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1.
Oxid Med Cell Longev ; 2022: 9318721, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35178163

RESUMO

Racemic salbutamol ((RS)-sal), which consist of the same amount of (R)-sal and (S)-sal, has been used for asthma and COPD due to its bronchodilation effect. However, the effect of (R)-sal on repeated dextran sulfate sodium (DSS)-induced chronic colitis has not yet been investigated. In this study evaluated the potential effect of (R)-, (S)-, and (RS)-sal in mice with repeated DSS-induced chronic colitis and investigated the underlying mechanisms. Here, we verified that chronic colitis was significantly attenuated by (R)-sal, which was evidenced by notably mitigated body weight loss, disease activity index (DAI), splenomegaly, colonic lengths shortening, and histopathological scores. (R)-sal treatment noticeably diminished the levels of inflammatory cytokines (such as TNF-α, IL-6, IL-1ß, and IFN-γ). Notably, the efficacy of (R)-sal was better than that of (RS)-sal. Further research revealed that (R)-sal mitigated colonic CD4 leukocyte infiltration, decreased NF-κB signaling pathway activation, improved the Nrf-2/HO-1 signaling pathway, and increased the expression of ZO-1 and occludin. In addition, (R)-sal suppressed the levels of TGF-ß1, α-SMA, and collagen in mice with chronic colitis. Furthermore, the 16S rDNA sequences analyzed of the intestinal microbiome revealed that (R)-sal could mitigate the intestinal microbiome structure and made it more similar to the control group, which mainly by relieving the relative abundance of pathogens (such as Bacteroides) and increasing the relative abundance of probiotics (such as Akkermansia). Therefore, (R)-sal ameliorates repeated DSS-induced chronic colitis in mice by improving inflammation, suppressing oxidative stress, mitigating intestinal barrier function, relieving intestinal fibrosis, and regulating the intestinal microbiome community. These results indicate that (R)-sal maybe a novel treatment alternative for chronic colitis.


Assuntos
Albuterol/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Albuterol/farmacologia , Animais , Doença Crônica , Humanos , Masculino , Camundongos
2.
Am J Physiol Cell Physiol ; 321(5): C884-C896, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34613841

RESUMO

Moderate elevations of extracellular K+ concentration ([K+]o) occur during exercise and have been shown to potentiate force during contractions elicited with subtetanic frequencies. Here, we investigated whether lactic acid (reduced chloride conductance), ß2-adrenoceptor activation, and increased temperature would influence the potentiating effect of potassium in slow- and fast-twitch muscles. Isometric contractions were elicited by electrical stimulation at various frequencies in isolated rat soleus and extensor digitorum longus (EDL) muscles incubated at normal (4 mM) or elevated K+, in combination with salbutamol (5 µM), lactic acid (18.1 mM), 9-anthracene-carboxylic acid (9-AC; 25 µM), or increased temperature (30-35°C). Elevating [K+]o from 4 mM to 7 mM (soleus) and 10 mM (EDL) potentiated isometric twitch and subtetanic force while slightly reducing tetanic force. In EDL, salbutamol further augmented twitch force (+27 ± 3%, P < 0.001) and subtetanic force (+22 ± 4%, P < 0.001). In contrast, salbutamol reduced subtetanic force (-28 ± 6%, P < 0.001) in soleus muscles. Lactic acid and 9-AC had no significant effects on isometric force of muscles already exposed to moderate elevations of [K+]o. The potentiating effect of elevated [K+]o was still well maintained at 35°C. Addition of salbutamol exerts a further force-potentiating effect in fast-twitch but not in slow-twitch muscles already potentiated by moderately elevated [K+]o, whereas lactic acid, 9-AC, or increased temperature does not exert any further augmentation. However, the potentiating effect of elevated [K+]o was still maintained in the presence of these, thus emphasizing the positive influence of moderately elevated [K+]o for contractile performance during exercise.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/farmacologia , Ácido Láctico/farmacologia , Contração Muscular/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Potássio/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Temperatura , Animais , Antracenos/farmacologia , Estimulação Elétrica , Feminino , Técnicas In Vitro , Masculino , Músculo Esquelético/fisiologia , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismo
3.
Basic Clin Pharmacol Toxicol ; 129(5): 369-375, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34359097

