Comparison of inhaled salbutamol and salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses: a randomized clinical trial.

OBJECTIVE: To compare the efficacy of inhaled salbutamol with salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses. STUDY DESIGN: Prospective, randomized, clinical study. ANIMALS: A total of 108 client-owned horses (American Society of Anesthesiologists status I-V) anaesthetized for elective and emergency procedures. METHODS: Horses were premedicated with acepromazine [intramuscularly 0.1 mg kg-1 or intravenously (IV) 0.05 mg kg-1] and xylazine (0.6 mg kg-1 IV). Midazolam (0.06 mg kg-1 IV) and ketamine (2.2 mg kg-1 IV) were combined to induce anaesthesia, and isoflurane in oxygen/air mixture (inspired oxygen fraction 0.7) was used for maintenance of anaesthesia. Mechanical ventilation was initiated without delay using the following ventilator settings: tidal volume 10 mL kg-1, respiratory rate 8 breaths minute-1, inspiratory-to-expiratory time ratio 1:2, no positive end-expiratory pressure. If arterial blood gas analysis revealed PaO2 < 100 mmHg (13.3 kPa), the administration of either inhaled salbutamol (2 µg kg-1) or salmeterol (0.5 µg kg-1) was randomly assigned Blood gas analysis was repeated 15 and 30 minutes after treatment. The intervention was considered successful when PaO2 after treatment ≥ 1.2 × PaO2 before treatment (i.e. ≥20% increase). PaO2 at 15 and 30 minutes was compared between groups using Mann-Whitney U test; p < 0.05 was considered significant. RESULTS: Of the 108 horses, 60 were administered salbutamol, 65% and 60% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 38% and 44%, respectively. The other 48 horses were administered salmeterol, 35% responded successfully at 15 and 30 minutes, increasing their initial PaO2 by 3% and 4%, respectively. PaO2 was significantly higher after salbutamol than after salmeterol at 15 and 30 minutes. CONCLUSIONS AND CLINICAL RELEVANCE: Using the described protocol, inhaled salbutamol was more effective than salmeterol in improving PaO2 in anaesthetized horses with value < 100 mmHg (13.3 kPa).

Nanoscale colocalized thermal and chemical mapping of pharmaceutical powder aerosols.

Inhalation of pharmaceutical aerosol formulations is widely used to treat respiratory diseases. Spatially resolved thermal characterization offers promise for better understanding drug release rates from particles; however, this has been an analytical challenge due to the small particle size (from a few micrometers down to nanometers) and the complex composition of the formulations. Here, we employ nano-thermal analysis (nanoTA) to probe the nanothermal domain of a pharmaceutical aerosol formulation containing a mixture of fluticasone propionate (FP), salmeterol xinafoate (SX), and excipient lactose, which is widely used to treat asthma and chronic obstructive pulmonary disease (COPD). Furthermore, atomic force microscopy-infrared spectroscopy (AFM-IR) and AFM force measurements are performed to provide nanochemical and nanomechanical information to complement the nanothermal data. The colocalized thermal and chemical mapping clearly reveals the surface heterogeneity of the drugs in the aerosol particles and demonstrates the contribution of the surface chemical composition to the variation in the thermal properties of the particles. We present a powerful analytical approach for in-depth characterization of thermal/chemical/morphological properties of dry powder inhaler particles at micro- and nanometer scales. This approach can be used to facilitate the comparison between generics and reference inhalation products and further the development of high-performance pharmaceutical formulations.

Preclinical evaluation of novel synthesised nanoparticles based on tyrosine poly(ester amide) for improved targeted pulmonary delivery.

Fixed dose combinations (FDCs) incorporating two or three medicines in a single inhaler have been created to enhance patient compliance and hence clinical outcomes. However, the development of dry powder inhalers (DPIs), particularly for FDCs, faces challenges pertinent to formulation uniformity and reproducibility. Therefore, this project aimed to employ nanotechnology to develop a FDC of DPIs for market-leading medicines-fluticasone propionate (FP) and salmeterol xinafoate (SAL)-for asthma management. Nanoaggregates were prepared using a novel biocompatible and biodegradable poly(ester amide) based on the amino acid tyrosine, utilising a one-step interfacial polymerisation process. The produced tyrosine poly (ester amide) drug-loaded nanoparticles were evaluated for content uniformity, PSA, FTIR, TEM, DSC, XRD and aerodynamic performance (in vitro and in vivo). The optimised formulation demonstrated high entrapment efficiency- > 90%. The aerodynamic performance in terms of the emitted dose, fine particle fraction and respirable dose was superior to the carrier-based marketed product. In-vivo studies showed that FP (above the marketed formulation) and SAL reached the lungs of mice in a reproducible manner. These results highlight the superiority of novel FDC FP/SAL nanoparticles prepared via a one-step process, which can be used as a cost-effective and efficient method to alleviate the burden of asthma.

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 µg FP/50 µg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.

Evaluating ß2-agonists as siRNA delivery adjuvants for pulmonary surfactant-coated nanogel inhalation therapy.

