Improvement of asthma control in adult patients using extrafine inhaled beclomethasone/formoterol fixed combination as maintenance therapy as well as maintenance and reliever therapy - CONTROL study.

INTRODUCTION: Extrafine formulation of beclomethasone/formoterol fixed combination (BDP/F pMDI HFA) is approved for both fixed maintenance and maintenance and reliever therapy (MART) of asthma, and recent data has proven that BDP/F pMDI HFA maintenance and reliever therapy is an effective alternative to other regimens. OBJECTIVE: This study aimed to assess the level of asthma control in a real-life setting in adult patients using extrafine BDP/F pMDI HFA fixed combination in a pressurized metered-dose inhaler (pMDI) as fixed maintenance dosing as well as maintenance and maintenance and reliever therapy. Additionally, we examined patients' satisfaction with the inhaler device and compliance with therapy as essential factors determining asthma control. METHODS: This multicenter prospective non-interventional observational study lasted 4 months with 3 patient visits. We used the Asthma Control Questionnaire 7 (ACQ-7) to evaluate the degree of asthma control and Morisky Medication Adherence Scale (MMAS-4) to assess compliance. A self-developed questionnaire was used to assess satisfaction with the inhaler device. RESULTS: 2179 patients using BDP/F pMDI HFA fixed combination as maintenance and reliever therapy or BDP/F pMDI HFA as maintenance therapy and SABA (short-acting beta2-agonist) as a reliever for at least 2 months were included. During the prospective follow-up, we observed an upward trend in the FEV1% (forced expiratory volume in 1 s) predicted values, improvement in the control of symptoms as indicated by a decline in the mean ACQ-7 score was noted (1.62 at Visit 1 vs. 1.21 at Visit 2 vs. 0.94 at Visit 3, p < 0.001) and increase in patients' compliance (the number of patients that reported forgetting at times to take their medication was reduced from 49.7 % to 27.1 %, p < 0.001). At the same time, we noted a reduction in the number of as-needed doses used for symptom relief (p < 0.001). Most patients were satisfied with the pMDI, considered it easy and convenient to use, and preferred it to a dry powder inhaler (p < 0.001). CONCLUSIONS: The use of extrafine BDP/F pMDI HFA as maintenance as well as reliever therapy seems to be associated with increased asthma control and better compliance to therapy.

Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study.

OBJECTIVE: When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. METHODS: After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. RESULTS: Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the -15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: -0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. CONCLUSIONS: The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.

Assessment of extrafine beclomethasone/formoterol for the treatment of chronic obstructive pulmonary disease: A non-interventional study in a Bulgarian population.

BACKGROUND: The beneficial effects of application of a fixed dose beclomethasone dipropionate (BDP) and formoterol fumarate (F) for the treatment of severe chronic obstructive disease (COPD) has been amply proven in well controlled clinical trials. Whether this also holds for real-world conditions and in such a heterogeneous patient population as is encountered in Bulgaria remained to be investigated. METHODS: In an observational, non-interventional study, 441 Bulgarian patients with severe COPD who were enrolled at 36 sites across the country received extrafine BDP/FF-combination therapy using the NEXThaler® DPI or the Foster® pMDI over a period of 16 weeks. At visits at the beginning, after 4 weeks and at the end of the study, alterations in lung function parameters FEV1 and FVC, disease symptoms, changes in CAT score, and patient distribution in GOLD 2017 categories A through D were assessed. RESULTS: A large share of the Bulgarian patients with severe COPD suffered from serious comorbidities, received additional medication, and about 2/3 were former or current smokers. Extrafine BDP/FF caused an increase in mean FEV1, FVC, a decrease of health impact as assessed by the CAT score, and a considerable shift of the share of category C and D patients towards A and B. In addition, the percentage of patients that were free of symptoms impacting everyday life such as fatigue and shortness of breath at rest increased throughout the study. A comparison of both application devices indicated that the NEXThaler® was superior in terms of lung functional aspects, as these parameters displayed a constant improvement over the observation period, whereas they plateaued at week 4 when using the pMDI. CONCLUSIONS: The therapeutic benefits of extrafine BDP/FF known from clinical trials could also be observed in a real-world setting, even in such a heterogenous patient population as the Bulgarian. The NEXThaler® appeared to be highly efficient in this setting, opening a new choice for the lung specialist and the patient to select the one device considered most suitable and practical.

