Legal demands of the tiotropium bromide for treatment of chronic obstructive pulmonary disease and their financial impact for the State of Paraná, Brazil / Demandas judiciais do uso de brometo tiotrópio para o tratamento da doença pulmonar obstrutiva crônica e o impacto financeiro para o Estado do Paraná, Brasil

ABSTRACT Objective To analyze the legal demands of tiotropium bromide to treat chronic obstructive pulmonary disease. Methods We included secondary data from the pharmaceutical care management systems made available by the Paraná State Drug Center. Results Public interest civil action and ordinary procedures, among others, were the most common used by the patients to obtain the medicine. Two Health Centers in Paraná (Londrina and Umuarama) concentrated more than 50% of the actions. The most common specialty of physicians who prescribed (33.8%) was pulmonology. There is a small financial impact of tiotropium bromide on general costs with medicines of the Paraná State Drug Center. However, a significant individual financial impact was observed because one unit of the medicine represents 38% of the Brazilian minimum wage. Conclusion Our study highlights the need of incorporating this medicine in the class of long-acting anticholinergic bronchodilator in the Brazilian public health system.

RESUMO Objetivo Analisar as demandas judiciais do brometo de tiotrópio para tratar a doença pulmonar obstrutiva crônica. Métodos Foram considerados dados secundários dos sistemas gerenciais de assistência farmacêutica, disponibilizados pelo Centro de Medicamentos do Paraná. Resultados Ações civis públicas e ações ordinárias, de procedimento comum, entre outras, foram as mais praticadas pelos pacientes para obter o medicamento. Duas Regionais de Saúde do Paraná (Londrina e Umuarama) concentraram mais de 50% das ações. Quanto à especialidade dos médicos prescritores, 33,8% eram pneumologistas. Verificou-se discreto impacto financeiro do brometo de tiotrópio nos gastos gerais com medicamentos pelo Centro de Medicamentos do Paraná. Entretanto, também houve relevante impacto financeiro individual, pois uma unidade do medicamento consome 38% do salário mínimo. Conclusão O estudo aponta para a necessidade de incorporação deste medicamento da classe broncodilatadores anticolinérgicos de longa duração, no Sistema Único de Saúde.

Systematic review and Meta-analysis on efficacy and safety of Buzhong Yiqi Decoction for stable chronic obstructive pulmonary disease / 中国中药杂志

To systematically review the efficacy and safety of Buzhong Yiqi Decoction in the treatment of stable chronic obstructive pulmonary disease(COPD) at the stable stage. Three English databases and four Chinese databases were systematically searched from the database establishment to August 1, 2020. Randomized controlled trials(RCTs) were screened according to the pre-determined inclusion and exclusion criteria, and then the data were extracted. Methodological quality of the included studies was assessed based on Cochrane bias risk tool, and RevMan 5.3 was used for data analysis. A total of 389 articles were retrieved and finally 18 RCTs were included in this study, involving 1 566 patients, and the overall quality of the included studies was not high. Meta-analysis showed that, in terms of improving 6-minute walk distance(6 MWD), and delaying the decline of forced expiratory volume in one second(FEV_1) or its % in the expected value as well as the decline in ratio of FEV_1 to forced vital capacity(FVC), Buzhong Yiqi Decoction alone or in combination with conventional Western medicine was superior to conventional therapy Western medicine alone. Subgroup analysis showed that, in terms of reducing traditional Chinese medicine symptom scores, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of reducing the grade of modified medical research council(mMRC), Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment. In terms of improving 6 MWD, Buzhong Yiqi Decoction combined with conventional treatment or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment alone or Tiotropium Bromide Powder for Inhalation alone. In terms of delaying the decline of FEV_1 or its % in the expected value, Buzhong Yiqi Decoction combined with conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation was superior to conventional treatment or Salmeterol Xinafoate and Fluticasone Propionate Powder for Inhalation or Tiotropium Bromide Powder for Inhalation alone, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. In terms of delaying the decline in FEV_1/FVC, Buzhong Yiqi Decoction combined with conventional treatment was superior to conventional treatment, and Buzhong Yiqi Decoction alone was superior to Theophylline alone. Meta-analysis of other outcome measures was not available and no conclusion can be drawn due to the inclusion of only one study. As some studies did not mention the adverse reactions, no safety comments can be made for Buzhong Yiqi Decoction alone or combined with conventional Western medicine. Due to the limitations of the quality and quantity of included studies, the conclusions of this research should be treated with caution. The efficacy of Buzhong Yiqi Decoction for stable COPD still needs more high-quality studies for confirmation, and its safety needs to be further verified.

