Efficacy and safety of different inhaled corticosteroids for bronchopulmonary dysplasia prevention in preterm infants: A systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of inhaled corticosteroids (budesonide, beclomethasone, or fluticasone propionate) in preventing bronchopulmonary dysplasia (BPD) for premature infants. METHOD: Electronic databases, including PubMed, EMBASE, Web of science, Scopus, and Cochrane library, were searched from databases inception to January 2022 for eligible randomized controlled trials. Clinical outcomes such as BPD, mortality, BPD or death, adverse events, and neurodevelopmental outcomes were assessed. RESULTS: Overall, budesonide was significantly associated with a reduction in BPD at 36 weeks' postmenstrual age (RR 0.48; 95 % CI [0.38, 0.62]) and patent ductus arteriosus (PDA) (RR 0.75; 95 % CI [0.63, 0.89]) compared with control treatments. Early longer duration inhalation of budesonide alone was associated with a lower risk of BPD at 36 weeks' postmenstrual age and PDA compared with controls. Early shorter duration intratracheal instillation of budesonide with surfactant as vehicle was associated with a lower risk of BPD at 36 weeks' postmenstrual age and all-cause mortality compared with surfactant. There was no statistically significant difference between budesonide and control groups regarding neurodevelopmental impairment. Beclomethasone and fluticasone propionate did not show any superior or inferior effect on clinical outcomes compared to control treatments. CONCLUSION: These findings suggest that budesonide, especially intratracheal instillation of budesonide using surfactant as a vehicle, is a safe and effective option in preventing BPD for preterm infants. More well-design large-scale trials with long-term follow-ups are necessary to verify the present findings.

A systematic review of randomised controlled trials on topical nasal steroids.

Introduction: Intranasal corticosteroids (INCs) are the first line of therapy for chronic sinonasal conditions such as rhinitis and rhinosinusitis. Among these, one of the most frequently used is beclomethasone dipropionate (BDP). Over the years many studies have evaluated the efficacy of BDP as part of therapy for chronic rhinosinusitis (CRS) and allergic rhinitis (AR) along with nasal washes, which seems to be very well tolerated. Objective: To analyse the data in the literature regarding the various therapeutic regimens of BDP in different sinonasal disease and their efficacy and tolerability. Materials and methods: Using different search engines, the posology, efficacy, and tolerability of BDP were reviewed and a total of 64 full-length articles were examined for eligibility. After applying inclusion and exclusion criteria, 4 articles were reviewed. Results: BDP is among the group of INCs with significant improvement of nasal symptoms and has good efficacy and safety. Conclusions: BDP nasal spray is one of the most frequently prescribed INC for rhinitis and rhinosinusitis. Treatment with BDP resulted in significant and clinically meaningful improvements in nasal symptoms associated with AR and CRS. BDP is well tolerated, and the safety profile is similar to that of placebo in most patients. These results, in conjunction with the significant benefit reported in subjects with CRS and AR, provide convincing evidence of the overall effectiveness of BDP for the treatment of the full spectrum of sinonasal disease.

Carbon footprint of pressurized gas metered dose inhalers (pMDI) in Brazil and Porto Alegre: impacts and alternatives / La huella de carbono de los dispositivos inhaladores dosificados de gas presurizado (pMDI) en Brasil y en Porto Alegre: impactos y alternativas / Pegada de carbono dos dispositivos inalatórios dosimetrados de gás pressurizado (pMDI) no Brasil e em Porto Alegre: impactos e alternativas

