanling (2-wk-old) and newborn (2-d-old) rats but not in adult (12-wk-old) animals compared to controls. This effect was associated with increased airway responsiveness and upregulation of growth-related oncogene/keratine-derived chemokine (GRO/KC; CXCL1, rat equivalent of human interleukin [IL]-8) in bronchoalveolar lavage fluid. These data show for the first time that exposure to nanoparticulate upregulates the expression of lung neurotrophins in an age-dependent fashion and that this effect is associated with airway hyperresponsiveness and inflammation. These results suggest the presence of a critical window of vulnerability in earlier stages of lung development, which may lead to a higher risk of developing asthma.
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http://dx.doi.org/10.1080/15287394.2010.497436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655524PMC
September 2010

The role of neurotrophins in inflammation and allergy.

Inflamm Allergy Drug Targets 2010 Jul;9(3):173-80

Department of Pediatrics, West Virginia University School of Medicine, Morgantown, USA.

Allergic inflammation is the result of a specific pattern of cellular and humoral responses leading to the activation of the innate and adaptive immune system which, in turn, results in physiological and structural changes affecting target tissues such as the airways and the skin. Eosinophils activation and production of soluble mediators such as IgE antibodies is a pivotal feature in the pathophysiology of allergic diseases. In the past few years, however, convincing evidence has shown that neurons and other neurosensory structures are not only a target of the inflammatory process but also participate in the regulation of immune responses by actively releasing soluble mediators. The main products of these activated sensory neurons are a family of protein growth factors called neurotrophins. They were first isolated in the central nervous system and identified as important factors for the survival and differentiation of neurons during fetal and post-natal development as well as neuronal maintenance later in life. Four members of this family have been identified and well defined: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), and neurotrophin 4/5 (NT-4/5). Neurotrophins play a critical role in the bidirectional signaling mechanisms between immune cells and the neurosensory network structures in the airways and the skin. Pruritus and airway hyperresponsiveness (AHR), two major features of atopic dermatitis and asthma, respectively, are associated with the disruption of the neurosensory network activities. In this review we provide a comprehensive description of the neuroimmune interactions underlying the pathophysiological mechanisms of allergic and inflammatory diseases.
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http://dx.doi.org/10.2174/187152810792231913DOI Listing
July 2010

Neurotrophic and neuroimmune responses to early-life Pseudomonas aeruginosa infection in rat lungs.

Am J Physiol Lung Cell Mol Physiol 2010 Sep 11;299(3):L334-44. Epub 2010 Jun 11.

Department of Pediatrics and Pediatric Research Institute, West Virginia University School of Medicine, Morgantown, West Virginia 26506-9214, USA.

Early-life respiratory infection with Pseudomonas aeruginosa is common in children with cystic fibrosis or immune deficits. Although many of its clinical manifestations involve neural reflexes, little information is available on the peripheral nervous system of infected airways. This study sought to determine whether early-life infection triggers a neurogenic-mediated immunoinflammatory response, the mechanisms of this response, and its relationship with other immunoinflammatory pathways. Weanling and adult rats were inoculated with suspensions containing P. aeruginosa (PAO1) coated on alginate microspheres suspended in Tris-CaCl(2) buffer. Five days after infection, rats were injected with capsaicin to stimulate nociceptive nerves in the airway mucosa, and microvascular permeability was measured using Evans blue as a tracer. PAO1 increased neurogenic inflammation in the extra- and intrapulmonary compartments of weanlings but not in adults. The mechanism involves selective overexpression of NGF, which is critical for the local increase in microvascular permeability and for the infiltration of polymorphonuclear leukocytes into infected lung parenchyma. These effects are mediated in part by induction of downstream inflammatory cytokines and chemokines, especially IL-1beta, IL-18, and leptin. Our data suggest that neurogenic-mediated immunoinflammatory mechanisms play important roles in airway inflammation and hyperreactivity associated with P. aeruginosa when infection occurs early in life.
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http://dx.doi.org/10.1152/ajplung.00017.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951071PMC
September 2010

Combined effects of chronic nicotine and acute virus exposure on neurotrophin expression in rat lung.

Pediatr Pulmonol 2009 Nov;44(11):1075-84

Ochsner Children's Health Center, New Orleans, Louisiana, USA.

