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1.
Viruses ; 13(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34372616

RESUMO

Treatment options for COVID-19, a disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, are currently severely limited. Therefore, antiviral drugs that efficiently reduce SARS-CoV-2 replication or alleviate COVID-19 symptoms are urgently needed. Inhaled glucocorticoids are currently being discussed in the context of treatment for COVID-19, partly based on a previous study that reported reduced recovery times in cases of mild COVID-19 after inhalative administration of the glucocorticoid budesonide. Given various reports that describe the potential antiviral activity of glucocorticoids against respiratory viruses, we aimed to analyze a potential antiviral activity of budesonide against SARS-CoV-2 and circulating variants of concern (VOC) B.1.1.7 (alpha) and B.1.351 (beta). We demonstrate a dose-dependent inhibition of SARS-CoV-2 that was comparable between all viral variants tested while cell viability remains unaffected. Our results are encouraging as they could indicate a multimodal mode of action of budesonide against SARS-CoV-2 and COVID-19, which could contribute to an improved clinical performance.


Assuntos
Antivirais/farmacologia , Budesonida/farmacologia , COVID-19/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Corticosteroides/farmacologia , Animais , Antivirais/administração & dosagem , Budesonida/administração & dosagem , COVID-19/virologia , Chlorocebus aethiops , Glucocorticoides/farmacologia , Humanos , Células Vero , Replicação Viral/efeitos dos fármacos
2.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34240225

RESUMO

Tracheal stenosis following injury cannot be effectively treated. The current study compared the protective effects of different anti­inflammatory drugs on tracheal stenosis and investigated their possible mechanisms. Rabbit tracheal stenosis models following injury were constructed and confirmed using hematoxylin and eosin (H&E) staining. A total of 30 rabbits were divided into the control (CON), penicillin (PEN), erythromycin (ERY), budesonide (BUD) and PEN + ERY + BUD groups (n=6). Stenotic tracheal tissue, serum and bronchoalveolar lavage fluid (BALF) were collected 10 days after continuous treatment. Pathological changes in the tracheas were observed by H&E staining. Histone deacetylase 2 (HDAC2) expression in tracheal tissues was detected by immunofluorescence. Immunohistochemistry was performed to detect collagen I (Col­I) and collagen III (Col­III) levels in tracheal tissues. Transforming growth factor ß1 (TGF­ß1), vascular endothelial growth factor (VEGF) and interleukin 8 (IL­8) levels in serum and BALF samples were determined using ELISA kits. Western blotting detected HDAC2, IL­8, TGF­ß1 and VEGF levels in tracheal tissues. H&E staining demonstrated that tracheal epithelial hyperplasia and fibroblast proliferation in the ERY and PEN + ERY + BUD groups markedly improved compared with the CON group. Furthermore, in tracheal tissues, HDAC2 expression was significantly increased and IL­8, TGF­ß1, VEGF, Col­I and Col­III levels were significantly decreased in the ERY and PEN + ERY + BUD groups compared with the CON group. Additionally, the results for the PEN + ERY + BUD were more significant compared with the ERY group. In serum and BALF samples, IL­8, TGF­ß1 and VEGF levels in the ERY and PEN + ERY + BUD groups were significantly lower compared with the CON group, with the results of the PEN + ERY + BUD group being more significant compared with the ERY group. There were no significant differences between the PEN, BUD and CON groups. ERY inhibited tracheal granulation tissue proliferation and improved tracheal stenosis following injury and synergistic effects with PEN and BUD further enhanced these protective effects. The mechanism may involve HDAC2 upregulation and inhibition of local airway and systemic inflammatory responses.