Efficacy and safety of single-inhaler extrafine triple therapy versus inhaled corticosteroid plus long-acting beta2 agonist in eastern Asian patients with COPD: the TRIVERSYTI randomised controlled trial.

BACKGROUND: A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. METHODS: TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) < 50% predicted, ≥ 1 exacerbation in the previous 12 months, and receiving inhaled maintenance medication. Patients received either extrafine BDP/FF/G 100/6/10 µg via pressurised metered-dose inhaler, or non-extrafine budesonide/formoterol (BUD/FF) 160/4.5 µg via dry-powder inhaler, both administered as two puffs twice-daily for 24 weeks. The co-primary objectives (analysed in the overall population) were to demonstrate superiority of BDP/FF/G over BUD/FF for change from baseline in pre-dose morning and 2-h post-dose FEV1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. RESULTS: Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p < 0.001]. The annualised moderate/severe exacerbation rate was 43% lower with BDP/FF/G [rate ratio 0.57 (95% CI 0.42, 0.77); p < 0.001]. Adverse events were reported by 61.1% and 67.0% patients with BDP/FF/G and BUD/FF. Results were similar in the China subgroup. CONCLUSIONS: In patients with COPD, FEV1 < 50% and an exacerbation history despite maintenance therapy, treatment with extrafine BDP/FF/G improved bronchodilation, and was more effective at preventing moderate/severe COPD exacerbations than BUD/FF. Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html ).

Treatment response according to small airways disease status: The effects of high-strength extrafine pMDI beclomethasone dipropionate/formoterol fumarate in fixed dose combination in moderate uncontrolled asthmatic patients.

BACKGROUND: Inflammation in small airways is particularly clinically active in severe asthma but they still continue to be ignored as considered silent. Recently, the Atlantis study reports small airways involvement in 91% of the asthma population. Therefore in the era of phenotype driven therapy, the aim of this study was to verify if high-strength extrafine ICS/LABA in fixed dose increases clinical efficacy in moderate asthmatic patients with small airways dysfunction and it could be proposed as phenotype driven therapy. METHODS: In this prospective, non-interventional, real-life pilot study we enrolled 37 consecutive patients with moderate asthma who were uncontrolled despite GINA step 3 treatment. All subjects at enrollment were divided in two groups according to the presence of small airways dysfunction:1) small airways phenotype (SAP) group: smokers (≥10 packs/die), ex-smokers (>20 packs/year) with air trapping (FVC <80% - VR >100% - FEF 25-75%<60%); 2) non-small airways phenotype (NSAP) group: non-smokers, without air trapping (FVC ≥80% - VR ≤ 100% - FEF 25-75%≥60%). We later proceeded in both groups with a step up in therapy with high-strength extrafine pMDI beclomethasone dipropionate/formoterol fumarate (BDP/FF) (200/6 µg) in fixed dose to achieve a better control and followed patients for 6 months. RESULTS: Treatment with extrafine BDP/FF(200/6 µg) in SAP group showed a more significant improvement of FEF25-75%, FVC, RV, and a reduction of alveolar inflammatory markers such as FENO350 and alveolar exhaled pH compared with NSAP patients. CONCLUSIONS: Our preliminary results support the use of high-strength extrafine pMDI BDP/FF (200/6 µg) as phenotype driven treatment directed to small airways dysfunction demonstrating an increase of clinical efficacy in moderate asthmatics with SAP.

Marginal and internal fit of CAD/CAM fiber post and cores.

