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1.
Biochem Med (Zagreb) ; 30(1): 010701, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31839721

RESUMO

Introduction: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition that can affect haemostasis. This study aimed to determine differences in platelet-related parameters between controls and COPD subjects. The hypothesis was that platelet indices are disturbed in COPD patients, and this would be accompanied by increased C-reactive protein (CRP), fibrinogen (Fbg) and white blood cells (WBC). Therefore, platelet count (Plt), platelet-related parameters - mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (Pct), their ratios (MPV/Plt, MPV/Pct, PDW/Plt, PDW/Pct), platelet to lymphocyte ratio (PLR), Plt index as well as CRP, Fbg and WBC were assessed. Materials and methods: Study included 109 patients with stable COPD and 95 control subjects, recruited at Clinical Department for Lung Diseases Jordanovac, University Hospital Centre Zagreb (Zagreb, Croatia). Complete blood count was performed on Sysmex XN-1000, CRP on Cobas c501, and Fbg on BCS XP analyser. Data were analysed with MedCalc statistical software. Results: Platelet (P = 0.007) and PLR (P = 0.006) were increased, while other platelet indices were decreased in COPD patients compared to controls. Combined model that included PLR, PDW and WBC showed great diagnostic performances, and correctly classified 75% of cases with an AUC of 0.845 (0.788 - 0.892), P < 0.001. Comorbidities (cardiovascular or metabolic diseases) had no effect on investigated parameters, while inhaled corticosteroids/long-acting ß2-agonists (ICS/LABA) therapy increased MPV and PDW values in COPD patients. Conclusion: Platelet indices were altered in COPD patients and they could be valuable as diagnostic markers of COPD development, especially if combined with already known inflammatory markers.


Assuntos
Biomarcadores/sangue , Plaquetas/citologia , Doença Pulmonar Obstrutiva Crônica/patologia , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Plaquetas/metabolismo , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Leucócitos/citologia , Modelos Logísticos , Linfócitos/citologia , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
2.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(11): 838-844, 2019 Nov 12.
Artigo em Chinês | MEDLINE | ID: mdl-31694094

RESUMO

Objective: To compare the efficacy and safety profiles of tiotropium/olodaterol with the mono-components in Chinese and total study population from TONADO trial. Methods: In the replicate, double-blind, parallel-group, active-controlled, randomized, 52-week, Phase Ⅲ TONADO studies (TONADO 1+2), patients received tiotropium/olodaterol, tiotropium, or olodaterol via the Respimat(®) Inhaler (Boehringer Ingelheim, Germany). Primary end points were forced expiratory volume in 1 second (FEV(1)) area under the curve from 0 to 3 hours (AUC(0-3h)) response and trough FEV(1) response, and St George's respiratory questionnaire (SGRQ) total score at 24 weeks. Adverse events were also collected. This subgroup analysis only focused on the efficacy and safety of the drug at the approved dose in China. Results: 548 Chinese patients were randomized, aged 41 to 82 years [mean age, (63±8) years] and most were male (526, 96%), 111 received tiotropium/olodaterol 5/5 µg, and 127 received tiotropium 5 µg and 95 received olodaterol 5 µg. The baseline characteristics of these groups were similar. After 24 weeks, treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg and olodaterol 5 µg resulted in an adjusted mean FEV(1) AUC(0-3h) response of 0.240, 0.157 and 0.079 L, and trough FEV(1) response of 0.117, 0.068 and-0.001 L, respectively. Tiotropium/olodaterol 5/5 µg significantly improved SGRQ scores in Chinese patients compared with olodaterol 5 µg (32.729 and 37.202, respectively). Generally, the safety profile of tiotropium/olodaterol was comparable with mono-components in 52 weeks. Conclusion: Compared with tiotropium or olodaterol, tiotropium/olodaterol in Chinese patients provided significant improvement in lung function and quality of life, and the safety profiles were similar.


