Comparative Efficacy of Generic Salmeterol Xinafoate/Fluticasone Propionate MDI Fixed Dose Combination and Seretide ® MDI in Asthmatic Patients: An Open Label, Randomized, Phase III Study.

The addition of an inhaled long-acting β2-agonist (LABA) to an inhaled corticosteroid (ICS) gives optimal control of asthma in most patients. The long-acting β2-agonist (LABA) Salmeterol xinafoate (Salmeterol) and inhaled corticosteroid (ICS) fluticasone propionate (fluticasone) are being made available as a combination product Seretide® pMDI (Salmeterol/ Fluticasone) in a single aerosol inhaler. This randomized, open label, non-inferior, multicentric, 12-week, phase III study compared the efficacy and safety of generic Salmeterol/Fluticasone with commercially available product Seretide®. Materials and methods:Patients aged > 12 years inclusive of either sex (N = 372) with persistent asthma as defined by NHLBI for > 6 months prior to screening were included in the study. After a screening phase (1 week), eligible patients were enrolled in the trial with 2 weeks run in period. Eligible patients were randomized to receive either of the two treatment groups [HFA-Propelled pMDI Salmeterol/Fluticasone (25/250mcg) or HFA-Propelled Seretide® (25/250mcg) pMDI] in a ratio of 1:1 for the 12- week treatment period. The primary objective was to demonstrate non-inferiority of Salmeterol/Fluticasone versus Seretide®, measured by mean pre-dose forced expiratory volume in the first second (FEV1), at week 12. Results: This study provides evidence for the primary efficacy endpoint that Salmeterol/Fluticasone was statistically as well as clinically non-inferior to Seretide® in the treatment of patients with persistent asthma. This was supported by secondary endpoints which demonstrate that Salmeterol/Fluticasone appeared to be comparable to Seretide® in terms of efficacy for the secondary efficacy endpoints (morning PEFR, evening PEFR, diurnal variability of PEFR, daytime and night-time asthma symptoms score, average need for short acting-β2-agonists, proportion of patients that required rescue medication, patients with nocturnal asthma, patients without asthma symptoms of score 0 and average number of days without asthma symptoms of score 0). Salmeterol/Fluticasone was safe and well tolerated; and safety profile is comparable to comparator Seretide®. Conclusion: The results of study demonstrate that generic and innovator HFA formulations of Salmeterol/Fluticasone are clinically interchangeable. Overall, the study indicates that HFA-Propelled Salmeterol/ Fluticasone (25/250mcg) pMDI was safe, well tolerated and non-inferior in efficacy compared to HFA-Propelled Seretide® (25/250mcg) pMDI.

Predictors of Pulmonary Function Response to Treatment with Salmeterol/fluticasone in Patients with Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and responses to therapies are highly variable. The aim of this study was to identify the predictors of pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD. A total of 127 patients with stable COPD from the Korean Obstructive Lung Disease (KOLD) Cohort, which were prospectively recruited from June 2005 to September 2009, were analyzed retrospectively. The prediction models for the FEV1, FVC and IC/TLC changes after 3 months of treatment with salmeterol/fluticasone were constructed by using multiple, stepwise, linear regression analysis. The prediction model for the FEV1 change after 3 months of treatment included wheezing history, pre-bronchodilator FEV1, post-bronchodilator FEV1 change and emphysema extent on CT (R = 0.578). The prediction models for the FVC change after 3 months of treatment included pre-bronchodilator FVC, post-bronchodilator FVC change (R = 0.533), and those of IC/ TLC change after 3 months of treatment did pre-bronchodilator IC/TLC and post-bronchodilator FEV1 change (R = 0.401). Wheezing history, pre-bronchodilator pulmonary function, bronchodilator responsiveness, and emphysema extent may be used for predicting the pulmonary function response to 3 months of treatment with salmeterol/fluticasone in patients with COPD.

Efeito de curto prazo do tiotrópio nos portadores de DPOC em tratamento com B2-agonista / Short-term effect of tiotropium in COPD patients being treated with a B2 agonist