RESUMO

PURPOSE: Relvar® (fluticasone furoate [FF]/vilanterol [VI]) is a once-daily inhaler with bronchodilator effect lasting 24 h. Our aim was to investigate the short- and long-term effects of FF/VI on exercise-induced asthma (EIA) in adolescents. METHODS: Ninety-three adolescent asthmatics aged 12-18 years were referred for evaluation of EIA. Following a positive exercise challenge test (ECT), 22/44 were allocated to a single administration of salbutamol (400 µg) and 22/44 to FF/VI (92/22 µg) in a double-blind method. Thirty-five subjects were reassessed by repeat ECT 30-60 days of FF/VI. RESULTS: Median FEV1 change post-ECT at baseline was -22.8% predicted (interquartile range [IQR] -26.1 and -18.0) for salbutamol and -21.0 (IQR -30.7 and -16.8) for FF/VI. Following bronchodilator, FEV1 improved similarly in both groups. Repeat ECT following 30-60 days of FF/VI resulted in negative ECT in 33/35 subjects; the median decrease in FEV1 of these 35 subjects was 22.6% predicted (IQR 29-18) before, and 4.6% predicted (IQR 8.7-2.5) after 30-60 days of FF/VI treatment (p < 0.0001). CONCLUSIONS: FF/VI is effective in reversing EIA after 15 min in adolescents and in protecting EIA after 30-60 days in adolescents. Larger studies are needed to assess the effect of FF/VI on EIA.


Assuntos
Albuterol/administração & dosagem , Androstadienos/administração & dosagem , Asma/tratamento farmacológico , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Administração por Inalação , Adolescente , Albuterol/farmacologia , Androstadienos/farmacologia , Asma/fisiopatologia , Álcoois Benzílicos/farmacologia , Broncodilatadores/farmacologia , Criança , Clorobenzenos/farmacologia , Método Duplo-Cego , Combinação de Medicamentos , Teste de Esforço , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Nebulizadores e Vaporizadores , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
4.
J Pharmacol Sci ; 146(4): 233-243, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34116737

RESUMO

Retinopathy of prematurity (ROP) is a proliferative retinal vascular disease, initiated by delayed retinal vascular growth after premature birth. In the majority of cases, ROP resolves spontaneously; however, a history of ROP may increase the risk of long-term visual problems. In this study, we evaluated the endothelial function of retinal blood vessels in adult rats with a history of ROP. ROP was induced in rats by subcutaneous injection of a vascular endothelial growth factor receptor tyrosine kinase inhibitor (KRN633) on postnatal day (P) 7 and P8. On P56, vasodilator responses to acetylcholine, GSK1016790A (an activator of transient receptor potential vanilloid 4 channels), NOR3 (a nitric oxide [NO] donor), and salbutamol (a ß2-adrenoceptor agonist) were assessed. Compared to age-matched controls, retinal vasodilator responses to acetylcholine and GSK1016790A were attenuated in P56 rats with a history of ROP. No attenuation of acetylcholine-induced retinal vasodilator response was observed under inhibition of NO synthase. Retinal vasodilator responses to NOR3 and salbutamol were unaffected. These results suggest that the production of and/or release of NO is impaired in retinal blood vessels in adult rats with a history of ROP. A history of ROP might increase the risk of impaired retinal circulation in adulthood.


Assuntos
Endotélio Vascular/fisiopatologia , Vasos Retinianos/fisiopatologia , Retinopatia da Prematuridade/fisiopatologia , Vasodilatação , Acetilcolina/farmacologia , Albuterol/farmacologia , Animais , Animais Recém-Nascidos , Circulação Sanguínea/efeitos dos fármacos , Feminino , Leucina/análogos & derivados , Leucina/farmacologia , Óxido Nítrico/fisiologia , Doadores de Óxido Nítrico/farmacologia , Gravidez , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Vasodilatação/efeitos dos fármacos
5.
Respir Physiol Neurobiol ; 291: 103695, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34052411

RESUMO

We have compared the prophylactic efficacies of quercetin and salbutamol in preventing pulmonary surfactants oxidation under hypoxia. Male SD rats supplemented orally with quercetin (50 mg/Kg BW) and salbutamol (2 mg/Kg BW) were exposed to hypobaric hypoxia (7,620 m for 6 h). Hypoxia-mediated elevation in oxidative stress, inflammation, and extravasations of LDH & albumin content in BALF of rats were assessed. Western blotting and mRNA studies determined the differential expressions of Nrf-2, HO-1, and associated surfactant proteins (SP-A, SP-B, SP-C, & SP-D) in rat lungs. Later, the lung configuration under hypoxia was assessed histopathologically. Quercetin and salbutamol pretreatment considerably restored the expressions of Nrf-2, HO-1, and surfactant proteins to normal by attenuating the increase in oxidative stress, inflammation, and extravasations of plasma proteins in the animals under hypoxia. The histopathology has also evidenced the protective effect of quercetin in retaining normal lung architecture under hypoxia over salbutamol. The present study indicates the effectiveness of quercetin prophylaxis in preventing pulmonary surfactants oxidation under hypoxia over salbutamol.