Assuntos
Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoxazinas/uso terapêutico , Broncodilatadores/uso terapêutico , China/epidemiologia , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/etnologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Brometo de Tiotrópio/uso terapêutico , Resultado do Tratamento
3.
Tidsskr Nor Laegeforen ; 139(17)2019 Nov 19.
Artigo em Norueguês | MEDLINE | ID: mdl-31746168

RESUMO

BACKGROUND: Since their introduction more than 50 years ago, use of ß-agonists for inhalation has been associated with increased mortality. Since the turn of the century, particular concern has been voiced regarding long-acting ß2-selective agonists. Our purpose was to investigate the evidence from recently published randomised trials of possible increased risks of death and serious adverse events related to exposure to these drugs. MATERIAL AND METHOD: A PubMed search identified ten clinical trials which fulfilled predefined inclusion criteria. RESULTS: The ten trials encompassed 66 664 patients. A total of 16 asthma-related deaths after exposure to long-acting ß2-selective agonists were recorded among 33 043 actively treated patients, whereas four such deaths were recorded among the 33 621 patients in the control groups. A single, large, pragmatic trial accounts for a majority of these fatalities. INTERPRETATION: Exposure to long-acting ß2-selective agonists is associated with a small increase in mortality. Whether concomitant use of inhalation steroids fully reverses this effect is not clear.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Asma , Administração por Inalação , Corticosteroides , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Agonistas Adrenérgicos beta , Asma/tratamento farmacológico , Humanos , Esteroides
4.
Ther Umsch ; 76(6): 311-316, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31762414

RESUMO

The data situation for the use of ICS in asthma is clear. In the case of COPD, on the other hand, where in recent years the pendulum has moved away from ICS towards a dual therapy based on LABA / LAMA, the discussion is open again thanks to new work. However, it would certainly be wrong to recommend ICS as a meaningful therapy for all COPD patients at this point in time, since therapy with ICS is associated with side effects, in particular an increase in the risk of developing pneumonia or osteoporosis. However, there is no doubt that patients with asthma COPD overlap require ICS therapy.


Assuntos
Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2 , Asma , Broncodilatadores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Asma/tratamento farmacológico , Quimioterapia Combinada , Humanos , Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
5.
FP Essent ; 486: 26-32, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31710455

RESUMO

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disease characterized by cough, dyspnea, and sputum production caused by inhalation of harmful chemicals, such as tobacco smoke. COPD should be suspected in patients with a significant smoking history, shortness of breath, and sputum production. The diagnosis is made by spirometry. A forced expiratory volume in the first second of expiration to forced vital capacity (FEV1/FVC) ratio of less than 0.7 after bronchodilator administration confirms the diagnosis. Therapy for patients with stable COPD should include a bronchodilator, either a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA). For patients who continue to experience dyspnea with a single bronchodilator, dual therapy with a LABA and LAMA is appropriate. For patients with continued exacerbations, inhaled corticosteroids can be added to LABA-LAMA therapy. Acute exacerbations are characterized by a worsening of symptoms that requires additional therapy. Short-acting beta2-agonists with or without short-acting muscarinic antagonists are the basic therapy for acute exacerbations of COPD. Systemic glucocorticoids have been shown to shorten exacerbations and improve lung function. Antibiotics have been shown to reduce rates of treatment failure and sputum purulence. Noninvasive mechanical ventilation is preferred for patients with respiratory failure.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Broncodilatadores , Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Corticosteroides , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Volume Expiratório Forçado , Humanos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
6.
Cochrane Database Syst Rev ; 9: CD006924, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553802

