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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.
J Sports Sci Med ; 18(4): 716-721, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31827356

RESUMO

The purpose of the study was to investigate the effect of inhaling 1600 µg of salbutamol (SAL) on 30 m sprint before and after the Yo-Yo Intermittent Recovery test. In a randomised cross over single blind study 13 male non-asthmatic, football players volunteered (mean ± SD; age 18.1 ± 0.9 years; weight 69.5 ± 8.3 kg; height 1.78 ± 0.07 m). Participants completed two visits and were randomly assigned to either (SAL) or (PLA) treatment and performed a set of three sprints of 30 m before and after the Yo-Yo Intermittent Recovery Test (Yo-Yo IRT). Best sprint and mean sprint were analysed in addition to the distance covered during the Yo-Yo IRT; rating of perceived exertion and heart rate were collected at the end of each level completed. Repeated measures ANOVA were performed to investigate changes in performance between groups. Following the inhalation of supra-therapeutic salbutamol dose (1600 µg) neither 30 m sprint time (PLA 4.43 ± 0.14 s; SAL 4.44 ± 0.15 s, p = 0.76) nor distance covered in the Yo-Yo IRT test reported significant variation between PLA conditions (1660 ± 217 m) and SAL (1610 ± 229 m, p = 0.16). Moreover, lactate values, heart rate and RPE did not differ significantly between groups. The inhalation of 1600 µg salbutamol does not enhance 30 m sprint performance in non-fatigued and fatigue conditions. Our findings suggest when football players acutely inhale double the permitted dose of salbutamol, as indicated in the World Anti-Doping Agency List of Prohibited Substances and Methods, they will not experience improvements in sprint or endurance performance.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/farmacologia , Teste de Esforço/métodos , Substâncias para Melhoria do Desempenho , Corrida/fisiologia , Futebol/fisiologia , Adolescente , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Afeto , Albuterol/administração & dosagem , Estudos Cross-Over , Frequência Cardíaca/efeitos dos fármacos , Humanos , Ácido Láctico/sangue , Masculino , Motivação , Percepção/efeitos dos fármacos , Esforço Físico/efeitos dos fármacos , Corrida/psicologia , Método Simples-Cego , Futebol/psicologia
3.
Exp Neurol ; 322: 113064, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31525347

RESUMO

In addition to local spinal cord dysfunction, spinal cord injury (SCI) can result in decreased skeletal muscle mitochondrial activity and muscle atrophy. Treatment with the FDA-approved ß2-adrenergic receptor (ADRB2) agonist formoterol has been shown to induce mitochondrial biogenesis (MB) in both the spinal cord and skeletal muscle and, therefore, has the potential to address comprehensive mitochondrial and organ dysfunction following SCI. Female C57BL/6 mice were subjected to moderate contusion SCI (80 Kdyn) followed by daily administration of vehicle or formoterol beginning 8 h after injury, a clinically relevant time-point characterized by a 50% decrease in mtDNA content in the injury site. As measured by the Basso Mouse Scale, formoterol treatment improved locomotor recovery in SCI mice compared to vehicle treatment by 7 DPI, with continued recovery observed through 21 DPI (3.5 v. 2). SCI resulted in 15% body weight loss in all mice by 3 DPI. Mice treated with formoterol returned to pre-surgery weight by 13 DPI, while no weight gain occurred in vehicle-treated SCI mice. Remarkably, formoterol-treated mice exhibited a 30% increase in skeletal muscle mass compared to those treated with vehicle 21 DPI (0.93 v. 0.72% BW), corresponding with increased MB and decreased skeletal muscle atrophy. These effects were not observed in ADRB2 knockout mice subjected to SCI, indicating that formoterol is acting via the ADRB2 receptor. Furthermore, knockout mice exhibited decreased basal spinal cord and skeletal muscle PGC-1α expression, suggesting that ADRB2 may play a role in mitochondrial homeostasis under physiological conditions. These data provide evidence for systemic ADRB2-mediated MB as a therapeutic avenue for the treatment of SCI.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Fumarato de Formoterol/farmacologia , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/metabolismo , Atrofia Muscular/etiologia , Biogênese de Organelas , Receptores Adrenérgicos beta 2 , Traumatismos da Medula Espinal/complicações
4.
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
5.
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
6.
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
7.
Drugs ; 79(9): 997-1008, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31119643

