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1.
Expert Opin Drug Metab Toxicol ; 16(2): 143-148, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31958237

RESUMO

Introduction: There is solid evidence that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of LAMAs, such as tiotropium, significantly increases the time to the first severe exacerbation and provides a modest but sustained bronchodilation. However, only a very limited number of pharmacokinetic studies with these agents have been performed in asthmatic patients.Areas covered: The pharmacokinetic profile of inhaled tiotropium, umeclidinium and glycopyrronium in healthy volunteers and that of inhaled tiotropium and umeclidinium in asthmatic patients have been reviewed.Expert opinion: In asthmatic patients, LAMAs are rapidly absorbed into the systemic compartment and demonstrate bi-exponential elimination (rapidly declining plasma concentrations followed by slow apparent terminal elimination). Apparently, the severity of asthma does not change the pharmacokinetics of LAMAs. The limited information available is focused on the plasma pharmacokinetic profile of these drugs and, consequently, although suitable for establishing a systemic safety profile, it does not tell us much about possible therapeutic efficacy of LAMAs in asthmatics because quantification of systemic plasma values is neither at the airways, which are their site of action nor representative of their transport to this site.


Assuntos
Asma/tratamento farmacológico , Antagonistas Muscarínicos/administração & dosagem , Receptor Muscarínico M3/antagonistas & inibidores , Administração por Inalação , Antiasmáticos/administração & dosagem , Antiasmáticos/farmacocinética , Antiasmáticos/farmacologia , Asma/fisiopatologia , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacocinética , Broncodilatadores/farmacologia , Humanos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M3/metabolismo , Índice de Gravidade de Doença
2.
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
3.
Medicine (Baltimore) ; 98(47): e17942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31764793

RESUMO

BACKGROUND: Anticholinergic administration prior to flexible bronchoscopy has been investigated, but studies have not yielded consistent results. METHODS: Patients were randomized 1:1 to receive nebulized 4 ml ipratropium bromide (1 mg, n = 125) or placebo (n = 125) for 15 minutes as premedication, 20 to 40 minutes before bronchoscopy. Airway secretions, bleeding, patient discomfort, procedure time, and procedure-related adverse events were compared between the groups. RESULTS: Nebulized ipratropium bromide prior to bronchoscopy could reduce airway secretions and patient discomfort (P = .02; P < .001, respectively), but not tracheobronchial bleeding or procedure time (P = .51, P = .36, respectively). Chest nodule or mass was the most common indication for performing bronchoscopy. The adverse events were higher in ipratropium bromide group, and hypertension was the most common complication. CONCLUSION: Nebulized ipratropium bromide prior to bronchoscopy is a more effective regimen that shows a practical benefit on the airway secretions and patient comfort, though these effects may not translate into any marked reduction in bleeding or of procedure time under general anesthesia. We suggest that routine nebulized ipratropium bromide premedication for bronchoscopy could be useful and beneficial. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1800016881.


Assuntos
Secreções Corporais/efeitos dos fármacos , Brônquios/efeitos dos fármacos , Broncodilatadores/administração & dosagem , Broncoscopia , Ipratrópio/administração & dosagem , Traqueia/efeitos dos fármacos , Administração por Inalação , Brônquios/fisiologia , Broncodilatadores/farmacologia , Método Duplo-Cego , Feminino , Humanos , Ipratrópio/farmacologia , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Pré-Medicação , Traqueia/fisiologia
4.
Iran J Allergy Asthma Immunol ; 18(3): 320-331, 2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31522439

RESUMO

In this study we aimed to examine the relaxant effect of berberine, a compound extracted from a variety of herbs, on rat tracheal smooth muscle (TSM) and its possible mechanism(s). Cumulative concentrations of berberine (20, 65, 200 and 600 µg/mL) were added on pre-contracted TSM by methacholine or KCl in non-incubated or incubated tissues with atropine, chlorpheniramine, propranolol, diltiazem, glibenclamide, indomethacin, L-NG-nitro arginine methyl ester (L-NAME) and papaverine. The relaxant effects of theophylline (0.2, 0.4, 0.6 and 0.8 mM) as positive control and saline (1 mL) as negative control were also examined in non-incubated tissues. Berberine showed significant and concentration-dependent relaxant effects in non-incubated tissues contracted by KCl and methacholine (p<0.01 to p<0.001). There was no significant difference in the relaxant effects of berberine between non-incubated and incubated tissues with atropine, propranolol, diltiazem, glibenclamide, and papaverine. The relaxant effects of second concentrations of berberine in incubated tissues with L-NAME, its three lower concentration in incubated tissues with chlorpheniramine and its all concentrations in incubated tissues with indomethacin were significantly lower than non-incubated tissues (p<0.05 to p<0.001). The EC50 values of berberine in incubated tissues with chlorpheniramine was significantly higher than the non-incubated condition (p<0.05). Our findings reveal a relatively potent relaxant effect of berberine that is lower than the effect of theophylline. Proposed mechanisms for the relaxant effect of berberine are histamine (H1) receptor blockade, inhibition of cyclooxygenase pathways and/or nitric oxide formation.