Assuntos
Albuterol/farmacologia , Antioxidantes/farmacologia , Broncodilatadores/farmacologia , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Surfactantes Pulmonares/metabolismo , Quercetina/farmacologia , Albuterol/administração & dosagem , Animais , Antioxidantes/administração & dosagem , Broncodilatadores/administração & dosagem , Modelos Animais de Doenças , Masculino , Quercetina/administração & dosagem , Ratos , Ratos Sprague-Dawley
6.
Kidney Int ; 100(2): 321-335, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33940111

RESUMO

The thiazide-sensitive sodium-chloride-cotransporter (NCC) in the kidney distal convoluted tubule (DCT) plays an essential role in sodium and potassium homeostasis. Here, we demonstrate that NCC activity is increased by the ß2-adrenoceptor agonist salbutamol, a drug prevalently used to treat asthma. Relative to ß1-adrenergic receptors, the ß2-adrenergic receptors were greatly enriched in mouse DCT cells. In mice, administration of salbutamol increased NCC phosphorylation (indicating increased activity) within 30 minutes but also caused hypokalemia, which also increases NCC phosphorylation. In ex vivo kidney slices and isolated tubules, salbutamol increased NCC phosphorylation in the pharmacologically relevant range of 0.01-10 µM, an effect observed after 15 minutes and maintained at 60 minutes. Inhibition of the inwardly rectifying potassium channel (Kir) 4.1 or the downstream with-no-lysine kinases (WNKs) and STE20/SPS1-related proline alanine-rich kinase (SPAK) pathway greatly attenuated, but did not prevent, salbutamol-induced NCC phosphorylation. Salbutamol increased cAMP in tubules, kidney slices and mpkDCT cells (model of DCT). Phosphoproteomics indicated that protein phosphatase 1 (PP1) was a key upstream regulator of salbutamol effects. A role for PP1 and the PP1 inhibitor 1 (I1) was confirmed in tubules using inhibitors of PP1 or kidney slices from I1 knockout mice. On normal and high salt diets, salbutamol infusion increased systolic blood pressure, but this increase was normalized by thiazide suggesting a role for NCC. Thus, ß2-adrenergic receptor signaling modulates NCC activity via I1/PP1 and WNK-dependent pathways, and chronic salbutamol administration may be a risk factor for hypertension.


Assuntos
Albuterol , Simportadores de Cloreto de Sódio , Agonistas Adrenérgicos/metabolismo , Albuterol/metabolismo , Albuterol/farmacologia , Animais , Pressão Sanguínea , Túbulos Renais Distais/metabolismo , Camundongos , Fosforilação , Simportadores de Cloreto de Sódio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo
7.
Pulm Pharmacol Ther ; 68: 102037, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33989812

RESUMO

BACKGROUND: Asthma is the most common chronic disorders of the respiratory tract. This study aimed to evaluate the effect of low-molecular-weight heparins (LMWHs) in the treatment of acute asthma. METHODS: In this randomized clinical trial, patients with acute asthma attacks were enrolled. The patients were divided randomly into two groups. Patients in the intervention group received nebulized LMWH (1 mg/kg) with albuterol (2.5 mg) every 20 min for 10 min. The patients in the control group received nebulized albuterol with the same dose. Then peak expiratory flow rates (PEFR) and forced expiratory volume in 1 s (FEV1), and hemodynamic parameters in both groups were assessed for every 20 min. RESULTS: In total 70 patients enrolled in this study. We found that the mean PEFR at 40 min was higher in the LMWH group than the control group (202.51 L/min and 180.2 L/min) (p = 0.001). Moreover, this difference remains significant in the 60th minute (p < 0.001). Further, FEV1 was significantly higher in the LMWH group after 60 min (1.82 L/min vs 1.48 L/min, p < 0.001). Moreover, we found that the hemodynamic parameters were sustainable in the intervention group. CONCLUSION: The study suggests that LMWH in mild-moderate asthma attacks may be beneficial in the short term and could be prescribed in addition to standard albuterol therapy.


Assuntos
Asma , Heparina de Baixo Peso Molecular , Albuterol/farmacologia , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Método Duplo-Cego , Volume Expiratório Forçado , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Nebulizadores e Vaporizadores , Pico do Fluxo Expiratório
8.
Physiol Rep ; 9(1): e14697, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427414