OBJETIVO: Avaliar o impacto de curto prazo do uso de tiotrópio em pacientes com DPOC grave e muito grave com queixas de dispneia apesar do tratamento com outros broncodilatadores. MÉTODOS: Estudo prospectivo incluindo pacientes com DPOC grave ou muito grave, com queixa de dispneia de pequenos esforços ou ao repouso. A cada 15 dias, o tratamento broncodilatador foi modificado: salmeterol, tiotrópio e associação salmeterol+tiotrópio. Ao final de cada regime, foram realizados testes de função pulmonar e teste de caminhada de seis minutos (TC6). Também foram avaliados o grau de dispneia e a capacidade de realização de atividades de vida diária. Para a avaliação das atividades de vida diária, foi utilizada a escala London Chest Activity of Daily Living (LCADL) validado para uso no Brasil. RESULTADOS: Foram avaliados 52 pacientes. Desses, 30 completaram o estudo. A introdução de tiotrópio como monoterapia resultou em uma melhora significativa (p < 0,05) da dispneia basal (média do escore da escala do Medical Research Council de 3,0 para 2,5) e ao final do TC6 (média do escore da escala de Borg de 6,1 para 4,5), e as diferenças foram significativas (p < 0,05 para ambos). O uso da associação salmeterol+tiotrópio resultou em um aumento significativo médio de 81 mL no VEF1 e na melhora de 5,7 pontos no escore da escala LCADL. CONCLUSÕES: A introdução de tiotrópio no tratamento de pacientes com DPOC grave a muito grave em uso de β2-agonistas de longa duração causa melhora na função pulmonar e alivio sintomático perceptível pelos pacientes a curto prazo. Esses resultados, obtidos em regime de atendimento de vida real, dão suporte ao uso da associação salmeterol+tiotrópio em protocolos de assistência específicos a esses pacientes.

OBJECTIVE: To evaluate the short-term impact of tiotropium in patients with severe or very severe COPD who complain of dyspnea despite being currently treated with other bronchodilators. METHODS: A prospective study including patients with severe or very severe COPD and complaining of dyspnea at rest or on minimal exertion. Every 15 days, the bronchodilator treatment regimen was altered, from salmeterol to tiotropium to salmeterol+tiotropium. At the end of each regimen, pulmonary function tests and the six-minute walk test (6MWT) were performed. The degree of dyspnea and the ability to perform activities of daily living were also assessed. To evaluate patient ability to perform activities of daily living, we employed the London Chest Activity of Daily Living (LCADL), validated for use in Brazil. RESULTS: We evaluated 52 patients, 30 of whom completed the study. The use of tiotropium in isolation resulted in significant improvement in dyspnea at baseline (mean Medical Research Council scale score reduced from 3.0 to 2.5) and at the end of 6MWT (mean Borg scale score reduced from 6.1 to 4.5), and the differences were significant (p < 0.05 for both). The use of the salmeterol+tiotropium combination resulted in a significant (81 mL) increase in FEV1 and a 5.7 point improvement in the LCADL score. CONCLUSIONS: The introduction of tiotropium into the treatment of patients with severe or very severe COPD and using long-acting β2 agonists improves pulmonary function and provides symptomatic relief, as perceived by patients in the short term. These results, obtained under real life treatment conditions, support the use of the salmeterol+tiotropium combination in specific treatment protocols for these patients.

Salmeterol vs. formoterol: a comparison of rapid bronchodilator effect in a randomized controlled trial.

We conducted this double blind randomized controlled trial to compare the rapid bronchodilator effect of salmeterol and formoterol in 60 children with stable asthma. Participants were randomized to receive either salmeterol (50 microg) (n=31) or formoterol (24 microg) (n=29) by metered dose inhaler and spacer. Spirometry was performed at baseline, at 30 minutes, and at 60 minutes. Bronchodilatation was assessed by changes in FEV(1) at 30 and 60 minutes. Baseline parameters were comparable in the two groups. There was no significant difference in the FEV(1) at 30 and 60 minutes between two groups. We conclude that salmeterol and formoterol both cause bronchodilator response at end of 60 minutes and are not different with regards to their rapid bronchodilator response.

Adesão ao tratamento de manutenção em asma (estudo ADERE) / Compliance with maintenance treatment of asthma (ADERE study)

OBJETIVO: Avaliar a adesão ao tratamento preventivo de asma persistente moderada e grave. MÉTODOS: Médicos de vários Estados do país foram contactados para selecionar asmáticos persistentes moderados ou graves, maiores de doze anos. Os pacientes receberam salmeterol/fluticasona 50/250 µg diskus durante 90 dias (sendo orientados a retornarem as embalagens ao final do estudo para conferência da dosagem total utilizada). Receberam telefonemas da equipe do estudo no início e ao final de 90 dias para que fosse avaliada a adesão. Foi considerado como aderente ao tratamento o asmático que utilizou no mínimo 85 por cento das doses prescritas. As variáveis estudadas foram sexo, idade, cor, estado civil, escolaridade, tabagismo atual, outras atopias, co-morbidades, gravidade da asma, uso de outras medicações e número de hospitalizações por asma. RESULTADOS: Foram incluídos 131 pacientes oriundos de quinze estados, com taxa geral de adesão de 51,9 por cento. Houve diferença significativa na adesão quanto à gravidade da asma (maior adesão nos casos graves; p = 0,02). Não houve diferença estatisticamente significativa nas demais variáveis. CONCLUSÃO: A taxa geral de adesão ao tratamento de manutenção da asma foi baixa.