Assuntos
Berberina/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Óxido Nítrico/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptores Histamínicos H1/metabolismo , Transdução de Sinais , Animais , Berberina/química , Broncodilatadores/química , Broncodilatadores/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Modelos Biológicos , Cloreto de Potássio/farmacologia , Ratos , Traqueia/efeitos dos fármacos , Traqueia/metabolismo
5.
Asian Pac J Cancer Prev ; 20(9): 2763-2774, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31554375

RESUMO

Objective: Interaction of methamphetamine and sigma (σ) receptors lead to up-regulation and activation of these receptors. The σ receptors induced apoptosis in some parts of the brain by increasing calcium, dopamine, ROS, mitochondrial pores and caspase activity. Ibudilast is a phosphodiesterase inhibitor and anti-inflammatory drug, which can decrease the inflammatory cytokines. Also, it has a neuroprotective effect. It seems that ibudilast can reduce the methamphetamine-induced cell death due to inhibition of σ receptors. Materials and Methods: There were seven treatments including; control: culture medium, Treatment 1: 1mM methamphetamine, Treatment 2: 1mM methamphetamine and 1nM ibudilast, Treatment 3: 1mM methamphetamine and 10nM ibudilast, Treatment 4: 1mM methamphetamine and 100nM ibudilast, Treatment 5: 1mM methamphetamine and 1uM ibudilast, Treatment 6: 1mM methamphetamine and 10uM ibudilast, and Treatment 7: 1mM methamphetamine and 100uM ibudilast. Finally, for inhibition of PKA, CREB, IP3 receptor, NMDA receptor, Sigma receptor antagonist, sigma receptor agonist, cells were preincubated with adding H89 dihydrochloride, 666-15, Heparin, Ketamine, BMY 14802, and Pentazocine. MTT and LDH tests were performed for cell viability and cytotoxicity measurement, respectively. In continuing, the caspase activity colorimetric assay kit used for caspase 3 activity diagnosis. Rhodamine-123 performed to detection of mitochondrial membrane potential. TUNEL test used to DNA fragmentation and apoptosis, Fura-2 used to Measurement of (Ca2+) ic and (Ca2+) m, and fluorescence microscope used to Measurement of antioxidant enzyme activities. Results: Ibudilast increased the cell viability and the rhodamine-123 absorbance in methamphetamin-treated PC12 cells. It reduced cell cytotoxicity, caspase 3 activity, ic and m Ca2+ concentration, (OH) generation and DNA fragmentation in all concentrations of 1 nM t0 100 µM (p<0.05) by the optimal concentration of 100 µM, between our tested treatments. Conclusion: Ibudilast as a phosphodiesterase inhibitor can reduce the methamphetamine-induced cell death due to inhibition of σ receptors through cAMP production.


Assuntos
Apoptose/efeitos dos fármacos , Metanfetamina/farmacologia , Mitocôndrias/patologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Broncodilatadores/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Combinação de Medicamentos , Mitocôndrias/efeitos dos fármacos , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
6.
Anesth Analg ; 129(3): 745-752, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31425216

