TRITRIAL: The Impact of Fixed Triple Therapy with Beclometasone/Formoterol/Glycopyrronium on Health Status and Adherence in Chronic Obstructive Pulmonary Disease in an Italian Context of Real Life.

Purpose: The TRITRIAL study assessed the effects of beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) fixed combination in patients with chronic obstructive pulmonary disease (COPD) in a real-world setting, focusing on patient's experience and perspective through the use of patients reported outcomes. Patients and Methods: TRITRIAL was a multicenter, prospective, observational study conducted on patients with moderate-severe COPD treated with BDP/FF/G fixed therapy for 12 months. The main objective was to evaluate the impact of BDP/FF/G on health status through the COPD Assessment Test (CAT) score. Additional assessments included adherence and satisfaction, measured by the TAI-10/12 questionnaire and a specifically designed eight-item questionnaire, quality of life through the EQ-5D-5L test, sleep quality through the COPD and Asthma Sleep Impact Scale (CASIS), as well as safety and disease-related outcomes. Results: Data from 655 patients were analyzed in the study. The mean total CAT score significantly improved (from 22.8 at baseline to 18.1 at 6 months and 16.5 at 12 months; p < 0.0001), as well as all the eight CAT sub-items, which decreased on average by 0.5-0.9 points during the study. Adherence and usability of the inhaler also improved during the study, with a decrease in poor compliance (from 30.1% to 18.3%) and an increase in good compliance (from 51.8% to 58.3%) according to the TAI score. Patients also benefited from significantly improved quality of life (EQ Index from 0.70 to 0.80; EQ-5D VAS score from 55.1 to 63.1) and sleep quality (CASIS score from 41.1 to 31.8). Finally, patients reported a significant reduction in exacerbation during the study. Conclusion: TRITRIAL showed that the BDP/FF/G fixed combination is effective and safe in patients with moderate-severe COPD and poorly controlled disease, improving patients' HRQoL, sleep quality, adherence and inhaler usability and reducing COPD symptoms and the risk of exacerbation in a real-life setting.

Service readiness for the management of non-communicable diseases in publicly financed facilities in Malawi: findings from the 2019 Harmonised Health Facility Assessment census survey.

INTRODUCTION: Non-communicable diseases (NCDs) are rising in low-income and middle-income countries, including Malawi. To inform policy-makers and planners on the preparedness of the Malawian healthcare system to respond to NCDs, we estimated NCD service readiness in publicly financed healthcare facilities in Malawi. METHODS: We analysed data from 564 facilities surveyed in the 2019 Harmonised Health Facility Assessment, including 512 primary healthcare (PHC) and 52 secondary and tertiary care (STC) facilities. To characterise service readiness, applying the law of minimum, we estimated the percentage of facilities with functional equipment and unexpired medicines required to provide NCD services. Further, we estimated permanently unavailable items to identify service readiness bottlenecks. RESULTS: Fewer than 40% of PHC facilities were ready to deliver services for each of the 14 NCDs analysed. Insulin and beclomethasone inhalers had the lowest stock levels at PHC facilities (6% and 8%, respectively). Only 17% of rural and community hospitals (RCHs) have liver and kidney diagnostics. STC facilities had varying service readiness, ranging from 27% for managing acute diabetes complications to 94% for chronic type 2 diabetes management. Only 38% of STC facilities were ready to manage chronic heart failure. Oral pain medicines were widely available at all levels of health facilities; however, only 22% of RCHs and 29% of STCs had injectable morphine or pethidine. Beclomethasone was never available at 74% of PHC and 29% of STC facilities. CONCLUSION: Publicly financed facilities in Malawi are generally unprepared to provide NCD services, especially at the PHC level. Targeted investments in PHC can substantially improve service readiness for chronic NCD conditions in local communities and enable STC to respond to acute NCD complications and more complex NCD cases.

Divergent Chemo- and Biocatalytic Route to 16ß-Methylcorticoids: Asymmetric Synthesis of Betamethasone Dipropionate, Clobetasol Propionate, and Beclomethasone Dipropionate.