RESUMO

Tiotropium/olodaterol (Stiolto® Respimat®; Spiolto® Respimat®) is an inhaled fixed-dose combination of the long-acting muscarinic antagonist tiotropium bromide (hereafter referred to as tiotropium) and the long-acting ß2-adrenergic agonist olodaterol. It is available in several countries, including the USA, Japan, China and those of the EU, where it is indicated for the long-term maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy of tiotropium/olodaterol 5/5 µg/day in patients with COPD was evaluated in phase III or IV trials of 6-52 weeks' duration. Tiotropium/olodaterol improved lung function to a greater extent than each of its individual components or placebo in 12- and 52-week trials. In 6-week trials, tiotropium/olodaterol provided greater lung function benefits over 24 h than the individual components, placebo or twice-daily fluticasone propionate/salmeterol. Tiotropium/olodaterol also demonstrated beneficial effects on health-related quality of life (HR-QoL), dyspnoea, inspiratory capacity, exercise endurance and the need for rescue medication. In an 8-week open-label trial, umeclidinium/vilanterol was superior to tiotropium/olodaterol for the primary endpoint of trough forced expiratory volume in 1 s. The tolerability profile of tiotropium/olodaterol was generally similar to that of the individual components. In conclusion, tiotropium/olodaterol provides a useful option for the maintenance treatment of COPD, with the convenience of once-daily administration via a single inhaler.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Benzoxazinas/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzoxazinas/farmacologia , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Fase IV como Assunto , Combinação de Medicamentos , Humanos , Antagonistas Muscarínicos/farmacologia , Qualidade de Vida , Brometo de Tiotrópio/farmacologia , Resultado do Tratamento
8.
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
9.
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
10.
J Pharmacol Exp Ther ; 370(1): 127-136, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31085697

RESUMO

AZD8871 is a novel muscarinic antagonist and ß 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M3 receptor (pIC50 in binding assays: 9.5) and shows kinetic selectivity for the M3 (half-life: 4.97 hours) over the M2 receptor (half-life: 0.46 hour). It is selective for the ß 2-adrenoceptor over the ß 1 and ß 3 subtypes (3- and 6-fold, respectively) and shows dual antimuscarinic and ß 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC50 in electrically stimulated trachea: 8.6; pEC50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2- and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacologia , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Receptor Muscarínico M3/antagonistas & inibidores , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Triazóis/efeitos adversos , Triazóis/farmacologia , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animais , Brônquios/efeitos dos fármacos , Brônquios/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Cães , Cobaias , Humanos , Masculino , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacocinética , Quinolinas/administração & dosagem , Quinolinas/farmacocinética , Receptor Muscarínico M2/metabolismo , Distribuição Tecidual , Traqueia/efeitos dos fármacos , Traqueia/fisiologia , Triazóis/administração & dosagem , Triazóis/farmacocinética
11.
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
12.
Expert Opin Pharmacother ; 20(9): 1075-1085, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30983423