RESUMO

BACKGROUND: The ability of inotropic agents to alter airway reactivity and lung tissue mechanics has not been compared in a well-controlled experimental model. Therefore, we compared the potential to alter lung tissue viscoelasticity and bronchodilator effects of commonly used inotropic agents in an isolated perfused rat lung model. METHODS: After achieving steady state lung perfusion, sustained bronchoconstriction was induced by acetylcholine (ACh). Isolated rat lungs were then randomly allocated to 6 groups treated with either saline vehicle (n = 8) or incremental concentrations of inotropes (adrenaline, n = 8; dopamine, n = 7; dobutamine, n = 7; milrinone, n = 8; or levosimendan, n = 6) added to the whole-blood perfusate. Airway resistance (Raw), lung tissue damping (G), and elastance were measured under baseline conditions, during steady-state ACh-induced constriction and for each inotrope dose. RESULTS: No change in Raw was observed after addition of the saline vehicle. Raw was significantly lower after addition of dopamine (maximum difference [95% CI] of 29 [12-46]% relative to the saline control, P = .004), levosimendan (58 [39-77]%, P < .001), and adrenaline (37 [21-53]%, P < .001), whereas no significant differences were observed at any dose of milrinone (5 [-12 to 22]%) and dobutamine (4 [-13 to 21]%). Lung tissue damping (G) was lower in animals receiving the highest doses of adrenaline (difference: 22 [7-37]%, P = .015), dobutamine (20 [5-35]%, P = .024), milrinone (20 [6-34]%, P = .026), and levosimendan (36 [19-53]%, P < .001) than in controls. CONCLUSIONS: Although dobutamine and milrinone did not reduce cholinergic bronchoconstriction, they reversed the ACh-induced elevations in lung tissue resistance. In contrast, adrenaline, dopamine, and levosimendan exhibited both potent bronchodilatory action against ACh and diminished lung tissue damping. Further work is needed to determine whether these effects are clinically relevant in humans.


Assuntos
Resistência das Vias Respiratórias/efeitos dos fármacos , Broncoconstrição/efeitos dos fármacos , Cardiotônicos/farmacologia , Colinérgicos/farmacologia , Pulmão/efeitos dos fármacos , Acetilcolina/farmacologia , Resistência das Vias Respiratórias/fisiologia , Animais , Broncoconstrição/fisiologia , Broncodilatadores/farmacologia , Dobutamina/farmacologia , Pulmão/fisiologia , Masculino , Técnicas de Cultura de Órgãos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Simendana/farmacologia
8.
Arch Pharm (Weinheim) ; 352(8): e1900002, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31353608

RESUMO

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC50 values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC50 = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity.


Assuntos
Broncodilatadores/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Drogas , Músculo Liso/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/farmacologia , Pirimidinas/farmacologia , Traqueia/efeitos dos fármacos , Triazóis/farmacologia , Animais , Broncodilatadores/síntese química , Broncodilatadores/química , Relação Dose-Resposta a Droga , Humanos , Masculino , Simulação de Acoplamento Molecular , Estrutura Molecular , Contração Muscular/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/química , Pirimidinas/síntese química , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química
9.
Int Immunopharmacol ; 73: 581-589, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31234092

RESUMO

Inhaled terbutaline is commercially available ß2-agonist which consists of equivalent amount of R- and S-enantiomer. In this study, we aimed to investigate the effects of single enantiomers of terbutaline and its racemate in an ovalbumin (OVA)-induced mouse model of asthma via. seven days inhalation and the potential mechanisms involved. In a standard experimental asthma model, BALB/c mice were sensitized and challenged with OVA. R-terbutaline (R-ter), S-terbutaline (S-ter) or racemic terbutaline (rac-ter) was given via. nose-only inhalation for one week. Airway responsiveness to methacholine was measured by the plethysmography in conscious mice. Eosinophils counts in blood and bronchoalveolar (BAL) fluid were determined. The OVA-sIgE in plasma and inflammatory cytokines and mediators in BAL fluid or lung tissue were analyzed by ELISA, qRT-PCR or western blotting. Airway inflammation and remodeling were evaluated with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson staining. Drug distribution and deposition after inhalation were determined by LC-MS/MS. Our data showed that R-ter efficiently ameliorated asthma responses, including airway hyperresponsiveness, eosinophils influx and IL-5 in BALF, plasma OVA-sIgE and significantly reduced pulmonary inflammation, peribronchial smooth muscle layer thickness, goblet cell hyperplasia, and deposition of collagen fibers, as well as downregulation of p38 MAPK phosphorylation and NF-κB expression. Racemic mixture exhibited diminished effects while S-ter enhanced airway responsiveness to methacholine and exerted pro-asthmatic effects.