RESUMO

INTRODUCTION: Anticoagulant-related nephropathy (ARN), that was described in humans first as warfarin-related nephropathy, is characterized by acute kidney injury and red blood cell (RBC) tubular casts in the kidney. 5/6 nephrectomy (5/7NE) rats treated with warfarin or dabigatran show changes in kidney function and morphology that are similar to human disease. The role of glomerular filtration rate (GFR) in the pathogenesis of ARN is not clear. The aim of these studies was to elucidate the role of GFR in the pathogenesis of dabigatran-induced ARN in 5/6NE rats. METHODS: 5/6NE rats were treated per os with 150 mg/kg/day dabigatran alone or with drugs that lower (enalapril, 1.5 mg/kg/day) or increase (albuterol, 4.0 mg/kg/day) GFR for 7 days. Changes in coagulation and kidney function were recorded daily. Kidney morphology was evaluated on day 7 after the treatment. RESULTS: Dabigatran resulted in activated partial thromboplastin time increase that was not affected by GFR-modifying drugs. Blood pressure was significantly lower in 5/6NE rats treated with enalapril and dabigatran as compared to dabigatran alone. The GFR was decreased by 35% in enalapril/dabigatran- and increased by 26% in albuterol/dabigatran-treated animals. There were no changes in serum creatinine, hematuria or urinary kidney injury molecule (KIM-1) levels when GFR-modifying drugs were added to dabigatran. All dabigatran-treated animals had RBC casts in the kidney regardless of the GFR modification. CONCLUSIONS: GFR does not play a significant role in the dabigatran-induced acute kidney injury in 5/6 nephrectomy model in rats. Based in these data, modification of GFR in patients with ARN is not warranted.


Assuntos
Injúria Renal Aguda/fisiopatologia , Albuterol/farmacologia , Enalapril/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Animais , Anti-Hipertensivos/farmacologia , Antitrombinas/efeitos adversos , Broncodilatadores/farmacologia , Dabigatrana/efeitos adversos , Dabigatrana/farmacologia , Modelos Animais de Doenças , Taxa de Filtração Glomerular/efeitos dos fármacos , Masculino , Nefrectomia/efeitos adversos , Nefrectomia/métodos , Ratos , Ratos Sprague-Dawley
10.
Minerva Pediatr (Torino) ; 73(3): 215-221, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32960007

RESUMO

BACKGROUND: The aim of this study was to investigate and discuss the salbutamol combined with budesonide in treatment of pediatric bronchial asthma (BA) and its effect on eosinophils (EOS). METHODS: Ninety-eight BA children admitted and treated in our hospital from July 2016 to June 2017 were collected and divided into control group (N.=49) and observation group (N.=49) according to random number table. The children in control group were treated with budesonide and those in observation group were treated with salbutamol combined with budesonide. The clinical efficacy, pulmonary functions and levels of T-lymphocyte subsets (including cluster of differentiation 3 (CD3)+, CD4+, CD8+ and CD4+/CD8+) in the immune system between two groups were compared after the treatment; the levels of eosinophil cationic protein (ECP) and eotaxin in the children were compared before the treatment and at 1, 4 and 8 weeks after the treatment; the changes in EOS counts in blood and induced sputum of the children before and after the treatment were compared, and the EOS apoptosis rate was compared at 1, 4 and 8 weeks after the treatment. RESULTS: The effective rate of treatment in observation group was significantly higher than that in control group (P<0.05). After the treatment, the indexes of pulmonary function in observation group were obviously better than those in control group (P<0.05). Compared with those in control group, the levels of CD3+, CD4+ and CD4+/CD8+ of the children in observation group were elevated remarkably, while the CD8+ level was lowered (P<0.05). The levels of ECP and eotaxin in the two groups were decreased after the treatment compared with those before the treatment, and the levels in observation group were superior to those in control group (P<0.05). After the treatment, the EOS counts of both groups of children were lower than those before the treatment, and the decrease in observation group was more notable than that in control group. At 1, 4 and 8 weeks after the treatment, the EOS apoptosis rate in observation group was obviously higher than that in control group (P<0.05). CONCLUSIONS: The treatment of salbutamol combined with budesonide for pediatric BA has significant therapeutic effects; it can restore the pulmonary functions rapidly and improve the immunity of the lung, reduce the levels of eotaxin, ECP and EOS of the child patients and promote EOS apoptosis.


Assuntos
Albuterol/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Eosinófilos/efeitos dos fármacos , Albuterol/farmacologia , Asma/sangue , Broncodilatadores/farmacologia , Budesonida/farmacologia , Estudos de Casos e Controles , Contagem de Células , Quimiocina CCL11/análise , Criança , Pré-Escolar , Quimioterapia Combinada/métodos , Proteína Catiônica de Eosinófilo/análise , Eosinófilos/citologia , Feminino , Humanos , Lactente , Recém-Nascido , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiologia , Contagem de Linfócitos , Subpopulações de Linfócitos/citologia , Masculino , Escarro , Fatores de Tempo
11.
J Aerosol Med Pulm Drug Deliv ; 34(4): 217-222, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33030386