Objective: To calculate the carbon footprint of pressurized gas-type metered-dose inhalers for asthma and chronic obstructive pulmonary disease control (COPD) dispensed by the brazilian national health service (SUS) in Brazil and in Porto Alegre (RS) in 2019. Method: Collection and analysis of data on the dispensation of salbutamol and beclomethasone by the SUS network and Farmácia Popular do Brasil in 2019, obtained by request to the Ministry of Health. Dispensations were multiplied by the proportional carbon footprint of each device using data already published in the literature. Results: In 2019, the prescription of pMDIs (pressurized metered-dose inhalers) within the Brazilian Unified Health System (SUS) resulted in the emission of approximately 24,889,141 to 60,878,728 metric tons of CO2 equivalent into the atmosphere across Brazil, which is equivalent to traveling by a typical gasoline-powered car from the northernmost to the southernmost point of the country between 23 to 57 million times. Furthermore, in the specific context of Porto Alegre, the emissions ranged from approximately 459,830 to 1,151,008 metric tons of CO2 equivalent, corresponding to traveling by a typical gasoline-powered car from the northernmost to the southernmost point of Brazil between 433,000 to 1 million times. Conclusion: The national health service in Brazil is responsible for emitting a massive amount of GHGs each year due to pMDI-type inhalation devices.  Switching to DPIs or SMIs in the indicated cases would avoid a great environmental damage, and at the same time would be of clinical benefit to patients, since they are the first choice currently recommended by the clinical guidelines for the treatment of asthma and COPD, promoting public health and, at the same time, planetary health.

Objetivo: Calcular la huella de carbono de los inhaladores de dosis medida de gas presurizado utilizados para el control del asma y la enfermedad pulmonar obstructiva crónica (EPOC) dispensados por el Sistema Único de Salud (SUS) en Brasil y en Porto Alegre (RS) en el año 2019. Método: Recopilación y análisis de datos de dispensación de salbutamol y beclometasona por la red SUS y Farmácia Popular do Brasil en 2019, obtenidos a través de una solicitud al Ministerio de Salud en virtud de la Ley de Acceso a la Información. Las dispensaciones se multiplicaron por la huella de carbono proporcional de cada dispositivo utilizando datos previamente publicados en la literatura. Resultados: La prescripción de los inhaladores de dosis medida de gas presurizado en el SUS en 2019 resultó en la emisión de entre 24,889,141 y 60,878,728 toneladas de CO2-eq en todo Brasil, equivalente a viajar en un automóvil de gasolina común desde el extremo norte hasta el extremo sur del país entre 23 y 57 millones de veces. En el caso de la ciudad de Porto Alegre, las emisiones oscilaron entre 459,830 y 1,151,008 toneladas de CO2-eq, lo que equivale a recorrer la distancia de norte a sur de Brasil entre 433,000 y 1 millón de veces en un automóvil de gasolina común. Conclusión: En el SUS, se emite una enorme cantidad de gases de efecto invernadero (GEE) cada año debido a los dispositivos inhaladores del tipo pMDI. El cambio a DPIs o SMIs en los casos indicados evitaría un gran daño ambiental y, al mismo tiempo, proporcionaría beneficios clínicos a los pacientes, ya que es la primera opción actualmente recomendada por las directrices clínicas para el tratamiento del asma y la EPOC, promoviendo la salud pública y al mismo tiempo la salud del planeta.

Objetivo: Calcular a pegada de carbono dos inaladores do tipo gás pressurizado dosimetrado para controle da asma e doença pulmonar obstrutiva crônica (DPOC) dispensados pelo Sistema Único de Saúde (SUS) no Brasil e em Porto Alegre (RS) no ano de 2019. Método: Coleta e análise de dados de dispensação de salbutamol e beclometasona pela rede SUS e Farmácia Popular do Brasil em 2019, obtidas por solicitação ao Ministério da Saúde através da Lei de Acesso à Informação. As dispensações foram multiplicadas pela pegada de carbono proporcional de cada dispositivo utilizando dados já publicados na literatura. Resultados: A prescrição de pMDI no SUS, em 2019, resultou entre 24.889.141 e 60.878.728 toneladas de CO2-eq liberados na atmosfera em todo o Brasil (equivalente a percorrer 23 a 57 milhões de vezes a distância de norte a sul do Brasil com um carro comum a gasolina); e entre 459.830 e 1.151.008 toneladas de CO2-eq na cidade de Porto Alegre (correspondente a percorrer 433mil a 1 milhão de vezes a distância de norte a sul do Brasil com um carro comum a gasolina). Conclusão: No SUS, emite-se enorme quantidade de GEEs a cada ano devido aos dispositivos inalatórios do tipo pMDI. A troca por DPIs ou SMIs nos casos indicados evitaria um grande dano ambiental, e ao mesmo tempo benefício clínico aos pacientes, pois trata-se da primeira escolha atual preconizada pelas diretrizes clínicas para o tratamento de asma e DPOC, promovendo a saúde pública e ao mesmo tempo a saúde planetária.