Assuntos
Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Terbutalina/uso terapêutico , Administração por Inalação , Animais , Asma/imunologia , Asma/patologia , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/farmacologia , Citocinas/imunologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Imunoglobulina E/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/imunologia , Ovalbumina , Estereoisomerismo , Terbutalina/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
10.
Ther Adv Respir Dis ; 13: 1753466619850725, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096854

RESUMO

Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting ß2 agonist (LAMA/LABA) dual-bronchodilator maintenance therapy used to relieve symptoms and reduce future risk of exacerbations in adults with chronic obstructive pulmonary disease (COPD). To date, there have been several clinical studies and post hoc analyses of AB/FF, assessing treatment outcomes in patients with moderate-to-severe COPD. These studies have looked at a range of outcomes, including lung function parameters, patient-reported symptom scores, quality-of-life measures assessing impaired health and perceived well-being, and the frequency, duration, and severity of exacerbations. In light of the major 2017 revision to the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, and the subsequent updates, we present an update on the latest evidence supporting the efficacy and safety of AB/FF. This review discusses the clinical relevance of the improvements in lung function, symptoms, quality of life, and exacerbations in patients with COPD reported in the phase III and IV trials of AB/FF. Given the current concerns over unnecessary inhaled corticosteroid (ICS) use in COPD, we also touch briefly on the use of blood eosinophils as a biomarker for identifying those patients with COPD already using LAMA/LABA therapy for whom the addition of ICS might be of benefit.


Assuntos
Fumarato de Formoterol/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tropanos/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Adulto , Broncodilatadores/administração & dosagem , Broncodilatadores/farmacologia , Combinação de Medicamentos , Fumarato de Formoterol/farmacologia , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida , Índice de Gravidade de Doença , Tropanos/farmacologia
11.
Ther Adv Respir Dis ; 13: 1753466619843426, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002020

RESUMO

Long-acting bronchodilators are the cornerstone of pharmacologic treatment of chronic obstructive pulmonary disease (COPD). Spiolto® or Stiolto® is a fixed-dose combination (FDC) containing two long-acting bronchodilators, the long-acting muscarinic receptor antagonist tiotropium (TIO) and the long-acting ß2-adrenoceptor agonist olodaterol (OLO), formulated in the Respimat® Soft Mist™ inhaler. A total of 13 large, multicentre studies of up to 52 weeks' duration have documented its efficacy in more than 15,000 patients with COPD. TIO/OLO 5/5 µg FDC significantly increases pulmonary function compared with placebo and its respective constituent mono-components TIO 5 µg and OLO 5 µg. TIO/OLO 5/5 µg also results in statistically and clinically significant improvements in patient-reported outcomes, such as dyspnoea, use of rescue medication, and health status. Addition of OLO 5 µg to TIO 5 µg reduces the rate of moderate-to-severe exacerbations by approximately 10%. Compared with placebo and TIO 5 µg, TIO/OLO 5/5 µg significantly improves exercise capacity (e.g. endurance time) and physical activity, the latter increase being reached by a unique combination behavioural modification intervention, dual bronchodilatation and exercise training. Overall, the likelihood for patients to experience a clinically significant benefit is higher with TIO/OLO 5/5 µg than with its constituent mono-components, which usually yield smaller improvements which do not always reach statistical significance, compared with baseline or placebo. This supports the early introduction of TIO/OLO 5/5 µg in the management of patients with symptomatic COPD.


Assuntos
Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Benzoxazinas/farmacologia , Broncodilatadores/farmacologia , Preparações de Ação Retardada , Combinação de Medicamentos , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Índice de Gravidade de Doença , Brometo de Tiotrópio/farmacologia
12.
Artigo em Inglês | MEDLINE | ID: mdl-31009988