AIM: To evaluate the marginal adaptation and internal fit of milled fiber post and cores using different scanning methods. MATERIALS AND METHODS: Thirty typodont tooth models (Nissin) with pulp cavity were endodontically treated and prepared to receive 30 fabricated fiber post and cores. Three different methods of scanning were used (n = 10): an intraoral scanner (IOS) (Trios 3; 3Shape) to directly digitalize the post space (Group T) and a laboratory scanner to indirectly digitalize the resin pattern (Group RP) and the silicone impression (Group S) of the post space. All the specimens were examined using an optical microscope for the measurement of the vertical marginal discrepancy (VMD), and five in each group were scanned using microcomputed tomography (µCT) for the assessment of the VMD, the internal fit at the corner (IFC), post apex (PA), and at four horizontal cross-sections (CS1-4) inside the canal. All data were analyzed using mixed-design ANOVA, followed by pairwise testing to identify the differences (α = 0.05). RESULTS: Statistical analysis revealed that Group T was associated with the smallest cement space compared with Group RP (P = 0.001) and Group S (P < 0.001) for VMD using µCT or direct microscopy (OM) (P < 0.001). Similarly, the cement space for Group T was smaller than that of Group S (P = 0.039) when measured at the IFC (µCT), and smaller than Group RP (P = 0.025) when measured at CS1-4 (µCT), with CS1 larger than CS3 (P = 0.015). There was no significant difference at PA (P = 0.271). CONCLUSION: Better adaptation was achieved with a complete digital workflow. Scanning the resin pattern or the silicone impression introduced more variables in the digital process or milling of a one-piece fiber post and core.

Predictors of clinical response to extrafine and non-extrafine particle inhaled corticosteroids in smokers and ex-smokers with asthma.

We performed a post-hoc analysis of the OLiVIA-study investigating whether current and ex-smoking asthmatics with small airways dysfunction (SAD) show a better response in airway hyperresponsiveness (AHR) to small particle adenosine after treatment with extrafine compared to non-extrafine particle inhaled corticosteroids (ICS), and to investigate which clinical parameters predict a favorable response to both treatments. We show that smoking and ex-smoking asthmatics with and without SAD have a similar treatment response with either extrafine or non-extrafine particle ICS. We also found that lower blood neutrophils are associated with a smaller ICS-response in smokers and ex-smokers with asthma, independent from the level of blood eosinophils.

Effectiveness of initiating extrafine-particle versus fine-particle inhaled corticosteroids as asthma therapy in the Netherlands.

BACKGROUND: Most randomised clinical trials typically exclude a significant proportion of asthma patients, including those at higher risk of adverse events, with comorbidities, obesity, poor inhaler technique and adherence, or smokers. However, these patients might differentially benefit from extrafine-particle inhaled corticosteroids (ICS). This matched cohort, database study, compared the effectiveness of extrafine-particle with fine-particle ICS in a real-life population initiating ICS therapy in the Netherlands. METHODS: Data were from the Pharmo Database Network, comprising pharmacy and hospital discharge records, representative of 20 % of the Dutch population. The study population included patients aged 12 - 60, with a General Practice-recorded diagnosis for asthma (International Classification of Primary Care code R96), when available, ≥2 prescriptions for asthma therapy at any time in their recorded history, and receiving first prescription of ICS therapy as either extrafine-particle (ciclesonide or hydrofluoroalkane beclomethasone dipropionate [BDP]) or fine-particle ICS (fluticasone propionate or non-extrafine-particle-BDP). Patients were matched (1:1) on relevant demographic and clinical characteristics over 1-year baseline. Primary outcomes were severe exacerbation rates, risk domain asthma control and overall asthma control during the year following first ICS prescription. Secondary outcomes, treatment stability and being prescribed higher versus lower category of short-acting ß2 agonists (SABA) dose, were compared over a 1-year outcome period using conditional logistic regression models. RESULTS: Following matching, 1399 patients were selected in each treatment cohort (median age: 43 years; males: 34 %). Median (interquartile range) initial ICS doses (fluticasone-equivalents in µg) were 160 (160 - 320) for extrafine-particle versus 500 (250 - 500) for fine-particle ICS (p < 0.001). Following adjustment for residual confounders, matched patients prescribed extrafine-particle ICS had significantly lower rates of exacerbations (adjusted rate ratio [95 % CI], 0.59 [0.47-0.73]), and significantly higher odds of achieving asthma control and treatment stability in the year following initiation than those prescribed fine-particle ICS, and this occurred at lower prescribed doses. Patients prescribed extrafine-particle ICS had lower odds of being prescribed higher doses of SABA (0.50 [0.44-0.57]). CONCLUSION: In this historical, matched study, extrafine-particle ICS was associated with better odds of asthma control than fine-particle ICS in patients prescribed their first ICS therapy in the Netherlands. Of importance, this was reached at significantly lower prescribed dose.