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.

Comparación clínica en el manejo remoto del asma bronquial durante la pandemia COVID-19 entre dos terapias controladoras: fluticasona y beclometasona / Clinical comparison in the remote management of bronchial asthma during the COVID-19 pandemic between two controller therapies: Fluticasone and beclomethasone

RESUMEN Objetivo: Comparar el nivel de control del asma mediante el uso del Asthma Control Test (ACT) y manifestaciones clínicas en dos grupos de pacientes tratados con diferentes corticosteroides inhalados (GCI): fluticasona y beclometasona. Materiales y métodos. Se realizó un estudio observacional, comparativo y prospectivo en 521 niños del programa de asma del Hospital III Yanahuara. Durante el periodo de junio de 2020 a diciembre de 2021, se evaluó el nivel de control del asma mediante consultas remotas utilizando el ACT y la recopilación de hallazgos clínicos. Los pacientes se agruparon según el tipo de GCI que se encontraban utilizando. Se registraron los datos en dos momentos diferentes para cada paciente, con un intervalo de 4 meses entre cada control, durante la pandemia de COVID-19 y se comparó el nivel de control mediante la puntuación obtenida en el ACT y las manifestaciones clínicas entre ambos grupos de pacientes en ambos momentos del estudio. Resultados . Ambos grupos tuvieron un control óptimo al inicio como al final del estudio. En las manifestaciones clínicas no hubo diferencia estadística (P > 0.05) a favor de ningún medicamento en ninguno de los dos controles. Sin embargo, en el segundo control (egreso) se encontró una diferencia significativa de la fluticasona frente a la beclometasona (p = 0.030). Conclusiones . Se encontró que la Fluticasona tuvo una superioridad en el nivel de control del asma frente a la beclometasona. Sin embargo, el factor determinante para lograr un buen control es el uso continuo de cualquier GCI.

ABSTRACT Objective: To compare the level of asthma control using the Asthma Control Test (ACT) and clinical manifestations in two groups of patients treated with different inhaled corticosteroids (ICG): fluticasone and beclometasone. Materials and methods: An observational, comparative and prospective study was conducted in 521 children in the asthma program of Hospital III Yanahuara. During the period from June 2020 to December 2021, the level of asthma control was assessed by remote consultations using ACT and collection of clinical findings. Patients were grouped according to the type of ICG they were using. Data were recorded at two different time points for each patient, with a 4-month interval between each control, during the COVID-19 pandemic and the level of control was compared by ACT score and clinical manifestations between the two groups of patients at both time points of the study. Results: Both groups had optimal control at baseline and at the end of the study. In clinical manifestations there was no statistical difference (P > 0.05) in favor of either drug in either control. However, in the second control (discharge) a significant difference was found for fluticasone versus beclometasone (P = 0.030). Conclusions: Fluticasone was found to have superiority in the level of asthma control over beclomethasone. However, the determining factor in achieving good control is the continuous use of any IGC.

Impact of inhaled and intranasal corticosteroids on glucose metabolism and diabetes mellitus: A mini review.