Strong epidemiologic evidence indicates that tobacco smoke influences frequency and severity of respiratory infections. Previously, we have shown that infection with respiratory syncytial virus upregulates expression of neurotrophic factors and receptors in the lungs, but the effect of tobacco exposure on neurotrophins is unknown. Therefore, we first sought to determine the expression of neurotrophic pathways in lungs of rats chronically exposed to nicotine, and then we studied the interactions between pollution and infection by inoculating virus after nicotine exposure. Expression of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor, of their high-affinity tyrosine kinase receptors (trkA and trkB, respectively), and of the low-affinity receptor p75(NTR) was measured in the lungs of nicotine-exposed rats both at the mRNA level by reverse-transcription polymerase chain reaction and at the protein level by enzyme-linked immunoassay. Nicotine increased NGF expression both at the mRNA and protein level and also created a receptor imbalance deriving from increased expression of the pro-inflammatory p75(NTR) receptor without any concomitant change in the high-affinity trkA receptor. Viral infection after chronic nicotine exposure exerted an additive effect on NGF expression, and resulted in exaggerated neurogenic airway inflammation that was abolished by selective inhibition. In conclusion, nicotine levels comparable to those found in smokers are per se able to upregulate the expression of critical neurotrophic molecules in the respiratory tract, and combination of an acute infection following chronic nicotine exposure produces more severe neurotrophic dysregulation and neurogenic-mediated inflammation compared to either infection or nicotine alone.
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http://dx.doi.org/10.1002/ppul.21099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632456PMC
November 2009

Hyaluronan blocks porcine pancreatic elastase-induced mucociliary dysfunction in allergic sheep.

J Appl Physiol (1985) 2007 Jun 29;102(6):2324-31. Epub 2007 Mar 29.

Division of Pulmonary and Critical Care Medicine, Miller School of Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, FL 33140, USA.

Neutrophil elastase is a mediator common to asthma, chronic obstructive pulmonary disease, and cystic fibrosis and thought to contribute to the pathophysiology of these diseases. Previously, we found that inhaled hyaluronan blocked elastase-induced bronchoconstriction in allergic sheep through its control of tissue kallikrein. Here, we extend those studies by determining if inhaled hyaluronan can protect against the elastase-induced depression in tracheal mucus velocity, a surrogate marker of whole lung mucociliary clearance. We measured tracheal mucus velocity in allergic sheep before, and sequentially for 6 h after, aerosol challenge with porcine pancreatic elastase alone and after pretreatment with 1.5 or 6 mg aerosolized hyaluronan. Elastase (2.55 U) decreased tracheal mucus velocity. Pretreatment with 6 mg, but not 1.5 mg, hyaluronan inhibited the elastase-induced decrease in tracheal mucus velocity. Hyaluronan (6 mg) given 1 h after elastase challenge was ineffective, suggesting the involvement of secondary mediators. The elastase-induced depression in mucus transport appeared to be mediated, in part, by reactive oxygen species and bradykinin because pretreatment with either aerosolized catalase (38 mg/3 ml) or the bradykinin B2-receptor antagonist HOE140 (400 nM/kg) was also effective in blocking the response. These latter two findings are consistent with oxygen radical-induced degradation of hyaluronan with concomitant loss of its regulatory effect on tissue kallikrein, resulting in kinin generation. This hypothesis is supported by the demonstration that hyaluronan failed to block the oxygen radical-induced fall in tracheal mucus velocity resulting from xanthine-xanthine oxidase challenge and that inhaled bradykinin itself can slow mucociliary transport.
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http://dx.doi.org/10.1152/japplphysiol.00568.2006DOI Listing
June 2007

A novel prognostic index to determine the impact of cardiac conditions and co-morbidities on one-year outcome in patients with heart failure.

Am J Cardiol 2006 Oct 30;98(8):1076-82. Epub 2006 Aug 30.

Dipartimento Cardiovascolare, Ospedali Riuniti, Bergamo, Italy.

Prognostic stratification is relevant in clinical decision making in heart failure (HF). Predictors identified during hospitalization or in clinical trials may be unrepresentative of HF in the community. The aim of this study was to derive and validate, in different clinical settings, a risk stratification model for the prediction of stable HF outcomes. The study included 807 patients, 350 enrolled at discharge from the hospital (44%), 309 in the outpatient clinic (38%), and 148 in the home-care setting (18%). There were 292 patients in the derivation cohort and 515 in the validation cohort. A multivariate logistic analysis was performed to obtain the CardioVascular Medicine Heart Failure (CVM-HF) index. One-year mortality was 20.8% in the derivation cohort and 20.7% in the validation cohort. The CVM-HF index included cardiac conditions and co-morbidities and stratified the 1-year mortality risk as low (death rate 4%), average (32%), high (63%), and very high (96%). The area under the curve of the receiver-operating characteristic curve was 0.844 (95% confidence interval [CI] 0.779 to 0.89) for the derivation cohort and 0.812 (95% CI 0.76 to 0.86) for the validation cohort. Model performance was equally good in the 3 different HF settings. In a subgroup of 409 patients, the CVM-HF index (area under the curve 0.821, 95% CI 0.79 to 0.89) outperformed the most-used prognostic models (the Charlson index and the Heart Failure Risk Scoring System). In conclusion, the CVM-HF index, a novel prognostic model that is easy to derive and applicable to unselected patients, may represent a valuable tool for the prognostication of stable HF outcomes.
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http://dx.doi.org/10.1016/j.amjcard.2006.05.031DOI Listing
October 2006

Peptide and non-peptide bradykinin receptor antagonists: role in allergic airway disease.

