Single-inhaler triple vs single-inhaler dual therapy in patients with chronic obstructive pulmonary disease: a meta-analysis of randomized control trials.

BACKGROUND: In some RCTs comparing triple therapy with dual therapy in COPD, there might be a bias resulting from the use of multiple inhaler devices. This meta-analysis included only RCTs that compared ICS/LABA/LAMA vs. LABA/LAMA or ICS/LABA using a single device. METHODS: We systematically reviewed randomized controlled trials (RCTs) of single-inhaler triple therapy in patients with COPD. We searched the PubMed, MEDLINE (OvidSP), EMBASE and Cochrane Library databases to investigate the effect of single-inhaler triple therapy in COPD. The primary end points were the effect of single-inhaler triple therapy compared with single-inhaler dual therapy on all-cause mortality, the risk of acute exacerbation of COPD (AECOPD), and some safety endpoints. The Cochrane Collaboration tool was used to assess the quality of each randomized trial and the risk of bias. RESULTS: A total of 25,171 patients suffering from COPD were recruited for the 6 studies. This meta-analysis indicated that single-inhaler triple therapy resulted in a significantly lower rate of all-cause mortality than LABA/LAMA FDC (risk ratio, 0.70; 95% CI 0.56-0.88). Single-inhaler triple therapy reduced the risk of exacerbation and prolonged the time to first exacerbation compared with single-inhaler dual therapy. The FEV1 increased significantly more under single-inhaler triple therapy than under ICS/LABA FDC (mean difference, 103.4 ml; 95% CI 64.65-142.15). The risk of pneumonia was, however, significantly higher with ICS/LAMA/LABA FDC than with LABA/LAMA FDC (risk ratio, 1.55; 95% CI 1.35-1.80). CONCLUSIONS: This meta-analysis suggests that single-inhaler triple therapy is effective in reducing the risk of death of any cause and of moderate or severe exacerbation in COPD patients. However, the risk of pneumonia is higher with ICS/LAMA/LABA FDC than with LABA/LAMA FDC. Trial registration PROSPERO #CRD42020186726.

Availability of substances for use in personal vaporisers on three online cryptomarkets.

BACKGROUND: Personal vaporisers are gaining popularity as an alternative route of administration for a range of substances. Online cryptomarkets are becoming increasingly popular among people who use substances due to their perceived anonymity, ease of use, and reduced risk of violence compared to traditional face-to-face dealers. We examined the diversity of substances marketed for use in a personal vaporiser on these marketplaces. METHODS: Vaping related listings were extracted from three online cryptomarkets ('Agartha', 'Cryptonia', and 'Tochka') using The Onion Router browser. Data collection occurred between October and November 2019. RESULTS: We identified 1929 listings from 201 unique sellers. The top product on Agartha, Cryptonia, and Tochka were vape cartridges prefilled with the e-liquid (70.4 %, 39.4 %, 52.3 % respectively). The most common substance in these products was cannabis oil (96.1 %, 82.1 %, 87.8 %), followed by synthetic cannabinoids (3.7 %, 9.7 %, 9.8 %) and psychedelic substances (0.2 %, 6.4 %, 1.2 %). Vendors were primarily from the USA. Many products offered worldwide shipping (96.3 %, 42.4 %, 51.2 %). CONCLUSION: Vaping products listed on online cryptomarkets in 2019 primarily contained cannabis oils. Future studies should continue to examine cryptomarkets to identify emerging trends of substances that can be used in personal vaporisers.