RESUMO

BACKGROUND: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about whether regular (daily) long-acting beta2-agonists (LABA) are safe when used in combination with inhaled corticosteroids (ICS). This updated Cochrane Review includes results from two large trials that recruited 23,422 adolescents and adults mandated by the US Food and Drug Administration (FDA). OBJECTIVES: To assess the risk of mortality and non-fatal serious adverse events (SAEs) in trials that randomly assign participants with chronic asthma to regular formoterol and inhaled corticosteroids versus the same dose of inhaled corticosteroid alone. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data as well as FDA submissions in relation to formoterol. The date of the most recent search was February 2019. SELECTION CRITERIA: We included randomised clinical trials (RCTs) with a parallel design involving adults, children, or both with asthma of any severity who received regular formoterol and ICS (separate or combined) treatment versus the same dose of ICS for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors of the studies. We assessed our confidence in the evidence using GRADE recommendations. The primary outcomes were all-cause mortality and all-cause non-fatal serious adverse events. MAIN RESULTS: We found 42 studies eligible for inclusion and included 39 studies in the analyses: 29 studies included 35,751 adults, and 10 studies included 4035 children and adolescents. Inhaled corticosteroids included beclomethasone (daily metered dosage 200 to 800 µg), budesonide (200 to 1600 µg), fluticasone (200 to 250 µg), and mometasone (200 to 800 µg). Formoterol metered dosage ranged from 12 to 48 µg daily. Fixed combination ICS was used in most of the studies. We judged the risk of selection bias, performance bias, and attrition bias as low, however most studies did not report independent assessment of causation of SAEs.DeathsSeventeen of 18,645 adults taking formoterol and ICS and 13 of 17,106 adults taking regular ICS died of any cause. The pooled Peto odds ratio (OR) was 1.25 (95% confidence interval (CI) 0.61 to 2.56, moderate-certainty evidence), which equated to one death occurring for every 1000 adults treated with ICS alone for 26 weeks; the corresponding risk amongst adults taking formoterol and ICS was also one death (95% CI 0 to 2 deaths). No deaths were reported in the trials on children and adolescents (4035 participants) (low-certainty evidence).In terms of asthma-related deaths, no children and adolescents died from asthma, but three of 12,777 adults in the formoterol and ICS treatment group died of asthma (both low-certainty evidence).Non-fatal serious adverse eventsA total of 401 adults experienced a non-fatal SAE of any cause on formoterol with ICS, compared to 369 adults who received regular ICS. The pooled Peto OR was 1.00 (95% CI 0.87 to 1.16, high-certainty evidence, 29 studies, 35,751 adults). For every 1000 adults treated with ICS alone for 26 weeks, 22 adults had an SAE; the corresponding risk for those on formoterol and ICS was also 22 adults (95% CI 19 to 25).Thirty of 2491 children and adolescents experienced an SAE of any cause when receiving formoterol with ICS, compared to 13 of 1544 children and adolescents receiving ICS alone. The pooled Peto OR was 1.33 (95% CI 0.71 to 2.49, moderate-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 8 had an non-fatal SAE; the corresponding risk amongst those on formoterol and ICS was 11 children and adolescents (95% CI 6 to 21).Asthma-related serious adverse eventsNinety adults experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 102 with ICS alone. The pooled Peto OR was 0.86 (95% CI 0.64 to 1.14, moderate-certainty evidence, 28 studies, 35,158 adults). For every 1000 adults treated with ICS alone for 26 weeks, 6 adults had an asthma-related non-fatal SAE; the corresponding risk for those on formoterol and ICS was 5 adults (95% CI 4 to 7).Amongst children and adolescents, 9 experienced an asthma-related non-fatal SAE with formoterol and ICS, compared to 5 on ICS alone. The pooled Peto OR was 1.18 (95% CI 0.40 to 3.51, very low-certainty evidence, 10 studies, 4035 children and adolescents). For every 1000 children and adolescents treated with ICS alone for 12.5 weeks, 3 had an asthma-related non-fatal SAE; the corresponding risk on formoterol and ICS was 4 (95% CI 1 to 11). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death (all-cause or asthma-related) in adults taking combined formoterol and ICS versus ICS alone (moderate- to low-certainty evidence). No deaths were reported in children and adolescents. The risk of dying when taking either treatment was very low, but we cannot be certain if there is a difference in mortality when taking additional formoterol to ICS (low-certainty evidence).We did not find a difference in the risk of non-fatal SAEs of any cause in adults (high-certainty evidence). A previous version of the review had shown a lower risk of asthma-related SAEs in adults taking combined formoterol and ICS; however, inclusion of new studies no longer shows a difference between treatments (moderate-certainty evidence).The reported number of children and adolescents with SAEs was small, so uncertainty remains in this age group.We included results from large studies mandated by the FDA. Clinical decisions and information provided to patients regarding regular use of formoterol and ICS need to take into account the balance between known symptomatic benefits of formoterol and ICS versus the remaining degree of uncertainty associated with its potential harmful effects.