Assuntos
Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Eritromicina/uso terapêutico , Penicilinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Estenose Traqueal/metabolismo , Estenose Traqueal/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/química , Budesonida/farmacologia , Colágeno/metabolismo , Modelos Animais de Doenças , Eritromicina/farmacologia , Tecido de Granulação/efeitos dos fármacos , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Penicilinas/farmacologia , Substâncias Protetoras/farmacologia , Coelhos , Traqueia/lesões , Traqueia/patologia , Estenose Traqueal/etiologia , Estenose Traqueal/patologia , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34062995

RESUMO

A single ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that causes inflammation of the colonic mucosa at the distal colon and rectum. The mainstay therapy involves anti-inflammatory immunosuppression based on the disease location and severity. The disadvantages of using systemic corticosteroids for UC treatment is the amplified risk of malignancies and infections. Therefore, topical treatments are safer as they have fewer systemic side effects due to less systemic exposure. In this context, pH sensitive and enzymatically triggered hydrogel of pectin (PC) and polyacrylamide (PAM) has been developed to facilitate colon-targeted delivery of budesonide (BUD) for the treatment of UC. The hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), swelling ratio, and drug release. FT-IR spectroscopy confirmed the grafting as well loading of BUD in hydrogel. XRD showed the amorphous nature of hydrogel and increment in crystallinity after drug loading. On the other hand, SEM showed that the hydrogels exhibited a highly porous morphology, which is suitable for drug loading and also demonstrated a pH-responsive swelling behaviour, with decreased swelling in acidic media. The in-vitro release of BUD from the hydrogel exhibited a sustained release behaviour with non-ficken diffusion mechanism. The model that fitted best for BUD released was the Higuchi kinetic model. It was concluded that enzyme/pH dual-sensitive hydrogels are an effective colon-targeted delivery system for UC.


Assuntos
Resinas Acrílicas/química , Budesonida/farmacologia , Liberação Controlada de Fármacos , Hidrogéis/química , Pectinas/química , Varredura Diferencial de Calorimetria , Preparações de Ação Retardada , Hidrogéis/síntese química , Concentração de Íons de Hidrogênio , Cinética , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
4.
Artigo em Inglês | MEDLINE | ID: mdl-33692621

RESUMO

Purpose: Among patients with chronic obstructive pulmonary disease (COPD), adherence to inhaled medication leads to fewer exacerbations and improved health status. The goal of the present study was to evaluate the effects of medication reminders via the BreatheMate device on adherence in patients with COPD. Patients and Methods: A 6-month, phase 4, randomized, multicenter, open-label US study (NCT02864342) enrolled 138 patients aged ≥40 years with moderate to very severe COPD and ≥10 pack-year smoking history. Patients in the intervention (n = 68) and control (n = 70) groups received the BreatheMate device, smartphone application, and vouchers to redeem pressurized metered-dose inhalers (pMDIs) for the prescribed 2 puffs of budesonide/formoterol 160/4.5 µg twice daily. The intervention group also received twice-daily electronic reminders to take budesonide/formoterol. The primary endpoint was the mean number of sets of adherent puffs/day (4 puffs: 2 puffs within 60 minutes, twice daily) over 6 months. Secondary endpoints included adherence by three 60-day intervals, usage days, prescription refills, and Clinical COPD Questionnaire (CCQ) score. Study enrollment terminated early due to issues with inconsistent syncing. Results: A higher mean proportion of adherent days (77.6% vs 60.2%; P <0.001) and sets of adherent puffs/day (1.61 vs 1.33; P <0.001) were recorded for the intervention group versus the control group. Intervention group adherence was higher than that of the control group for each 60-day interval (P <0.001); the intervention group was 3.07 (95% confidence interval: 1.49-6.52) times more likely than the control group to be adherent for ≥80% of study days. Overuse (>2 sets of 2 puffs/day), underuse (<2 sets of 2 puffs/day), and no use days were lower in the intervention group versus control (P <0.05). Patients aged ≥65 years had higher adherence (P <0.001). Conclusion: Medication reminders through the BreatheMate device and application produced greater adherence to inhaled therapy in patients with COPD.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/uso terapêutico , Budesonida/farmacologia , Método Duplo-Cego , Combinação de Medicamentos , Etanolaminas/uso terapêutico , Feminino , Volume Expiratório Forçado , Fumarato de Formoterol/uso terapêutico , Humanos , Masculino , Inaladores Dosimetrados , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
5.
Carbohydr Polym ; 258: 117600, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33593531