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.

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.

Risk of Pneumonia in Patients with COPD Initiating Fixed Dose Inhaled Corticosteroid (ICS) / Long-Acting Bronchodilator (LABD) Formulations Containing Extrafine Beclometasone Dipropionate versus Patients Initiating LABD Without ICS.

Background: Combined ICS and long-acting bronchodilators (LABD) more effectively reduce COPD exacerbations than LABD therapy alone. Corticosteroid-related adverse effects, including pneumonia, limit ICS use. Previous data suggest this risk is lower for extrafine beclometasone (ef-BDP). We compared pneumonia risk among new users of fixed dose ICS/LABD formulations containing ef-BDP, versus patients initiating LABD without any ICS. Methods: A propensity-matched historical cohort study design used data from OPCRD. COPD patients with ≥1 year of continuous data who initiated LABD or ICS/LABD formulations containing ef-BDP were matched. Primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions, with non-inferiority boundary of 15%. Results: 23,898 COPD patients were matched, who were 68±11 years, 54.3% male and 56% current-smokers, while 43% were former-smokers. Initiation of ef-BDP/LABD was not associated with an increased risk of pneumonia versus LABD, for either a sensitive 0.89 (0.78-1.02), P = 0.08 or a specific 0.91 (0.78-1.05), P = 0.18 definition of pneumonia. The probability of remaining pneumonia free 1-year after ef-BDP/LABD was 98.4%, which was comparable to LABD at 97.7%, and was sustained up to 6 years of observation; non-inferiority criterion was met for both definitions. Initiation of ef-BDP/LABD was also associated with a reduced risk of developing LRTIs in the propensity matched cohort. Conclusion: Risk of pneumonia when using ICS for the management of COPD reported in several randomised controlled trials may not be relevant with ef-BDP in a diverse real-world clinical population.

Extrafine single inhaler triple therapy effectiveness in COPD patients previously treated with multiple-inhaler triple therapy: the TRIWIN study.