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

BACKGROUND: Indacaterol maleate delivered with the Breezhaler® inhalation device is a long-acting ß2-agonist approved for chronic obstructive pulmonary disease. In the development of a once daily, inhaled fixed dose combination (FDC) of indacaterol, glycopyrronium bromide (a long-acting muscarinic antagonist), and mometasone furoate (an inhaled corticosteroid [ICS]) for the treatment of patients with asthma, the acetate salt of indacaterol is used instead of the maleate salt. Here, we investigated the lung function, pharmacokinetics (PK) and safety of indacaterol maleate 150 µg once daily (o.d.) and indacaterol acetate 150 µg o.d. in comparison with placebo. METHODS: This was a randomised, double-blind, three-period crossover study (ClinicalTrials.gov identifier, NCT03257995) in patients with asthma on background ICS therapy. Patients with percent predicted pre-bronchodilator forced expiratory volume per second (FEV1) ≥50% and ≤ 90% were included in the study. Patients received indacaterol maleate 150 µg o.d., indacaterol acetate 150 µg o.d., or placebo on top of stable background ICS in randomised sequence. Trough FEV1 was assessed after 14 days of treatment. PK of indacaterol salts were assessed at steady state after 14 days of treatment; peak expiratory flow (PEF) rate and rescue medication use were collected with a combined PEF-meter/electronic diary throughout the study. RESULTS: Of the 54 adult patients (median age of 48 years), 51 patients completed the study. Both indacaterol salts demonstrated statistically significant improvements in trough FEV1 of 186 mL (maleate) and 146 mL (acetate) compared with placebo (both P < 0.001). FEV1 AUC0-4h improved by 248 mL (maleate) and 245 mL (acetate), and PEF by 33 L/min (maleate) and 30.8 L/min (acetate) versus placebo. Systemic exposure of indacaterol (AUC0-24h,ss and Cmax,ss on Day 14) was comparable after administration of both salt forms. Both salt forms demonstrated a good safety profile and were well tolerated, with a difference in the reporting frequency of AEs of coughing (maleate, 23.5%; acetate, 0%). CONCLUSIONS: In patients with asthma, indacaterol maleate and acetate elicited comparable and significant improvements in lung function compared with placebo and achieved comparable systemic exposure. Both indacaterol salts were safe and well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov NCT03257995 June 06, 2017.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol and umeclidinium/vilanterol in patients with COPD: results on cardiovascular safety from the IMPACT trial.

BACKGROUND: This analysis of the IMPACT study assessed the cardiovascular (CV) safety of single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI and UMEC/VI dual therapy. METHODS: IMPACT was a 52-week, randomized, double-blind, multicenter Phase III study comparing the efficacy and safety of FF/UMEC/VI 100/62.5/25 mcg with FF/VI 100/25 mcg or UMEC/VI 62.5/25 mcg in patients ≥40 years of age with symptomatic chronic obstructive pulmonary disease (COPD) and ≥1 moderate/severe exacerbation in the previous year. The inclusion criteria for the study were intentionally designed to permit the enrollment of patients with significant concurrent CV disease/risk. CV safety assessments included proportion of patients with and exposure-adjusted rates of on-treatment CV adverse events of special interest (CVAESI) and major adverse cardiac events (MACE), as well as time-to-first (TTF) CVAESI, and TTF CVAESI resulting in hospitalization/prolonged hospitalization or death. RESULTS: Baseline CV risk factors were similar across treatment groups. Overall, 68% of patients (n = 7012) had ≥1 CV risk factor and 40% (n = 4127) had ≥2. At baseline, 29% of patients reported a current/past cardiac disorder and 58% reported a current/past vascular disorder. The proportion of patients with on-treatment CVAESI was 11% for both FF/UMEC/VI and UMEC/VI, and 10% for FF/VI. There was no statistical difference for FF/UMEC/VI versus FF/VI or UMEC/VI in TTF CVAESI (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.85, 1.11; p = 0.711 and HR: 0.92, 95% CI: 0.78, 1.08; p = 0.317, respectively) nor TTF CVAESI leading to hospitalization/prolonged hospitalization or death (HR: 1.19, 95% CI: 0.93, 1.51; p = 0.167 and HR: 0.96, 95% CI: 0.72, 1.27; p = 0.760, respectively). On-treatment MACE occurred in ≤3% of patients across treatment groups, with similar prevalence and rates between treatments. CONCLUSIONS: In a symptomatic COPD population with a history of exacerbations and a high rate of CV disease/risk, the proportion of patients with CVAESI and MACE was 10-11% and 1-3%, respectively, across treatment arms, and the risk of CVAESI was low and similar across treatment arms. There was no statistically significant increased CV risk associated with the use of FF/UMEC/VI versus FF/VI or UMEC/VI, and UMEC/VI versus FF/VI. TRIAL REGISTRATION: NCT02164513 (GSK study number CTT116855).

Pharmacodynamic effects of vaporized and oral cannabidiol (CBD) and vaporized CBD-dominant cannabis in infrequent cannabis users.