Assuntos
Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Antiasmáticos/efeitos adversos , Asma/tratamento farmacológico , Fumarato de Formoterol/efeitos adversos , Administração por Inalação , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Quimioterapia Combinada , Fumarato de Formoterol/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
N Engl J Med ; 381(13): 1227-1239, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31553835

RESUMO

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Afro-Americanos , Asma/tratamento farmacológico , Broncodilatadores/administração & dosagem , Fluticasona/administração & dosagem , Glucocorticoides/administração & dosagem , Xinafoato de Salmeterol/administração & dosagem , Administração por Inalação , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Masculino , Estudos Prospectivos
10.
Herz ; 44(6): 517-521, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31297545

RESUMO

Chronic heart and lung diseases are very common in the elderly population. The combination of chronic heart failure and chronic obstructive pulmonary disease (COPD) is also common and, according to current guidelines, these patients should be treated for both diseases. In patients with heart failure, beta-blockers are very important drugs because their use is associated with significantly improved morbidity and mortality. These beneficial effects were documented in patients with and without COPD, although theoretically there is a risk for bronchoconstriction, particularly with non-beta1 selective blockers. In COPD patients, long-acting sympathomimetics (LABA) improve lung function, dyspnea, and quality of life and their combination with a beta-blocker makes sense from a pharmacological and a clinical point of view, because any potential arrhythmogenic effects of the LABA will be ameliorated by the beta-blocker. Inhaled tiotropium, a long-acting muscarinic antagonist (LAMA), has been extensively investigated and no safety concerns were reported in terms of cardiac adverse effects. The same applies for the other approved LAMA preparations and LAMA-LABA combinations. Severe COPD causes air-trapping with increasing pressures in the thorax, leading to limitations in blood return into the thorax from the periphery of the body. This causes a decrease in stroke volume and cardiac index and is associated with dyspnea. All these adverse effects can be ameliorated by potent anti-obstructive therapy as recently shown by means of a LABA-LAMA combination.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Antagonistas Muscarínicos , Doença Pulmonar Obstrutiva Crônica , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Interações de Medicamentos , Humanos , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida
11.
BMC Res Notes ; 12(1): 413, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31307541

RESUMO

OBJECTIVE: 5-HOB is a novel tissue selective, 5-hydroxybenzothiazolone-derived ß2 adrenoceptor agonist with minimized cardiovascular effects while retaining efficacy on skeletal muscle in preclinical experiments unlike conventional ß2 adrenoceptor agonists, however its effect on the nervous system has not been evaluated yet. Therefore, 5-HOB was evaluated in a mouse model of neuropathic pain. RESULTS: 5-HOB alleviated neuropathic allodynia in a dose dependent manner and reversed the changes in hind paw withdrawal thresholds to the sham control levels. The dose attenuating neuropathic allodynia was slightly lower than the dose inducing skeletal muscle hypertrophy. In conclusion, as reported with known ß2 adrenoceptor agonists, 5-HOB was also effective in attenuating neuropathic pain in mice in addition to its effect on skeletal muscle.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Hiperalgesia/prevenção & controle , Neuralgia/prevenção & controle , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/química , Animais , Benzotiazóis/química , Benzotiazóis/farmacologia , Modelos Animais de Doenças , Humanos , Hiperalgesia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Medição da Dor/métodos
12.
Respir Res ; 20(1): 141, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31286970

RESUMO

There is increasing focus on understanding the nature of chronic obstructive pulmonary disease (COPD) during the earlier stages. Mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 or the now-withdrawn GOLD stage 0) represents an early stage of COPD that may progress to more severe disease. This review summarises the disease burden of patients with mild COPD and discusses the evidence for treatment intervention in this subgroup.Overall, patients with mild COPD suffer a substantial disease burden that includes persistent or potentially debilitating symptoms, increased risk of exacerbations, increased healthcare utilisation, reduced exercise tolerance and physical activity, and a higher rate of lung function decline versus controls. However, the evidence for treatment efficacy in these patients is limited due to their frequent exclusion from clinical trials. Careful assessment of disease burden and the rate of disease progression in individual patients, rather than a reliance on spirometry data, may identify patients who could benefit from earlier treatment intervention.