Expression of Muscarinic Receptors and the Effect of Tiotropium Bromide in Aged Mouse Model of Chronic Asthma / 결핵및호흡기질환

BACKGROUND: Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling. METHODS: BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M2 and M3 receptors were examined. RESULTS: Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M2 but decreased expression of M3 in all aged groups of OVA. CONCLUSION: Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M3 and M2 muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.

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.

Índice de hospitalização e custos associados à doença pulmonar obstrutiva crônica (DPOC) entre estados que padronizaram versus que não padronizaram o tiotrópio ­ dados do mundo real / Hospitalization rates and costs associated with chronic obstructive pulmonary disease among states standardized versus not standardized tiotropium ­ real-world data

Objetivo: Avaliar, por meio de dados do mundo real (DATASUS) e análises estatísticas, o impacto da inclusão do tiotrópio no tratamento da doença pulmonar obstrutiva crônica (DPOC), comparando o índice de hospitalização e custos associados à internação nos estados que possuem o tiotrópio padronizado em suas diretrizes de tratamento comparados aos estados que não o incluem. Método: Estudo retrospectivo histórico realizado entre 2013 e 2015, a partir de dados obtidos do DATASUS, portais de compras públicas estaduais e Secretarias de Saúde Estaduais. Todos os índices foram normalizados pelo número da população, de acordo com os dados atualizados do IBGE. Foi utilizado o teste Z para avaliar a significância estatística dos resultados. Resultados: A análise combinada do grupo com tiotrópio apresentou 52,4% menos hospitalizações em comparação ao grupo sem tiotrópio (90,0/100.000 versus 43,3/100.000, respectivamente, p < 0,01). O gasto total para o sistema único de saúde com hospitalização por DPOC foi de R$ 2,3 milhões e R$ 4,8 milhões para o grupo com tiotrópio vs. grupo sem tiotrópio, respectivamente (p = 0,0003). Houve diferença significativa entre os grupos quanto ao número total e gastos totais de internação por DPOC, nos estados nos quais o tiotrópio estava padronizado e nos estados sem o tiotrópio padronizado. Conclusão: A análise dos resultados sugere redução significativa no número de internações por DPOC e seus respectivos gastos nos estados nos quais o tiotrópio está padronizado.

Objective: To evaluate the impact of the inclusion of tiotropium in the treatment of chronic obstructive pulmonary disease (COPD) using real world data (DATASUS) and statistical analyzes, comparing hospitalization rates and costs associated with hospitalization in states where tiotropium is reimbursed in their treatment guidelines compared to states where tiotropium is not included. Method: A retrospective historical study conducted between 2013 and 2015, based on data obtained from DATASUS, state public purchasing portals and State Health Secretariats. All indexes were normalized by the number of the population, according to the IBGE updated data. The Z tests were used to evaluate the statistical significance of the results. Results: The combined analysis of the tiotropium reimbursed group presented 52.4% fewer hospitalizations compared to the tiotropium non-reimbursed group (90.0/100,000 versus 43.3/100,000, respectively). The total expenditure for the public healthcare system with hospitalization for COPD was R$ 2.3 million and R$ 4.8 million for the tiotropium group vs. the non-tiotropium group, respectively. Statistical analysis, both in total number and total costs of hospitalization for COPD, showed a statistically significant difference in the states in which tiotropium was reimbursed vs non-reimbursed. Conclusion: Analysis of the results suggests a significant reduction in the number of hospitalizations due to COPD in the states in which tiotropium is reimbursed, as well as a reduction in the total expenditure related to hospitalizations associated with COPD.