BACKGROUND: The extrafine single inhaler triple therapy (efSITT) containing beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 µg has proved to be efficacious in patients with chronic obstructive pulmonary disease (COPD) in randomized control trials. OBJECTIVE: TRIWIN study evaluated the effectiveness of efSITT delivering beclomethasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 µg in COPD patients previously treated with multiple-inhaler triple therapy (MITT) in a real-world study in Greece. DESIGN: Prospective, multicenter, observational, non-interventional study was conducted over 24 weeks. METHODS: A total of 475 eligible patients had moderate-to-severe COPD, an indication for treatment with efSITT, and were symptomatic despite receiving MITT. COPD Assessment Test (CAT) score, pulmonary function parameters, use of rescue medication, and adherence to inhaler use were recorded at baseline (Visit 1), 3 (Visit 2), and 6 months (Visit 3) after treatment. RESULTS: Mean CAT score decreased from 21.4 points at Visit 1, to 16.6 at Visit 2 and 15.1 at Visit 3 (p < 0.001 for all pair comparisons). At Visit 3, 79.8% of patients reached a CAT improvement exceeding minimal clinically important difference (⩾2), compared to baseline. Mean forced expiratory volume in 1 s (%pred.) increased from 55.4% at Visit 1 to 63.5% at the end of study period (p < 0.001), while mean forced vital capacity (%pred.) increased from 71.1% at Visit 1, to 76.7% at Visit 3 (p < 0.001). The mean Test of Adherence to Inhalers score increased from 42.5 to 45.3 and 46.3 points, for the three visits, respectively (p < 0.001 comparing Visits 1/2 and Visits 1/3; p = 0.006 comparing Visits 2/3). The percentage of patients showing good adherence rose from 33.7% at baseline to 58.3% at Visit 3. The percentage of patients using rescue medication during the last month dropped from 16.2% to 7.4% at the end of study period (p < 0.001). Pulmonary function parameters also improved. CONCLUSION: The TRIWIN results suggest that extrafine beclomethasone dipropionate/formoterol fumarate/glycopyrronium is effective in improving health status, pulmonary function, and adherence and in reducing rescue medication use in COPD patients previously treated with MITT, in a real-world setting in Greece.

Stepping-across controlled asthmatic patients to extrafine beclometasone/formoterol combination.

BACKGROUND: Asthma management focuses on achieving and maintaining asthma control. Few studies have assessed whether complete and sustained asthma control is maintained in clinical practice after stepping-across ICS/LABA fixed combinations. Aim of this double-blind, double-dummy, randomized, parallel group, controlled study was to demonstrate clinical equivalence between equipotent doses of extrafine beclometasone/formoterol (BDP/F) pMDI and fluticasone/salmeterol (FP/S) Diskus® in maintaining lung function and asthma control. METHODS: A total of 416 asthmatic patients already controlled with FP/S 500/100 µg/day (Diskus®, pMDI or separate inhalers) were randomized to a 12-week treatment with extrafine BDP/F 400/24 µg/day pMDI or FP/S 500/100 µg/day Diskus®. Pre-dose 1-s forced expiratory volume (FEV(1)) was the primary efficacy variable; secondary variables included asthma control questionnaire (ACQ-7) and FEV(1)0-1 h area under the curve (FEV(1)AUC(0-1h)). Safety was assessed through adverse events monitoring and vital signs. RESULTS: After 12 weeks of treatment, pre-dose FEV(1) did not differ between treatments (difference between means 0.01 L; 95% CI -0.03-0.06 L) with no significant changes from baseline in both groups (p = 0.726 and p = 0.783 in BDF/F arm and FP/S, respectively). ACQ-7 score showed that control was maintained after stepping-across to extrafine BDP/F. FEV(1)AUC(0-1h) was significantly higher in BDP/F arm at the beginning (p = 0.004) and at the end of the 12-week treatment period (p = 0.019). No safety issues were reported in both groups. CONCLUSIONS: Patients previously controlled with FP/S in any device formulation can effectively step-across to extrafine BDP/F pMDI, maintaining lung function and asthma control with a 5-min onset of action.

Evolving to a single inhaler extrafine LABA/LAMA/ICS - Inhalation technique and adherence at the heart of COPD patient care (TRIVOLVE).