RESUMO

Background: Currently, there are no regulatory guidelines indicating spacer devices/valved holding chamber (VHC) should be used routinely during pulmonary function tests, and few studies evaluated if spacer devices reduce beta-agonist bronchodilators' side effects. Methods: A prospective study compared salbutamol's cardiovascular effects and bronchodilation response during spirometry tests with and without a spacer device/VHC. Heart rate (HR), the corrected QT interval (QTc), and systolic and diastolic blood pressure were measured 10 minutes after the first spirometry test, before the drug administration, and 20 minutes after inhalation in both groups. Spirometric parameters (forced expiratory volume in the first second [FEV1], forced vital capacity [FVC], and FEV1/FVC) were also measured for both groups. Results: HR and QTc increase were significantly higher in the pressurized meter dose inhalers alone group versus the VHC group [mean SD] [73.1 ± 10 bpm to 74.3 + 10 bpm, p = 0.021] and [median (25%-75% interquartile range)] [389 ms (381-404) to 398 ms (387-407), p = 0.045] vs. [mean SD] [75.4 ± 9 to 73.8 + 8 bpm, p = 0.4] and [median (25%-75% interquartile range)] [388 ms (347-408) to 385 ms (366-408), p = 0.35], respectively. FEV1 variation before and after salbutamol were similar between both groups. Discussion: Although VHC significantly reduces HR and QTc variation when using beta-agonist bronchodilators in healthy patients, no clinical repercussions of this variation were found in this study, since no event of tachycardia or pathological QTc was recorded. Conclusion: VHC has a diminished clinical impact for healthy patients when considering cardiovascular effects and spirometric parameters. Beta-agonist bronchodilators may be administrated despite the use of spacer devices in patients without known cardiovascular diseases. Its significance for other populations still needs to be determined.


Assuntos
Albuterol , Preparações Farmacêuticas , Administração por Inalação , Albuterol/farmacologia , Broncodilatadores/efeitos adversos , Volume Expiratório Forçado , Humanos , Espaçadores de Inalação , Estudos Prospectivos
12.
Respirology ; 26(3): 225-232, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33043552

RESUMO

BACKGROUND AND OBJECTIVE: Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 µg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION: ACTRN12618000306213 at https://www.anzctr.org.au.


Assuntos
Albuterol , Asma , Administração por Inalação , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Albuterol/farmacologia , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Bisoprolol/farmacologia , Bisoprolol/uso terapêutico , Broncodilatadores/farmacologia , Broncodilatadores/uso terapêutico , Estudos Cross-Over , Método Duplo-Cego , Volume Expiratório Forçado/efeitos dos fármacos , Humanos
13.
J Asthma ; 58(5): 573-585, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-31958254

RESUMO

Objective. Asthma is a chronic inflammatory airway disorder known to induce small airways dysfunction (SAD). It is important to develop tools to assess the presence and extent of SAD in daily clinical practice. An Impulse Oscillometry System (IOS) might detect SAD, but the validity of the underlying model (serial Resistive airway and Compliant tissue model: RC model) in diseased lungs remains questionable.Methods. Our objective was to evaluate the usefulness of parameters obtained from six electrical circuit models that were fitted to the measurements of impedance obtained with IOS in asthmatic children characterized by an abnormal lung function defined by an increased baseline interrupter resistance (Rint, z-score > +1.645).Results. The six models were tested in 102 asthmatic children (median age: 5.5 years). Two models allowed the description of 92/102 (90%) children: 74 by the extended RIC model (central and peripheral Resistance, Inertance and peripheral airway Compliance) and 18 by the Mead1969 model (extended RIC plus lung compliance). Thus, peripheral airway compliance and resistance were essential to describe lung function abnormalities of these asthmatic children. Parenchyma impairment (increased lung compliance) which was responsive to salbutamol was present in 18% of asthmatic children. After salbutamol, peripheral airway resistance decreased while peripheral airway compliance increased, arguing for asthma-related SAD. R5-20Hz independently correlated with the two latter parameters but was increased in two thirds of children with increased Rint only.Conclusion. Additional modeling of IOS results can be a reliable tool to assess the presence and extent of SAD in young asthmatic children.