Optimal Bronchodilation for COPD Patients: Are All Long-Acting β₂-Agonist/Long-Acting Muscarinic Antagonists the Same? / 결핵및호흡기질환

Bronchodilators provide improvements in lung function and reductions in symptoms and exacerbations, and are the mainstay of pharmacological management of chronic obstructive pulmonary disease (COPD). The Global Initiative for Chronic Obstructive Lung Disease strategy recommends the use of a combination of long-acting β₂-agonist/long-acting muscarinic antagonists (LABA/LAMA) as the first-line treatment option in the majority of symptomatic patients with COPD. This review provides an indirect comparison of available LABA/LAMA fixed-dose combinations (FDCs) through discussion of important efficacy and safety data from the key literature, with the objective of providing physicians with a framework for informed decision-making. LABA/LAMA FDCs provided greater benefits compared with placebo and similar or greater benefits compared with tiotropium and salmeterol/fluticasone in improving lung function, dyspnea, health-related quality of life, reducing rescue medication use and preventing exacerbations, although with some variability in efficacy between individual FDCs; further, tolerability profiles were comparable among LABA/LAMA FDCs. However, there is a disparity in the amount of evidence generated for different LABA/LAMA FDCs. Thus, this review shows that all LABA/LAMA FDCs may not be the same and that care should be taken when extrapolating individual treatment outcomes to the entire drug class. It is important that physicians consider the efficacy gradient that exists among LABA/LAMA FDCs, and factors such as inhaler devices and potential biomarkers, when choosing the optimal bronchodilator treatment for long-term management of patients with COPD.

Add-on Therapy for Symptomatic Asthma despite Long-Acting Beta-Agonists/Inhaled Corticosteroid / 결핵

Asthma, remains symptomatic despite ongoing treatment with high doses of inhaled corticosteroids (ICS) in conjunction with long-acting beta-agonists (LABA), is classified as “severe” asthma. In the course of caring for those patients diagnosed with severe asthma, stepping up from ICS/LABA to more aggressive therapeutic measures would be justified, though several aspects have to be checked in advance (including inhaler technique, adherence to therapy, and possible associated comorbidities). That accomplished, it would be advisable to step up care in accordance with the Global Initiative for Asthma (GINA) recommendations. Possible strategies include the addition of a leukotriene receptor antagonist or tiotropium (to the treatment regimen). The latter has been shown to be effective in the management of several subgroups of asthma. Oral corticosteroids have commonly been used for the treatment of patients with severe asthma in the past; however, the use of oral corticosteroids is commonly associated with corticosteroid-related adverse events and comorbidities. Therefore, according to GINA 2017 these patients should be referred to experts who specialize in the treatment of severe asthma to check further therapeutic options including biologics before starting treatment with oral corticosteroids.

The Role of Tiotropium+Olodaterol Dual Bronchodilator Therapy in the Management of Chronic Obstructive Pulmonary Disease / 결핵

Bronchodilator therapy is central to the management of chronic obstructive pulmonary disease and are recommended as the preferred treatment by the Global Obstructive Lung Disease Initiative (GOLD). Long acting anti-muscarinics (LAMA) and long acting β₂ agonists (LABA) are both more effective than regular short-acting drugs but many patients remain symptomatic despite monotherapy with these drugs. Combination therapy with LAMA and LABA increases the therapeutic benefit while minimizing dose-dependent side effects of long-acting bronchodilator therapy. The TOviTO programme has investigated the benefits of treatment with a combination of tiotropium and olodaterol administered via a single inhaler. Tiotropium+olodaterol 5/5 µg significantly improved forced expiratory volume in 1 second (FEV₁) area under the curve from 0 to 3 hours, trough FEV₁ health status and breathlessness versus the mono-components and placebo. Tiotropium+olodaterol 5/5 µg also increased endurance time and reduced dynamic hyperinflation during constant work rate cycle ergometry. On the basis of these and other studies the 2017 GOLD report recommends escalating to dual bronchodilator therapy in patients in groups B and C if they remain symptomatic or continue to have exacerbations and as initial therapy for patients in group D.