The lung is an attractive target organ for inhalation of RNA therapeutics, such as small interfering RNA (siRNA). However, clinical translation of siRNA drugs for application in the lung is hampered by many extra- and intracellular barriers. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel (nanogel) core coated with Curosurf®, a clinically used pulmonary surfactant. The surfactant shell was shown to markedly improve particle stability and promote intracellular siRNA delivery, both in vitro and in vivo. However, the full potential of siRNA nanocarriers is typically not reached as they are rapidly trafficked towards lysosomes for degradation and only a fraction of the internalized siRNA cargo is able to escape into the cytosol. We recently reported on the repurposing of widely applied cationic amphiphilic drugs (CADs) as siRNA delivery enhancers. Due to their physicochemical properties, CADs passively accumulate in the (endo)lysosomal compartment causing a transient permeabilization of the lysosomal membrane, which facilitates cytosolic drug delivery. In this work, we assessed a selection of cationic amphiphilic ß2-agonists (i.e., salbutamol, formoterol, salmeterol and indacaterol) for their ability to enhance siRNA delivery in a lung epithelial and macrophage cell line. These drugs are widely used in the clinic for their bronchodilating effect in obstructive lung disease. As opposed to the least hydrophobic drugs salbutamol and formoterol, the more hydrophobic long-acting ß2-agonist (LABA) salmeterol promoted siRNA delivery in both cell types for both uncoated and surfactant-coated nanogels, whereas indacaterol showed this effect solely in lung epithelial cells. Our results demonstrate the potential of both salmeterol and indacaterol to be repurposed as adjuvants for nanocarrier-mediated siRNA delivery to the lung, which could provide opportunities for drug combination therapy.

Exclusão do Xinafoato de Salmeterol aerossol bucal 50 mcg para tratamento da Asma e da Doença Pulmonar Obstrutiva Crônica / Exclusion of Salmeterol Xinafoate Oral Aerosol 50 mcg for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

CONTEXTO: A asma é uma doença heterogênea caracterizada por inflamação crônica das vias aéreas, enquanto a DPOC possui caráter não totalmente reversível caracterizada pela limitação crônica ao fluxo aéreo frequentemente associada a uma resposta inflamatória crônica das vias aéreas e do tecido pulmonar. O tratamento da asma e do DPOC visa melhorar a qualidade de vida do paciente por meio do controle dos sintomas e melhora ou estabilização da função pulmonar, além da diminuição das exacerbações na DPOC. O xinafoato de salmeterol, ß2-agonista de longa duração (LABA), é um dos medicamentos utilizado no tratamento dessas enfermidades, todavia sua forma farmacêutica de aerossol bucal 50 mcg não possui registro válido na ANVISA. Existem ainda outros medicamentos da mesma classe LABA disponibilizados no âmbito do SUS, como formoterol e formoterol + budesonida (cápsula ou pó inalante). Sendo assim, a exclusão do salmeterol aerossol bucal 50 mcg não traria prejuízo à população devido à existência de alternativas terapêuticas para essas condições no SUS. TECNOLOGIA: Xinafoato de salmeterol aerossol bucal 50 mcg. JUSTIFICATIVA DA EXCLUSÃO: Ausência de registro válido do xinafoato de salmeterol 50 mcg aerossol bucal na ANVISA. RECOMENDAÇÃO PRELIMINAR DA CONITEC: A matéria teve sua apreciação inicial na 94ª reunião ordinária da Conitec, no dia 03 de fevereiro de 2021. O Plenário deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à exclusão do salmeterol aerossol bucal para o tratamento da asma e do DPOC, considerando o cancelamento do registro em 2017. CONSULTA PÚBLICA: A Consulta Pública nº 08 foi realizada entre os dias 18/02/2021 e 09/03/2021. Foram recebidas 26 contribuições, sendo seis pelo formulário para contribuições técnico-científicas e 20 pelo formulário para contribuições sobre experiência ou opinião. Dentre as contribuições técnico-científicas, quatro (67%) foram a favor e duas (33%) discordaram da recomendação preliminar da Conitec; dentre as de experiência e opinião, seis (30%) concordaram, três (15%) não concordaram e nem discordaram e onze (55%) discordaram. Embora tenham sido apresentadas contribuições contra a exclusão do salmeterol aerossol, ressalta-se que ele não apresenta registro junto à Anvisa. O SUS disponibiliza outros tratamentos para o controle das condições clínicas, de modo que os pacientes não ficariam desassistidos. Nenhuma das contribuições apresentou novos estudos ou documentos que pudessem agregar novas evidências a esse relatório. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do Plenário da Conitec presentes na 96ª Reunião Ordinária, recomendaram, por unanimidade, a exclusão do salmeterol na apresentação de aerossol bucal (50mcg). Embora tenham sido apresentados relatos positivos acerca deste medicamento, seu registro foi cancelado e deferido pela Anvisa em 2017. Foi assinado o Registro de Deliberação nº 601/2021. DECISÃO: excluir o xinafoato de salmeterol aerossol bucal 50 mcg para tratamento da Asma e da Doença Pulmonar Obstrutiva Crônica (DPOC), conforme Portaria nº 16, publicada no Diário Oficial da União nº 79, seção 1, página 328/329, em 29 de abril de 2021.