OBJECTIVE: To determine the rate of compliance with preventive treatment of moderate and severe persistent asthma. METHODS: Physicians at various medical centers across the country were invited to nominate patients for participation in the study. Inclusion criteria were being over the age of 12 and presenting moderate or severe persistent asthma. Participating patients received salmeterol/fluticasone 50/250 µg by dry powder inhaler for 90 days and were instructed to return the empty packages at the end of the study as a means of determining the total quantity used. In order to evaluate compliance, a member of the research team contacted each patient via telephone at the study outset and again at the end of the 90-day study period. Asthma patients were considered compliant with the treatment if they used at least 85 percent of the prescribed dose. The following variables were studied: gender, age, race, marital status, years of schooling, smoking habits, other atopic conditions, comorbidities, asthma severity, use of other medication and number of hospital admissions for asthma. RESULTS: A total of 131 patients from fifteen states were included. The overall rate of compliance was found to be 51.9 percent. There was a significant difference in compliance in relation to asthma severity: compliance was greater among patients with severe persistent asthma than among those with moderate persistent asthma (p = 0.02). There were no statistically significant differences among any of the other variables. CONCLUSION: The overall rate of compliance with maintenance treatment of asthma was low.

Calidad de vida del cuidador del niño asmático

A pesar del mejor entendimiento de la fisiopatología del asma, del hecho de contar con más y mejores fármacos (como anti-inflamatorios potentes y agonistas beta dos de acción prolongada) los síntomas y la presencia de la enfermedad puede ser persistentes, así como la exacerbaciones que llegan a comprometer la integridad del paciente y hacen necesario valorar el impacto de la enfermedad sobre la vida del paciente y sus cuidadores. Esto ha llevado a incluir en su evaluación general, cuestionarios de calidad de vida. El objetivo de nuestro estudio fue aplicar un cuestionario de calidad de vida a la persona encargada del cuidado de niños asmáticos en dos grupos de pacientes los cuales recibieron diferentes esquemas terapéuticos: uno con un esteroide inhalado (EI) y el otro con el EI más un broncodilatador de acción prolongada (BAP), para valorar los cambios percibidos en los cuestionarios y compararlos de acuerdo al tratamiento. Material y métodos: se realizó un estudio clínico controlado experimental y comparativo, aplicando un cuestionario a la persona encargada del cuidado del niño asmático. Este cuestionario fue elaborado, validado y autorizado su uso por la doctora Efizabeth Juniper y se le conoce como el PACQLQ. Los pacientes y sus cuidadores se distribuyeron al azar en dos grupos: grupo A tratados inicialmente con EI (Beclometasona) más BAP (Salmeterol) por un periodo de seis semanas posterior a lo cual permanecieron dos semanas sin manejo y continuaron las siguientes seis semanas con EI solo. En tanto el grupo B inició con EI solo y después de dos semanas de lavado continuo seis semanas con EI más BAP. A los cuidadores se les realizó el cuestionario al iniciar el tratamiento y en las semanas dos, cuatro y seis. Resultados: se incluyeron a 30 pacientes con sus cuidadores. Se encontró una mejoría en la calidad de vida de los cuidadores de acuerdo al cuestionario en los dos grupos al compararlos con el basal, mientras que los del grupo que recibieron EI mas BAP fue mayor este cambio siendo estadísticamente significativo. Conclusiones: nuestro estudio primero que se realiza en nuestro medio, demuestra que al realizar una intervención en el tratamiento del asma (usar EI o BAP) condiciona una mejoría significativa en la valoración del cuestionario PACQLQ desde las primeras semanas de tratamiento y que los que recibieron terapia de EI más BAP al inicio del tratamiento la mejoría fue mayor. Estos resultados coinciden con lo publicado hasta la fecha. Por lo anterior recomendamos el uso de cuestionario de calidad de vida desde el inicio del tratamiento de los pacientes como parte de su evaluación integral.