OBJECTIVE: Incorrect inhaler use and poor treatment adherence have a negative impact on COPD outcomes. This multi-centre, single arm, non-interventional, phase IV study investigated whether inhalation technique, treatment adherence and patient outcomes change in patients who evolve from dual therapy or multiple inhaler triple therapy to single inhaler extrafine triple therapy (beclomethasone dipropionate (BDP, 87 µg), formoterol fumarate (FF, 5 µg) and glycopyrronium (G, 9 µg)) in combination with inhalation technique training. METHODS: A total of 126 COPD patients were included in the per protocol set. Inhalation technique and treatment adherence were assessed at baseline and at two visits at approximately 3 and 6 months of treatment with extrafine BDP/FF/G. In addition, lung function, symptom score, patient satisfaction and exacerbations (exploratory) were followed up. RESULTS: Before switching to single inhaler extrafine BDP/FF/G (baseline), any device errors and critical errors were detected for 28.8% and 9.6% of patients, respectively. After switching to BDP/FF/G, the percentage of patients with any device errors decreased to 14.0% (visit 2) and 16.3% (visit 3), without critical errors at the two follow-up visits. Treatment adherence increased from 67.5% at baseline to 75.8% (visit 2) and 80% (visit 3). In addition, lung function, symptom and patient satisfaction scores improved, whilst exacerbation rates substantially decreased. CONCLUSIONS: This observational study demonstrates that in eligible COPD patients in a real-life setting, the switch from dual therapy or multiple inhaler triple therapy to single inhaler extrafine BDP/FF/G in combination with inhalation technique training is associated with improved inhalation technique and adherence.

Dual-Network Structured Nanofibrous Membranes with Superelevated Interception Probability for Extrafine Particles.

Airborne particulate matter (PM) pollution has caused a public health threat, including nanoscale particles, especially with emerging infectious diseases and indoor and vehicular environmental pollution. However, most existing indoor air filtration units are expensive, energy-intensive, and bulky, and there is an unavoidable trade-off between low-efficiency PM0.3/pathogen interception, PM removal, and air resistance. Herein, we designed and synthesized a two-dimensional continuous cellulose-sheath/net with a unique dual-network corrugated architecture to manufacture high-efficiency air filters and even N95 particulate face mask. Combined with its sheath/net structured pores (size 100-200 nm) consisting of a cellulose framework (1-100 nm diameter), the cellulose sheath/net filter offers high-efficiency air filtration (>99.5338%, Extrafine particles; >99.9999%, PM2.5), low-pressure drops, and a robustness quality factor of >0.14 Pa-1, utilizing their ultralight weight of 30 mg/m2 and physical adhesion and sieving behaviors. Simultaneously, masks prepared with cellulose-sheath/net filters are more likely to capture and block smaller particles than the N95 standard. The synthesis of such materials with their nanoscale features and designed macrostructures may suggest new design criteria for a novel generation of high-efficiency air filter media for different applications such as personal protection products and industrial dust removal.

"Extrafine single inhaler triple therapy effect on health status, lung function and adherence in COPD patients: A Panhellenic prospective non-interventional study - The TRIBUNE study".

The extrafine single inhaler triple therapy (efSITT) containing beclometasone dipropionate/formoterol fumarate/glycopyrronium 87/5/9 µg has proved to be efficacious in patients with Chronic Obstructive Pulmonary Disease (COPD) in randomized control trials. TRIBUNE study aimed to assess the efSITT effectiveness on health status, lung function, adherence and rescue medication use in COPD patients in Greece in a real-world setting. This was a 24-week prospective, multicenter, observational study in 1,195 patients with moderate/severe COPD and history of at least one exacerbation during the previous year despite dual therapy. Health status (COPD Assessment Test/CAT), lung function parameters and rescue medication use were recorded at baseline, 3 (Visit 2/V2) and 6 months (Visit 3/V3) after treatment. Adherence (Test of Adherence to Inhalers/TAI) and self-reported overall impression of health condition change (Visual Analogue Scale/VAS) were recorded at V2 and V3. Mean CAT score decreased from 20.9 points at V1, to 15.1 at V2 and 13 at V3 (p < 0.001, all pair comparisons). 85.9% of patients achieved a CAT decrease of minimal clinically important difference (MCID) or more (≥2) at V3, compared to V1. Mean FEV1 increased from 1.4 ± 0.5 L on V1, to 1.6 ± 0.5 L on V3 (p < 0.001, N = 275). The percentage of patients with "good adherence" increased from 58.4% (V2) to 64.0% (V3). Rescue medication use and VAS also significantly improved. The efSITT achieves improved outcomes on health status, lung function and rescue medication use as well as satisfactory adherence and patient-reported improvement of health condition, in moderate/severe COPD patients previously treated with a dual combination in a Greek real-world setting.