Efficacy and safety of salmeterol/fluticasone compared with montelukast alone (or add-on therapy to fluticasone) in the treatment of bronchial asthma in children and adolescents: a systematic review and meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Despite the recommendation of inhaled corticosteroids (ICSs) plus long-acting beta 2-agonist (LABA) and leukotriene receptor antagonist (LTRA) or ICS/LTRA as stepwise approaches in asthmatic children, there is a lack of published systematic review comparing the efficacy and safety of the two therapies in children and adolescents aged 4 to 18 years. This study aimed to compare the safety and efficacy of salmeterol/fluticasone (SFC) vs. montelukast (MON), or combination of montelukast and fluticasone (MFC) in children and adolescents aged 4 to 18 years with bronchial asthma.@*METHODS@#A systematic search was conducted in MEDLINE, EMBASE, the Cochrane Library, China BioMedical Literature Database, Chinese National Knowledge Infrastructure, VIP Database for Chinese Technical Periodical, and Wanfang for randomized controlled trials (RCTs) published from inception to May 24, 2021. Interventions are as follows: SFC vs. MON, or combination of MFC, with no limitation of dosage or duration. Primary and secondary outcome measures were as follows: the primary outcome of interest was the risk of asthma exacerbation. Secondary outcomes included risk of hospitalization, pulmonary function, asthma control level, quality of life, and adverse events (AEs). A random-effects (I2 ≥ 50%) or fixed-effects model (I2 < 50%) was used to calculate pooled effect estimates, comparing the outcomes between the intervention and control groups where feasible.@*RESULTS@#Of the 1006 articles identified, 21 studies met the inclusion criteria with 2643 individuals; two were at low risk of bias. As no primary outcomes were similar after an identical treatment duration in the included studies, meta-analysis could not be performed. However, more studies favored SFC, instead of MON, owing to a lower risk of asthma exacerbation in the SFC group. As for secondary outcome, SFC showed a significant improvement of peak expiratory flow (PEF)%pred after 4 weeks compared with MFC (mean difference [MD]: 5.45; 95% confidence interval [CI]: 1.57-9.34; I2 = 95%; P = 0.006). As for asthma control level, SFC also showed a higher full-controlled level (risk ratio [RR]: 1.51; 95% CI: 1.24-1.85; I2 = 0; P < 0.001) and higher childhood asthma control test score after 4 weeks of treatment (MD: 2.30; 95% CI: 1.39-3.21; I2 = 72%; P < 0.001) compared with MFC.@*CONCLUSIONS@#SFC may be more effective than MFC for the treatment of asthma in children and adolescents, especially in improving asthma control level. However, there is insufficient evidence to make firm conclusive statements on the use of SFC or MON in children and adolescents aged 4 to 18 years with asthma. Further research is needed, particularly a combination of good-quality long-term prospective studies and well-designed RCTs.@*PROSPERO REGISTRATION NUMBER@#CRD42019133156.

Systematic review and Meta-analysis on efficacy and safety of Liujunzi Decoction combined with Western medicine for stable chronic obstructive pulmonary disease / 中国中药杂志

To systematically review the efficacy and safety of Liujunzi Decoction combined with Western medicine in the treatment of stable chronic obstructive pulmonary disease(COPD). Three English databases and four Chinese databases were systematically searched from the database establishment to April 1, 2020. We screened randomized controlled trial(RCT) according to the pre-determined inclusion and exclusion criteria, then extracted data. Methodological quality of included studies was assessed with Cochrane bias risk evaluation tool. Data were analyzed by using RevMan 5.3. A total of 401 articles were retrieved and finally 17 RCTs were included in this study, involving 1 447 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in reducing traditional Chinese medicine symptom score, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing the grade of modified medical research council(mMRC), Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing COPD assessment test(CAT) score, Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone. In delaying the decline of forced expiratory volume in one second(FEV_1) or % in the expected value, Liujunzi Decoction combined with conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation was superior to conventional Western medicine or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In delaying the decline of ratio of FEV_1 to forced vital capacity(FEV_1/FVC), Liujunzi Decoction combined with conventional Western medicine was superior to conventional Western medicine alone, but there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. In reducing acute exacerbation rate, there was no statistical difference between Liujunzi Decoction combined with Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation and Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation alone. On the other outcome measures of Liujunzi Decoction combined with other Western medicine, Meta-analysis could not be conducted and conclusions due to the inclusion of only one study. In terms of the occurrence of adverse reactions, some studies did not mention, so the safety of Liujunzi Decoction combined with Wes-tern medicine could not be determined in this paper. Due to the limitations of the quality and quantity of inclu-ded studies, the efficacy of Liujunzi Decoction combined with Western medicine for COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

Treatment adherence and level of control in moderate persistent asthma in children and adolescents treated with fluticasone and salmeterol / Adesão ao tratamento e nível de controle da asma persistente moderada em crianças e adolescentes tratados com fluticasona e salmeterol

Abstract Objective: There is a scarcity of studies that assessed the association between adherence to combination therapy and asthma control in pediatric patients. The authors investigated the association between adherence to fluticasone propionate/salmeterol xinafoate combination-metered aerosol and the level of asthma control in children. Methods: This was a prospective observational study of 84 patients aged 5-16 years with moderate persistent asthma, who remained uncontrolled despite the use of 1000 µg/day of inhaled nonextrafine-hydrofluoric alkane-beclomethasone dipropionate in the three months prior to study enrollment. Participants were prescribed two daily doses of FP (125 µg)/salmeterol xinafoate (25 µg) combination by metered aerosol/spacer for six months. Adherence rates were assessed using the device's dose counter after the 2nd, 4th, and 6th months of follow up. Asthma control was assessed using a simplified Global Initiative for Asthma 2014 Report classification. Results: Mean adherence rates after the second, fourth, and sixth months were 87.8%, 74.9%, and 62.1% respectively, for controlled asthma, and 71.7%, 56.0%, and 47.6% respectively, for uncontrolled asthma (all p-values ≤ 0.03). The proportion of children achieving asthma control increased to 42.9%, 67.9% and 89.3% after the 2nd, 4th and 6th months of follow-up, respectively (p ≤ 0.001). Conclusion: Adherence rates between 87.8% in the 2nd month and 62.1% in the 6th month were strong determinants of asthma control.