Despite better understanding of the pathophysiology of asthma, the application of better drugs (potent anti-inflammatory medications and beta2 adrenergics with long-lasting effects), some symptoms persist and the illness itself, at the same time with exacerbation, may compromise the integrity of the patient. This calls for an evaluation of the impact of the ailment in different aspects of daily life of patients and of his/her caregivers. To address these situations, quality-of-life questionnaires for patients and caregivers were designed. With this study, our objective was to make up a quality-of-life questionnaire to be filled out by caregivers of asthmatic children treated with one of two therapeutic schemes: with inhaled steroids (EI), or the EI plus prolonged action bronchodilator (BAP). Materials and methods: controlled, experimental, and comparative clinical trial polling asthmatic child caregivers, applying a questionnaire designed by Elizabeth Juniper (PACQLQ). Patients and caregivers were randomized in two groups: group A was treated with IE (Beclomethasone) plus BAP (Salmeterol) during a 6-week period, followed by a 2-week wash-out period followed by a 6-week period with only IE. Group B were treated only with EI followed by a 2-week period of wash-out and a six-week period with IE plus BAP. Caregivers filled in the questionnaires at the beginning, and at second, fourth, and sixth-weeks of treatment. Results: we included 30 patients and their caregivers who were randomized in two groups. Values in every group showed significant improvement in quality of life, as compared to basal values. Values between groups showed greater improvement in groups who received El plus BAP at the beginning. Conclusions: our study shows that administering treatment for asthma improves significantly the caregiver's appreciation of quality of life with respect to the PACQLQ questionnaire. The group that received El therapy plus BAP at the beginning showed greater improvement. These results coincide with those published to date. We recommend the use of questionnaires at the beginning of the treatment as part of the integral evaluation of every patient with asthma.

Anti-inflammatory effects of salmeterol, compared to beclomethasone, and sustained-release theophylline measured by serum levels of tumor necrosis factor-alpha, and eosinophilic cationic protein in asthmatic children

Inhaled steroids are increasingly used in the management of asthma and although effective, they may cause systemic side effects. Theophylline is among the least expensive drugs used to treat asthma and consequently it remains a commonly used drug for this indication in many countries. In industrialized countries, the advent of inhaled corticosteroids, beta-2 agonists, and leukotriene modifying drugs has significantly diminished the extent to which theophylline is used. In addition to their bronchodilating effects, long acting inhaled beta2 agonists have recently been shown to have some anti-inflammatory properties. This work was designed to study the anti inflammatory effects of salmeterol compared to beclomethasone and theophylline by measuring of serum levels of tumor necrosis factor-alpha [TNF-alpha] and eosinophilic cationic protein [ECP] in children with mild and moderate to severe asthma. The study was carried out in The Chest and Allergy Unit, Pediatric Department, Tanta University Hospital, from October 2000 to January 2003. It comprised ninety asthmatic children who were presented by mild, and moderate to severe attack of asthma exacerbations, their ages ranged from 6-15 years. The asthmatic children were classified into 2 groups: Group I: Included thirty children with mild asthmatic attack with FEV1 of 70-80% of the expected normal value for age and sex at the time of presentation. These patients were subdivided into three sub-groups to receive one of the following drugs for eight weeks: Inhaled beclomethasone dipropionate by metered dose inhaler [MDI] in a dose of 200 microgram / 8 hours [Steroid subgroup-I], oral sustained-release theophylline in a dose of 15 mg / kg / day [12 Hourly] [Theophylline subgroup-I], and Inhaled long acting beta 2 agonist [Salmeterol] by MDI in a dose of 50 microgram [2 buffs] / 12 hours [Salmetemi subgroup-I]. Group II: Included sixty children with moderate to severe asthma exacerbation with FEV1 less than 70% of the expected values for the age and sex. Conventional therapy was given as required to these patients to control the exacerbations of the asthmatic attack, and to achieve FEV1 of 70-80% of the expected normal values of their age and sex. Then the patients were subdivided to three sub-groups [Steroid subgroup-Il, Theophylline subgroup-Il, and Salmeterol subgroup-Il] to receive either one of the three drug modalities by the same dose and for the same duration as mentioned before in children with mild asthma [group I]. Absolute eosinophilic count [AEC], serum levels of eosinophilic cationic protein [ECP] and tumor ncrosis factor-alpha [TNF-alpha] were measured at presentation during the acute exacerbation and 8 weeks after beginning of the different treatment modalities. We concluded that beclomethasone dipropionate had effectively diminished serum levels of TNF-alpha and ECP to a greater extent than the Ophylline and salmeterol in children with bronchial asthma. Long acting theophylline also diminished significantly serum levels of TNF-alpha and ECP at a lower than customarily recommended blood theophylline level after 8 weeks of regular treatment. On the other hand, salmeterol decreased serum levels of TNF-alpha and ECP in asthmatic children but this reduction was not significant after 8 weeks of regular administration in cases of mild and moderately severe asthma

An evaluation of salmeterol in the treatment of chronic obstructive pulmonary diseases.