Efficacy and safety of tiotropium bromide in chronic obstructive pulmonary disease: a systematic review of randomized clinical trials / Eficácia e segurança do brometo de tiotrópio na doença pulmonar obstrutiva crônica. Revisão sistemática de ensaios clínicos randomizados

Chronic obstructive pulmonary disease (COPD) is among the most prevalent pulmonary diseases. This study aimed at assessing the efficacy and safety of anticholinergic tiotropium bromide (TB) in Chronic obstructive pulmonary disease patients. This is a systematic review of randomized clinical trials performed in the Brazilian Cochrane Center. Electronic database searched: Cochrane library, Medline, LILACS, Pubmed. There were no language, date or other restrictions. Participants: Patients with Chronic obstructive pulmonary disease. Intervention: tiotropium bromide. Comparison: Other bronchodilators or placebo. Outcomes: Mortality, Chronic obstructive pulmonary disease exacerbation, hospitalizations, adverse effects. Results: 14 studies were included in this systematic review. Mortality was lower in the tiotropium bromide group when compared with the salmeterol group [statistical significance: relative risk (RR) 0.16, confidence interval 95% (CI) 0.03 to 0.89, number needed to treat (NNT) of 100]. There was not a statistical difference in the mortality outcome in the comparison between tiotropium bromide and placebo groups (RR 0.88, CI 0.74 to 1.06). Chronic obstructive pulmonary disease exacerbation decreases significantly in the tiotropium bromide group when compared to placebo (statistical significance: RR 0.85, CI 0.77 to 0.93, NNT 25), but in comparison to the salmeterol group there was no statistical difference (RR 0.93, CI 0.80 to 1.08). The number of hospitalizations was lower in the tiotropium bromide group than in the placebo group (statistical significance:RR 0.77, CI 0.59 to 0.99, NNT 50). The results indicate that tiotropium bromide is an effective once-daily bronchodilator. Tiotropium bromide was associated with consistent health benefits, including reduced chronic obstructive pulmonary disease exacerbations, hospitalizations and even mortality when compared with salmeterol.(AU)

A doença pulmonar obstrutiva crônica está entre as doenças pulmonares mais prevalentes. O objetivo deste estudo foi verificar a eficácia e segurança do brometo de tiotrópio em pacientes com doença pulmonar obstrutiva crônica. Trata-se de revisão sistemática de ensaios clínicos randomizados realizada no Centro Cochrane do Brasil. A estratégia de busca eletrônica foi realizada nos nas bases LILACS, MEDLINE, Biblioteca Cochrane, PubMed. Não houve restrições à linguagem e nem à data. Participaram pacientes com doença pulmonar obstrutiva crônica. A intervenção foi o uso de brometo de tiotrópio comparado a outros broncodilatadores ou placebo. Os desfechos analisados foram mortalidade, exacerbações da doença pulmonar obstrutiva crônica, hospitalização e efeitos adversos. A mortalidade foi menor no grupo brometo de tiotrópio quando comparado com o grupo salmeterol (significância estatística: risco relativo de 0,16; intervalo de confiança de 95% de 0,03-0,89, número necessário para tratar de 100). Não houve diferença estatística no desfecho mortalidade na comparação entre os grupos brometo de tiotrópio e placebo (risco relativo de 0,88; intervalo de confiança de 95% de 0,74-1,06). As exacerbações da doença pulmonar obstrutiva crônica diminuíram significantemente no grupo brometo de tiotrópio quando comparado ao placebo (significância estatística: risco relativo de 0,85; intervalo de confiança de 95% de 0,77-0,93; número necessário para tratar de 25), porém, quando comparado ao salmeterol não obteve significância estatística (risco relativo de 0,93; intervalo de confiança de 95% 0,80-1,08). O número de hospitalizações foi menor no grupo brometo de tiotrópio do que no grupo placebo (significância estatística: risco relativo de 0,77; intervalo de confiança de 95% 0,59-0,99; número necessário para tratar de 50). Os resultados indicam que o brometo de tiotrópio é um broncodilatador eficaz em dose única diária. O brometo de tiotrópio traz benefícios à saúde com resultados consistentes, incluindo redução de exacerbações da doença pulmonar obstrutiva crônica, internações e até mesmo a mortalidade quando comparados com salmeterol.(AU)

