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1.
Expert Rev Clin Pharmacol ; 13(2): 103-113, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31951778

RESUMO

Introduction: Treatment options for COPD have evolved rapidly in the last decade and inhaled bronchodilators have largely supplanted the use of oral bronchodilators because of their increased efficacy and excellent safety with topical delivery to the lung. Recently added to the therapeutic armamentarium are fixed-dose combinations (FDC) of two long acting bronchodilators. LAMAs (long acting muscarinic antagonists) and LABAs (long acting beta agonists) are the main classes available and use different pathways to effectively produce bronchial smooth muscle relaxation.Areas covered: The most recent inhaled FDC LAMA/LABA to come to market is Aclidinium Bromide and Formoterol Fumarate. We searched databases of PubMed, Cochrane Library, and manufacturers' websites and retrieved all the randomized-controlled trials (RCTs) conducted with these drugs up to September 2019.Expert opinion: It is likely that FDCs will become the core of our COPD pharmacotherapy for all but the mildest COPD patients. These individual drugs have excellent efficacy and safety records for the maintenance treatment of COPD. Studies have demonstrated that twice daily treatment with aclidinium/formoterol resulted in significant improvement in lung function and an improved exercise tolerance when compared to placebo. Adverse effects are within the range of what is seen with other LAMA/LABA combinations.


Assuntos
Fumarato de Formoterol/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacologia , Combinação de Medicamentos , Fumarato de Formoterol/efeitos adversos , Fumarato de Formoterol/farmacologia , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Tropanos/efeitos adversos , Tropanos/farmacologia
2.
Ter Arkh ; 91(3): 76-85, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31094464

RESUMO

Currently, combinations of long-acting beta2-agonists and long-acting anticholinergics are considered as the basic therapy for majority of patients with chronic obstructive pulmonary disease (COPD). These combinations have different pharmacological characteristics and delivery devices that provides different clinical effects and new opportunities for personalized treatment of COPD. Aclidinium/formoterol fixed combination differs from other dual bronchodilators by twice-daily dosing regimen, good safety profile and a specific delivery system. Recent information on clinical efficacy and safety of aclidinium/formoterol combination in COPD patients is given in this article.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/uso terapêutico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Combinação de Medicamentos , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/efeitos adversos , Humanos , Pulmão/fisiopatologia , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Resultado do Tratamento , Tropanos/administração & dosagem , Tropanos/efeitos adversos
3.
JAMA ; 321(17): 1693-1701, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31063575

RESUMO

Importance: There is concern that long-acting muscarinic antagonists increase cardiovascular morbidity or mortality in patients with chronic obstructive pulmonary disease (COPD). Objective: To determine the cardiovascular safety (noninferiority) and efficacy (superiority) of aclidinium bromide, 400 µg twice daily, in patients with COPD and cardiovascular disease or risk factors. Design, Setting, and Participants: Multicenter, randomized, placebo-controlled, double-blind, parallel-design study conducted at 522 sites in North America. A total of 3630 patients with moderate to very severe COPD and either a history of cardiovascular disease or at least 2 atherothrombotic risk factors were randomized; follow-up occurred for up to 3 years until at least 122 major adverse cardiovascular events (MACE) occurred. The first patient was enrolled on October 16, 2013 and the last on August 22, 2016. The final patient completed follow-up on September 21, 2017. Interventions: Patients were randomized to receive aclidinium (n = 1812) or placebo (n = 1818) by dry-powder inhaler, twice daily for up to 3 years. Main Outcomes and Measures: The primary safety end point was time to first MACE over up to 3 years (hazard ratio [HR] 1-sided 97.5% CI noninferiority margin = 1.8). The primary efficacy end point was the annual COPD exacerbation rate during the first year of treatment. Secondary outcomes included an expanded MACE definition (time to first MACE or serious cardiovascular event of interest) and annual rate of exacerbations requiring hospitalization. Results: Among 3589 patients analyzed (mean age, 67.2 years; 58.7% male), 2537 (70.7%) completed the study. Of these, 69 (3.9%) aclidinium and 76 (4.2%) placebo patients had a MACE (HR, 0.89; 1-sided 97.5% CI, 0-1.23); the expanded MACE definition included 168 (9.4%) aclidinium vs 160 (8.9%) placebo patients with events (HR, 1.03; 1-sided 97.5% CI, 0-1.28). Annual moderate to severe exacerbation rates (aclidinium, 0.44; placebo, 0.57; rate ratio, 0.78; 2-sided 95% CI, 0.68-0.89; P < .001) and rate of exacerbations requiring hospitalization (aclidinium, 0.07; placebo, 0.10; rate ratio, 0.65; 2-sided 95% CI, 0.48-0.89; P = .006) decreased significantly with aclidinium vs placebo. The most common adverse events were pneumonia (aclidinium, 109 events [6.1%]; placebo, 105 events [5.8%]), urinary tract infection (aclidinium, 93 events [5.2%]; placebo, 89 events [5.0%]), and upper respiratory tract infection (aclidinium, 86 events [4.8%]; placebo, 101 events [5.6%]). Conclusions and Relevance: Among patients with COPD and increased cardiovascular risk, aclidinium was noninferior to placebo for risk of MACE over 3 years. The rate of moderate to severe COPD exacerbations was reduced over the first year. Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.