Inhaled corticosteroids (ICS) and intranasal corticosteroids (INS) are the mainstays of treatment for chronic respiratory diseases like asthma, chronic obstructive pulmonary disease, and allergic rhinosinusitis. In addition, these localized forms of steroid therapy are generally considered to have fewer systemic side effects compared to long-term oral corticosteroids. However, concern and controversy remain over the impact of ICS and INS on the incidence and control of diabetes mellitus (DM). Given the widespread use of ICS and INS, even small individual effects on DM could lead to large consequences for the global popu-lation. Multiple large observational studies suggest that high dose ICS is associated with increased incident DM and worsened DM control, though the contribution of other risk factors is less certain. In addition, only two studies were done to investigate the association of INS and DM, with both studies demon-strating a short-term association of INS use with hyperglycemia. While more research evaluating the risk of ICS/INS for DM-related adverse events is needed, high doses of ICS/INS should be avoided when possible. The following strategies for ICS/INS dose minimization can be considered: Use of non-pharmacological measures (trigger avoidance, smoking cessation, vaccination to avoid infection), control of comorbid conditions, use of non-ICS-containing medications, inter-mittent rather than regular ICS dosing, and appropriate de-escalation of high ICS doses.

Efficacy and safety of oral beclomethasone dipropionate and budesonide MMX versus 5-aminosalicylates or placebo in ulcerative colitis: a systematic review and meta-analysis.

Background: Low bioavailability steroids, including beclomethasone dipropionate (BDP) and budesonide MMX, have been developed to ensure colonic targeting and low systemic activity than systematic corticosteroids in treating patients with ulcerative colitis (UC). Objectives: This systematic review and meta-analysis evaluated the efficacy and safety of BDP and budesonide MMX® compared with 5-aminosalicylic acid (5-ASAs) or placebo, in patients with mild-to-moderate UC. Design: Systematic review and meta-analysis. Methods: We searched MEDLINE, EMBASE, and the Cochrane central register of controlled trials from inception to December 2021. We included all available randomized controlled trials (RCTs) comparing oral BDP or budesonide MMX with 5-ASAs or with placebo in induction of remission of mild-to-moderate UC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: We identified two RCTs comparing BDP 5 mg with 5-ASA, one RCTs comparing BDP 10 mg with 5-ASA, two RCTs BDP 5 mg versus placebo, one RCT BDP 10 mg versus placebo, two RCTs budesonide MMX 9 mg versus 5-ASA, and six RCTs budesonide MMX 9 mg versus placebo. In terms of achieving clinical remission or improvement, BDP 5 mg, BDP 10 mg, and budesonide MMX 9 mg were more effective than placebo (OR 2.36, 95% CI 1.37-4.08; OR 2.23, 95% CI 1.02-4.87; and OR 2.03, 95% CI 1.45-2.85, respectively). The drugs were also more effective than placebo in achieving endoscopic remission. Regarding the comparisons with 5-ASA, we found no differences between 5-ASA and BDP 5 mg or BDP 10 mg or budesonide MMX 9 mg in achieving clinical remission or improvement (OR 0.90, 95% CI 0.51-1.57; OR 1.54, 95% CI 0.42-5.64; and OR 1.17, 95% CI 0.82-1.66). However, 5-ASA was more effective than budesonide MMX 9 mg in achieving histological remission (OR 0.33, 95% CI 0.16-0.70). Overall, all the drugs were safe and well tolerated. Conclusion: Low bioavailability steroids were more effective than placebo in achieving clinical remission, clinical and endoscopic remission, and histological remission. No differences were found between 5-ASA and BDP or budesonide MMX. Surely, more RCTs, also comparing BDP and budesonide MMX, are mandatory to confirm or not these results.

Instant Formulation of Inhalable Beclomethasone Dipropionate-Gamma-Cyclodextrin Composite Particles Produced Using Supercritical Assisted Atomization.