Resumo Objetivo: São escassos os estudos que avaliaram a relação entre a taxa de adesão à combinação de proprionato de fluticasona/xinafoato de salmeterol e o nível de controle da asma na infância. O presente estudo teve como objetivo avaliar essa relação. Métodos: Estudo prospectivo observacional com 84 participantes, de 5 a 16 anos, todos eles com asma persistente moderada que permaneceram não controlados apesar do uso de 1.000 µg/dia de dipropionato de beclometasona em partículas não extrafinas nos três meses que antecederam a admissão no estudo. Os participantes receberam prescrição de 125 µg de propionato de fluticasona e 25 µg xinafoato de salmeterol através de inalador pressurizado, duas vezes ao dia, e foram avaliados após o 2°, 4° e 6° meses de tratamento. A taxa de adesão foi obtida por meio do contador analógico de doses incorporado ao inalador. A classificação do nível de controle da asma foi baseada numa simplificação das recomendações da Global Initiative for Asthma. Resultados: As taxas de adesão aos 2, 4 e 6 meses para a asma controlada foram 87,8%, 74,9% e 62,1% e para a asma não controlada de 71,7%, 56,0% e 47,6% (p ≤ 0,03), respectivamente. A proporção de pacientes com asma controlada elevou- se para 42,9%, 67,9% e 89,3% nas três avaliações subsequentes (p ≤ 0,001). Conclusões: Taxas de adesão entre 87,8% no 2° mês e de 62,1% no 6° mês foram determinantes para o nível de controle da asma.

Add-on Tiotropium in Chinese Patients With Moderate Asthma: A Pooled Subgroup Analysis of MezzoTinA-Asthma 1 and 2

PURPOSE: Asthma affects approximately 30 million patients in China; however, tiotropium data for Chinese patients is limited. This study aimed to assess the efficacy and safety of tiotropium in Chinese patients with moderate symptomatic asthma. METHODS: A post hoc subgroup analysis was conducted on 430 Chinese patients pooled from two 24-week, replicate phase 3 trials (NCT01172808 and NCT01172821), in which they received once-daily tiotropium 2.5 µg (Tio R2.5) or 5 µg (Tio R5) (n = 106 or 109, respectively), twice-daily salmeterol 50 µg (Sal 50) (n = 110), or placebo (n = 105), while maintaining inhaled corticosteroids (ICS). The co-primary endpoints assessed in week 24 were forced expiratory volume in 1 second (FEV1) peak0–3h response, trough FEV1 response, and responder rate as assessed using the Asthma Control Questionnaire (ACQ). RESULTS: For both FEV1 peak0–3h responses and trough FEV1 responses, the mean treatment differences were greater for Tio R2.5, Tio R5, and Sal 50 compared with placebo at 0.249 L, 0.234 L, and 0.284 L, and 0.172 L, 0.180 L, and 0.164 L, respectively (P< 0.001). The ACQ responder rate in placebo, Tio R2.5, Tio R5, and Sal 50 was 58.7%, 62.3%, 59.3%, and 69.1%, respectively. Furthermore, 11 (2.6%) of 430 patients had serious adverse events (Tio R5, n = 4; Tio R2.5, n = 1; Sal 50, n = 1; and placebo, n = 5). CONCLUSIONS: Once-daily tiotropium, as add-on to medium-dose ICS, was effective and well tolerated for Chinese patients with moderate symptomatic asthma, consistent with the main analysis.

Eficacia de la budesonida/formoterol comparado con la fluticasona/salmeterol en la mejoría de la capacidad pulmonar de personas mayores con Enfermedad Pulmonar Obstructiva Crónica: revisión sistemática de literatura / Effectiveness of budesonide/formoterol compared to fluticasone / salmeterol in improving the lung capacity of older people with Chronic Obstructive Pulmonary Disease: systematic literature review / Eficiência da budesonida/formoterol comparado com fluticasona/salmeterol na melhora da capacidade pulmonar de idosos com Doença Pulmonar Obstrutiva Crônica: revisão sistemática da literatura

Introducción. La Enfermedad Pulmonar Obstructiva Crónica (EPOC) es una patología no transmisible, caracterizada por una limitación de flujo de aire en las vías respiratorias debido a una respuesta inmunológica anormal frente a partículas. Objetivo. Conocer la eficacia que tiene la budesonida/formoterol comparado con la fluticasona/salmeterol en la mejoría de la capacidad pulmonar en personas mayores de 40 años con Enfermedad Pulmonar Obstructiva Crónica. Materiales y métodos. Se realizó una revisión sistemática de documentos producidos entre el año 2000 y 2018 en distintas bases de datos, donde se incluyeron ensayos clínicos. Se identificaron cuatro artículos para el análisis final. Resultados. Durante la evaluación comparativa de budesonida con formoterol, los artículos muestran un total de 709 personas evaluadas, con un promedio de edad de 53,5 años. El 65,4 % eran varones, el 21 % manifestaba no haber consumido tabaco, todos con diagnóstico de Enfermedad Pulmonar Obstructiva Crónica moderada-severa, según la escala GOLD (Global Initiative For Chronic Obstrutive Lung Disease). Los estudios determinaron que al administrar budesonida/formoterol de 400/12 mcg y 320/9 mcg, los pacientes tuvieron una leve mejoría en el Volumen Espiratorio Forzado del primer segundo (VEF1). Solo dos pacientes presentaron efectos adversos. No obstante, para los resultados mencionados anteriormente no se encontró diferencias significativas. Conclusiones. El uso de budesonida/formoterol es eficaz al mejorar la capacidad ventilatoria pulmonar, disminuye el número de exacerbaciones anuales y genera un adecuado control de los síntomas, sin embargo, es igual de efectivo a la fluticasona/salmeterol.