RESUMO

The evolution of lung function, including assessment of small airways, was assessed in individuals enrolled in the World Trade Center Environmental Health Center (WTC-EHC). We hypothesized that a bronchodilator response at initial evaluation shown by spirometry or in small airways, as measured by forced oscillation technique (FOT), would be associated with improvement in large and small airway function over time. Standardized longitudinal assessment included pre and post bronchodilator (BD) spirometry (forced vital capacity, FVC; forced expiratory volume in 1 second, FEV1) and FOT (resistance at 5 Hz, R5; resistance at 5 minus 20 Hz, R5-20). Longitudinal changes were assessed using linear mixed-effects modelling with adjustment for potential confounders (median follow-up 2.86 years; 95% measurements within 4.9 years). Data demonstrated: (1) parallel improvement in airflow and volume measured by spirometry and small airway function (R5 and R5-20) measured by FOT; (2) the magnitude of longitudinal improvement was tightly linked to the initial BD response; and (3) longitudinal values for small airway function on FOT were similar to residual abnormality observed post BD at initial visit. These findings suggest presence of reversible and irreversible components of small airway injury that are identifiable at initial presentation. These results have implications for treatment of isolated small airway abnormalities that can be identified by non-invasive effort independent FOT particularly in symptomatic individuals with normal spirometry indices. This study underscores the need to study small airway function to understand physiologic changes over time following environmental and occupational lung injury.


Assuntos
Broncodilatadores/farmacologia , Poeira , Volume Expiratório Forçado , Ataques Terroristas de 11 de Setembro , Capacidade Vital , Brônquios/efeitos dos fármacos , Brônquios/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espirometria
13.
Pulm Pharmacol Ther ; 56: 39-50, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30876907

RESUMO

Combining a long-acting ß2-agonist (LABA) with a long-acting muscarinic antagonist (LAMA) is the cornerstone to treat patients with chronic obstructive pulmonary disease (COPD). In this study we have characterized the interaction between the LAMA tiotropium bromide, and the LABA olodaterol, on the contractile tone of human medium bronchi and small airways. The response to a combination of tiotropium bromide and olodaterol was assessed at sub-maximal contractile tone induced by carbachol. The duration of action was studied in tissue contracted by transmural stimulation. Relaxation of bronchial tone was expressed as % of maximal response to papaverine. Drug interactions were analyzed by the Bliss Independence method and Unified Theory. Tiotropium bromide/olodaterol combination induced a significant synergistic relaxant response (P < 0.05 vs. expected additive effect) in medium bronchi and small airways pre-contracted by carbachol, by enhancing relaxation +22.13 ± 4.42% and +26.31 ± 12.39%, respectively. The combination of tiotropium bromide and olodaterol also reduced the airway smooth muscle contractility elicited by transmural stimulation by 73.60 ± 3.10%. The extent of synergy was strong to very strong, and was supported by the release of neuronal acetylcholine, cyclic adenosine monophosphate levels, and activation of iberiotoxin-sensitive KCa++ channels. Conversely, the interaction between tiotropium bromide and olodaterl was independent of the activity at M2 muscarinic receptors. These results indicate that tiotropium bromide/olodaterol combination leads to a potent and durable synergistic relaxation of human medium bronchi and small airways. Further pharmacological studies are needed to confirm these results in clinical settings.


Assuntos
Benzoxazinas/farmacologia , Brônquios/efeitos dos fármacos , Broncodilatadores/farmacologia , Músculo Liso/efeitos dos fármacos , Brometo de Tiotrópio/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Idoso , Benzoxazinas/administração & dosagem , Brônquios/metabolismo , Broncodilatadores/administração & dosagem , Combinação de Medicamentos , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacologia , Músculo Liso/metabolismo , Brometo de Tiotrópio/administração & dosagem
14.
Adv Clin Exp Med ; 28(6): 771-776, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30843675

RESUMO

BACKGROUND: Fenspiride is an antagonist of H1-histamine receptors that is used to treat acute and chronic respiratory tract infections and otitis media in children and adolescents. OBJECTIVES: The aim of the study was to assess the influence of long-term administration of fenspiride on bone mineral density (BMD) and bone turnover in young growing rats. MATERIAL AND METHODS: The experiment was carried out on 18 young (8-week-old) male Wistar rats receiving either fenspiride 15 mg/kg intragastrically (ig) (group F) or saline solution 4 mL/kg ig (group C) for 3 months. On days 1 and 93, blood samples were collected and serum levels of calcium, phosphorus and markers of bone turnover were measured. On days 2 and 92, BMD was measured with dual-energy x-ray absorptiometry (DXA) using small animal software. RESULTS: We detected no influence of fenspiride on weight gain, total body BMD (0.212 ±0.010 g/cm2 vs 0.204 ±0.024 g/cm2), hind limb BMD (0.264 ±0.016 g/cm2 vs 0.252 ±0.027 g/cm2), or bone macroscopic parameters. There were no significant differences between group F and group C in serum levels of osteocalcin (group F: 0.42 ±0.09 ng/mL vs group C: 0.43 ±0.08 ng/mL), C-terminal telopeptide of type I collagen (F: 0.31 ±0.08 ng/mL vs C: 0.29 ±0.08 ng/mL), osteoprotegerin (F: 5.47 ±0.78 pg/mL vs C: 5.35 ±1.65 pg/mL), receptor activator of nuclear factor kappa B ligand (F: 0.65 ±0.85 pg/mL vs C: 0.56 ±0.86 pg/mL), parathormone (F: 237 ±182 pg/mL vs C: 289 ±200 pg/mL), total calcium (F: 6.38 ±1.50 mg/dL vs C: 6.83 ±1.71 mg/dL), or inorganic phosphorus (F: 5.19 ±1.76 mg/dL vs C: 5.50 ±1.32 mg/dL). CONCLUSIONS: Long-term administration of fenspiride has no negative impact on BMD and bone metabolism in young growing rats.