Medical composites derived from Gamma-cyclodextrin (γ-CD) and beclomethasone dipropionate-gamma-cyclodextrin (BDP-γ-CD) are synthesized over supercritical-assisted atomization (SAA) herein. Carbon dioxide, which serves the dual function of spraying medium and co-solute, is incorporated in this process along with the ethanolic solvent. Results indicate that, for fine spherical particles, optimized aerosol performance could be obtained with 50.0% (w/w) ethanolic solvent, precipitator, and saturator at 373.2 K and 353.2 K, respectively, and carbon dioxide-to-γ-CD flow ratio of 1.8 in the presence of 10 wt% leucine (LEU) as dispersion enhancer. It is also noted that γ-CD solution at low concentration typically renders better aerosol performance of the particles. During drug particle-derivation, the solubility of drug BDP elevated considerably due to the formation of inclusion complexes, further assisted by the ethanolic solvent which increases the lipophilicity of BDP. Meanwhile, the in vitro aerosolization and dissolution performance of drug composites derived from varied γ-CD-to-BDP mass ratio (Z) were also evaluated. It was found that high Z promises higher fine particle fraction in the obtained drug composite while the dissolution rate of active ingredient (BDP) exhibits positive correlation to the content of water-soluble excipient (γ-CD) in the formulation. This study offers a new avenue for instant drug formulation with promising pulmonary delivery over the SAA technique.

Compatibility and aerosol characteristics of beclomethasone mixed with N-acetylcysteine.

Mixing different kind inhalation medications for simultaneous inhalation is widely used in the treatment of chronic respiratory diseases, and it can minimize the administration time and improve patient adherence. To our knowledge, it is unclear whether beclomethasone (BDP, Clenil®) can bemixed with acetylcysteine (NAC, Fluimucil®), because the in vitro physico-chemical compatibility and aerosol characteristics of the mixture are unknown. In this study, we investigated physical compatibility, including the appearance, pH, osmotic pressure and chemical stability, as well as aerosol characteristics, including particle size corresponding to 10%/50%/90% of the cumulative percentage of total particle volume (X10/X50/X90), volume median droplet diameter (VMD), mass median aerodynamic diameter (MMAD), fine particle fraction (FPF), fine particle dose (FPD) and geometric standard deviation (GSD), delivery rate, and total delivery of the above solutions. After mixing, there were no significant changes in visual appearance, pH, osmolality and drug content of the mixtures at room temperature for 12 h. The FDP of BDP in the mixture decreased by 16.49%, whereas the NAC increased by 10.85%. The delivery rates of BDP and NAC in the mixture decreased by 66.05% and 45.54%, and total delivery increased by 13.20% and 25.29%, respectively. However, the MMAD, FPF, particle size and GSD of the mixture were almost unchanged. We demonstrated that these admixtures are physico-chemically compatible but that coadministration of beclomethasone with acetylcysteine can markedly affect output and aerosol characteristics.

Comparison of Intranasal Steroid Application Using Nasal Spray and Spray-Sol to Treat Allergic Rhinitis: A Preliminary Investigation.

Allergic Rhinitis (AR) is a chronic inflammatory disease of sino-nasal mucosa, is IgE-mediated, and affects 10-40% of the global population. This study aimed to compare the efficacy of nasal administration of Beclomethasone Dipropionate (BDP) delivered via Spray-sol with nasal spray in patients suffering from AR. We included 28 AR patients assigned to one of the two following treatments: the Spray-sol group (BDP via Spray-sol) (n = 13) and the spray group (BDP using a common nasal spray) (n = 15). Both treatments were administered twice daily for 4 weeks. A nasal endoscopy evaluation and Total Nasal Symptom Score were performed at baseline and after treatment. The Spray-sol group showed better results than the spray group regarding nasal endoscopy (edema, p < 0.01; irritation, p < 0.01; secretion, p < 0.01) and nasal symptoms (nasal congestion, p < 0.05; rhinorrhea, p < 0.05; sneezing, p < 0.05; and total score, p < 0.05). No side effects were recorded. These data supported the fact that the use of BDP delivered with Spray-sol is more effective than BDP nasal spray in AR patients. Further studies are needed to confirm these encouraging results.