RESUMO

INTRODUCTION: Inhaled corticosteroid/long-acting ß-2 agonists (ICS/LABA) combination inhalers have been a lifeline for a generation of chronic obstructive pulmonary disease (COPD) and asthma patients. Fluticasone furoate and Vilanterol (FF/VI) as a once-daily ICS/LABA combination have an extensive clinical trial and real-world data to support its use in COPD patients. Areas covered: The authors provide pharmacological profiles of fluticasone furoate, vilanterol and the FF/VI fixed dose combination. Salient clinical trials evaluating efficacy and safety of the FF/VI combination, and studies demonstrating the impact on COPD exacerbation risk and mortality are also discussed. Expert opinion: ICS/LABA combinations provide bronchodilation and decrease the frequency of COPD exacerbations. Individualizing treatment of each COPD patient based on unique phenotypes will maximize chances of therapeutic responsiveness. Asthma-COPD overlap (ACO), patients with sputum and/or blood eosinophilia, patients with a brisk bronchodilator response, and patients with frequent exacerbations are more likely to show a therapeutic response to ICS than populations who have none of these features. FF/VI will likely remain a popular ICS/LBA combination to treat COPD, as a once-daily inhaled therapy delivered via the Ellipta device popular with COPD patients, with extensive clinical trial and real-world data to support its use.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Androstadienos/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Clorobenzenos/uso terapêutico , Combinação de Medicamentos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Androstadienos/farmacologia , Humanos , Doença Pulmonar Obstrutiva Crônica/patologia
13.
PLoS One ; 14(4): e0215539, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30986276

RESUMO

In skeletal muscle, the major isoform of ß-adrenergic receptor (ß-AR) is ß2-AR and the minor isoform is ß1-AR, which is opposite to the situation in cardiac muscle. Despite extensive studies in cardiac muscle, the physiological roles of the ß-AR subtypes in skeletal muscle are not fully understood. Therefore, in this work, we compared the effects of chronic ß1- or ß2-AR activation with a specific ß1-AR agonist, dobutamine (DOB), or a specific ß2-AR agonist, clenbuterol (CB), on masseter and cardiac muscles in mice. In cardiac muscle, chronic ß1-AR stimulation induced cardiac hypertrophy, fibrosis and myocyte apoptosis, whereas chronic ß2-AR stimulation induced cardiac hypertrophy without histological abnormalities. In masseter muscle, however, chronic ß1-AR stimulation did not induce muscle hypertrophy, but did induce fibrosis and apoptosis concomitantly with increased levels of p44/42 MAPK (ERK1/2) (Thr-202/Tyr-204), calmodulin kinase II (Thr-286) and mammalian target of rapamycin (mTOR) (Ser-2481) phosphorylation. On the other hand, chronic ß2-AR stimulation in masseter muscle induced muscle hypertrophy without histological abnormalities, as in the case of cardiac muscle, concomitantly with phosphorylation of Akt (Ser-473) and mTOR (Ser-2448) and increased expression of microtubule-associated protein light chain 3-II, an autophagosome marker. These results suggest that the ß1-AR pathway is deleterious and the ß2-AR is protective in masseter muscle. These data should be helpful in developing pharmacological approaches for the treatment of skeletal muscle wasting and weakness.


Assuntos
Sistema de Sinalização das MAP Quinases , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Clembuterol/farmacologia , Dobutamina/farmacologia , Masculino , Músculo Masseter , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
14.
Am J Physiol Regul Integr Comp Physiol ; 316(5): R666-R677, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30892909

RESUMO

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual ß2-/ß3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, ß2-adrenoceptor desensitization, ß-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of ß2-adrenoceptors, with a similar potency and efficacy to that of the nonselective ß-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit ß-arrestin1/2 to the ß2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a ß2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Etanolaminas/farmacologia , Transportador de Glucose Tipo 4/metabolismo , Glucose/metabolismo , Músculo Esquelético/efeitos dos fármacos , Mioblastos Esqueléticos/efeitos dos fármacos , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Animais , Linhagem Celular , AMP Cíclico/metabolismo , Feminino , Transportador de Glucose Tipo 4/genética , Humanos , Cinética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos Knockout , Músculo Esquelético/citologia , Músculo Esquelético/metabolismo , Mioblastos Esqueléticos/metabolismo , Transporte Proteico , Ratos , Receptores Adrenérgicos beta 2/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Transdução de Sinais
15.
Pulm Pharmacol Ther ; 56: 20-28, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30876906