16ß-Methylcorticoids are among the most important glucocorticoid steroids for the treatment of various dermatological disorders, respiratory infections, and other allergic reactions elicited during inflammatory responses of the human body. Betamethasone dipropionate, clobetasol propionate, and beclomethasone dipropionate are particularly noteworthy for their synthetic intractability. Despite five decades of research, these 16ß-methylcorticoids have remained challenging synthetic targets owing to insurmountable issues of reactivity, selectivity, and cost efficiency associated with all previously explored strategies. We herein report our practicability-oriented strategy toward the unified stereoselective synthesis of 16ß-methylcorticoids in 12.6-14.0 % overall yield from commercially available 9α-hydroxyandrost-4-ene-3,17-dione (9α-OH-AD). In this approach, the chiral C16ß-Me and C17α-OH groups of the corticosteroid D ring were installed via a substrate-controlled diastereo- and enantioselective Mn-catalyzed oxidation-reduction hydration of Δ4,9(11),16 -triene-3,20-dione. The C1-C2 double bond of the corticosteroid A ring was constructed using an unprecedented engineered 3-ketosteroid-Δ1 -dehydrogenase (MK4-KstD)-catalyzed regioselective Δ1 -dehydrogenation of Δ4,9(11) -diene-3,21-dione. This strategy provides a general method and a key precursor for the divergent synthesis of a variety of glucocorticoids and related steroidal drugs.

Inhaled beclomethasone in the treatment of early COVID-19: a double-blind, placebo-controlled, randomised, hospital-based trial in Sri Lanka.

OBJECTIVES: To study if early initiation of inhaled beclomethasone 1200 mcg in patients with asymptomatic, mild or moderate COVID-19 reduces disease progression to severe COVID-19. DESIGN: Double-blinded, parallel-groups, randomised, placebo-controlled trial. SETTING: A hospital-based study in Sri Lanka. PARTICIPANTS: Adults with asymptomatic, mild or moderate COVID-19, presenting within the first 7 days of symptom onset or laboratory diagnosis of COVID-19, admitted to a COVID-19 intermediate treatment centre in Sri Lanka between July and November 2021. INTERVENTIONS: All participants received inhaled beclomethasone 600 mcg or placebo two times per day, for 10 days from onset of symptoms/COVID-19 test becoming positive if asymptomatic or until reaching primary endpoint, whichever is earlier. PRIMARY OUTCOME MEASURE: Progression of asymptomatic, mild or moderate COVID-19 to severe COVID-19. SECONDARY OUTCOME MEASURES: The number of days with a temperature of 38°C or more and the time to self-reported clinical recovery. RESULTS: A total of 385 participants were randomised to receive beclomethasone(n=193) or placebo(n=192) stratified by age (≤60 or >60 years) and sex. One participant from each arm withdrew from the study. All participants were included in final analysis. Primary outcome occurred in 24 participants in the beclomethasone group and 26 participants in the placebo group (RR 0.90 ; p=0.763). The median time for self-reported clinical recovery in all participants was 5 days (95% CI 3 to 7) in the beclomethasone group and 5 days (95% CI 3 to 8) in the placebo group (p=0.5). The median time for self-reported clinical recovery in patients with moderate COVID-19 was 5 days (95% CI 3 to 7) in the beclomethasone group and 6 days (95% CI 4 to 9) in the placebo group (p=0.05). There were no adverse events. CONCLUSIONS: Early initiation of inhaled beclomethasone in patients with asymptomatic, mild or moderate COVID-19 did not reduce disease progression to severe COVID-19. TRIAL REGISTRATION NUMBER: Sri Lanka Clinical Trials Registry; SLCTR/2021/017.

Can single-inhaler Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium therapy postpone or save biologics for severe asthma?