Assuntos
Doenças Cardiovasculares/induzido quimicamente , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/uso terapêutico , Administração por Inalação , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Gravidade do Paciente , Fatores de Risco , Tropanos/efeitos adversos
4.
Artigo em Inglês | MEDLINE | ID: mdl-30962681

RESUMO

Background: AMPLIFY assessed the efficacy and safety of aclidinium bromide/formoterol fumarate (AB/FF) vs its monocomponents and tiotropium (TIO) in patients with moderate-to-very severe symptomatic COPD (NCT02796677). Methods: In this 24-week, Phase III, double-dummy, active-controlled study, symptomatic patients (COPD Assessment Test score ≥10) were randomized to twice-daily AB/FF 400/12 µg, AB 400 µg, or FF 12 µg, or once-daily TIO 18 µg. Co-primary endpoints were change from baseline at week 24 in 1-hour morning post-dose FEV1 (AB/FF vs AB) and in pre-dose (trough) FEV1 (AB/FF vs FF). Non-inferiority of AB vs TIO in pre-dose FEV1 was also an objective. Normalized area under the curve (AUC)0-3/3 h FEV1 and nighttime and early morning symptoms were also assessed. A subgroup participated in a 24-hour serial spirometry sub-study. Results: A total of 1,594 patients were randomized; 566 entered the sub-study. At week 24, 1-hour post-dose FEV1 significantly improved with AB/FF vs AB, FF, and TIO (84, 84, and 92 mL; all P<0.0001). AB/FF significantly improved trough FEV1 vs FF (55 mL, P<0.001) and AB was non-inferior to TIO. AB/FF significantly improved AUC0-3/3 h FEV1 vs all comparators (P<0.0001) and provided significant improvements in early morning symptoms vs TIO. The 24-hour spirometry demonstrated significantly greater improvements with AB/FF in AUC12-24/12 h vs all comparators, and in AUC0-24/24 h vs FF or TIO at week 24. Conclusion: In patients with moderate-to-very severe symptomatic COPD, twice-daily AB/FF significantly improved lung function vs monocomponents and TIO, and early morning symptom control vs TIO.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Tropanos/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Broncodilatadores/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Europa (Continente) , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/efeitos adversos , Humanos , Israel , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento , Tropanos/efeitos adversos , Estados Unidos , Capacidade Vital
5.
Artigo em Inglês | MEDLINE | ID: mdl-30880938