Positioning of Long-Acting Muscarinic Antagonists in the Management of Asthma

Despite a range of efficacious therapies for asthma, including inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA), a significant proportion of patients have poor asthma control and retain a risk of future worsening of their symptoms. Long-acting muscarinic antagonist (LAMA) bronchodilators offer a well-tolerated, efficacious, and cost-effective add-on to a patient's treatment. Of the LAMAs currently under investigation or available for the treatment of asthma, evidence from a comprehensive clinical trial program in adults and children shows that once-daily treatment with tiotropium provides benefits for patients with uncontrolled asthma despite the use of ICS and LABAs. Tiotropium is included in the Global Initiative for Asthma (GINA) strategy document as an add-on therapy option for patients at Step 4 or 5 with a history of asthma exacerbations. Tiotropium Respimat® has demonstrated safety and efficacy in patients with a range of disease severities, ages, and phenotypes. This review describes the evidence for the use of LAMA as add-on therapy for patients with asthma who remain uncontrolled despite the use of ICS and LABA treatments.

A Comparison of International Guidelines for Pediatric Asthma Pharmacotherapy

OBJECTIVE: International institutes such as Global institute for Asthma(GINA), KAAACI(Republic of Korea), NHLBI(USA), BTS(UK) and JSA(Japan) have published guidelines for asthma treatment. The aim of this study was to compare the representatives' international guidelines of pharmacotherapy for pediatric asthma. METHODS: The recommendations related to pharmacotherapy for pediatric asthma were extracted from the latest representatives' international guidelines, and comprehensive comparisons were conducted. RESULTS: Major comparison outcomes between international guidelines were evaluated as follows: classification system on severity and pediatric age group, recommendation for inhaled corticosteroid dose, recommendation for pediatric age group of theophylline in mild asthma, and recommendation for pediatric age group of tiotropium in severe asthma. Clinical trials emphasized the adverse effects of theophylline, whereas tiotropium demonstrated beneficial actions for pediatric asthma. Therefore, theophylline was recommended for older patients with persistent asthma, and tiotropium was considered to be suitable for younger patients with severe asthma according to GINA guidelines. CONCLUSION: These findings address the requirement to harmonize international guidelines of pharmacotherapy in pediatric asthma. In addition, the findings suggest that KAAACI needs to update its pharmacotherapy guidelines of theophylline, tiotropium and other medicines recently approved.

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.

Effects of indacaterol versus tiotropium on exercise tolerance in patients with moderate COPD: a pilot randomized crossover study / Efeitos do indacaterol versus tiotrópio na tolerância ao exercício em pacientes com DPOC moderada: estudo cruzado randomizado piloto

Abstract Objective: To compare a once-daily long-acting β2 agonist (indacaterol 150 µg) with a once-daily long-acting anticholinergic (tiotropium 5 µg) in terms of their effects on exercise endurance (limit of tolerance, Tlim) in patients with moderate COPD. Secondary endpoints were their effects on lung hyperinflation, exercise-related dyspnea, and daily-life dyspnea. Methods: This was a randomized, single-blind, crossover pilot study involving 20 patients (mean age, 60.9 ± 10.0 years; mean FEV1, 69 ± 7% of predicted). Spirometric parameters, Transition Dyspnea Index scores, Tlim, and exertional dyspnea were compared after three weeks of each treatment (with a one-week washout period between treatments). Results: Nineteen patients completed the study (one having been excluded because of COPD exacerbation). Improvement in Tlim from baseline tended to be greater after treatment with tiotropium than after treatment with indacaterol (96 ± 163 s vs. 8 ± 82 s; p = 0.06). Tlim significantly improved from baseline after treatment with tiotropium (having increased from 396 ± 319 s to 493 ± 347 s; p = 0.010) but not after treatment with indacaterol (having increased from 393 ± 246 to 401 ± 254 s; p = 0.678). There were no differences between the two treatments regarding improvements in Borg dyspnea scores and lung hyperinflation at "isotime" and peak exercise. There were also no significant differences between treatments regarding Transition Dyspnea Index scores (1.5 ± 2.1 vs. 0.9 ± 2.3; p = 0.39). Conclusions: In patients with moderate COPD, tiotropium tends to improve Tlim in comparison with indacaterol. No significant differences were observed between the two treatments regarding their effects on lung hyperinflation, exercise-related dyspnea, and daily-life dyspnea. Future studies, including a larger number of patients, are required in order to confirm our findings and explore mechanistic explanations. (ClinicalTrials.gov identifier: ...