Inhaled corticosteroids, along with beta2-agonists and anti-muscarinics, represent the cornerstone of asthma treatment. Although the advent of monoclonal antibodies has dramatically changed severe asthma management, there are still patients ineligible or with poor response to biologics. Moreover, high costs associated with monoclonal antibodies prescription are still an open issue, leading clinicians to carefully assess cost-benefit ratio before their administration. From this perspective, the use of single-inhaler Beclometasone Dipropionate/Formoterol Fumarate/Glycopyrronium in patients with severe asthma could not only improve their clinical and functional performance, but also postpone biologic prescription, with positive repercussions on healthcare costs.

The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN).

BACKGROUND: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. METHODS: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. RESULTS: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001). CONCLUSIONS: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021.

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.

An application of QVAR dynamic connectedness between geopolitical risk and renewable energy volatility during the COVID-19 pandemic and Russia-Ukraine conflicts.

The article is the first to employ a quantile vector autoregression (QVAR) to identify the connectedness between geopolitical risks and energy volatility from January 1, 2015, to April 03, 2023. This paper is also the first to examine the mediating roles of uncertain events like the COVID-19 pandemic and the Russia-Ukraine conflict on this interlinkage. Dynamic connectedness is 29% in the short term and approximately 6% in the long term. Dynamic net total directional connectedness over a quantile also indicates that connectedness is very intense for both highly positive changes (above the 80% quantile) and negative changes (below the 20% quantile). In the short term, the geopolitical risks remained net receivers of shock, but they turned into net shock transmitters during 2020 in the long term. Clean energy, in the short term, transmits shocks to other markets, and it plays the same role in the long term. Crude oil was a net receiver of shocks during COVID-19 and turned into a net transmitter of shocks in early 2022. Dynamic net pairwise directional connectedness over a quantile suggests that uncertain events like the COVID-19 epidemic or the Russia-Ukraine conflict influence the dynamic interlinkages between geopolitical risks and renewable energy volatility and change their roles in the designed system. These findings are critical since they help authorities develop effective policies to lessen the vulnerabilities of these indicators and minimize how widely the renewable and non-renewable energy market is exposed to risk or uncertainty.

[Respiratory disorders of post-COVID-19 syndrome].

AIM: Assess the functional state of trespiratory system and effectiveness of therapeutic tactics for broncho-obstructive syndrome (BOS) in patients in the post-COVID period. MATERIALS AND METHODS: A two-center cohort prospective study included 10 456 and 89 patients, respectively. A comprehensive assessment of the respiratory system included clinical, laboratory and functional data, spirometry, body plethysmography, and a study of diffusive capacity of the lungs (DLCO). Therapy consisted of budesonide suspension or fixed combination beclomethasone dipropionate/formoterol (EMD BDP/FORM). RESULTS: The frequency of BOS in the cohort was 72% (7497 patients). In 13% (n=974) of cases, bronchial asthma was diagnosed for the first time, in 4.4% (n=328) - chronic obstructive pulmonary disease. Risk factors for the development and decrease in DLCO in the post-COVID period were identified. In the group of complex instrumental examination of lung function, the absence of violations of spirometric data and indicators determined by body plethysmography was determined. CONCLUSION: Risk factors for BOS in post-COVID period are atopy, a history of frequent acute respiratory infections, smoking, blood eosinophilia, moderate and severe forms of COVID-19. The advantage of a fixed combination of EMD BDP/FORM in MART mode compared with nebulized suspension budesonide + solution of salbutamol in treatment of BOS was shown. Risk factors for DLCO disorders were established: severe COVID-19, hospitalization in the intensive care unit, the need for additional oxygen therapy.

DrugRep-KG: Toward Learning a Unified Latent Space for Drug Repurposing Using Knowledge Graphs.