Introduction. Chronic Obstructive Pulmonary Disease (COPD) is a not transmissible disease, characterized by a limitation of airflow in the respiratory tract, due to an abnormal immune response to particles. Objective. This article aims to show that the application of budesonide / formoterol improves lung capacity in people over 40 years with Chronic Obstructive Pulmonary Disease. Materials and methods. A systematic review was conducted in the period between 2000 and 2018 in different databases where clinical trials were included. Four articles were identified for the final analysis. Results. During the comparative evaluation of budesonide with formoterol, a total of 709 people were evaluated, with an average age of 53.5 years, 65.4% were male, 21% reported not having used tobacco, all with a diagnosis of moderate-severe Chronic Obstructive Pulmonary Disease according to the GOLD scale (Global Initiative For Chronic Obstrutive Lung Disease). The studies determined that when budesonide / formoterol of 400/12 mcg and 320/9 mcg was administered, the patients had a slight improvement in the Forced Expiratory Volume of the first second (FEV1). Only two patients presented adverse effects. However, for the results mentioned above no significant differences were found. Conclusions. The use of budesonide / formoterol is effective in improving pulmonary ventilatory capacity, decreases the number of annual exacerbations and generates adequate control of symptoms, however, it is equally effective in fluticasone / salmeterol.

Introdução. A Doença Pulmonar Obstrutiva Crônica (DPOC) é uma patologia não transmissível, caraterizada por uma limitação do fluxo de ar nas vias aéreas devido a uma resposta imune anormal contra partículas. Objetivo. Conhecer a eficiência que apresenta a budesonida/formoterol comparado com fluticasona/salmeterol na melhora da capacidade pulmonar em pessoas com mais de 40 anos com Doença Pulmonar Obstrutiva Crônica. Materiais e métodos. Foi realizada uma revisão sistemática dos documentos produzidos entre 2000 e 2018 em diferentes bancos de dados, onde foram incluídos ensaios clínicos. Quatro artigos foram identificados para a análise final. Resultados. Durante a avaliação comparativa de budesonida com formoterol, os artículos mostram um total de 709 pessoas avaliadas, com uma idade média de 53,5 anos. O 65,4 % eram do sexo masculino, o 21 % disseram que não usavam tabaco, todos diagnosticados com Doença Pulmonar Obstrutiva Crônica moderada a grave, de acordo com a escala GOLD (Global Initiative For Chronic Obstrutive Lung Disease). Os estudos determinaram que administrar budesonida/formoterol de 400/12 mcg e 320/9 mcg, os pacientes apresentaram uma leve melhora no Volume Expiratório Forçado no primeiro segundo (VEF1). Apenas dois pacientes tiveram efeitos adversos. No entanto, não foram encontradas diferenças significativas para os resultados mencionados acima. Conclusões. O uso de budesonida/formoterol é eficaz na melhora da capacidade ventilatória pulmonar, diminui o numero de exacerbações anuais e gera controle adequado dos sintomas, no entanto, é igualmente eficaz para a fluticasona/salmeterol.

Pharmacokinetic characteristics of fluticasone, salmeterol and tiotropium after concurrent inhalation

Chronic obstructive pulmonary disease (COPD) is a type of progressive, obstructive lung disease characterized by long-term poor airflow. The symptoms of COPD may be relieved and its progression delayed by fluticasone (FTS), salmeterol (SM), and tiotropium (TTP). The aim of this study is to investigate pharmacokinetic (PK) characteristics of inhaled FTS, SM, and TTP after co-administration. An open-label, single-arm, three-period, simple ascending dose study was conducted in 10 healthy male subjects. A single dose of FTS/SM (250/50 µg) and TTP (18 µg) were concomitantly inhaled in period 1, and the dose of each drug was escalated to two- and three-fold in periods 2 and 3, respectively, with a 2-week washout between periods. Activated charcoal was co-administered before and after inhalation to block gastrointestinal absorption. Blood samples for PK analysis were collected up to 24 hours. PK parameters were obtained by non-compartmental analysis. FTS, SM, and TTP rapidly reached maximum plasma concentration after inhalation (0.08–3.00 h, 0.03–0.10 h and 0.03–0.10 h, respectively) and were eliminated with mean half-lives of 9.29–10.44 h, 6.09–12.39 h and 0.25–47.42 h, respectively. PK assessment of the lowest dose of TTP was limited due to relatively low systemic exposure compared to the lower limit of quantification. In conclusion, PK characteristics of FTS, SM, and TTP by pulmonary absorption were evaluated after concurrent inhalation. FTS and SM showed dose-proportional PK profiles between 250–750 µg and 50–150 µg, respectively, while TTP presented dose-proportionality in the early phase exposure between 18-54 µg.