INTRODUCTION: The use and availability of oral and inhalable products containing cannabidiol (CBD) as the principal constituent has increased with expanded cannabis/hemp legalization. However, few controlled clinical laboratory studies have evaluated the pharmacodynamic effects of oral or vaporized CBD or CBD-dominant cannabis. METHODS: Eighteen healthy adults (9 men; 9 women) completed four, double-blind, double-dummy, drug administration sessions. Sessions were separated by ≥1 week and included self-administration of 100 mg oral CBD, 100 mg vaporized CBD, vaporized CBD-dominant cannabis (100 mg CBD; 3.7 mg THC), and placebo. Study outcomes included: subjective drug effects, vital signs, cognitive/psychomotor performance, and whole blood THC and CBD concentrations. RESULTS: Vaporized CBD and CBD-dominant cannabis increased ratings on several subjective items (e.g., Like Drug Effect) relative to placebo. Subjective effects did not differ between oral CBD and placebo and were generally higher for CBD-dominant cannabis compared to vaporized CBD. CBD did not increase ratings for several items typically associated with acute cannabis/THC exposure (e.g., Paranoid). Women reported qualitatively higher ratings for Pleasant Drug Effect than men after vaporized CBD and CBD-dominant cannabis use. CBD-dominant cannabis increased heart rate compared to placebo. Cognitive/psychomotor impairment was not observed in any drug condition. CONCLUSIONS: Vaporized CBD and CBD-dominant cannabis produced discriminable subjective drug effects, which were sometimes stronger in women, but did not produce cognitive/psychomotor impairment. Subjective effects of oral CBD did not differ from placebo. Future research should further elucidate the subjective effects of various types of CBD products (e.g., inhaled, oral, topical), which appear to be distinct from THC-dominant products.

Impact on survival of combination inhalers in patients with COPD at high risk of cardiovascular events.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular disease often co-exist and are both leading causes of death worldwide. Published data have previously suggested trends toward improved survival for patients taking long-acting ß agonists combined with inhaled corticosteroids (LABA-ICS) through beneficial actions on the respiratory and cardiovascular systems. We sought to explore this in a real-world setting. METHODS: A population-based longitudinal propensity score-matched cohort study was conducted in the United Kingdom, 1998-2015. Patients were identified from the Clinical Practice Research Datalink (CPRD) which is linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records. All patients had a validated diagnosis of COPD and were at high risk for cardiovascular events (history of myocardial infarction, diabetes mellitus, ischaemic heart disease, stroke and peripheral arterial disease). The primary outcome was all-cause mortality. RESULTS: The treatment group was composed of 2687 new users of LABA-ICS with COPD and comparisons were made in a control population of 2687 COPD patients prescribed LABAs alone. At three years follow-up death occurred in 358 (13.3%) patients in the treatment group and 427 (15.9%) patients in the control group. The use of LABA-ICS was modestly associated with improved survival compared to use of LABAs (hazard ratio 0.82, 95% CI 0.71-0.95, P = 0.007). CONCLUSIONS: Among patients with COPD with either established cardiovascular disease or at high risk of an index cardiovascular event, LABA-ICS inhaled therapy, compared with LABAs alone, was associated with a significantly improved survival.

Design Features in Multiple Generations of Electronic Cigarette Atomizers.

The design of electronic cigarette (EC) atomizing units has evolved since their introduction over 10 years ago. The purpose of this study was to evaluate atomizer design in ECs sold between 2011-2017. Atomizers from 34 brands representing three generations of ECs were dissected and photographed using a stereoscopic microscope. Five distinct atomizer design categories were identified in first generation products (cig-a-like/cartomizer) and three categories were found in the third generation. Atomizers in most cig-a-like ECs contained a filament, thick wire, wire joints, air-tube, wick, sheath, and fibers, while some later models lacked some of these components. Over time design changes included an increase in atomizer size; removal of solder joints between wires; removal of Polyfil fibers; and removal of the microprocessor from Vuse. In second and third generation ECs, the reservoirs and batteries were larger, and the atomizing units generally lacked a thick wire, fibers, and sheath. These data contribute to an understanding of atomizer design and show that there is no single design for ECs, which are continually evolving. The design of the atomizer is particularly important as it affects the performance of ECs and what transfers into the aerosol.

A mesh nebulizer is more effective than jet nebulizer to nebulize bronchodilators during non-invasive ventilation of subjects with COPD: A randomized controlled trial with radiolabeled aerosols.