Eur J Pharmacol 2006 Mar 7;533(1-3):215-21. Epub 2006 Feb 7.

Miller School of Medicine, University of Miami at Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, Florida 33140, USA.

Kinins are proinflammatory peptides that mediate a variety of pathophysiological responses. These actions occur through stimulation of two pharmacologically distinct receptor subtypes B1 and B2. In both human and animal airways, the majority of kinin-induced effects including bronchoconstriction, increases in vascular permeability and mucus secretion and cholinergic and sensory nerve stimulation appear to be bradykinin B2-receptor mediated. Peptidic and non-peptidic receptor antagonists have been developed as potential therapeutic agents. These antagonists are effective in blocking kinin-induced effects in a variety of animal models and in some instances, have been used effectively in animal models of allergic airway disease to alleviate allergen-induced pathophysiological airway responses. This review summarizes relevant studies supporting the evidence that bradykinin B2 receptor antagonism and/or upstream inhibition of tissue kallikrein will be beneficial in the treatment of inflammatory airway diseases.
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http://dx.doi.org/10.1016/j.ejphar.2005.12.071DOI Listing
March 2006

Hyaluronan blocks human neutrophil elastase (HNE)-induced airway responses in sheep.

Pulm Pharmacol Ther 2003 ;16(6):335-40

Division of Pulmonary and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140, USA.

Hyaluronan (HA) blocks inhaled porcine pancreatic elastase-induced bronchoconstriction in sheep with airway hypersensitivity to Ascaris suum antigen. Since elastases from other species may display different catalytic properties compared to the human enzyme, we tested the efficacy of HA on human neutrophil elastase (HNE)-induced airway responses. We measured pulmonary resistance in allergic sheep before and after inhalation of HNE alone and after pretreatment with a 150 kD-HA (LKDHA; 3 and 15 mg), or a 300 kD-HA (HKDHA; 6, 7.5, and 15 mg). HKDHA (3 mg) was given either 0.5, 4, or 8 h before HNE challenge; LKDHA (15 mg) and HKDHA (6, 7.5, and 15 mg) were given 8 h before challenge. HNE caused an acute bronchoconstriction which was blocked by 3 mg LKDHA given 0.5 or 4 h before challenge. LKDHA (3 mg) given 8 h before challenge was ineffective, but protection was achieved by increasing the dose to 15 mg. When HKDHA at 6, 7.5, and 15 mg was given 8 h before challenge a dose-dependent inhibition of the HNE-induced airway response was observed. We conclude that HA inhibits HNE-induced airway responses and that within the range of 150-300 kD, dose rather than molecular weight may be the most important determinant of pretreatment time resulting in a protective effect.
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http://dx.doi.org/10.1016/S1094-5539(03)00089-0DOI Listing
June 2004

Recombinant alpha 1-proteinase inhibitor blocks antigen- and mediator-induced airway responses in sheep.

J Appl Physiol (1985) 2002 Dec;93(6):1900-6

Division of Pulmonary and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140, USA.

Alpha(1)-proteinase inhibitor (alpha(1)-PI) is a natural serine protease inhibitor. Although mainly thought to protect the airways from neutrophil elastase, alpha(1)-PI may also regulate the development of airway hyperresponsiveness (AHR), as indicated by our previous findings of an inverse relationship between lung alpha(1)-PI activity and the severity of antigen-induced AHR. Because allergic stimulation of the airways causes release of elastase, tissue kallikrein, and reactive oxygen species (ROS), all of which can reduce alpha(1)-PI activity and contribute to AHR, we hypothesized that administration of exogenous alpha(1)-PI should protect against pathophysiological airway responses caused by these agents. In untreated allergic sheep, airway challenge with elastase, xanthine/xanthine oxidase (which generates ROS), high-molecular-weight kininogen, the substrate for tissue kallikrein, and antigen resulted in bronchoconstriction. ROS and antigen also induced AHR to inhaled carbachol. Treatment with 10 mg of recombinant alpha(1)-PI (ralpha(1)-PI) blocked the bronchoconstriction caused by elastase, high-molecular-weight kininogen, and ROS, and the AHR induced by ROS and antigen. One milligram of ralpha(1)-PI was ineffective. These are the first in vivo data demonstrating the effects of ralpha(1)-PI. Our results are consistent with and extend findings obtained with human plasma-derived alpha(1)-PI and suggest that alpha(1)-PI may be important in the regulation of airway responsiveness.
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http://dx.doi.org/10.1152/japplphysiol.00400.2002DOI Listing
December 2002
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