RESUMO

Background: Aclidinium/formoterol 400/12 µg is a twice-daily maintenance bronchodilator for COPD. This post hoc study evaluated aclidinium/formoterol vs aclidinium 400 µg, formoterol 12 µg, or placebo in patient subgroups. Patients and methods: Data were pooled from two 24-week Phase III clinical trials (ACLIFORM and AUGMENT). Patients (N=3,394) were analyzed by baseline airflow obstruction severity (moderate/severe), age (<65/≥65 years), sex, and exacerbation history (0/≥1 exacerbation in the previous 12 months). Changes from baseline vs placebo and mono-therapies were evaluated: morning pre-dose (trough) and morning 1-hour post-dose FEV1, Transition Dyspnea Index (TDI), and moderate/severe exacerbation rates (healthcare resource utilization [HCRU] and EXAcerbations of Chronic pulmonary disease Tool [EXACT] criteria). Results: Aclidinium/formoterol improved the post-dose FEV1 vs placebo and monotherapy in all subgroups (all P<0.01) and trough FEV1 vs placebo (P<0.001) and formoterol (P<0.05) across all subgroups. Improvements in trough FEV1 were observed vs aclidinium in patients with severe airflow obstruction, patients aged <65 years, males, and patients with exacerbation history (P<0.05). Improvements in TDI were observed vs placebo in all subgroups (all P<0.001), monotherapies for patients with moderate (formoterol P<0.05) or severe airflow obstruction (aclidinium P<0.05), patients aged <65 years (aclidinium P<0.01, formoterol P<0.05), males (formoterol P<0.05), and patients with no exacerbation history (formoterol P<0.05). HCRU exacerbation rates were lower for aclidinium/formoterol vs placebo in patients with no exacerbation history (P<0.01). EXACT exacerbation rates were lower for aclidinium/formoterol in patients with moderate airflow obstruction vs placebo and aclidinium, patients aged <65 years vs placebo and ≥65 years vs formoterol, males vs placebo, and patients with no exacerbation history vs placebo (all P<0.05). Conclusion: Aclidinium/formoterol significantly improved post-dose FEV1, trough FEV1, and TDI vs placebo across all subgroups and vs monotherapy in many subgroups. These findings further support the benefits of aclidinium/formoterol for all patients with COPD.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Fatores Etários , Idoso , Broncodilatadores/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/efeitos adversos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Tropanos/efeitos adversos
6.
Periodontol 2000 ; 78(1): 47-58, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30198137

RESUMO

Drug use for both therapeutic and recreational purposes is very widespread in most societies. The range of drugs used, the variations in response to these drugs and other health and behavioral confounders mean that drug use may be an important contributor to individualized periodontal diagnoses. In this narrative review, we review the main reported effects of drugs on the periodontal tissues and periodontal disease processes. Although some of the more common adverse drug reactions on periodontal tissues are well described, in many other cases the evidence for these drug effects is quite limited and based on small case series or isolated reports. Prescription drugs are responsible for a range of effects, including drug-induced gingival overgrowth and increased gingival bleeding, and influence periodontal inflammation and periodontal breakdown. The effects of recreational drugs on the periodontal tissues is less well researched, perhaps for the obvious reason that assembling large cohorts of recreational drug users presents particular challenges. Use of nearly all of these substances is associated with poorer periodontal and dental health, although there is almost certainly a large degree of behavioral confounding in these findings. Overall, further studies of adverse drug reactions on the periodontal tissues are required as this continues to be an important and increasing factor in periodontal health determination.


Assuntos
/efeitos adversos , Doenças Periodontais/complicações , Periodonto/efeitos dos fármacos , Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Antineoplásicos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Cannabis/efeitos adversos , Anticoncepcionais Orais/efeitos adversos , Ciclosporina/efeitos adversos , Difosfonatos/efeitos adversos , Gengiva/efeitos dos fármacos , Crescimento Excessivo da Gengiva/complicações , Alucinógenos/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Imunossupressores/efeitos adversos , Inflamação , Metadona/efeitos adversos , Índice Periodontal , Fenitoína/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Tropanos/efeitos adversos
7.
Expert Opin Drug Discov ; 13(6): 563-577, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29616842

RESUMO

INTRODUCTION: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.


Assuntos
Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Administração por Inalação , Animais , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacologia , Preparações de Ação Retardada , Desenvolvimento de Medicamentos/métodos , Humanos , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tropanos/efeitos adversos , Tropanos/farmacologia
8.
Int J Chron Obstruct Pulmon Dis ; 12: 2545-2558, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28883722

RESUMO

The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 µg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD. Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair® dry powder inhaler for 8 weeks. From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals). The primary end point was trough functional residual capacity (FRC) at Week 4. Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI). Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise. After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690). However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P<0.0001). AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 (P<0.01 and P<0.0001, respectively) and Week 8 (P<0.05 and P<0.0001, respectively). AB/FF achieved higher step counts (P<0.01) with fewer inactive patients (P<0.0001) at Week 4 versus placebo. Following BI, AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo. AB/FF 400/12 µg demonstrated improvements in lung hyperinflation, exercise capacity, and physical activity versus placebo that were maintained following the addition of BI. A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Exercício , Fumarato de Formoterol/uso terapêutico , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Broncodilatadores/efeitos adversos , Canadá , Método Duplo-Cego , Combinação de Medicamentos , Europa (Continente) , Feminino , Fumarato de Formoterol/efeitos adversos , Capacidade Residual Funcional , Humanos , Capacidade Inspiratória , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Tropanos/efeitos adversos
9.
Int J Chron Obstruct Pulmon Dis ; 12: 1731-1740, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28652725