Síndrome de Cushing iatrogénico por corticoides inhalados en paciente VIH / Cushing syndrome in a HIV patient using inhaled steroids: report of one case

We report a 41-year-old man with HIV and a chronic obstructive pulmonary disease, treated for seven months with Fluticasone/Salmeterol and antiretroviral therapy (Lamivudine, Tenofovir, Atazanavir and Ritonavir). While using these medications, the patients developed a Cushing syndrome in a period of five months. After performing laboratory and imaging tests, it was concluded that the most probable cause of the syndrome was the interaction of inhaled steroids with Ritonavir. After discontinuing these medications the syndrome reverted in a period of 8 months.

Mesenchymal Stem Cells Combined with Budesonide, Almeterol and Azithromycin for the Treatment of Bronchiolitis Obliterans Syndrome after Hematopoietic Stem Cell Transplantation / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To evaluate the safety and effectiveness of a novel therapeutic regimen for bronchiolitis obliterans sydrome (BOS) affter hematopoietic stem cell transplantation (HSCT).</p><p><b>METHODS</b>Seven patients who had received HSCT and had been diagnosed as BOS were enrolled in this study. They received weekly intravenous injection of umbilical cord-derived mesenchymal stem cells (MSC) at a dose of 1 × 10(6)/kg for 4 weeks. Budesonide was given orally at a daily dose of 0.25 g, and salmeterol was inhaled at a dose of 4.5 µg for 3 times per day. Methylprednisolone was given at a dose of 1 mg/(kg·d) for 2 weeks when respiratory failure occured. The dose of methylprednisolone was tapered to 0.25 mg/(kg·d) after 4 weeks and was adjusted according to the occurrence and severity of chronic graft-versus-host disease (cGVHD).</p><p><b>RESULTS</b>The therapy was generally safe and no severe acute toxicity was observed. One patient died of heart failure during the treatment, the other 6 patients were alive and the pulmonary function parameters including FEV1, FEV1/FVC, PaO2 and AaDO2 were significantly improved after 6 months as compared with the baseline parameters (P < 0.05).</p><p><b>CONCLUSION</b>MSC combined with budesonide, almeterol and azithromycin has been confirmed to be generally safe and can reduce the dose of glucocorticoid in treatment of BOS after HSCT.</p>

Glicopirrônio para o tratamento da síndrome de Swyer-James-Macleod / Glycopyrronium for the treatment of Swyer-James-Macleod syndrome

CONTEXTO: A Síndrome de Swyer-James-Macleod (SSJM) ou síndrome pulmonar hiperlucente unilateral é uma rara bronquiolite constritiva com obstrução do fluxo de ar e uma diminuição do número e diâmetro dos vasos pulmonares periféricas ipsilaterais. Esta síndrome é caracterizada por hiperlucência unilateral na radiografia de tórax, sendo que a tomografia computadorizada fornece informações adicionais úteis. A doença geralmente se apresenta com dispnéia, diminuição da tolerância ao exercício, tosse, hemoptise, e infecções pulmonares recorrentes. SSJM pode ser confundida com asma ou embolia pulmonar devido a sintomas semelhantes e podem resultar em terapia inapropriada. ). Pode se manifestar de duas formas: assintomática, sendo a maioria diagnosticada na fase adulta, quando o paciente se submete a exames radiológicos de rotina, e a forma sintomática, que é mais encontrada em crianças. Segundo a Classificação Internacional de Doenças 10 (CID-10) é classificada como um tipo de enfisema (J43) dentro do grupo de doenças respiratórias crônicas das vias inferiores. TECNOLOGIA: Glicopirrônio (Seebri®). PERGUNTA: Glicopirrônio é eficaz e seguro para o tratamento da síndrome de Swyer-James-Macleod? EVIDÊNCIAS: Não foram encontrados estudos específicos que avaliassem o uso de glicopirrônio para o tratamento da Síndrome de Swyer-James-Macleod. Foram selecionadas três revisões sistemáticas que avaliaram glicopirrônio para DPOC. No primeiro estudo foi demonstrado que glicopirrônio apresenta resultados semelhantes a outros antagonistas muscarínicos de longa duração (LAMA), como o tiotrópio, para os desfechos de eficácia e qualidade de vida. No segundo estudo, verificou-se que o uso de glicopirrônio em associação com um agonista ß2 de longa duração (indacaterol) é mais eficaz do que o uso desses medicamentos em monoterapia e mais seguro quando comparado a esquemas que utilizam corticoides, quando em monoterapia ou associado a indacaterol. Por fim, o último estudo demonstrou por meio de comparações indiretas que antagonistas muscarínicos apresentam eficácia comparável, especialmente em 12 semanas, a dos agonistas ß2 de longa duração. CONCLUSÕES: A SSJM é uma condição rara e o seu tratamento ainda não é bem estabelecido na literatura. Broncodilatadores são utilizados para tratar os sintomas da doença, dentre os quais está o glicopirrônio. Os resultados das revisões sistemáticas demonstraram que glicopirrônio não apresenta diferenças estatisticamentes significantes para tiotrópio e outros LAMA e para agonistas ß2 de longa duração (LABA), incluindo salmeterol e formoterol que estão disponíveis no SUS para DPOC e asma. Entretanto, o uso associado de glicopirrônio a um agonista ß2 de longa duração (indacaterol) demonstrou melhores resultados do que a monoterapia. Como limitação, ressalta-se que os pacientes avaliados não eram portadores de SSJM, mas de DPOC em geral.