No-shaking and shake-fire delays affect respirable dose for suspension but not solution pMDIs.

It has long been accepted that suspension pressurized metered-dose inhalers (pMDIs) must be shaken if a correct dose is to be delivered, if not, it will usually be higher than the label claim. The purpose of this work was to investigate the influence of the device being unshaken, shaken and after a period of delay in pMDI actuation on the Fine Particle Mass (<5 µm), Extra Fine Particle Mass (<2 µm) and MMAD. Solution and suspension commercial pMDIs containing one, two or three components were used in the study. Most of the suspension pMDIs produced variable amounts of respirable size drug following the shake-fire delays tested in terms of the label claim dose. The effect was even more critical if the inhaler was not shaken and the FPM was found to be between -82 % for Symbicort and 363 % for Ventolin compared with the control values. In the case of MMAD measurements, Seretide and Serzyl inhalers showed the largest change from around 3 µm to 4.2-5.1 µm when not shaken. Conversely, the FPM and MMAD for the solution aerosols remained unchanged whether or not they were shaken or when a progressive increase in the delay in actuation after shaking was employed.

Cyclosporine A-loaded chitosan extra-fine particles for deep pulmonary drug delivery: In vitro and in vivo evaluation.

In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 µm and 1.94 ± 0.02 µm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 µm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.

Why small particle fixed dose triple therapy? An excursus from COPD pathology to pharmacological treatment evolution.

Although bronchodilators are the cornerstone in chronic obstructive pulmonary disease (COPD) therapy, the treatment with a single-agent bronchodilator may not provide adequate symptoms control in COPD. The combination of drugs with different mechanisms of action may be more effective in inducing bronchodilation and preventing exacerbations, with a lower risk of side-effects in comparison with the increase of the dose of a single molecule. Several studies comparing the triple therapy with the association of long-acting ß2 agonist (LABA)/inhaled corticosteroid (ICS) or long-acting muscarinic antagonist (LAMA)/LABA reported improvement of lung function and quality of life. A significant reduction in moderate/severe exacerbations has been observed with a fixed triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) in a single inhaler. The TRILOGY, TRINITY and TRIBUTE studies have provided confirming evidence for a clinical benefit of triple therapy over ICS/LABA combination treatment, LAMA monotherapy and LABA/LAMA combination, with prevention of exacerbations being a key finding. A pooled post hoc analysis of the published clinical studies involving BDP/FF/G fixed combination demonstrated a reduction in fatal events in patients treated with ICS-containing medications, with a trend of statistical significance [hazard ratio = 0.72, 95% confidence interval (CI) 0.50-1.02, p = 0.066], that becomes significant if we consider reduction in fatal events for non-respiratory reasons (hazard ratio = 0.65, 95% CI 0.43-0.97, p = 0.037). In conclusion, a fixed combination of more drugs in a single inhaler can improve long-term adherence to the therapy, reducing the risk of exacerbations and hospital resources utilization. The twice a day administration may provide a better coverage of night, particularly in COPD patients who are highly symptomatic. The inhaled extrafine formulation that allows drug deposition in both large and small - peripheral - airways, is the value added.

Interclass Difference in Pneumonia Risk in COPD Patients Initiating Fixed Dose Inhaled Treatment Containing Extrafine Particle Beclometasone versus Fine Particle Fluticasone.

BACKGROUND: Inhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP). METHODS: A propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥40 years with ≥1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions. RESULTS: A total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 µg; propionate 710 µg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 µg), irrespective of definition (sensitive HR 1.38 95% CI 1.14-1.68; specific HR 1.31 95% CI 1.05-1.62). CONCLUSION: In the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.