RESUMO

BACKGROUND: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study. METHODS: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 µg twice daily (BID), tiotropium 18 µg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed. RESULTS: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV1) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P<0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P<0.05). Aclidinium improved trough FEV1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P<0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P<0.05). Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks. Tolerability showed similar incidence of AEs in each arm. CONCLUSION: In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 µg BID provided additional improvements compared with tiotropium 18 µg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity.


Assuntos
Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Tropanos/uso terapêutico , Atividades Cotidianas , Idoso , Broncodilatadores/efeitos adversos , Ritmo Circadiano , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento , Tropanos/efeitos adversos
10.
Respir Res ; 18(1): 106, 2017 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-28558833

RESUMO

BACKGROUND: 'Clinically important deterioration' (CID) is a composite endpoint measuring worsening of the key clinical features of chronic obstructive pulmonary disease (COPD), namely lung function, patient-reported outcomes, and exacerbations. ACLIFORM and AUGMENT were two 24-week, randomized, double-blind, phase III studies assessing twice-daily (BID) aclidinium bromide (AB) 400 µg/formoterol fumarate (FF) 12 µg. This pooled post-hoc analysis assessed the effects of AB/FF 400/12 µg on both first and sustained CID events versus placebo and monotherapies in patients with moderate to severe COPD. METHODS: A first CID event was defined as the occurrence of a moderate/severe exacerbation or the worsening from baseline in ≥1 of the following: trough forced expiratory volume in 1 second (FEV1; ≥100 mL), Transition Dyspnea Index (TDI) focal score (≥1 unit), or St George's Respiratory Questionnaire (SGRQ) total score (≥4 units). A 'sustained' CID was defined as a worsening maintained at all subsequent visits from appearance to week 24 or a moderate/severe exacerbation at any time. CID events were assessed at three visits (weeks 4, 12, and 24); trough FEV1 was also measured at weeks 1 and 18. RESULTS: AB/FF 400/12 µg reduced the risk of a first CID event by 45% versus placebo (hazard ratio [HR] 0.55, p < 0.001), 18% versus FF 12 µg (HR 0.82, p < 0.01), and 15% versus AB 400 µg (HR 0.85, p < 0.05). Similarly, AB/FF 400/12 µg reduced the risk of a sustained CID event by 48% versus placebo (HR 0.52, p < 0.001) and 22% versus FF 12 µg (HR 0.78, p < 0.01). AB/FF 400/12 µg reduced the risk of a first or sustained CID event for all four components versus placebo (trough FEV1 and TDI, first and sustained CID, all p < 0.001; SGRQ first CID p < 0.001; SGRQ sustained CID, p < 0.01; exacerbations first and sustained CID, both p < 0.05) and TDI and SGRQ versus FF 12 µg (TDI, first and sustained CID both p < 0.05; SGRQ first CID p < 0.01), and SGRQ versus AB 400 µg (first CID, p < 0.05). CONCLUSIONS: AB/FF 400/12 µg BID may provide greater airway stability and fewer exacerbations or deteriorations in lung function, health status, or dyspnea compared with placebo or monotherapies. TRIAL REGISTRATION: Clinicaltrials.gov NCT01462942 (ACLIFORM); registered 26 October 2011. Clinicaltrials.gov NCT01437397 (AUGMENT); registered 19 September 2011.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Deterioração Clínica , Fumarato de Formoterol/uso terapêutico , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Broncodilatadores/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/efeitos adversos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Tropanos/efeitos adversos
11.
Int J Chron Obstruct Pulmon Dis ; 12: 1145-1152, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28442901