BACKGROUND: Beneficial effects from non-invasive ventilation (NIV) in acute COPD are well-established, but the impact of nebulization during NIV has not been well described. AIM: To compare pulmonary deposition and distribution across regions of interest with administration of radiolabeled aerosols generated by vibrating mesh nebulizers (VMN) and jet nebulizer (JN) during NIV. METHODS: A crossover single dose study involving 9 stable subjects with moderate to severe COPD randomly allocated to receive aerosol administration by the VMN Aerogen and the MistyNeb jet nebulizer operating with oxygen at 8 lpm during NIV. Radiolabeled bronchodilators (fill volume of 3 mL: 0.5 mL salbutamol 2.5 mg + 0.125 mL ipratropium 0.25 mg and physiologic saline up to 3 mL) were delivered until sputtering during NIV (pressures of 12 cmH2O and 5 cmH2O - inspiratory and expiratory, respectively) using an oro-nasal facemask. Radioactivity counts were performed using a gamma camera and regions of interest (ROIs) were delimited. Aerosol mass balance based on counts from the lungs, upper airways, stomach, nebulizer, circuit, inspiratory and expiratory filters, and mask were determined and expressed as a percentage of the total. RESULTS: Both inhaled and lung doses were greater with VMN (22.78 ±â€¯3.38% and 12.05 ±â€¯2.96%, respectively) than JN (12.51 ±â€¯6.31% and 3.14 ±â€¯1.71%; p = 0.008). Residual drug volume was lower in VMN than in JN (3.08 ±â€¯1.3% versus 46.44 ±â€¯5.83%, p = 0.001). Peripheral deposition of radioaerosol was significantly lower with JN than VMN. CONCLUSIONS: VMN deposited > 3 fold more radioaerosol into the lungs of moderate to severe COPD patients than JN during NIV.

Topical application of nebulized human IgG, IgA and IgAM in the lungs of rats and non-human primates.

BACKGROUND: Recurrent and persistent infections are known to affect airways of patients with Primary Immunodeficiency despite appropriate replacement immunoglobulin serum levels. Interestingly, patients with Chronic Obstructive Pulmonary Disease or with non-CF bronchiectasis also show similar susceptibility to such infections. This may be due to the limited availability of immunoglobulins from the systemic circulation in the conductive airways, resulting in local immunodeficiency. Topical application of nebulized plasma-derived immunoglobulins may represent a means to address this deficiency. In this study, we assessed the feasibility of nebulizing plasma-derived immunoglobulins and delivering them into the airways of rats and non-human primates. METHODS: Distinct human plasma-derived immunoglobulin isotype preparations were nebulized with an investigational eFlow® nebulizer and analyzed in vitro or deposited into animals. Biochemical and immunohistological analysis of nebulized immunoglobulins were then performed. Lastly, efficacy of topically applied human plasma-derived immunoglobulins was assessed in an acute Streptococcus pneumoniae respiratory infection in mice. RESULTS: Characteristics of the resulting aerosols were comparable between preparations, even when using solutions with elevated viscosity. Neither the structural integrity nor the biological function of nebulized immunoglobulins were compromised by the nebulization process. In animal studies, immunoglobulins levels were assessed in plasma, broncho-alveolar lavages (BAL) and on lung sections of rats and non-human primates in samples collected up to 72 h following application. Nebulized immunoglobulins were detectable over 48 h in the BAL samples and up to 72 h on lung sections. Immunoglobulins recovered from BAL fluid up to 24 h after inhalation remained structurally and functionally intact. Importantly, topical application of human plasma-derived immunoglobulin G into the airways of mice offered significant protection against acute pneumococcal pneumonia. CONCLUSION: Taken together our data demonstrate the feasibility of topically applying plasma-derived immunoglobulins into the lungs using a nebulized liquid formulation. Moreover, topically administered human plasma-derived immunoglobulins prevented acute respiratory infection.

Effect of tiotropium inhaler use on mortality in patients with tuberculous destroyed lung: based on linkage between hospital and nationwide health insurance claims data in South Korea.