Assuntos
Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Broncodilatadores/farmacologia , Compostos de Espiro/farmacologia , Absorciometria de Fóton , Animais , Biomarcadores , Broncodilatadores/administração & dosagem , Masculino , Ratos , Ratos Wistar , Compostos de Espiro/administração & dosagem
15.
Drug Test Anal ; 11(7): 1048-1056, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30836453

RESUMO

While studies have demonstrated substantial differences in beta2 -adrenergic agonist enantiomer pharmacology, enantioselective disposition of long-acting beta2 -adrenergic ligand racemic (rac)-formoterol in blood is inadequately explored after inhaled therapy given analytical challenges. Furthermore, information on enantioselective disposition and partitioning of beta2 -adrenergic agonist in skeletal muscle is absent despite its promising data on muscle anabolism in humans. Using a sensitive ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay, we determined disposition of (R,R)-formoterol and (S,S)-formoterol in plasma and skeletal muscle samples from 11 non-asthmatic men who had inhaled rac-formoterol at therapeutic doses (2 × 27 µg). Mean (SD) concentrations of (R,R)- and (S,S)-formoterol in plasma and in muscle biopsies of the vastus lateralis 1 hour after inhalation of formoterol were 31 (15) and 45 (18) pg × mL-1 for (R,R)-formoterol and (S,S)-formoterol, respectively, in plasma, and 0.56 (0.32) and 0.51 (0.29) pg × mgwet wt -1 , respectively, in muscle. Formoterol exhibited different enantioselective disposition in plasma and muscle (p < 0.0001). In plasma, mean log (R,R):(S,S)-formoterol ratio was lower than 0 [-0.17(0.07), p < 0.0001], whereas in muscle, mean log (R,R):(S,S)-formoterol ratio was slightly higher than 0 [0.04(0.07), p < 0.05]. Log (R,R):(S,S)-formoterol ratio in muscle was related to muscle fiber-type composition. Furthermore, formoterol induced an approximately two-fold increase in muscle p-PKASer/thr phosphorylation (p < 0.01), indicating a substantial beta2 -adrenergic response. Collectively, these findings suggest that formoterol exhibits modest enantioselective disposition in plasma after inhaled therapy in humans, which appear related to a greater (R,R)-enantiomer disposition in skeletal muscle that may be dependent on fiber-type composition.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Broncodilatadores/farmacocinética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fumarato de Formoterol/farmacocinética , Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/sangue , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Adulto , Broncodilatadores/administração & dosagem , Broncodilatadores/sangue , Broncodilatadores/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Fumarato de Formoterol/administração & dosagem , Fumarato de Formoterol/sangue , Fumarato de Formoterol/farmacologia , Humanos , Músculo Esquelético/metabolismo , Estereoisomerismo , Espectrometria de Massas em Tandem/métodos , Adulto Jovem
16.
BMC Res Notes ; 12(1): 94, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786914