Sustained-Release Powders Based on Polymer Particles for Pulmonary Delivery of Beclomethasone Dipropionate in the Treatment of Lung Inflammation.

Inhaled corticosteroids are the mainstay in the management of lung inflammation associated to chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Nonetheless, available inhalation products are mostly short-acting formulations that require frequent administrations and do not always produce the desired anti-inflammatory effects. In this work, the production of inhalable beclomethasone dipropionate (BDP) dry powders based on polymeric particles was attempted. As starting material, the PHEA-g-RhB-g-PLA-g-PEG copolymer was chosen, obtained by grafting 0.6, 2.4 and 3.0 mol%, respectively, of rhodamine (RhB), polylactic acid (PLA) and polyethylene glycol 5000 (PEG) on alpha,beta-poly(N-2-hydroxyethyl)DL-aspartamide (PHEA). The drug was loaded into the polymeric particles (MP) as an inclusion complex (CI) with hydroxypropyl-cyclodextrin (HP-ß-Cyd) (at a stoichiometric ratio of 1:1) or as free form. The spray-drying (SD) process to produce MPs was optimized by keeping the polymer concentration (0.6 wt/vol%) constant in the liquid feed and by varying other parameters such as the drug concentration. The theoretical aerodynamic diameter (daer) values among the MPs are comparable and potentially suitable for inhalation, as confirmed also through evaluation of the experimental mass median aerodynamic diameter (MMADexp). BDP shows a controlled release profile from MPs that is significantly higher (more than tripled) than from Clenil®. In vitro tests on bronchial epithelial cells (16HBE) and adenocarcinomic human alveolar basal epithelial cells (A549) showed that all the MP samples (empty or drug-loaded) were highly biocompatible. None of the systems used induced apoptosis or necrosis. Moreover, the BDP loaded into the particles (BDP-Micro and CI-Micro) was more efficient than free BDP to counteract the effects of cigarette smoke and LPS on release of IL-6 and IL-8.

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.

Combined analysis of five non-interventional studies of the effectiveness, tolerability, and safety of the extrafine fixed dose beclomethasone/formoterol combination in the treatment of asthma in Austria.

OBJECTIVE: The real-world effectiveness and tolerability of an extrafine fixed dose beclomethasone/formoterol (BDP/FF) treatment of patients with partially or non-controlled asthma was evaluated in five non-interventional studies (NISs) from Austria. METHODS: Asthma patients enrolled in these five NISs were treated with beclomethasone/formoterol (Foster® or Foster® Nexthaler®) as maintenance and reliever over 12 weeks. Asthma control, lung function and symptom scores were assessed at baseline, after 4-8 weeks and at the end of the investigations in week 12. In addition, tolerability and handling of the devices were evaluated by questionnaires. RESULTS: The combined analysis included 891 patients (53% female, aged 49.3 years) demonstrating significant improvements in asthma control, lung function parameters (PEF, FEV1 and FVC) and symptom scores (reduction of breathlessness, wheezing, chest tightness and cough). These changes were already detectable after 4-8 weeks. The treatment was effective irrespective of smoking status, exercise, or previous medication. Tolerability of the therapy with extrafine BDP/FF was rated as "very good" or "good" in 98% of the patients. 95% of the patients intended to continue the treatment, and nearly all (99%) rated the handling of the device as "very good" or "good". No serious adverse reactions were reported. CONCLUSIONS: This combined analysis of five non-interventional studies confirms the effectiveness and tolerability of the extrafine fixed-dose BDP/FF combination (Foster® and Foster® Nexthaler®) in a heterogenous patient population suffering from partially or non-controlled asthma. Therapy was associated with a high patient satisfaction and the absence of serious adverse reactions.