RESUMO Objetivo: Comparar um β2-agonista de longa duração administrado uma vez por dia (indacaterol 150 µg) a um anticolinérgico de longa duração administrado uma vez por dia (tiotrópio 5 µg) quanto a seus efeitos na resistência ao exercício (limite de tolerância, Tlim) em pacientes com DPOC moderada. Os desfechos secundários foram seus efeitos na hiperinsuflação pulmonar, na dispneia causada pelo exercício e na dispneia na vida diária. Métodos: Estudo piloto randomizado cruzado e simples cego com 20 pacientes (média de idade: 60,9 ± 10,0 anos; média do VEF1: 69 ± 7% do previsto). Parâmetros espirométricos, pontuação no Transition Dyspnea Index, Tlim e dispneia aos esforços foram comparados após três semanas de cada tratamento (com uma semana de intervalo entre os tratamentos). Resultados: Dezenove pacientes completaram o estudo - um foi excluído por causa de exacerbação da DPOC. A melhora no Tlim tendeu a ser maior com tiotrópio do que com indacaterol (96 ± 163 s vs. 8 ± 82 s; p = 0,06). Em comparação com os valores basais, o Tlim melhorou significativamente com tiotrópio (aumentando de 396 ± 319 s para 493 ± 347 s; p = 0,010), mas não com indacaterol (aumentando de 393 ± 246 para 401 ± 254 s; p = 0,678). Não houve diferença entre os tratamentos quanto à melhora na pontuação na escala de dispneia de Borg e na insuflação pulmonar no "isotempo" e no pico do exercício. Também não houve diferenças significativas entre os tratamentos quanto à pontuação no Transition Dyspnea Index (1,5 ± 2,1 vs. 0,9 ± 2,3; p = 0,39). Conclusões: Em pacientes com DPOC moderada, o tiotrópio tende a melhorar o Tlim em comparação com o indacaterol. Não houve diferenças significativas entre os tratamentos quanto a seus efeitos na insuflação pulmonar, na dispneia durante o exercício e na dispneia na vida diária. São necessários mais estudos, com um número maior de pacientes, para confirmar nossos achados e explorar explicações mecanicistas. (ClinicalTrials.gov ...

Efficacy of tiotropium as add-on therapy for adults with uncontrolled asthma

@#<p style="text-align: justify;"><strong>OBJECTIVE:</strong> The study aimed to evaluate efficacy of tiotropium as add-on therapy on top of standard regimens for uncontrolled asthma, specifically in terms of FEV1, morning and evening PEF, reduction in exacerbations, rescue medication use, and quality of life improvement.<br /><strong>METHODS:</strong> A search was done for eligible trials after which validity screen and data extraction was performed. Results were presented as mean differences, standard errors, and 95% confidence intervals, and graphically as forest plots. Estimates were pooled using the random effects model with I2 and Chi2 tests used to assess heterogeneity. Adverse events were reported as dichotomous variables.<br /><strong>RESULTS:</strong> Four studies were included totaling 1617 participants. The tiotropium group had statistically significant improvement in FEV1 (95% Cl, 0.14 [0.09, 0.19], p<0.00001), morning (95% Cl, 20.03 [11.71, 28.35], p<0.00001) with trend towards benefit in reduction of rescue medications (95% Cl, 0.12 [-0.17,0.4],p=0.42) and quality of life improvements (95% Cl, 0.1 [-0.05,0.25], p=0.20). Homogeneity (I2= 0%, Chi2= 0.47-3.22) was found across studies.<br /><strong>CONCLUSION:</strong> Tiotropium is associated with significant improvement in pulmonary function among patients with uncontrolled asthma, with possible benefit in reduction of rescue medications and quality of life improvement.</p>

Efficacy and Safety of Tiotropium in the Treatment of Severe Persistent Asthma:Meta-analysis / 中国医学科学院学报