Assuntos
Tolerância ao Exercício/efeitos dos fármacos , Volume Expiratório Forçado/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Corticosteroides/farmacologia , Corticosteroides/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Tolerância ao Exercício/fisiologia , Volume Expiratório Forçado/fisiologia , Humanos , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Resultado do Tratamento
14.
Int J Chron Obstruct Pulmon Dis ; 14: 1019-1031, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190787

RESUMO

Purpose: Global evidence-based treatment strategies for chronic obstructive pulmonary disease (COPD) recommend using long-acting bronchodilators (LABDs) as maintenance therapy. However, COPD patients are often undertreated. We examined COPD treatment patterns among Medicare beneficiaries who initiated arformoterol tartrate, a nebulized long-acting beta2 agonist (LABA), and identified the predictors of initiation. Methods: Using a 100% sample of Medicare administrative data, we identified beneficiaries with a COPD diagnosis (ICD-9 490-492.xx, 494.xx, 496.xx) between 2010 and 2014 who had ≥1 year of continuous enrollment in Parts A, B, and D, and ≥2 COPD-related outpatient visits within 30 days or ≥1 hospitalization(s). After applying inclusion/exclusion criteria, three cohorts were identified: (1) study group beneficiaries who received nebulized arformoterol (n=11,886), (2) a subset of the study group with no LABD use 90 days prior to initiating arformoterol (n=5,542), and (3) control group beneficiaries with no nebulized LABA use (n=220,429). Logistic regression was used to evaluate predictors of arformoterol initiation. Odds ratios (ORs), 95% confidence intervals (CIs), and p values were computed. Results: Among arformoterol users, 47% (n=5,542) had received no LABDs 90 days prior to initiating arformoterol. These beneficiaries were being treated with a nebulized (50%) or inhaled (37%) short-acting bronchodilator or a systemic corticosteroid (46%), and many received antibiotics (37%). Compared to controls, beneficiaries who initiated arformoterol were significantly more likely to have had an exacerbation, a COPD-related hospitalization, and a pulmonologist or respiratory therapist visit prior to initiation (all p<0.05). Beneficiaries with moderate/severe psychiatric comorbidity or dual-eligible status were significantly less likely to initiate arformoterol, as compared to controls (all p<0.05). Conclusion: Medicare beneficiaries who initiated nebulized arformoterol therapy had more exacerbations and hospitalizations than controls 90 days prior to initiation. Findings revealed inadequate use of maintenance medications, suggesting a lack of compliance with evidence-based treatment guidelines.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Fumarato de Formoterol/administração & dosagem , Pulmão/efeitos dos fármacos , Medicare , Conduta do Tratamento Medicamentoso/tendências , Padrões de Prática Médica/tendências , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Demandas Administrativas em Assistência à Saúde , Aerossóis , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Progressão da Doença , Feminino , Fidelidade a Diretrizes/tendências , Hospitalização , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Guias de Prática Clínica como Assunto , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
15.
Planta Med ; 85(9-10): 738-744, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31185502

RESUMO

Chronic heart failure is the terminal stage of various cardiovascular diseases. Despite the availability of several classes of drugs, there is still an unmet need for effective treatment. Based on bench work during the past two decades, we have proposed that enhancement of ß 2-adrenergic receptor signaling in combination with the presently preferred ß 1-adrenergic receptor blockade would be a promising strategy. Chinese herbal medicines have been shown to be effective in the treatment of heart failure, although the mechanisms largely remain unknown. In the present study, we screened an herbal medicine compound/extract library for ß-adrenergic receptor ligands to determine the target of certain effective botanical remedies and seek a leading compound(s) for chronic heart failure treatment. Using a high-throughput screening assay, we identified higenamine, which has a long history in chronic heart failure treatment in traditional Chinese medicine, to be a potent ß-adrenergic receptor agonist. Further experiments using specific inhibitors showed that higenamine activated both ß 1-adrenergic receptor and ß 2-adrenergic receptor. Inhibition of its action by pertussis toxin (a Gi inhibitor) indicated that it is a ß 2-adrenergic receptor Gs/Gi dual agonist. Contractility experiments demonstrated a positive inotropic effect of higenamine. In conclusion, we found an herbal compound, higenamine, to be a dual agonist for ß 1/ß 2-adrenergic receptors with no preference in stimulating the Gs and Gi pathways in ß 2-adrenergic receptor signaling. Our results elucidated not only the target of higenamine to explain its pharmacological effect in treating chronic heart failure, but also the mechanisms of its cardiac toxicity.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Alcaloides/farmacologia , Medicamentos de Ervas Chinesas/química , Ensaios de Triagem em Larga Escala/métodos , Tetra-Hidroisoquinolinas/farmacologia , Alcaloides/química , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/genética , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Tetra-Hidroisoquinolinas/química
16.
Int J Chron Obstruct Pulmon Dis ; 14: 1251-1265, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239659