Drug repurposing or repositioning (DR) refers to finding new therapeutic applications for existing drugs. Current computational DR methods face data representation and negative data sampling challenges. Although retrospective studies attempt to operate various representations, it is a crucial step for an accurate prediction to aggregate these features and bring the associations between drugs and diseases into a unified latent space. In addition, the number of unknown associations between drugs and diseases, which is considered negative data, is much higher than the number of known associations, or positive data, leading to an imbalanced dataset. In this regard, we propose the DrugRep-KG method, which applies a knowledge graph embedding approach for representing drugs and diseases, to address these challenges. Despite the typical DR methods that consider all unknown drug-disease associations as negative data, we select a subset of unknown associations, provided the disease occurs because of an adverse reaction to a drug. DrugRep-KG has been evaluated based on different settings and achieves an AUC-ROC (area under the receiver operating characteristic curve) of 90.83% and an AUC-PR (area under the precision-recall curve) of 90.10%, which are higher than in previous works. Besides, we checked the performance of our framework in finding potential drugs for coronavirus infection and skin-related diseases: contact dermatitis and atopic eczema. DrugRep-KG predicted beclomethasone for contact dermatitis, and fluorometholone, clocortolone, fluocinonide, and beclomethasone for atopic eczema, all of which have previously been proven to be effective in other studies. Fluorometholone for contact dermatitis is a novel suggestion by DrugRep-KG that should be validated experimentally. DrugRep-KG also predicted the associations between COVID-19 and potential treatments suggested by DrugBank, in addition to new drug candidates provided with experimental evidence. The data and code underlying this article are available at https://github.com/CBRC-lab/DrugRep-KG.

The rising cost of rhinologic medications.

BACKGROUND: The high prescription drug cost in the United States may negatively affect patient prognosis and treatment compliance. OBJECTIVE: To fill the knowledge gap and inform clinicians regarding rhinology medications price changes by evaluating trends in price changes of highly used nasal sprays and allergy medications. METHODS: The 2014-2020 Medicaid National Average Drug Acquisition Cost database was queried for drug pricing information for the following classes of medications: intranasal corticosteroids, oral antihistamines, antileukotrienes, intranasal antihistamines, and intranasal anticholinergics. Individual medications were identified by Food and Drug Administration-assigned National Drug Codes. Per unit, drug prices were analyzed for average annual prices, average annual percentage price changes, and inflation-adjusted annual and composite percentage price changes. RESULTS: Beclometasone (Beconase AQ, 56.7%, QNASL, 77.5%), flunisolide (Nasalide, -14.6%), budesonide (Rhinocort Aqua, -1.2%), fluticasone (Flonase, -6.8%, Xhance, 11.7%), mometasone (Nasonex, 38.2%), ciclesonide (Omnaris, 73.8%), combination azelastine and fluticasone (Dymista, 27.3%), loratadine (Claritin, -20.5%), montelukast (Singulair, 14.5%), azelastine (Astepro, 21.9%), olopatadine (Patanase, 27.3%), and ipratropium bromide (Atrovent, 56.6%) had an overall change in inflation-adjusted per unit cost between 2014 and 2020 (% change). Of 14 drugs evaluated, 10 had an increase in inflation-adjusted prices, for an average increase of 42.06% ± 22.27%; 4 of 14 drugs had a decrease in inflation-adjusted prices, for an average decrease of 10.78% ± 7.36%. CONCLUSION: The rising cost of highly used medications contributes to increased patient acquisition costs and may pose barriers of drug adherence to particularly vulnerable populations.

Beclometasone inhaler-induced recovery of refractory peri-ileostomy skin complications.

Peristomal skin complications (PSCs) are relatively common in ostomy patients, particularly in those with ileostomies. Non-healing irritation presents a clinical challenge and leads to pain and impaired quality of life for patients. METHODS: The cases of four ileostomy patients experiencing severe, challenging PSCs refractory to appliance changes, conventional dressings and barrier creams are discussed. FINDINGS: The cases of one male and one female patient with an end ileostomy post-subtotal colectomy for ulcerative colitis, one female with a defunctioning ileostomy post-anterior resection for sigmoid carcinoma and one male with an end ileostomy with a complex Crohn's surgical history are described. Two puffs of a 250 mcg metered dose beclometasone inhaler were applied to the affected skin once or twice daily. Treatment ranged from 6 to 21 days. Complete resolution was seen in all cases. CONCLUSION: Topical use of a beclometasone inhaler was effective for severe peri-ileostomy PSC secondary to four different aetiologies. Further studies are warranted to determine the effectiveness of this treatment in a larger patient cohort.