BACKGROUND: Although bronchodilator inhaler therapy can improve lung function in patients with tuberculous destroyed lung (TDL), its effect on mortality has not been studied. We evaluated the effect of tiotropium inhaler therapy on mortality in patients with TDL. METHODS: A retrospective cohort of 963 patients with TDL was followed for up to ten years by linking hospital and nationwide health insurance claims data. We compared patients receiving tiotropium inhaler with patients without tiotropium after matching with propensity scores. In addition, we elucidated the risk factors of mortality using Cox proportional hazards model. RESULTS: After the propensity score matching, the baseline characteristics were balanced in both the tiotropium group (n = 105) and the non-tiotropium group (n = 105); including mean age (63.9 vs. 64.4 years, P = 0.715), mean forced expiratory volume in 1 s (FEV1) (45.0 vs. 45.3%, P = 0.903), and others. After the propensity score matching, the tiotropium group showed better survival than the non-tiotropium group (median survival period: not reached for the tiotropium group vs. 7.24 years for the non-tiotropium group, Prentice-Wilcoxon test, P = 0.008). Multivariate Cox proportional hazard analysis revealed that tiotropium inhaler usage was associated with lower risk of mortality in the multivariate analysis (HR, 0.560; 95% CI, 0.380-0.824; P = 0.003) after adjusting age, sex, BMI, smoking history, mMRC dyspnea score, Charlson Comorbidity Index, concomitant COPD diagnosis, FEV1, X-ray severity score, and home oxygen usage. CONCLUSIONS: Our results suggest that tiotropium inhaler is associated with decreased all-cause mortality in TDL. Further prospective study is required for validation.

Changes in COPD inhaler prescriptions in the United Kingdom, 2000 to 2016.

BACKGROUND: Over the past two decades, there have been significant changes in the pharmacological management of COPD, due to an explosion of inhaler trials, and timely updation of national and international guidelines. We sought to describe temporal changes in prescribing practices in the United Kingdom, and some of the factors that may have influenced them. PATIENTS AND METHODS: COPD patients were identified from UK primary care nationally representative electronic healthcare records (Clinical Practice Research Datalink), between 2000 and 2016. Prescription data were described by the three maintenance inhaled medication classes used, inhaled corticosteroids (ICS), long-acting beta agonist (LABA), long-acting muscarinic antagonist (LAMA), and their combinations, dual LABA-ICS, dual LAMA-LABA, or triple therapy LABA-ICS-LAMA. Differing patient characteristics across the six different therapy regimens were measured in 2016. RESULTS: COPD patients were identified: 187,588 prevalent and incident inhaler users and 169,511 incident inhaler users. Since 2002, LAMA showed increasing popularity, while ICS alone exhibited an inverse trend. Triple therapy prescriptions rapidly increased as the first-line therapy until 2014 when LAMA-LABA prescriptions started to increase. By 2014, 41% of all COPD patients were maintained on triple therapy, and 13% were maintained on LAMA only. Characterizing the patients in 2016 revealed that those on triple therapy were more likely to have more severe disease, yet, over a third of patients on triple therapy had only mild disease. CONCLUSION: UK prescribing practices were not in keeping with national guidelines but did appear to align with evidence from major drug trials and updated international guidelines. There has been a huge upsurge in triple therapy but incident data show this trend is beginning to reverse for initial management.

Recent advances in aerosolised drug delivery.

Pulmonary route is extensively studied for the diagnosis and treatment of pulmonary and extra pulmonary disease conditions such as asthma, tuberculosis, emphysema, and bronchitis. Formulation design, inhalation device and particle size play key role in determining the aerosol performance. The lack of desired clinical outcome along with the problem regarding efficacy or any adverse drug effect may arise due to improper training and education in use of the device to control the actuation and aerosol inhalation. This review summarizes the difference in the mechanistic features of current marketed aerosol delivery devices with respect to mechanism of aerosol generation with possible advancements in the aerosol design. The delivery options in the pulmonary route and its merits together with the limitations are also discussed. An update is provided regarding the current research and clinical outcome of the use of inhalational technology.

Nuevos inhaladores o mejora en el manejo de los actuales. La parábola de los ciegos (Brueghel) / Inhaler Devices: Better Management or New Devices? The Blind Leading the Blind

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Mesh nebulizers have become the first choice for new nebulized pharmaceutical drug developments.

In the 24 years since first being marketed, the mesh nebulizer has been developed by five main manufacturers into a viable solution for the delivery of high-value nebulized drugs. Mesh nebulizers provide increased portability, convenience and energy efficiency along with similar lung deposition and increased ease of use compared with jet nebulizers. An analysis of EU and US clinical trial databases has shown that mesh nebulizers are now preferred over jet nebulizers for clinical trials sponsored by pharmaceutical companies. The results show a strong preference for the use of mesh nebulizers in trials involving high cost and niche therapy areas. Built-in capability to optimize the way patients use their mesh nebulizer and manage their disease will further increase uptake. [Formula: see text].