RESUMO

The use of inhaled, fixed-dose, long-acting muscarinic antagonists (LAMA) combined with long-acting, beta2-adrenergic receptor agonists (LABA) has become a mainstay in the maintenance treatment of chronic obstructive pulmonary disease (COPD). One of the fixed-dose LAMA/LABA combinations is the dry powder inhaler (DPI) of umeclidinium bromide (UMEC) and vilanterol trifenatate (VI) (62.5 µg/25 µg) approved for once-a-day maintenance treatment of COPD. This paper reviews the use of fixed-dose combination LAMA/LABA agents focusing on the UMEC/VI DPI inhaler in the maintenance treatment of COPD. The fixed-dose combination LAMA/LABA inhaler offers a step beyond a single inhaled maintenance agent but is still a single device for the COPD patient having frequent COPD exacerbations and persistent symptoms not well controlled on one agent. Currently available clinical trials suggest that the once-a-day DPI of UMEC/VI is well-tolerated, safe and non-inferior or better than other currently available inhaled fixed-dose LAMA/LABA combinations for COPD.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Álcoois Benzílicos/efeitos adversos , Álcoois Benzílicos/farmacocinética , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacocinética , Clorobenzenos/efeitos adversos , Clorobenzenos/farmacocinética , Combinação de Medicamentos , Inaladores de Pó Seco , Medicina Baseada em Evidências , Humanos , Pulmão/fisiopatologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Quinuclidinas/efeitos adversos , Quinuclidinas/farmacocinética , Recuperação de Função Fisiológica , Resultado do Tratamento
17.
Int J Chron Obstruct Pulmon Dis ; 14: 1167-1176, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31213796

RESUMO

Background: Dynamic lung hyperinflation (DLH) following metronome-paced incremental hyperventilation (MPIH) was reported to be useful for assessment of pathophysiological impairment in patients with chronic obstructive pulmonary disease (COPD), and the effects of tiotropium and olodaterol on DLH following MPIH have not been reported. Methods: Treatment consisted of administration of tiotropium/olodaterol 5/5 µg inhalation solution (2.5/2.5 µg per actuation) using a soft-mist inhaler once a day. We compared outcomes before and after 8 weeks of treatment. The primary outcome was defined as a decrease in inspiratory capacity (IC) from rest by MPIH, which is an index of DLH. The secondary outcomes were COPD assessment test (CAT), forced expiratory volume in 1 s (FEV1), and 6-min walking distance (6MWD). In addition, we investigated whether there were correlations between changes with treatment in DLH and FEV1, 6MWD, and dyspnea. Results: Thirty-three of the 38 registered patients completed this study. Most of these 33 patients had mild to moderate COPD. Decreasing IC by MPIH was significantly reduced by treatment for 8 weeks, with a mean change of about -0.11 to -0.13 mL (P <0.05). In addition, CAT score, FEV1, and 6MWD improved with treatment (P <0.05). There were no significant correlations between changes in DLH, FEV1, 6MWD, or dyspnea with treatment. Conclusions: The results of this study showed that the combination of tiotropium and olodaterol is effective for improvement of DLH following hyperventilation.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Dispneia/tratamento farmacológico , Hiperventilação/fisiopatologia , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Idoso , Benzoxazinas/efeitos adversos , Broncodilatadores/efeitos adversos , Combinação de Medicamentos , Dispneia/diagnóstico , Dispneia/fisiopatologia , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado , Humanos , Hiperventilação/diagnóstico , Japão , Pulmão/fisiopatologia , Masculino , Antagonistas Muscarínicos/efeitos adversos , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do Tratamento
18.
Mol Pharmacol ; 96(1): 56-72, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31036559