Transport and deposition of beclomethasone dipropionate drug aerosols with varying ethanol concentration in severe asthmatic subjects.

This study aims to assess the effects of varying an ethanol co-solvent on the deposition of drug particles in severe asthmatic subjects with distinct airway structures and lung functions using computational fluid dynamics. The subjects were selected from two quantitative computed tomography imaging-based severe asthmatic clusters, differentiated by airway constriction in the left lower lobe. Drug aerosols were assumed to be generated from a pressurized metered-dose inhaler (MDI). The aerosolized droplet sizes were varied by increasing the ethanol co-solvent concentration in the MDI solution. The MDI formulation consists of 1,1,2,2-tetrafluoroethane (HFA-134a), ethanol, and beclomethasone dipropionate (BDP) as the active pharmaceutical ingredient. Since HFA-134a and ethanol are volatile, both substances evaporate rapidly under ambient conditions and trigger condensation of water vapor, increasing the size of aerosols that are predominantly composed of water and BDP. The average deposition fraction in intra-thoracic airways for severe asthmatic subjects with (or without) airway constriction increased from 37%±12 to 53.2%±9.4 (or from 20.7%± 4.6 to 34.7%±6.6) when the ethanol concentration was increased from 1 to 10%wt/wt. However, when the ethanol concentration was further increased from 10 to 20%wt/wt, the deposition fraction decreased. This indicates the importance of selecting appropriate co-solvent amounts during drug formulation development for the treatment of patients with narrowed airway disease. For severe asthmatic subjects with airway narrowing, the inhaled aerosol may benefit from a low hygroscopic effect by reducing ethanol concentration to penetrate the peripheral region effectively. These results could potentially inform the selection of co-solvent amounts for inhalation therapies in a cluster-specific manner.

Impact of dispersion media and carrier type on spray-dried proliposome powder formulations loaded with beclomethasone dipropionate for their pulmonary drug delivery via a next generation impactor.

Drug delivery via aerosolization for localized and systemic effect is a non-invasive approach to achieving pulmonary targeting. The aim of this study was to prepare spray-dried proliposome (SDP) powder formulations to produce carrier particles for superior aerosolization performance, assessed via a next generation impactor (NGI) in combination with a dry powder inhaler. SDP powder formulations (F1-F10) were prepared using a spray dryer, employing five different types of lactose carriers (Lactose monohydrate (LMH), lactose microfine (LMF), lactose 003, lactose 220 and lactose 300) and two different dispersion media. The first dispersion medium was comprised of water and ethanol (50:50% v/v ratio), and the second dispersion medium comprised wholly of ethanol (100%). In the first dispersion medium, the lipid phase (consisting of Soya phosphatidylcholine (SPC as phospholipid) and Beclomethasone dipropionate (BDP; model drug) were dissolved in ethanol and the lactose carrier in water, followed by spray drying. Whereas in second dispersion medium, the lipid phase and lactose carrier were dispersed in ethanol only, post spray drying. SDP powder formulations (F1-F5) possessed significantly smaller particles (2.89 ± 1.24-4.48 ± 1.20 µm), when compared to SDP F6-F10 formulations (10.63 ± 3.71-19.27 ± 4.98 µm), irrespective of lactose carrier type via SEM (scanning electron microscopy). Crystallinity of the F6-F10 and amorphicity of F1-F15 formulations were confirmed by XRD (X-ray diffraction). Differences in size and crystallinity were further reflected in production yield, where significantly higher production yield was obtained for F1-F5 (74.87 ± 4.28-87.32 ± 2.42%) then F6-F10 formulations (40.08 ± 5.714-54.98 ± 5.82%), irrespective of carrier type. Negligible differences were noted in terms of entrapment efficiency, when comparing F1-F5 SDP formulations (94.67 ± 8.41-96.35 ± 7.93) to F6-F10 formulations (78.16 ± 9.35-82.95 ± 9.62). Moreover, formulations F1-F5 demonstrated significantly higher fine particle fraction (FPF), fine particle dose (FPD) and respirable fraction (RF) (on average of 30.35%, 890.12 µg and 85.90%) when compared to counterpart SDP powder formulations (F6-F10). This study has demonstrated that when a combination of water and ethanol was employed as dispersion medium (formulations F1-F5), superior formulation properties for pulmonary drug delivery were observed, irrespective of carrier type employed.