Assuntos
Asma/fisiopatologia , Pulmão/fisiopatologia , Modelos Biológicos , Resistência das Vias Respiratórias , Albuterol/farmacologia , Broncodilatadores/farmacologia , Criança , Pré-Escolar , Feminino , Humanos , Complacência Pulmonar , Masculino , Oscilometria , Fenótipo
14.
J Clin Pharmacol ; 61(5): 649-655, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33128239

RESUMO

Treatment with ß2-agonists may cause elevated lactic acid, the end product of anaerobic metabolism of glucose. It has been proposed that lactic acidosis associated with ß2-agonists is caused by changes to direct biochemical impacts on glycolysis, gluconeogenesis, pyruvate metabolism, and free fatty acid production. However, much remains unknown, and there is a paucity of evidence regarding the underlying chemical changes associated with this lactic acidosis. The goal of our study was to investigate the impact of 1 hour of continuous albuterol on the untargeted serum metabolome of healthy subjects. Twenty-four healthy participants received 7.5 mg of continuous albuterol for 1 hour. Baseline, 1-hour, and 2-hour lactic acid levels were drawn. Samples obtained at baseline and 1 hour were sent for untargeted metabolomic profiling. Participants had a baseline lactic acid of 1.45 ± 0.46 mmol/L. On average, lactate levels increased 0.33 ± 0.67 mmol/L after 1 hour (P = .02) and remained elevated at 2 hours (0.32 ± 0.72 mmol/L, P = .02), although there was overlap in lactate levels across times. For metabolomic analysis, fatty acids, organic acids, and sugars were elevated, and amino acids were reduced. Lactic acid and pyruvic acid metabolites, however, did not significantly change (after false discovery rate adjustment). In healthy participants, continuous albuterol alters the serum metabolome, but this change may not be clinically significant. The data support recent hypotheses that ß2-receptor activation stimulates lactic acid production, altering aerobic glycolysis, gluconeogenesis, and free fatty acid production.


Assuntos
Albuterol/farmacologia , Broncodilatadores/farmacologia , Ácido Láctico/sangue , Metaboloma/efeitos dos fármacos , Administração por Inalação , Adulto , Albuterol/administração & dosagem , Aminoácidos/sangue , Broncodilatadores/administração & dosagem , Ácidos Graxos/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Açúcares/sangue , Adulto Jovem
15.
Cytokine ; 137: 155341, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33128919

RESUMO

The adipokine, leptin exerts inhibitory effect on both spontaneous and oxytocin-induced contractions in myometrium. However, the mechanisms involved in leptin-induced effect are not clear. In the present study, we studied the altered characteristics of uterine contractions in the presence of leptin and the possible mechanisms of its effect in late pregnant (18.5 day) mouse uterus. We conducted functional, biochemical and molecular biology studies to demonstrate the mechanism of leptin-induced response. Leptin exerted an inhibitory response (Emax 40.5 ± 3.99%) on basal uterine contractions. The extent of inhibition was less than that obtained with known uterine relaxants, salbutamol (Emax103 ± 8.66%) and BRL-37344 (Emax 84.79 ± 8.12%). Leptin-induced uterine response was inhibited by leptin receptor antagonist SHLA and JAK-STAT pathway inhibitor, AG-490. The relaxant response was also subdued by NO-cGMP-PK-G pathway blockers L-NAME, 1400W, ODQ and KT-5823. Further, leptin enhanced the levels of NO and cGMP in uterine tissues. Also, SHLA, AG-490 and a combination of 1400 W and L-NAME prevented leptin-induced increase in NO. Similar effect was observed on cGMP levels in presence of leptin and SHLA. However, leptin did not influence CaCl2-induced response in potassium-depolarized tissues. We also detected leptin receptor protein in late pregnant mouse uterus located in endometrial luminal epithelium and myometrial layers. Real-time PCR studies revealed significantly higher expression of short forms of the receptor (ObRa and ObRc) in comparison to the long form (ObRb). In conclusion, the results of the present study suggest that leptin inhibits mouse uterine contraction by stimulating short forms of the leptin receptors and activating NO pathway in a JAK-STAT-dependent manner.


Assuntos
GMP Cíclico/metabolismo , Leptina/farmacologia , Óxido Nítrico/metabolismo , Receptores para Leptina/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Albuterol/farmacologia , Animais , Relação Dose-Resposta a Droga , Etanolaminas/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Gravidez , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores para Leptina/agonistas , Receptores para Leptina/genética , Útero/metabolismo , Útero/fisiologia
16.
Respir Physiol Neurobiol ; 285: 103597, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33301965