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of tiotropium in treatment of severe persistent asthma.</p><p><b>METHODS</b>Reports of randomized controlled trials (RCTs) describing tiotropium for treatment of severe persistent asthma published from January 1946 to February 2015 were searched in Cochrane Library, ClinicalTrials.gov, PubMed, Ovid Medline, CNKI, and CSJD. The data of the included RCTs were extracted and the data quality was evaluated. Meta-analyses were performed with Revman 5.3 software.</p><p><b>RESULTS</b>Five RCTs including 1433 patients were analyzed. Meta-analysis of the data showed that compared with the placebo group, tiotropium treatment significantly improved the patients' peak forced expiratory volume in one second (FEV1) [weighted mean difference (WMD): 0.13 L, 95% confidence interval (CI): 0.10-0.16 L, P<0.00001], trough FEV1 (WMD: 0.09 L, 95%CI: 0.06-0.12 L, P<0.00001), peak forced vital capacity (FVC) (WMD: 0.10 L, 95%CI: 0.06-0.14 L, P<0.00001), trough FVC (WMD: 0.12 L, 95%CI: 0.08-0.17 L, P<0.00001), morning peak expiratory flow (PEF) (WMD: 9.21 L/min, 95%CI: 4.2-14.23 L/min, P=0.0003), evening PEF (WMD: 22.06 L/min, 95%CI 13.05-31.08 L/min, P<0.00001). The scores of asthma control questionnaire (ACQ) (WMD: 0.01, 95% CI: -0.07-0.09, P=0.86) or asthma quality of life questionnaire (AQLQ)(WMD: 0.06, 95% CI:-0.18-0.06, P=0.33) were not affected by tiotropium. No significant difference with adverse events between tiotropium group and placebo group were reported in these included studies (P>0.05).</p><p><b>CONCLUSIONS</b>Tiotropium for severe persistent asthma treatment can improve FEV1, FVC, and PEF but may not improve the quality of life of the patients. Tiotropium is well tolerated and can be an add-on therapy for severe persistent asthma.</p>

Effect of Inhaled Tiotropium on Spirometric Parameters in Patients with Tuberculous Destroyed Lung / 결핵및호흡기질환

BACKGROUND: In Korea, patients with destroyed lung due to tuberculosis (TB) account for a significant portion of those affected by chronic pulmonary function impairment. The objective of our research was to evaluate the efficacy of inhaled tiotropium bromide in TB destroyed lung. METHODS: We compared the effectiveness of inhaled tiotropium bromide for 2 months between pre- and post-treatment pulmonary function tests performed on 29 patients with destroyed lung due to TB. RESULTS: The mean age of the total number of patients was 63+/-9 years, where 15 patients were male. The pre-treatment mean forced expiratory volume in 1 second (FEV1) was 1.02+/-0.31 L (44.1+/-16.0% predicted). The pre-treatment mean forced vital capacity (FVC) was 1.70+/-0.54 L (52.2+/-15.8% predicted). Overall, the change in FEV1% predicted over baseline with tiotropium was 19.5+/-19.1% (p<0.001). Twenty patients (72%) got better than a 10% increase in FEV1 over baseline with tiotropium, but one patient showed more than a 10% decrease in FEV1. Overall, the change in FVC% predicted over baseline with tiotropium was 18.5+/-19.9% (p<0.001). Seventeen patients (59%) experienced greater than a 10% increase in FVC over baseline with tiotropium; 12 (41%) patients had stable lung function. CONCLUSION: The inhaled tiotropium bromide therapy may lead to improve lung functions in patients with TB destroyed lung. However, the long-term effectiveness of this treatment still needs to be further assessed.