RESUMO

The effects of phosphodiesterase (PDE) 4 inhibitors on gene expression changes in BEAS-2B human airway epithelial cells are reported and discussed in relation to the mechanism(s) of action of roflumilast in chronic obstructive pulmonary disease (COPD). Microarray-based gene expression profiling failed to identify mRNA transcripts that were differentially regulated by the PDE4 inhibitor 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) after 1, 2, 6, or 18 hours of exposure. However, real-time polymerase chain reaction analysis revealed that GSK 256066 was a weak stimulus, and the negative microarray results reflected low statistical power due to small sample sizes. Furthermore, GSK 256066, roflumilast, and its biologically active metabolite roflumilast N-oxide generally potentiated gene expression changes produced by the long-acting ß 2-adrenoceptor agonists (LABAs) salmeterol, indacaterol, and formoterol. Many of these genes encode proteins with antiviral, anti-inflammatory, and antibacterial activities that could contribute to the clinical efficacy of roflumilast in COPD. RNA-sequencing experiments established that the sensitivity of genes to salmeterol varied by ∼7.5-fold. Consequently, the degree to which a PDE4 inhibitor potentiated the effect of a given concentration of LABA was gene-dependent. Operational model fitting of concentration-response curve data from cells subjected to fractional, ß 2-adrenoceptor inactivation determined that PDE4 inhibition increased the potency and doubled the efficacy of LABAs. Thus, adding roflumilast to standard triple therapy, as COPD guidelines recommend, may have clinical relevance, especially in target tissues where LABAs behave as partial agonists. Collectively, these results suggest that the genomic impact of roflumilast, including its ability to augment LABA-induced gene expression changes, may contribute to its therapeutic activity in COPD.


Assuntos
Perfilação da Expressão Gênica/métodos , Indanos/farmacologia , Pulmão/citologia , Inibidores da Fosfodiesterase 4/farmacologia , Quinolonas/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Aminopiridinas/farmacologia , Aminoquinolinas/farmacologia , Benzamidas/farmacologia , Linhagem Celular , Ciclopropanos/farmacologia , Sinergismo Farmacológico , Células Epiteliais/química , Células Epiteliais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pulmão/química , Pulmão/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos , Xinafoato de Salmeterol/farmacologia , Sulfonas/farmacologia
20.
J Pharmacol Exp Ther ; 370(1): 104-110, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31068382

RESUMO

ß 2-Adrenoceptors (ß 2ARs) are concentrated in caveolar lipid raft domains of the plasma membrane in airway smooth-muscle (ASM) cells, along with adenylyl cyclase type 6 (AC6). This is believed to contribute to how these receptors can selectively regulate certain types of cAMP-dependent responses in these cells. The goal of the present study was to test the hypothesis that ß 2AR production of cAMP is localized to specific subcellular compartments using fluorescence resonance energy transfer-based cAMP biosensors targeted to different microdomains in human ASM cells. Epac2-MyrPalm and Epac2-CAAX biosensors were used to measure responses associated with lipid raft and nonraft regions of the plasma membrane, respectively. Activation of ß 2ARs with isoproterenol produced cAMP responses that are most readily detected in lipid raft domains. Furthermore, overexpression of AC6 somewhat paradoxically inhibited ß 2AR production of cAMP in lipid raft domains without affecting ß 2AR responses detected in other subcellular locations or cAMP responses to EP2 prostaglandin receptor activation, which were confined primarily to nonraft domains of the plasma membrane. The inhibitory effect of overexpressing AC6 was blocked by inhibition of phosphodiesterase type 4 (PDE4) activity with rolipram, inhibition of protein kinase A (PKA) activity with H89, and inhibition of A kinase anchoring protein (AKAP) interactions with the peptide inhibitor Ht31. These results support the idea that overexpression of AC6 leads to enhanced feedback activation of PDE4 via phosphorylation by PKA that is part of an AKAP-dependent signaling complex. This provides insight into the molecular basis for localized regulation of cAMP signaling in human ASM cells.


Assuntos
Adenilil Ciclases/metabolismo , Brônquios/citologia , AMP Cíclico/biossíntese , Miócitos de Músculo Liso/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Traqueia/citologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Humanos , Isoproterenol/farmacologia , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos
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