BACKGROUND: Salmeterol has been shown a useful drug for the treatment of chronic obstructive pulmonary disease (COPD). However, its positioning in the current treatment of COPD remains to be defined. The present study was carried out to evaluate its role as an add-on drug to the current first-line drug, ipratropium. METHODS: A double-blind randomized, parallel group, placebo-controlled design was used in an outpatient setting. Thirty-three patients with moderate or severe COPD were included. After a run-in period of two weeks on 40 microg four-times-daily ipratropium and 400 microg twice-daily beclomethasone dipropionate, they were randomized into two groups to receive either salmeterol (50 microg twice daily) or placebo for eight weeks. The outcome parameters were: (i) spirometry, (ii) six-minute walking test, (iii) SF-36 health-related quality of life (HRQoL) questionnaire score, (iv) baseline dyspnoea index (BDI), (v) patient's self-assessment and (vi) supplemental use of salbutamol. RESULTS: The mean FEV1 and FVC increased significantly over the initial values in the salmeterol group but not in the placebo group. Salmeterol produced greater improvements in almost all the dimensions of HRQoL as well as in the BDI and the supplemental use of salbutamol was lower in this group. However, the six-minute walk distance was similar in the two groups. CONCLUSIONS: The present study shows that eight weeks treatment with salmeterol 50 microg twice-daily added to the existing regimen of ipratropium bromide and beclomethasone dipropionate provides greater symptomatic relief and improvement in lung function than placebo. This is accompanied by an improvement in the health-related quality of life.

Estudo da eficácia e tolerabilidade do salmeterol comparativamente ao salbutamol em pacientes com asma brônquica / Efficacy and safety of unhaled salmeterol compared to salbutamol in patients with mild-to-moderate asthma

Os Beta2-agonistas constituem um dos pilares do tratamento da asma brônquica, porém sua curta duraçao de açao exige uso freqüente e a associaçao com outras drogas broncodilatadoras. O surgimento dos Beta2-agonistas de longa açao pode representar um avanço na terapêutica da asma brônquica. Objetivo. O presente estudo propoe-se a avaliar, em nosso meio, a eficácia e a tolerabilidade do salmeterol (SM), comparativamente ao salbutamol (SB), em pacientes com asma leve e moderada. Métodos. Após uma etapa de estabilizaçao de duas semanas, os pacientes utilizaram salmeterol 50mcg duas vezes ao dia, e salbutamol 200mcg quatro vezes ao dia, durante o período de quatro semanas, seguindo um esquema duplo cego, aleatório, de grupos paralelos. Foram estudados 60 pacientes que preencheram os seguintes critérios de inclusao: VEF1 (Volume Expiratório Forçado no 1 segundo)>50 por cento: variaçao diurna do PFE (Pico do Fluxo Expiratório) > 15 por cento ou resposta do VEF1 ao BD> 15 por cento, gradaçao de sintomas >2 (escala de 0 a 5) em quatro dos últimos sete dias. Resultados. Dos 60 pacientes estudados, sete foram excluídos no período de tratamento (ver Métodos), sendo concluído o estudo com 25 pacientes no grupo salmeterol e 28 no grupo salbutamol. No período de estabilizaçao, nao houve diferença significante entre os grupos, comparando-se os valores de VEF1 em porcentagem do prev., PFE matinal, gradaçao de sintomas e gravidade da asma. O percentual de melhora do VEF1 e do PFE matinal nos pacientes que receberam salmeterol foi significantemente mais elevado entre 2 e 4 semanas de tratamento, em relaçao aos pacientes que receberam salbutamol (p<0,05). Da mesma forma, o grupo salmeterol apresentou reduçao significante nos valores médios dos sintomas no período noturno na 1 quinzena de tratamento. Em relaçao ao número de inalaçao de socorro utilizadas, efeitos colaterais, freqüência cardíaca, pressao arterial sistêmica e dosagem de potássio, nao houve diferença significante entre os grupos. Conclusao. Este estudo demonstrou que, em pacientes com asma leve a moderada, o salmeterol na dose de 100mcg/dia elevou o VEF1, o PFE matinal e apresentou diminuiçao significantemente maior dos sintomas noturnos em relaçao aos observados no grupo salbutamol, e que a tolerância aos medicamentos estudados foi semelhante nos dois grupos.