How to engineer aerosol particle properties and biopharmaceutical performance of propellant inhalers.

Given the environmental compulsion to reformulate pressurised metered dose inhalers (pMDI) using new propellants with lower global warming potential, this study investigated how non-volatile excipients can be used to engineer aerosol particle microphysics and drug release. The dynamics of change in particle size, wetting and physical state were measured for single particles (glycerol/ethanol/beclomethasone dipropionate; BDP) in the aerosol phase at different relative humidity (RH) using an electrodynamic balance. BDP dissolution rates were compared for aerosols from pMDI containing different ratios of BDP:glycerol or BDP:isopropyl myristate (IPM). In 45 % RH, ethanol loss was followed by evaporation of condensed water to generate spherical particles with solid inclusions or compact irregular-shaped solid particles, according to the presence or absence of glycerol. In RH > 95 %, condensed water did not evaporate and BDP formed solid inclusions in water/glycerol or water droplets. Varying the non-volatile component, 0-50 % w/w, in pMDI resulted in a concentration-dependent 4-8-fold reduction in BDP dissolution rate. These findings demonstrate that non-volatile excipients provide a means of engineering aerosol properties and, modifying the rate of drug release from aerosol medicines. We also demonstrated differences between particles formed in vitro in ambient humidity versus higher humidity, more like that encountered during oral inhalation.

HPLC-UV/VIS for Determination of Ipratropium Bromide Mixed with Salbuterol, Beclomethasone Propionate and Budesonide using Dual Wavelength-Detection Method.

BACKGROUND: Inhalation preparation involves liquid or solid raw materials for delivering to lungs as aerosol or vapor. The liquid preparation for nebulizer is effective for convenient use and patient compliance and it has been extensively used in the treatment of clinical lung diseases. Clinical staff often mixes the compound ipratropium bromide with beclomethasone propionate and budesonide inhaler but reference values of inhalants for clinical use need to be established for simplifying the operation procedure. The high-performance liquid chromatography (HPLC) method of compound ipratropium bromide solution, beclomethasone propionate suspension and budesonide suspension after mixed atomization was studied. METHODS: The specificity, linearity, recovery (accuracy), precision and stability of compound ipratropium bromide, beclomethasone propionate and budesonide were tested to verify the developed liquid phase method. RESULTS: The developed liquid phase method had high specificity, linear R2≥0,999, recovery (accuracy) RSD (relative standard deviation) less than 2%, precision RSD less than 2,0%, and stability RSD less than 2,0%. CONCLUSION: The liquid phase methodology developed in this study can be used for the determination of compound ipratropium bromide mixed with beclomethasone propionate and budesonide. The current methodology can also be used to provide a reference for the determination of its content after mixing, and further data support for its clinical medication.

Real-life therapeutic effects of beclomethasone dipropionate/formoterol fumarate/glycopyrronium combined triple therapy in patients with chronic obstructive pulmonary disease.