RESUMO

Forced mid-expiratory flow (i.e., isoFEF25-75) may increase with a short-acting ß2-agonist in nonasthmatic children without bronchodilator responsiveness. This could also increase estimated ventilatory capacity along mid-expiration (V̇Ecap25-75), especially in vulnerable children with obesity who exhibit altered breathing mechanics. We estimated V̇Ecap25-75 pre- and post-albuterol treatment in 8-12yo children without (n = 28) and with (n = 46) obesity. A two-way ANOVA was performed to determine effects of an inhaled bronchodilator (pre-post) and obesity (group) on isoFEF25-75 and V̇Ecap25-75. There was no group by bronchodilator interaction or main group effect on outcome variables. However, a significant main effect of the bronchodilator was detected in spirometry parameters, including a substantial increase in isoFEF25-75 (17.1 ±â€¯18.0 %) and only a slight (non-clinical) but significant increase in FEV1 (2.4 ±â€¯4.3 %). V̇Ecap25-75 significantly increased with albuterol (+11.7 ±â€¯10.6 L/min; +15.8 ±â€¯13.9 %). These findings imply potentially important increases in ventilatory reserve with a bronchodilator in nonasthmatic children without and with obesity, which could potentially influence respiratory function at rest and during exercise.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/farmacologia , Broncodilatadores/farmacologia , Obesidade Pediátrica , Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Criança , Feminino , Humanos , Masculino , Espirometria
17.
Exp Dermatol ; 29(12): 1216-1224, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33015872

RESUMO

While human eccrine sweat glands respond to adrenergic agonists, there remains a paucity of information on the factors modulating this response. Thus, we assessed the relative contribution of α- and ß-adrenergic sweating during a heat exposure and as a function of individual factors of sex and training status. α- and ß-adrenergic sweating was assessed in forty-eight healthy young men (n = 35) and women (n = 13) including endurance-trained (n = 12) and untrained men (n = 12) under non-heat exposure (temperate, 25°C; n = 17) and heat exposure (hot, 35°C; n = 48) conditions using transdermal iontophoresis of phenylephrine (α-adrenergic agonist) and salbutamol (ß-adrenergic agonist) on the ventral forearm, respectively. Adrenergic sweating was also measured after iontophoretic administration of atropine (muscarinic receptor antagonist) or saline (control) to evaluate how changes in muscarinic receptor activity modulate the adrenergic response to a heat exposure (n = 12). α- and ß-adrenergic sweating was augmented in hot compared with temperate conditions (both P ≤ .014), albeit the relative increase was greater in ß (~5.4-fold)- as compared to α (~1.5-fold)-adrenergic-mediated sweating response. However, both α- and ß-adrenergic sweating was abolished by atropinization (P = .001). Endurance-trained men showed an augmentation in α- (P = .043) but not ß (P = .960)-adrenergic sweating as compared to untrained men. Finally, a greater α- and ß-adrenergic sweating response (both P ≤ .001) was measured in habitually active men than in women. We show that heat exposure augments α-and ß-adrenergic sweating differently via mechanisms associated with altered muscarinic receptor activity. Sex and training status modulate this response.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Albuterol/farmacologia , Fenilefrina/farmacologia , Condicionamento Físico Humano/fisiologia , Sudorese/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Albuterol/administração & dosagem , Atropina/farmacologia , Feminino , Antebraço , Temperatura Alta , Humanos , Iontoforese , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Fenilefrina/administração & dosagem , Pilocarpina/farmacologia , Fatores Sexuais , Sudorese/fisiologia , Adulto Jovem
18.
Pulm Pharmacol Ther ; 63: 101943, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32889156

RESUMO

PURPOSE: The development of inhaled drug products is expensive and involves time-consuming pharmacokinetic (PK) and pharmacodynamic (PD) studies. There are few in vitro cell-based assays to evaluate the disposition and action of orally inhaled drugs to guide early product development and minimise risk. The aim of the present study was to develop a co-culture bioassay, combining an airway epithelial cell line (Calu-3) with cultured human primary airway smooth muscle cells (ASM), integrated with apparatus to deliver pharmaceutical aerosols. METHODS: An assay for measuring cyclic adenosine monophosphate (cAMP) in ASM derived from healthy donors was adapted to provide a biochemical surrogate for ASM relaxation. Concentration-response curves for cAMP were established for three drugs that elicit ASM relaxation: isoprenaline (ISO), forskolin (FOR) and salbutamol sulphate. The ASM bioassay was incorporated into a co-culture model in which air-interfaced Calu-3 cell layers, representing the permeability barrier of the airway epithelium, were grown on transwell inserts above ASM cells cultured in the well of the base-plate. The sensitivity of this bioassay to salbutamol delivered using different formulations and aerosol products was evaluated. RESULTS: ASM responded with concentration dependent increases in cAMP when exposed to 10-9 to 10-5 M ISO, FOR or salbutamol sulphate solutions for 15 or 30 min. Salbutamol formulated with different counter ions elicited differential cAMP responses in ASM (xinafoate > base = sulphate) suggesting that this bioassay could discriminate between formulations with different potency. A similar rank order of potency was observed for the different salbutamol salts when applied as aerosols to the co-culture model. DISCUSSION: We have developed a novel bioassay using human ASM in co-culture with human respiratory epithelial cells to better mimic various elements that contribute to the rate and extent of local drug availability in the lungs following topical administration. The bioassay offers an opportunity to investigate the factors determining the activity of inhaled bronchodilator drugs in a more biologically relevant system than that has previously been described and with further development and validation, this novel bioassay could provide a method to guide the more efficient development of inhaled bronchodilators, reducing the current reliance on in vivo studies.