RESUMO

OBJECTIVE: To describe and compare demographic and clinical profile of patients newly initiated on aclidinium (ACL) or tiotropium (TIO) and identify factors associated with newly initiated ACL in real-life clinical practice during 2013 in Catalonia. DESIGN: We performed a population-based, retrospective, observational study with data obtained from the Information System for Research Development in Primary Care, a population database that contains information of 5.8 million inhabitants (more than 80% of the Catalan population). Patients over 40 years old, with a recorded diagnosis of COPD and newly initiated treatment with either ACL or TIO during the study period (January to December 2013), were selected. A descriptive analysis of demographic and clinical characteristics was performed, and treatment adherence was also assessed for both cohorts. RESULTS: A total of 8,863 individuals were identified, 4,293 initiated with ACL and 4,570 with TIO. They had a mean age of 69.4 years (standard deviation: 11.3), a median COPD duration of 3 years (interquartile range: 0-8), and 71% were males. Patients treated with ACL were older, with more respiratory comorbidities, a longer time since COPD diagnosis, worse forced expiratory volume in 1 second (% predicted), and with a higher rate of exacerbations during the previous year compared with TIO. It was found that 41.3% of patients with ACL and 62.3% of patients with TIO had no previous COPD treatment. Inhaled corticosteroid and long-acting ß2-agonist were the most frequent concomitant medications (32.9% and 32.6%, respectively). Approximately 75% of patients were persistent with ACL or TIO at 3 months from the beginning of treatment, and more than 50% of patients remained persistent at 9 months. CONCLUSION: Patients initiated with ACL had more severe COPD and were taking more concomitant respiratory medications than patients initiated with TIO. ACL was more frequently initiated as part of triple therapy, while TIO was more frequently initiated as monotherapy.


Assuntos
Broncodilatadores/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Tropanos/administração & dosagem , Administração por Inalação , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/efeitos adversos , Bases de Dados Factuais , Quimioterapia Combinada , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Atenção Primária à Saúde , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Espanha , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento , Tropanos/efeitos adversos
12.
Respir Med ; 125: 39-48, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28340861

RESUMO

INTRODUCTION: Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg efficacy and safety was demonstrated in two 6-month Phase III studies (AUGMENT and ACLIFORM) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease (COPD). This Phase III, double-blind, placebo-controlled, 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 µg (NCT01572792). METHODS: Patients were randomised in AUGMENT (1:1:1:1:1) to twice-daily AB/FF 400/12 µg, AB/FF 400/6 µg, AB 400 µg, FF 12 µg or placebo. Patients completing AUGMENT were invited to continue the same treatment in the extension. Adverse events (AEs), major adverse cardiovascular events (MACE), laboratory tests, electrocardiograms and vital signs were recorded. Efficacy was assessed. RESULTS: Of 1322 patients completing AUGMENT, 921 enrolled and 780 completed the extension. AE incidence was low and comparable across treatment groups; most common were nasopharyngitis (range 4.8%-9.3%), urinary tract infection (range 4.1%-8.8%) and upper respiratory tract infection (range 2.7%-5.5%). Serious AEs (SAEs) and MACE were low (ranges 6.8%-7.7% and 0.5%-1.5%, respectively). Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo. Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies. AB/FF combinations increased the time to first exacerbation by approximately 30% versus placebo (p < 0.05). CONCLUSION: AB/FF 400/12 µg was well tolerated over 52 weeks with low incidences of AEs, SAEs and MACE that were comparable across treatment groups. Improvements in bronchodilation, symptoms and health status were maintained across 52 weeks.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Fumarato de Formoterol/farmacologia , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Idoso , Broncodilatadores/farmacologia , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Dispneia/fisiopatologia , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/efeitos adversos , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Tropanos/administração & dosagem , Tropanos/efeitos adversos
13.
Value Health ; 20(1): 132-140, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28212954