BACKGROUND: The small airway disease has been recognized as a central feature of chronic obstructive pulmonary disease (COPD). Triple fixed combination beclomethasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) is provided as a pressurized single-dose inhaler based on an extra-fine formulation, which has been approved for patients with COPD experiencing frequent disease exacerbations. METHODS: The aim of our real-life single-center observational study was to investigate, in 22 patients with COPD, the effects of BDP/FF/G on lung function, respiratory symptoms, health status, and exacerbation rate. Several clinical and lung functional parameters were evaluated at baseline and after 12 months of treatment with combined inhaled triple therapy. RESULTS: With respect to baseline, after 12 months of treatment with BDP/FF/G, significant changes were recorded with regard to forced expiratory flow at 75% of forced vital capacity (FVC) (p < 0.01), forced expiratory flow at 50% of FVC (p < 0.01), forced expiratory flow at 25% of FVC (p < 0.05), and forced mid-expiratory flow between 25% and 75% of FVC (p < 0.01). Moreover, we observed reductions of total resistance (p < 0.01), effective resistance (p < 0.01), and effective specific resistance (p < 0.01). In the same period, residual volume diminished (p < 0.01) and forced expiratory volume in 1 s increased (p < 0.01). Moreover, in a subgroup of 16 patients, an enhancement of diffusion lung capacity (p < 0.01) was also detected. These functional results were paralleled by concomitant clinical effects, as evidenced by the improvements of modified British Medical Research Council (mMRC) dyspnea scale (p < 0.001), COPD Assessment Test (CAT) score (p < 0.0001), and COPD exacerbations (p < 0.0001). CONCLUSION: In conclusion, the valuable findings of our observational study consist in the corroboration in a real-life context of the therapeutic effects evidenced by randomized controlled trials with regard to the use of the triple inhaled BDP/FF/G therapy in patients with COPD.

The impact of possible improper use on the performance in vitro of NEXThaler in comparison with Ellipta inhaler.

The correct use of dry powder inhalers by the patients is essential to ensure effective treatment and management of the disease. The purpose of the work was to assess the consequence of inhaler misuse in terms of emitted dose and aerodynamic parameters. One reservoir multidose device (Foster-NEXThaler®) and one pre-dosed device (Relvar-Ellipta®), both sharing the "open, inhale and close" procedure, were the subject of the study. NEXThaler activated at different degrees of inclination showed a consistent dose delivery for both the drugs included in the formulation (beclometasone dipropionate/formoterol fumarate). Contrary, Ellipta showed a decrease of the emitted dose for both fluticasone furoate (FluF) and vilanterol trifenatate (VT) when the device was operated facing downward (-14% at 45° and -22% at 90°). Similarly, the delivered dose of NEXThaler was unaffected by an accidental fall, while Ellipta released FluF and VT doses 50% lower than control values. The presence of the dose protector in NEXThaler offers the advantage of retaining the powder if the inhaler is subjected to incorrect manipulations. Both products proved to be reliable in double activation. Finally, simulation exhalation conditions impaired, although not significantly, the aerodynamic profile of the two products.

Platelet-derived growth factor D expression in adrenal cells is modulated by corticosteroids: putative role in adrenal suppression.

BACKGROUND: Adrenal suppression is a clinically concerning side effect of inhaled corticosteroid (ICS) treatment in patients with asthma. Increased susceptibility to ICS-induced adrenal suppression has previously been identified in those with the rs591118 polymorphism in platelet-derived growth factor D (PDGFD). The mechanism underpinning this relationship is not known. METHODS: H295R cells were genotyped for rs591118 using a validated Taqman PCR allelic discrimination assay. H295R cell viability was determined after treatment with beclometasone and fluticasone (range 0-330 µM). Cortisol was measured in cell culture medium using competitive enzyme immunoassay. RESULTS: PDGFD protein expression in H295R cells was confirmed using Western blotting. When ACTH and forskolin were added to H295R cells, a reduction in PDGFD expression was seen, which was then restored by incubation with prochloraz, a known inhibitor of steroidogenesis. A dose-dependent, decrease in PDGFD expression was observed with beclometasone (over a 24 h incubation period) but not with beclometasone incubations beyond 24 h nor with fluticasone (at 24 or 48 h). CONCLUSIONS: H295R cells express PDGFD protein, which can be modulated by incubation with steroidogenesis agonists and antagonists and additionally with exogenous beclometasone. IMPACT: PDGFD is expressed in the human adrenal cell line, H295R, and expression can be modulated by beclometasone as well as agonists/antagonists of steroidogenesis. This builds on previous research that identified a SNP in PDGFD (rs591118) as an independent risk factor for adrenal suppression in adults and children with obstructive airway disease treated with inhaled corticosteroids. First in vitro experiments to support a link between the PDGF and cortisol production pathways, supporting the hypothesis that PDGFD variants can affect an individual's sensitivity to corticosteroid-induced adrenal suppression.