Assuntos
Músculo Liso , Albuterol/farmacologia , Bioensaio , Broncodilatadores/farmacologia , Humanos , Relaxamento Muscular/efeitos dos fármacos
19.
ACS Chem Neurosci ; 11(14): 2104-2116, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32520518

RESUMO

Potential drug treatments for Alzheimer's disease (AD) may be found by identifying compounds that block the assembly of the microtubule-associated protein tau into neurofibrillar tangles associated with neuron destabilization and cell death. Here, a small library of structurally diverse compounds was screened in vitro for the ability to inhibit tau aggregation, using high-throughput synchrotron radiation circular dichroism as a novel tool to monitor the structural changes in the protein as it assembles into filaments. The catecholamine epinephrine was found to be the most effective tau aggregation inhibitor of all 88 screened compounds. Subsequently, we tested chemically similar phenolamine drugs from the ß-adrenergic receptor agonist class, using conventional circular dichroism spectroscopy, thioflavin T fluorescence, and transmission electron microscopy. Two compounds, salbutamol and dobutamine, used widely in the treatment of respiratory and cardiovascular disease, impede the aggregation of tau in vitro. Dobutamine reduces both the rate and yield of tau filament formation over 24 h; however, it has little effect on the structural transition of tau into ß-sheet structures over 24 h. Salbutamol also reduces the yield and rate of filament formation and additionally inhibits tau's structural change into ß-sheet-rich aggregates. Salbutamol has a good safety profile and a half-life that facilitates permeation through the blood-brain barrier and could represent an expediated approach to developing AD therapeutics. These results provide the motivation for the in vivo evaluation of pre-existing ß-adrenergic receptor agonists as a potential therapy for AD through the reduction of tau deposition.


Assuntos
Albuterol , Doença de Alzheimer , Agonistas Adrenérgicos beta , Albuterol/farmacologia , Dicroísmo Circular , Humanos , Receptores Adrenérgicos , Proteínas tau
20.
Naunyn Schmiedebergs Arch Pharmacol ; 393(11): 2043-2052, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32500188

RESUMO

Circulating catecholamines contribute to the regulation of retinal vascular tone. Our previous studies have demonstrated that the activation of large-conductance Ca2+-activated K+ (BKCa) channels is involved in the ß2-adrenoceptor-mediated dilation of retinal arterioles in rats. The present study aimed to examine the role of Gi protein in the ß2-adrenoceptor-mediated activation of BKCa channels in the retinal arterioles. Images of in vivo rat ocular fundi were captured, and the diameters of retinal arterioles were measured. Systemic blood pressure and heart rate were recorded continuously. Intravenous infusion of formoterol (0.01-0.3 µg/kg/min), a ß2-adrenoceptor agonist, increased the diameter of retinal arterioles but decreased mean arterial pressure in a dose-dependent manner. Intravitreal injection of iberiotoxin (20 pmol/eye), an inhibitor of BKCa channels, significantly attenuated the formoterol-induced dilation of retinal arterioles. Similar results were obtained when salbutamol (0.03-3 µg/kg/min), another ß2-adrenoceptor agonist, was used instead of formoterol. However, iberiotoxin had no significant effect on retinal vasodilator responses to intravenous infusion of denopamine (1-30 µg/kg/min; a ß1-adrenoceptor agonist), CL316243 (0.3-10 µg/kg/min; a ß3-adrenoceptor agonist), prostaglandin I2 (0.03-10 µg/kg/min; a prostanoid IP receptor agonist), and forskolin (1-10 µg/kg/min; an adenylyl cyclase activator). Intravitreal injection of pertussis toxin (66 ng/eye; a Gi protein inhibitor) significantly attenuated the dilation of retinal arterioles induced by formoterol but not by denopamine and CL316243. In the presence of pertussis toxin, iberiotoxin had no inhibitory effect on formoterol-induced dilation of retinal arterioles. These results suggest that stimulation of ß2-adrenoceptors dilates retinal arterioles through pertussis toxin-sensitive Gi protein-dependent activation of BKCa channels in rats in vivo.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Arteríolas/efeitos dos fármacos , Fumarato de Formoterol/farmacologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Vasos Retinianos/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Albuterol/farmacologia , Animais , Arteríolas/metabolismo , Sinalização do Cálcio , Masculino , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismo , Vasos Retinianos/metabolismo
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