RESUMO

OBJECTIVE: COPD patients have challenges for effective use of inhalers due to advanced age, fixed airflow obstruction and comorbid medical conditions. Published clinical trials investigate drug efficacy but rarely consider the inhaler device. This trial investigates device efficacy, comparing clinical outcomes for the same medication via two different devices. Our intention was to communicate the results and to critically appraise the study protocol to inform planning of future device comparison research. Subjects with spirometry confirming at least moderate COPD were randomly assigned to inhaler sequence; starting with Accuhaler or metered dose inhaler and spacer (MDI/s). After baseline testing, subjects were assigned to fluticasone propionate/salmeterol xinafoate (SFC) 500/50 mcg twice daily via the first device for 6 weeks' duration, then changed to the alternate device for the following 6 weeks. Subjects were reassessed in terms of health-related quality of life (HRQL), exercise endurance and lung function after each exposure period. RESULTS: The recruitment target was not achieved due to unanticipated developments within the pharmaceutical industry, potentially compromising the study's power. Study outcomes did not differ significantly according to the allocated inhaler device even after adjusting for baseline lung function or inhaler technique. Recommendations for future device comparison protocols are offered. Trial registration Australia and New Zealand Clinical Trials Registry, Current Controlled Trials ACTRN12618000075280, date of registration: 18.01.2018. Retrospectively registered.


Assuntos
Broncodilatadores/farmacologia , Fluticasona/farmacologia , Inaladores Dosimetrados , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Xinafoato de Salmeterol/farmacologia , Idoso , Broncodilatadores/administração & dosagem , Estudos Cross-Over , Feminino , Fluticasona/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Xinafoato de Salmeterol/administração & dosagem , Método Simples-Cego
17.
Pulm Pharmacol Ther ; 56: 1-7, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30797981

RESUMO

The traditional theophylline bronchodilator, aminophylline, is still widely used, especially in the treatment of COPD. The effects of aminophylline on ventilation and action of the costal diaphragm have been previously defined, but other respiratory muscles - notably the chest wall, are not well determined. Therefore, we investigated the effects of aminophylline on the Parasternal intercostal, a key obligatory inspiratory muscle, examining muscle length, shortening and EMG. We studied 11 awake canines, chronically implanted with sonomicrometer crystals and fine-wire EMG electrodes in the parasternal muscle. Ventilatory parameters, muscle length (shortening), and moving average muscle EMG activity, were measured at baseline and with aminophylline, during resting and hypercapnic stimulated breathing. Experiments were carried out prior to administration of aminophylline (baseline), and 1.5 h after loading and ongoing infusion. Minute ventilation, tidal volume and respiratory frequency all increased significantly with aminophylline, both during resting breathing and at equivalent levels of hypercapnic stimulated breathing. Parasternal baseline muscle length was entirely unchanged with aminophylline. Parasternal shortening increased significantly with aminophylline while corresponding parasternal EMG activity remained constant, consistent with increased contractility. Thus, in awake, intact mammals, aminophylline, in the usual therapeutic range, elicits increased ventilation and increased contractility of all primary inspiratory respiratory muscles, including both chest wall and diaphragm.


Assuntos
Aminofilina/farmacologia , Broncodilatadores/farmacologia , Contração Muscular/efeitos dos fármacos , Músculos Respiratórios/efeitos dos fármacos , Animais , Diafragma/efeitos dos fármacos , Diafragma/metabolismo , Cães , Eletromiografia , Masculino , Músculos Respiratórios/metabolismo , Parede Torácica/efeitos dos fármacos , Parede Torácica/metabolismo , Volume de Ventilação Pulmonar/efeitos dos fármacos , Vigília
18.
Expert Rev Clin Pharmacol ; 12(4): 293-298, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30803279

RESUMO

INTRODUCTION: Acetylcholine is the predominant parasympathetic neurotransmitter in the airways, and plays a key role in the pathophysiology of chronic obstructive pulmonary disease (COPD). Muscarinic receptors are found in smooth muscle cells and submucosal glands. Binding of acetylcholine to muscarinic receptors could trigger bronchoconstriction. Muscarinic antagonists prevent acetylcholine from binding to its receptors and produce bronchodilation. Revefenacin is the first once-daily dosed nebulized long-acting muscarinic antagonist indicated for the maintenance treatment of patients with COPD. Areas covered: In this paper, the chemical properties, mechanism of action, pharmacokinetics, clinical efficacy and safety of Revefenacin was introduced, and the evolution of muscarinic antagonists is also briefly described. Expert commentary: Revefenacin is a new M3 muscarinic receptor antagonist, which could prevent acetylcholine from binding with the muscarinic receptor, making bronchodilation and relieving COPD symptoms. Revefenacin has a rapid onset of action, and the curative effect is to maintain a long time. Clinical trials showed that Revefenacin could significantly increase forced expiratory volume in 1 s (FEV1) in patients with COPD and improve their quality of life. The recommended dose of Revefenacin inhalation solution is 175 µg once daily. Adverse reactions were mild and the drug was well tolerated.