RESUMO

BACKGROUND: Comparisons of the use of aclidinium bromide and tiotropium bromide for the treatment of chronic obstructive pulmonary disease often concentrate on key end points (exacerbations) at the expense of other benefits and risks. Multicriteria decision analysis (MCDA) can help overcome this by using stakeholder preferences to combine multiple end points into an overall value estimate. OBJECTIVES: To evaluate the use of aclidinium bromide twice daily via Pressair™ (AstraZeneca Pharmaceuticals LP, Wilmington, DE) and of tiotropium once daily via HandiHaler® (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) from the perspective of patients using MCDA. METHODS: Literature reviews and clinician engagement were used to identify value criteria. Performance of criteria was estimated from a clinical trial and clinician opinion. Scores and swing weights came from six clinicians who, during a 2-day workshop, reflected their patients' preferences. Scenario and sensitivity analyses were used to explore uncertainty in model designs and inputs. RESULTS: Fourteen criteria, covering clinical effectiveness, safety, and convenience of the treatments of chronic obstructive pulmonary disease, were identified. Exacerbations and device preloading were identified as the most important to patients; the least important was rescue medication use. Tiotropium's higher overall clinical effectiveness score was offset by aclidinium's better performance on safety and convenience outcomes. The MCDA generated a -42 (worst performance) to 100 (best performance) scale. The net impact of benefits over risks of aclidinium (38.5) exceeded that of tiotropium (13.2), and patients preferred aclidinium 79.7% of the time. CONCLUSIONS: When considering clinical benefits and risks, aclidinium and tiotropium generate similar value to patients, but when convenience criteria are considered, aclidinium may be preferred. Further work is required to replicate these results, including eliciting preferences directly from patients.


Assuntos
Broncodilatadores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Tropanos/uso terapêutico , Administração por Inalação , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Volume Expiratório Forçado , Humanos , Nebulizadores e Vaporizadores , Preferência do Paciente , Índice de Gravidade de Doença , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/efeitos adversos , Tropanos/administração & dosagem , Tropanos/efeitos adversos , Estados Unidos
14.
Br J Pharmacol ; 174(5): 396-408, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28012176

RESUMO

BACKGROUND AND PURPOSE: Reducing glucocorticoid exposure in the brain via intracellular inhibition of the cortisol-regenerating enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has emerged as a therapeutic strategy to treat cognitive impairment in early Alzheimer's disease (AD). We sought to discover novel, brain-penetrant 11ß-HSD1 inhibitors as potential medicines for the treatment of AD. EXPERIMENTAL APPROACH: Medicinal chemistry optimization of a series of amido-thiophene analogues was performed to identify potent and selective 11ß-HSD1 inhibitors with optimized oral pharmacokinetics able to access the brain. Single and multiple ascending dose studies were conducted in healthy human subjects to determine the safety, pharmacokinetic and pharmacodynamic characteristics of the candidate compound. RESULTS: UE2343 was identified as a potent, orally bioavailable, brain-penetrant 11ß-HSD1 inhibitor and selected for clinical studies. No major safety issues occurred in human subjects. Plasma adrenocorticotropic hormone was elevated (a marker of systemic enzyme inhibition) at doses of 10 mg and above, but plasma cortisol levels were unchanged. Following multiple doses of UE2343, plasma levels were approximately dose proportional and the terminal t1/2 ranged from 10 to 14 h. The urinary tetrahydrocortisols/tetrahydrocortisone ratio was reduced at doses of 10 mg and above, indicating maximal 11ß-HSD1 inhibition in the liver. Concentrations of UE2343 in the CSF were 33% of free plasma levels, and the peak concentration in CSF was ninefold greater than the UE2343 IC50 . CONCLUSIONS AND IMPLICATIONS: UE2343 is safe, well tolerated and reaches the brain at concentrations predicted to inhibit 11ß-HSD1. UE2343 is therefore a suitable candidate to test the hypothesis that 11ß-HSD1 inhibition in brain improves memory in patients with AD.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Encéfalo/metabolismo , Inibidores Enzimáticos/administração & dosagem , Tiofenos/administração & dosagem , Tropanos/administração & dosagem , Adolescente , Adulto , Animais , Cães , Relação Dose-Resposta a Droga , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Meia-Vida , Humanos , Hidrocortisona/sangue , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Tetra-Hidrocortisol/urina , Tetra-Hidrocortisona/urina , Tiofenos/efeitos adversos , Tiofenos/farmacocinética , Distribuição Tecidual , Tropanos/efeitos adversos , Tropanos/farmacocinética , Adulto Jovem
15.
Int J Chron Obstruct Pulmon Dis ; 11: 3043-3050, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27980401

RESUMO

The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity.