Involvement of esterases in the pulmonary metabolism of beclomethasone dipropionate and the potential influence of cannabis use.

Beclomethasone dipropionate (BDP) is an inhaled glucocorticoid used for maintenance treatment of asthma in adults and children. BDP is a prodrug activated in lung when hydrolyzed to its major active metabolite beclomethasone-17-monopropionate (17-BMP), which can be further deactivated to beclomethasone (BOH). The specific hydrolases contributing to these processes have not been identified which warrants an investigation to enable a better assessment of the drug-drug interaction (DDI) liability and a better management of drug efficacy and systemic toxicity. In the present study, the pulmonary metabolism of BDP was investigated using both human lung S9 (HLuS9) and recombinant carboxylesterase 1 (CES1) S9. By employing the relative activity approach, we tested the hypothesis of CES1 being the major enzyme involved. Assessment of other hydrolases were conducted in an assay with selective esterase inhibitors. In addition, the DDI potentials between BDP and Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) were evaluated due to the increasing use of inhaled cannabis both recreationally and medically. The mechanism of DDI was conducted in an in vitro time-dependent inhibition assay, and further interpreted utilizing a proposed model. In HLuS9, BDP was efficiently metabolized almost completely to 17-BMP, which was then converted to BOH at a much lower rate. CES1 was found as a minor contributor accounting for only 1.4% of BDP metabolism in HLuS9, while arylacetamide deacetylase might be the main enzyme involved. Both THC and CBD inhibited the HLuS9 mediated BDP hydrolysis in a reversible manner, with reported IC50 values estimated as 8.98 and 36.8 µM, respectively. Our proposed model suggested a moderately decreased 17-BMP exposure in lung by concomitant THC from a cannabis cigarette, while the effects from orally administered CBD was expected to be of no clinical relevance.

Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Triple Therapy Compared with Other Therapies for the Treatment of COPD: A Network Meta-Analysis.

INTRODUCTION: Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting ß2-agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD. METHODS: This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV1), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible). RESULTS: The NMA was informed by five trials reporting FEV1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6). CONCLUSION: The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available.

Effect of Agmatine on a mouse model of allergic airway inflammation: A comparative study.

INTRODUCTION: Asthma is a chronic lung disease that injures and constricts the airways. This study evaluates the effects of agmatine on ovalbumin (OVA)-induced allergic inflammation of the airways. METHODS: OVA sensitization by intraperitoneal injection was used to induce airway inflammation in mice on days 0 and 7; then the mice were challenged using beclomethasone (150 µg/kg, inhalation), a standard anti-asthmatic drug, from day 14 to day 16. Furthermore, agmatine (200 mg/kg) was intraperitoneally injected on day 0 and then daily for 16 days, followed by OVA challenge. The lung weight ratio, total and differential cell counts, TNF-α, interleukin-5 (IL-5) and IL-13 in bronchoalveolar lavage fluid (BALF), lung nitrite/nitrate (NO), and oxidative parameters were determined. Moreover, histopathological and immunohistochemical staining was employed. RESULTS: Injection of agmatine (200 mg/kg) for 16 days significantly attenuated inflammation of the airways. The levels of BALF inflammatory cells, TNF-α, IL-5, IL-13, lung NO, and malondialdehyde (MDA), significantly decreased with concomitant elevation of superoxide dismutase (SOD) levels. Histological and immunohistochemical analyses of mast cells paralleled to biochemical improvements. CONCLUSION: Finally, this study illustrated that agmatine attenuates the allergic inflammation of airways caused by OVA by mitigating cytokines release, NO expression, and oxidative stress.

Oral beclomethasone dipropionate as an add-on therapy and response prediction in Korean patients with ulcerative colitis.