Three-month Treatment Response and Exacerbation in Chronic Obstructive Pulmonary Disease

The aim of this study was to investigate relationships between acute exacerbation and Forced Expiratory Volume 1 second (FEV1) improvement after treatment with combined long-acting beta-agonist (LABA) and inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD). A total of 137 COPD patients were classified as responders or nonresponders according to FEV1 improvement after 3 months of LABA/ICS treatment in fourteen referral hospitals in Korea. Exacerbation occurrence in these two subgroups was compared over a period of 1 yr. Eighty of the 137 COPD patients (58.4%) were classified as responders and 57 (41.6%) as nonresponders. Acute exacerbations occurred in 25 patients (31.3%) in the responder group and in 26 patients (45.6%) in the nonresponder group (P=0.086). FEV1 improvement after LABA/ICS treatment was a significant prognostic factor for fewer acute exacerbations in a multivariate Cox proportional hazard model adjusted for age, sex, FEV1, smoking history, 6 min walk distance, body mass index, exacerbation history in the previous year, and dyspnea scale.Three-month treatment response to LABA/ICS might be a prognostic factor for the occurrence of acute exacerbation in COPD patients.

Efficacy on chronic obstructive pulmonary disease at stable stage treated with cutting method and western medication / 中国针灸

<p><b>OBJECTIVE</b>To compare the difference in clinical efficacy on chronic obstructive pulmonary disease (COPD) at stable stage in the patients among the combined therapy of cutting method and western medication (combined therapy), simple cutting method and simple western medication.</p><p><b>METHODS</b>One hundred and twenty cases of COPD were randomized into three groups, 40 cases in each one. In the cutting method group, for excessive phlegm pattern/syndrome, Feishu (BL 13), Danzhong (CV 17), Dingchuan (EX-B 1) and Yuji (LU 10) were selected as the main acupoints, and Lieque (LU 7) and Pianli (LI 6) were as the supplementary acupoints. For the pattern/syndrome of failure to consolidate kidney primary, Shenshu (BL 23), Pishu (BL 20), Guanyuan (CV 4) and Yuji (LU 10) were selected as main acupoints, and Jueyinshu (BL 14) and Zusanli (ST 36) were as the supplementary acupoint. Three acupoints were selected alternatively in each treatment and the cutting method was applied once every 10 days. Three treatments made one session. Two sessions of treatment were required. In the western medication group, salbutamol sulfate aerosol, one press (200 μg/press) was used each night, as well as salmeterol xinafoate and fluticasone propionate powder for inhalation, one inhalation each night. The treatment of 1 month made one session. Two sessions were required. In the combined therapy group, the cutting method and western medication were applied in combination. The results of clinical symptom score, lung function test, arterial blood gas analysis, degree of inflation as well as clinical efficacy were observed before and after treatment in each group.</p><p><b>RESULTS</b>Except the degree of lung inflation, the clinical symptom score, indices of lung function test, partial pressure of arterial blood gas (PaO2) and partial pressure of carbon dioxide (PaCO2) were all obviously improved after treatment as compared with those before treatment in each group (all P<0.05). They were apparently improved after treatment in the combined therapy group and the cutting method group as compared with those in the western medication group (all P<0.05). The total effective rate was 77.5% (31/40) in the combined therapy group and was 75.0% (30/40) in the cutting method group, both better than 60.0% (24/40) in the western medication group (both P<0.05).</p><p><b>CONCLUSION</b>The simple cutting method based on syndrome differentiation and the combined therapy with western medication achieve the superior efficacy on COPD at stable stage as compared with the simple western medication. The effect mechanism is possibly related to the improvement of bronchial airway function through constant acupoint stimulation.</p>

Budesonida, Beclometasona, Fenoterol, Salbutamol, Formoterol e Salmeterol para o tratamento da Doença Pulmonar Obstrutiva Crônica (DPOC) / Budesonide, Beclomethasone, Fenoterol, Salbutamol, Formoterol and Salmeterol for the treatment of Chronic Obstructive Pulmonary Disease