Assuntos
Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Tropanos/uso terapêutico , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/efeitos adversos , Humanos , Pulmão/fisiopatologia , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Tropanos/efeitos adversos
16.
Artigo em Inglês | MEDLINE | ID: mdl-27621610

RESUMO

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) experience respiratory symptoms, which impair quality of life. This pooled analysis of two Phase III studies assessed the impact of aclidinium/formoterol on patients with COPD categorized by symptom status. METHODS: Data were pooled from two 24-week, randomized, placebo-controlled studies of twice-daily aclidinium/formoterol 400/12 µg in moderate-to-severe COPD (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). These post hoc analyses evaluated the efficacy of aclidinium/formoterol versus placebo or monotherapies in patients defined as less/more symptomatic by a) Evaluating Respiratory Symptoms (E-RS™) score ≥10/<10 and b) Baseline Dyspnea Index score <7/≥7. Endpoints included trough and 1-hour morning postdose forced expiratory volume in 1 second (FEV1), Transition Dyspnea Index, E-RS total score, early-morning and nighttime symptom severity, early-morning limitation of activities, and exacerbation rate. RESULTS: Data for 3,394 patients were analyzed (mean age: 63.5 years; 60.5% male). In both definitions of less and more symptomatic patients, aclidinium/formoterol improved 1-hour morning postdose FEV1 from baseline at week 24 versus placebo (P<0.001) and both monotherapies (P<0.05). Aclidinium/formoterol improved trough FEV1 from baseline in both groups versus placebo (P<0.05) and formoterol (P<0.05); improvements were greater in more symptomatic patients. Improvements versus aclidinium were also observed in more symptomatic patients (P<0.05). Aclidinium/formoterol improved dyspnea, early-morning symptom severity, and limitation of activities versus placebo in both less and more symptomatic patients (P<0.001). In more symptomatic patients, aclidinium/formoterol also improved E-RS total score and severity of nighttime symptoms from baseline versus placebo and one or both monotherapies (P<0.05). The rate of moderate/severe exacerbations was reduced with aclidinium/formoterol versus placebo in more symptomatic patients. CONCLUSION: Aclidinium/formoterol 400/12 µg provided consistent improvements in bronchodilation and symptoms versus monotherapies and reduced exacerbations versus placebo in more symptomatic patients with moderate-to-severe COPD, regardless of the definition used. Furthermore, patients with a low symptom burden achieved benefits with aclidinium/formoterol versus monotherapies in postdose FEV1, dyspnea, and early-morning symptoms.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Broncodilatadores/efeitos adversos , Ritmo Circadiano , Ensaios Clínicos Fase III como Assunto , Combinação de Medicamentos , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/efeitos adversos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Tropanos/efeitos adversos
17.
Respir Med ; 116: 41-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27296819

RESUMO

TRIAL DESIGN: This was a one-year, Phase III randomized, double-blind, parallel-group, active-control study investigating the long-term safety and tolerability of twice-daily aclidinium 400 µg/formoterol 12 µg versus formoterol 12 µg. METHODS: Eligible patients were male or female, current or ex-smokers (history of ≥10 pack-years) aged ≥40 years with a diagnosis of moderate to severe chronic obstructive pulmonary disease (COPD): post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <70%, and post-bronchodilator FEV1≥30% and <80% predicted. Patients were randomized 2:1 to twice-daily aclidinium 400 µg/formoterol 12 µg or formoterol 12 µg, administered via a multidose dry powder inhaler (Genuair™/Pressair(®))(1). The objective was to evaluate the one-year safety of aclidinium 400 µg/formoterol 12 µg versus formoterol 12 µg. RESULTS: All 590 patients were included in the safety population; 392 patients received aclidinium 400 µg/formoterol 12 µg and 198 patients received formoterol 12 µg. Of these, 581 patients were included in the intent-to-treat (ITT) population (385 patients received aclidinium 400 µg/formoterol 12 µg; 196 patients received formoterol 12 µg). In the safety population, the percentage of patients with ≥1 treatment-emergent adverse event was similar between aclidinium 400 µg/formoterol 12 µg (71.4%) and formoterol 12 µg (65.7%). Mean baseline post-bronchodilator FEV1 was 51.3% of predicted (ITT population). Aclidinium 400 µg/formoterol 12 µg significantly improved morning pre-dose (trough) FEV1 and trough FVC versus formoterol 12 µg at each assessment, with improvements at Week 1 (least squares mean difference [LSMD]: 87.4 mL and 157.8 mL, respectively) maintained at study end (LSMD: 81.5 mL and 185.4 mL, respectively). CONCLUSIONS: Aclidinium 400 µg/formoterol 12 µg was well tolerated, with a safety profile similar to formoterol 12 µg and consistent with that seen in two Phase III studies. Additionally, aclidinium 400 µg/formoterol 12 µg improved lung function versus formoterol 12 µg, with a sustained effect over one year.