Evaluation of the efficacy and safety of tiotropium bromide (5 µg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>A pharmacokinetic study in an Asian population showed that tiotropium 5 µg via Respimat leads to the same plasma levels compared to 18 µg via HandiHaler. The objective of the trial was to compare the efficacy and safety of longterm treatment (1 year) with tiotropium bromide (5 µg) via Respimat® with placebo in patients with chronic obstructive pulmonary disease (COPD).</p><p><b>METHODS</b>A total of 3991 patients were randomized in this double-blind, placebo controlled, parallel group study, while in China 338 patients (309 males, 29 females) received either tiotropium bromide (n = 167) or placebo (n = 171). Tiotropium bromide solution or matching placebo was delivered via Respimat® at a dosage of 5 µg (2×2.5 µg/puff) once daily for 48 weeks. Co-primary endpoints were trough forced expiratory volume in one second (FEV1) and the time to first exacerbation.</p><p><b>RESULTS</b>Statistically significant improvements in trough FEV1 and trough forced vital capacity (FVC) in the tiotropium group were achieved at weeks 4, 24, and 48 compared with those in the placebo group. A statistically significant difference (P = 0.0027) in favour of tiotropium was also observed for the time to first exacerbation. The total numbers of exacerbations during treatment were 90 and 128 in the tiotropium and placebo groups, respectively, with a rate ratio of 0.69 (P = 0.0164). The difference between the treatment groups in the adjusted mean changes from baseline of St. George Respiratory Questionnaire (SGRQ) total score was -3.9 (95% CI: -7.5, -0.2) and was of statistical significance (P = 0.0367). The incidences of serious adverse events (SAEs) in the tiotropium and placebo groups were 16.2% and 17.0%, respectively. Seven deaths occurred whilst patients were on treatment, four in the tiotropium group and three in the placebo group, all of which were assessed as non-related study drugs by the investigators.</p><p><b>CONCLUSIONS</b>Tiotropium significantly improved lung function and quality of life, delayed the time to first exacerbation, reduced the number of exacerbations. Overall, tiotropium was well tolerated.</p>

The role of tiotropium in the management of asthma

Asthma is a chronic respiratory disease characterized by reversible airway obstruction that is secondary to an allergic inflammation and excessive smooth muscle contraction. Cholinergic signals were known to contribute significantly to the pathophysiology of asthma. However, the use of anti-cholinergic agents in asthma has been justified only in acute asthma exacerbations, until tiotropium bromide, a long-acting anti-cholinergic agent was introduced. Recent reports showing a promising role of tiotropium in the treatment of asthma have aroused interest of the use of anti-cholinergic agent for the management of asthma. This report describes pharmacological characteristics, potential effects on inflammatory cells, and the current status of tiotropium in the treatment of asthma.

Issues on Safety of Long-Acting Muscarinic Antagonist / 결핵및호흡기질환

The prevention of and the controlling of symptoms, reductions in the frequency of exacerbations, and disease severity are central to the pharmacologic therapy of chronic obstructive pulmonary disease (COPD). COPD patients are inclined to be older, have more comorbidities, and use polypharmacy as a result. Long-acting inhaled muscarinic antagonists (LAMAs) is a preferred treatment modality. However, the cardiovascular (CV) safety of anti-cholinergics, including LAMA, has been an issue. In contrast, the results of the UPLIFT trial and a pooled analysis of data from 30 trials of tiotropium illustrates the association of tiotropium with reductions in the risk of all cause mortality, CV mortality and CV events. And, the UPLIFT trial provides clues regarding the additive advantages of tiotropium in COPD patients who already are using long-acting inhaled beta2 agonists and inhaled corticosteroids. Following the contribution of tiotropium as a first LAMA, new LAMAs such as aclidinium and glycopyrrolate (NVA-237) seem to be emerging.

Therapeutic effect of tiotropium bromide powder inhalation in patients with stable bronchiectasis / 南方医科大学学报

<p><b>OBJECTIVE</b>To observe the therapeutic effect of tiotropium bromide powder inhalation on stable bronchiectasis.</p><p><b>METHODS</b>Twenty-two patients with stable bronchiectasis received inhalation of totropium bromide powder at the daily dose of 18 microg, and on days 1 and 28, the patients were examined for forced expiratory volume in one second (FEVl), predicted value [FEVl(%)], forced expiratory volume (FEV), and FEVl/FVC. The symptom score and BODE index were also recorded.</p><p><b>RESULTS</b>After 1 month of inhalation therapy, the FEV1% of the patients showed a moderate increase but the increment was not statistically significant (t=-1.875, P>0.05); the symptom score and BODE index decreased significantly after the therapy (t=7.091, P<0.001; t=2.982, P<0.05).</p><p><b>CONCLUSION</b>Long-term inhalation of tiotropium bromide powder can improve the clinical symptoms and BODE index and enhance the exercise tolerance and quality of life of the patients with bronchiectasis.</p>