Assuntos
Benzamidas/administração & dosagem , Broncodilatadores/administração & dosagem , Carbamatos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Acetilcolina/metabolismo , Animais , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacologia , Carbamatos/efeitos adversos , Carbamatos/farmacologia , Volume Expiratório Forçado , Humanos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Qualidade de Vida
19.
Respir Physiol Neurobiol ; 259: 104-110, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30171906

RESUMO

While alveolar liquid clearance (ALC) mediated by the ß2-adrenergic receptor (ß2-AR) plays an important role in lung edema resolution in certain models of lung injury, in more severe lung injury models, this response might disappear. Indeed, we have shown that in an ischemia-reperfusion-induced lung injury model, ß2-agonists do not enhance ALC. The objective of this study was to determine if downregulation of the ß2-AR could explain the lack of response to ß2-agonists in this lung injury model. In an in vivo canine model of lung transplantation, we observed no change in ß2-AR concentration or affinity in the injured transplanted lungs compared to the native lungs. Furthermore, we could not enhance ALC in transplanted lungs with dcAMP + aminophylline, a treatment that bypasses the ß2-adrenergic receptor and is known to stimulate ALC in normal lungs. However, transplantation decreased αENaC expression in the lungs by 50%. We conclude that the lack of response to ß2-agonists in ischemia-reperfusion-induced lung injury is not associated with significant downregulation of the ß2-adrenergic receptors but is attributable to decreased expression of the ENaC channel, which is essential for sodium transport and alveolar liquid clearance in the lung.


Assuntos
Lesão Pulmonar , Alvéolos Pulmonares/fisiopatologia , Receptores Adrenérgicos beta 2/uso terapêutico , Traumatismo por Reperfusão/complicações , Aminofilina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Broncodilatadores/farmacologia , AMP Cíclico/farmacologia , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Canais Epiteliais de Sódio/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Imidazóis/uso terapêutico , Radioisótopos do Iodo/farmacocinética , Iodocianopindolol/farmacocinética , Lesão Pulmonar/etiologia , Lesão Pulmonar/fisiopatologia , Masculino , Propanolaminas/uso terapêutico , Ligação Proteica/efeitos dos fármacos , Edema Pulmonar/etiologia , RNA Mensageiro
20.
Respir Physiol Neurobiol ; 259: 136-142, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217723

RESUMO

A certain amount of time is required to achieve a maximal contraction from airway smooth muscle (ASM) and stretches of substantial magnitude, such as the ones imparted by deep inspirations (DIs), interfere with contraction. The duration of ASM contraction without interference may thus affect its shortening, its mechanical response to DIs and the overall toll it exerts on the respiratory system. In this study, the effect of changing the interval between DIs on the dynamics of ASM was examined in vitro. Isolated bronchi derived from guinea pigs were held isotonically and stimulated to both contract and relax, in a randomized order, in response to 10-5 M of methacholine and 10-6 M of isoproterenol, respectively. Interference to ASM was inflicted after 2, 5, 10 and 30 min in a randomized order, by imposing a stretch that simulated a DI. The shortening before the stretch, the stiffness before and during the stretch, the post-stretch elongation of ASM and the ensuing re-shortening were measured. These experiments were also performed in the presence of simulated tidal breathing achieved through force fluctuations. The results demonstrate that, with or without force fluctuations, increasing the interval between simulated DIs increased shortening and post-stretch elongation, but not stiffness and re-shortening. These time-dependent effects were not observed when ASM was held in the relaxed state. These findings may help understand to which extent ASM shortening and the regulatory effect of DI are affected by changing the interval between DIs. The potential consequences of these findings on airway narrowing are also discussed.


Assuntos
Resistência das Vias Respiratórias/fisiologia , Brônquios/citologia , Inalação/fisiologia , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Dinâmica não Linear , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Feminino , Cobaias , Técnicas In Vitro , Inalação/efeitos dos fármacos , Isoproterenol/farmacologia , Cloreto de Metacolina/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Estimulação Física , Fatores de Tempo
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