Assuntos
Fumarato de Formoterol/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Tolerância a Medicamentos , Inaladores de Pó Seco , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fumar/epidemiologia , Resultado do Tratamento , Tropanos/administração & dosagem , Tropanos/efeitos adversos , Capacidade Vital/efeitos dos fármacos
18.
Respir Res ; 17(1): 61, 2016 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-27215749

RESUMO

BACKGROUND: Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 µg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(™): COPD) scale (formerly EXACT-RS). METHODS: Data were pooled from the aclidinium 400 µg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed. RESULTS: Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 µg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 µg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D. CONCLUSIONS: Aclidinium 400 µg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms. TRIAL REGISTRATION: ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 ).


Assuntos
Broncodilatadores/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Respiração/efeitos dos fármacos , Tropanos/administração & dosagem , Administração por Inalação , Idoso , Broncodilatadores/efeitos adversos , Ensaios Clínicos Fase III como Assunto , Progressão da Doença , Esquema de Medicação , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Tropanos/efeitos adversos
19.
Adv Ther ; 33(3): 379-99, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26883661

RESUMO

INTRODUCTION: The objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 µg twice daily compared to tiotropium 18 µg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: A systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV1)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George's Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control. RESULTS: Regarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV1, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV1 [DCFB 26 mL (95% CrI -2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB -0.52 (95% CrI -2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization. CONCLUSION: Based on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile. FUNDING: AstraZeneca.


Assuntos
Broncodilatadores/uso terapêutico , Fumarato de Formoterol/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Tropanos/uso terapêutico , Teorema de Bayes , Broncodilatadores/administração & dosagem , Broncodilatadores/efeitos adversos , Combinação de Medicamentos , Dispneia/fisiopatologia , Volume Expiratório Forçado , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/efeitos adversos , Hospitalização , Humanos , Razão de Chances , Doença Pulmonar Obstrutiva Crônica/mortalidade , Qualidade de Vida , Índice de Gravidade de Doença , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/efeitos adversos , Tropanos/administração & dosagem , Tropanos/efeitos adversos
20.
Lung ; 194(2): 259-66, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26758884

RESUMO

INTRODUCTION: Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) in COPD. The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium (TIO) or aclidinium (ACL) when used as triple therapy and to assess if impulse oscillometry (IOS) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response. METHODS: Patients with moderate to severe COPD already taking ICS/LABA were randomized to receive add-on therapy in cross-over fashion with either TIO 18 µg od or ACL 322 µg bid for 2-3 weeks each. Measurements of IOS, spirometry, 6-min walk test, St George's Respiratory Questionnaire (SGRQ) and Baseline/Transition Dyspnoea Index (TDI) were made at baseline and after chronic dosing at trough (12 h for ACL and 24 h for TIO), in addition to domiciliary diurnal spirometry. RESULTS: 13 patients were completed: mean age 69 years, FEV1 52 % predicted, FEV1/FVC 0.48, and R5 202 % predicted. There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL. Resonant frequency but not total airway resistance at 5 Hz (R5) significantly improved from baseline with both treatments while peripheral airway resistance (R5-R20) significantly improved with ACL. Visit-based FEV1, and forced and relaxed vital capacity were also significantly improved from baseline with both treatments. There were no significant differences in diurnal FEV1 and FEV6 profiles between treatments. 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL, while post-walk dyspnea improved with TIO. SGRQ symptom score significantly improved to a similar degree with both treatments. TDI significantly improved with ACL versus TIO by 1.54 units. CONCLUSION: We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD, while IOS was no more sensitive than spirometry.


Assuntos
Broncoconstrição/efeitos dos fármacos , Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/uso terapêutico , Oscilometria/métodos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Tropanos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistência das Vias Respiratórias , Broncodilatadores/efeitos adversos , Estudos Cross-Over , Quimioterapia Combinada , Teste de Esforço , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Valor Preditivo dos Testes , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Escócia , Espirometria , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento , Tropanos/efeitos adversos , Capacidade Vital
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