RESUMO

Airway smooth muscle cell (ASMC) hyperplasia causes airway wall remodelling, which is resisting to therapy. Long acting ß2-agonists (LABA) relax airway muscles, but their effect on remodelling is unclear. This study compared the anti-proliferative effect of LABA in human primary ASMC, in situations where LABA were applied before, together, or after platelet derived growth factor (PDGF-BB). Cells obtained from controls (n = 5), and asthma patients (n = 5) were stimulated by PDGF-BB (10 ng/ml) before or after the application of formoterol or salmeterol. Proliferation was determined by direct cell counts over three days, cell cycle control proteins p21(Waf1/Cip1), p27(Kip1), signalling proteins Erk1/2 and p38 mitogen activated protein kinase (MAPK) were detected by immuno-blotting. PDGF-BB induced proliferation was significantly stronger in asthmatic ASMC versus controls. Proliferation was prevented by 30 min pre-incubation with LABA. When LABA were applied together or after PDGF-BB, their anti-proliferative effect was no longer significant. In untreated ASMC, LABA increased the expression of p21(Waf1/Cip1) and p27(Kip1) through cAMP, and this mechanism was abolished by the presence of PDGF-BB. The data show that the anti-proliferative effect of cAMP signalling cannot overcome the mitogenic signalling cascade once it was activated. Therefore, remodelling in asthma cannot be reduced by LABA.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Asma/tratamento farmacológico , AMP Cíclico/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/fisiopatologia , Becaplermina/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Preparações de Ação Retardada , Feminino , Fumarato de Formoterol/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mitógenos/metabolismo , Miócitos de Músculo Liso/metabolismo , Xinafoato de Salmeterol/farmacologia
16.
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
17.
J Pharmacol Exp Ther ; 369(2): 188-199, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30819762

RESUMO

The anabolic effects of ß 2-adrenoceptor (ß 2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of ß 2-AR agonists for skeletal muscle wasting conditions has been limited by their undesired cardiovascular effects. Here, we describe the preclinical pharmacological profile of a novel 5-hydroxybenzothiazolone (5-HOB) derived ß 2-AR agonist in comparison with formoterol as a representative ß 2-AR agonist that have been well characterized. In vitro, 5-HOB has nanomolar affinity for the human ß 2-AR and selectivity over the ß 1-AR and ß 3-AR. 5-HOB also shows potent agonistic activity at the ß 2-AR in primary skeletal muscle myotubes and induces hypertrophy of skeletal muscle myotubes. Compared with formoterol, 5-HOB demonstrates comparable full-agonist activity on cAMP production in skeletal muscle cells and skeletal muscle tissue-derived membranes. In contrast, a greatly reduced intrinsic activity was determined in cardiomyocytes and cell membranes prepared from the rat heart. In addition, 5-HOB shows weak effects on chronotropy, inotropy, and vascular relaxation compared with formoterol. In vivo, 5-HOB significantly increases hind limb muscle weight in rats with attenuated effects on heart weight and ejection fraction, unlike formoterol. Furthermore, changes in cardiovascular parameters after bolus subcutaneous treatment in rats and rhesus monkeys are significantly lower with 5-HOB compared with formoterol. In conclusion, the pharmacological profile of 5-HOB indicates superior tissue selectivity compared with the conventional ß 2-AR agonist formoterol in preclinical studies and supports the notion that such tissue-selective agonists should be investigated for the safe treatment of muscle-wasting conditions without cardiovascular limiting effects.


Assuntos
Benzotiazóis/química , Benzotiazóis/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Receptores Adrenérgicos beta 2/metabolismo , Segurança , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Anabolizantes/efeitos adversos , Anabolizantes/química , Anabolizantes/farmacologia , Anabolizantes/uso terapêutico , Animais , Benzotiazóis/efeitos adversos , Benzotiazóis/uso terapêutico , Células CHO , Cricetulus , Coração/efeitos dos fármacos , Humanos , Hipertrofia/tratamento farmacológico , Cinética , Macaca mulatta , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Miócitos Cardíacos/efeitos dos fármacos , Ratos
18.
Food Chem ; 288: 15-21, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902275