BACKGROUND/AIMS: We aimed to investigate the oral beclomethasone dipropionate's (BDP) efficacy as an add-on therapy and to clarify the predictive factor for response to oral BDP in Korean ulcerative colitis (UC) patients. METHODS: Patients with a stable concomitant drug regimen with exposure to oral BDP (5 mg/day) within 30 days before BDP initiation were included. Partial Mayo score (pMS) was used to evaluate response to oral BDP. Clinical remission (CREM) was defined as a post-treatment pMS ≤ 1 point. Clinical response (CRES) was defined as an at least 2-point decrease in post-treatment pMS and an at least 30% decrease from baseline pMS. Patients without CREM or CRES were considered nonresponders (NRs). RESULTS: Of all, 37 showed CREM, 19 showed CRES, and 44 were NRs. The CREM group included more patients with mild disease activity (75.7% vs. 43.2%, p = 0.011) than NRs. In contrast to NRs, CREM and CRES patients showed significant improvement of post-treatment erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (ESR with p = 0.001, CRP with p = 0.004, respectively). Moreover, the initial rectal bleeding subscore (RBS) was significantly different between CREM and CRES, or NR (both with p < 0.001). In multivariate analyses, initial stool frequency subscore (SFS) of 0 and RBS of 0 were predictive factors for CREM (odds ratio [OR], 15.359; 95% confidence interval [CI], 1.085 to 217.499; p = 0.043 for SFS, and OR, 11.434; 95% CI, 1.682 to 77.710; p = 0.013 for RBS). CONCLUSION: Oral BDP is an efficacious add-on therapy in Korean UC patients. Patients with initial SFS or RBS of 0 may be particularly good candidates for oral BDP.

Immediate Release Formulation of Inhaled Beclomethasone Dipropionate-Hydroxypropyl-Beta-Cyclodextrin Composite Particles Produced Using Supercritical Assisted Atomization.

In this study, the enhanced solubilization performance of a poorly soluble drug, beclomethasone dipropionate (BDP), was investigated using hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and ethanol. The enhanced solubility of the drug was determined using the phase solubility method and correlated as a function of both HP-ß-CD and ethanol concentrations. The effective progress of drug solubility originated from the formation of cyclodextrin and BDP inclusion complexes and increase in the lipophilicity of the medium, by aqueous ethanol, for hydrophobic BDP. BDP and HP-ß-CD composite particles were produced using supercritical assisted atomization (SAA) with carbon dioxide as the spraying medium, 54.2% (w/w) aqueous ethanol as the solvent, and an optimal amount of the dispersion enhancer leucine. The effect of the mass ratio of HP-ß-CD to BDP (Z) on the in vitro aerosolization and in vitro dissolution performance of BDP-HP-ß-CD composite particles was evaluated. The aerosolization performance showed that the fine particles fraction (FPF) of the composite particles increased with increasing mass ratio. The water-soluble excipient (HP-ß-CD) effectively enhance the dissolution rate of BDP from composite particles. This study suggests that BDP-HP-ß-CD composite particles produced using SAA can be employed in immediate-release drug formulations for pulmonary delivery.

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.

Practical and scalable synthesis of beclomethasone dipropionate.

Beclomethasone dipropionate (1) is a synthetic corticosteroid with anti-inflammatory, antipruritic, and anti-allergy properties. It is widely used to treat asthma, allergic rhinitis, and dermatoses. However, existing synthetic routes to this active pharmaceutical ingredient (API) contain steps resulting in low and/or inconsistent yields, and use obsolete reagents. Such inconsistencies coupled with a lack of reliable experimental data makes laboratory-scale and large-scale synthesis of this API difficult and time-consuming. In this paper, we report a practical and scalable approach to synthesize 1 from the readily available steroidal intermediate, 16ß-methyl epoxide (3, DB-11). A gram-scale to kilogram-scale synthesis of 1 was achieved with 82% yield, using a cost-effective and scalable methodology. Selective propionylation of the hydroxyl groups at C17 and C21 demonstrate the fact that this approach can be conveniently implemented in fine chemical industries.