A doença pulmonar obstrutiva crônica (DPOC) caracteriza-se por sinais e sintomas respiratórios associados à limitação da capacidade ventilatória, sendo geralmente causada por exposição inalatória crônica a material particulado, principalmente decorrente de tabagismo. Broncodilatadores inalatórios constituem a base do tratamento sintomático da DPOC, promovendo alívio da dispneia e melhorando a capacidade para o exercício. São os medicamentos de escolha para o manejo sintomático de portadores da doença em todos os estádios. Quando administrados por aerossol, os broncodilatadores ß2-adrenérgicos de ação curta levam à broncodilatação de início rápido, em 1-5 min, e o efeito terapêutico entre 2-4 horas. São usados sob demanda nos casos de DPOC leve com sintomas intermitentes, e em esquema fixo em pacientes com sintomas freqüentes, diários ou contínuos. Podem ser usados em esquema "se necessário" em associação com broncodilatadores de longa ação. A falta de resposta espirométrica aguda ao broncodilatador não exclui um possível benefício em longo prazo. Portadores de DPOC em estádio avançado (III e IV) frequentemente persistem sintomáticos e com limitação funcional significativa, apesar do uso de broncodilatadoresde curta ação em esquema fixo. Salmeterol e formoterol são administrados por via inalatória e levam à broncodilatação através dos mesmos mecanismos dos agonistas adrenérgicos de curta ação, com a diferença de que a broncodilatação dura por até 12 horas. O salmeterol é o mais seletivo de todos os agonistas ß2, tendo menor atividade sobre os receptores ß1 cardíacos em relação ao formoterol. Tratamento com corticoide inalatório em portadores de DPOC moderada e grave levou à pequena redução nas exacerbações em estudos clínicos em comparação a placebo. O benefício é de baixa magnitude e possivelmente transitório, sendo que portadores de DPOC com VEF1 (volume expiratório forçado) inferior a 50% do previsto e com mais de duas exacerbações ao ano apresentaram os maiores benefícios. O benefício dos corticóides inalatórios é considerado um efeito de classe, não havendo diferenças de eficácia entre os representantes. As diferenças são basicamente farmacocinéticas, e maior potência não se traduz em maior eficácia clínica. Os membros da CONITEC presentes na 1ª reunião extraordinária do plenário do dia 04/07/2012 recomendaram a incorporação dos medicamentos budesonida, beclometasona, fenoterol, salbutamol, formoterol e salmeterol para o tratamento da DPOC, conforme PCDT a ser elaborado pelo Ministério da Saúde, com ampliação para os seguintes CIDs: J44.0 Doença pulmonar Obstrutiva Crônica com infecção respiratória aguda do trato respiratório inferior; J44.1 Doença pulmonar obstrutiva crônica com exacerbação aguda não especificada e J44.8 Outras formas especificadas de Doença Pulmonar Obstrutiva Crônica.

Salmeterol/fluticasone treatment reduces circulating C-reactive protein level in patients with stable chronic obstructive pulmonary disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Evidence suggests that systemic inflammation may play an important role in the progression and morbidity of chronic obstructive pulmonary disease. It remains controversial whether inhaled corticosteroid in combination with a long-acting beta(2)-adrenoceptor agonist can attenuate systemic inflammation. We evaluated the effect of salmeterol/fluticasone propionate on circulating C-reactive protein level in stable chronic obstructive pulmonary disease patients.</p><p><b>METHODS</b>An open-label clinical trial was conducted to recruit 122 outpatients with stable moderate-to-severe chronic obstructive pulmonary disease from department of respiratory medicine in two teaching hospitals between June 2007 and March 2008. Patients were randomized into two groups (1:1) to receive either the combination of 50 microg salmeterol and 500 microg fluticasone twice daily (n = 61), or the combination of 206 microg albuterol and 36 microg ipratropium q.i.d (n = 61) over 6 months. Circulating C-reactive protein concentrations were measured before randomization and during the follow-up. The efficacy of treatment was also assessed by spirometry, as well as health status and dyspnea score at baseline and after 6-month treatment.</p><p><b>RESULTS</b>Baseline characteristics of two groups were similar. Compared with ipratropium/albuterol, the combination of salmeterol/fluticasone significantly reduced circulating level of C-reactive protein (-1.73 vs. 0.08 mg/L, respectively, P < 0.05) after 6-month treatment. Forced expiratory volume in one second (FEV(1)) and health status also improved significantly in salmeterol/fluticasone group compared with ipratropium/albuterol. Salmeterol/fluticasone treatment subjects who had a decrease of circulating C-reactive protein level had a significant improvement in FEV(1) and St George's Respiratory Questionnaire total scores compared with those who did not (185 vs. 83 ml and -5.71 vs. -1.79 units, respectively, both P < 0.01).</p><p><b>CONCLUSION</b>Salmeterol/fluticasone treatment reduced circulating C-reactive protein concentration in clinically stable moderate-to-severe chronic obstructive pulmonary disease patients after 6-month treatment.</p>

Comparison for the Effects of Triple Therapy with Salmeterol/Fluticasone Propionate and Tiotropium Bromide versus Individual Components in Patients of Severe COPD Combined with Bronchial Hyperresponsiveness / 결핵및호흡기질환

BACKGROUND: A combination of salmeterol and fluticasone propionate (SFC) and tiotropium bromide (TIO) is commonly prescribed for COPD patients but there is little data on their effectiveness, particularly in COPD patients with bronchial hyperresponsiveness. This study compared the spirometric improvement based on the change in FEV1, FEV1/FVC, and IC as well as the clinical outcomes of the therapeutic strategies with SFC and TIO versus the individual components in patients with severe COPD and bronchial hyperresponsiveness. METHODS: This study examined the spirometric data and clinical outcomes of 214 patients with COPD and hyperresponsiveness, who were divided into three groups according to the therapeutic regimen (TIO only, SFC only, and a triple therapy regimen). RESULTS: All regimen groups showed early improvement in the FEV1 and IC (at 3- and 6 months after treatment). However, long-term beneficial effects were observed only in the SFC group (at 24 months after treatment). However, these beneficial effects decreased after a 36-month follow up. In all spirometric results, the 12-, 24-, and 36-months data showed a similar degree of improvement in the three groups. The triple therapy group showed higher St. George's Respiratory Questionnaire scores and lower acute exacerbations and hospitalization. CONCLUSION: SFC can be a more important component in the pharmacological treatment of severe COPD patients with hyperresponsiveness than TIO, particularly in the spirometric and clinical outcomes.