RESUMO

miRNA sequencing was applied in this work to screen miRNA biomarkers related to ß2-agonists from the test and control goat samples. A total of 10 selected miRNAs were proven by qRT-PCR to be able to separate treatment cell groups from the control. With previously reported differentially expressed genes (DEGs), we used target gene prediction to build a miRNA-mRNA regulatory network related to ß2-agonists, which validated the miRNA biomarkers and provided a reference for identifying the mechanism of ß2-agonists. Our subsequent in vivo experiments revealed that the regulation trends of the miRNAs were the same as in vitro experiments. DD-SIMCA and heatmap analysis also indicated concordant separation effects with the 10 miRNAs, which could therefore be used as biomarkers to monitor illegal use of ß2-agonists in goats.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Biomarcadores/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Cabras/genética , MicroRNAs/metabolismo , Animais , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Masculino , RNA Mensageiro/metabolismo
19.
Life Sci ; 224: 128-137, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30905783

RESUMO

AIM: To evaluate the therapeutic potential of ligands of beta-adrenoceptors in cognitive disorders. Testosterone and adrenergic pathways are involved in hippocampal and emotional memory. Moreover, is strongly suggested that androgen diminishing in aging is involved in cognitive deficit, as well as beta-adrenoceptors, particularly beta2-adrenoceptor, participate in the adrenergic modulation of memory. In this regard, some animal models of memory disruption have shown improved performance after beta-drug administration. MATERIAL AND METHODS: In this work, we evaluated the effects of agonists (isoproterenol and salbutamol) and antagonists (propranolol and carvedilol) on beta-adrenoceptors in orchiectomized rats, as well as their effects in the performance on avoidance task and damage in hippocampal neurons by immunohistochemistry assays. KEY FINDINGS: Surprisingly, we found that both antagonists and salbutamol (but not isoproterenol) modulate the effects of hormone deprivation, improving memory and decreasing neuronal death and amyloid-beta related changes in some regions (particularly CA1-3 and dentate gyrus) of rat hippocampus. SIGNIFICANCE: Two ß-antagonists and one ß2-agonist modulated the effects of hormone deprivation on memory and damage in brain. The mechanisms of signaling of these drugs for beneficial effects remain unclear, even if used ß-ARs ligands share a weak activity on ß-arrestin/ERK-pathway activation which can be involved in these effects as we proposed in this manuscript. Our observations could be useful for understanding effects suggested of adrenergic drugs to modulate emotional memory. But also, our results could be related to other pathologies involving neuronal death and Aß accumulation.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Albuterol/farmacologia , Comportamento Animal/efeitos dos fármacos , Emoções/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Orquiectomia/efeitos adversos , Receptores Adrenérgicos beta/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Ratos Wistar
20.
Iran J Allergy Asthma Immunol ; 18(1): 12-26, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30848570

RESUMO

Medicinal plants have been identified and used as primary sources in prevention and treatment of pulmonary diseases (mainly obstructive pulmonary diseases) from ancient times due to various pharmacological activities. In this review, the stimulatory effects of extracts, some fractions and constituents of medicinal plants on ß2-adrenoceptors which could be used as possible therapeutic agents in the future were reviewed. Various databases including; Medline, PubMed, ScienceDirect, Scopus, and Google Scholar were searched using stimulatory effect, ß2-adrenoceptors, possible mechanism, tracheal smooth muscle (TSM), medicinal plants and their constituents as keywords from 1985 to 2017. All studied plants including; Nigella sativa, Rosa damascena, Thymus vulgaris, Carum copticom, Carum carvi, Zataria multiflora, Crocus sativus, Cuminum cyminum, Liomnia acidissima, Portulaca oleraceae, Satureja hortensis, Ephedra sinica and Achillea millefolium showed relaxant effect on tracheal smooth muscle with a stimulatory effect on ß2-adrenoceptors mechanism. The studied plants and their constituents could be of therapeutic value in clinical practice as a bronchodilatory drug by ß2-adrenoceptors stimulatory mechanism for treatment of obstructive pulmonary diseases.


Assuntos
Músculo Liso/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores Adrenérgicos beta 2/fisiologia , Traqueia/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Animais , Humanos , Músculo Liso/fisiologia , Plantas Medicinais , Traqueia/fisiologia
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