RESUMO

Rheumatoid arthritis (RA) is a chronic autoimmune disorder and serious cause of disability. Despite considerable advances in RA management, challenges like extensive drug metabolism and rapid clearance causes poor bioavailability. Core-shell nanocarriers for co-delivery of glycyrrhizic acid (GA) and budesonide against RA were developed. GA-loaded gelatin nanoparticles (NPs) were synthesized and coated with budesonide encapsulated aminocellulose-grafted polycaprolactone (PCL-AC). GA- and budesonide-loaded PCL-AC-gel NPs had diameter of 200-225 nm. Dual drug-loaded (DDL) NPs reduced joint swelling and erythema in rats while markedly ameliorating bone erosion evidenced by radiological analysis, suppressed collagen destruction, restored synovial tissue, bone and cartilage histoarchitecture with reduced inflammatory cells infiltration. NPs also reduced various inflammatory biomarkers such as TNF-α, IL-1ß, COX-2, iNOS. Results of this study suggest that dual NPs exerted superior therapeutic effects in RA compared to free drugs which may be attributed to slow and sustained drug release and NPs' ability to inhibit inflammatory mediators.


Assuntos
Artrite Reumatoide/metabolismo , Artrite Reumatoide/terapia , Celulose/química , Gelatina/química , Nanopartículas/química , Poliésteres/química , Animais , Biomarcadores/metabolismo , Osso e Ossos/efeitos dos fármacos , Budesonida/farmacologia , Cartilagem/efeitos dos fármacos , Colágeno/química , Ciclo-Oxigenase 2/biossíntese , Sistemas de Liberação de Medicamentos , Feminino , Fibroblastos/metabolismo , Ácido Glicirrízico/farmacologia , Humanos , Inflamação , Interleucina-1beta/biossíntese , Cinética , Espectroscopia de Ressonância Magnética , Óxido Nítrico Sintase Tipo II/biossíntese , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossíntese
6.
Mol Pharmacol ; 99(3): 197-216, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33376135

RESUMO

In 2019, the Global Initiative for Asthma treatment guidelines were updated to recommend that inhaled corticosteroid (ICS)/long-acting ß 2-adrenoceptor agonist (LABA) combination therapy should be a first-in-line treatment option for asthma. Although clinically superior to ICS, mechanisms underlying the efficacy of this combination therapy remain unclear. We hypothesized the existence of transcriptomic interactions, an effect that was tested in BEAS-2B and primary human bronchial epithelial cells (pHBECs) using formoterol and budesonide as representative LABA and ICS, respectively. In BEAS-2B cells, formoterol produced 267 (212 induced; 55 repressed) gene expression changes (≥2/≤0.5-fold) that were dominated by rapidly (1 to 2 hours) upregulated transcripts. Conversely, budesonide induced 370 and repressed 413 mRNAs, which occurred predominantly at 6-18 hours and was preceded by transcripts enriched in transcriptional regulators. Significantly, genes regulated by both formoterol and budesonide were over-represented in the genome; moreover, budesonide plus formoterol induced and repressed 609 and 577 mRNAs, respectively, of which ∼one-third failed the cutoff criterion for either treatment alone. Although induction of many mRNAs by budesonide plus formoterol was supra-additive, the dominant (and potentially beneficial) effect of budesonide on formoterol-induced transcripts, including those encoding many proinflammatory proteins, was repression. Gene ontology analysis of the budesonide-modulated transcriptome returned enriched terms for transcription, apoptosis, proliferation, differentiation, development, and migration. This "functional" ICS signature was augmented in the presence of formoterol. Thus, LABAs modulate glucocorticoid action, and comparable transcriptome-wide interactions in pHBECs imply that such effects may be extrapolated to individuals with asthma taking combination therapy. Although repression of formoterol-induced proinflammatory mRNAs should be beneficial, the pathophysiological consequences of other interactions require investigation. SIGNIFICANCE STATEMENT: In human bronchial epithelial cells, formoterol, a long-acting ß 2-adrenoceptor agonist (LABA), enhanced the expression of inflammatory genes, and many of these changes were reduced by the glucocorticoid budesonide. Conversely, the ability of formoterol to enhance both gene induction and repression by budesonide provides mechanistic insight as to how adding a LABA to an inhaled corticosteroid may improve clinical outcomes in asthma.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Brônquios/citologia , Budesonida/farmacologia , Fumarato de Formoterol/farmacologia , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes/efeitos dos fármacos , Glucocorticoides/farmacologia , Administração por Inalação , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Linhagem Celular , Sinergismo Farmacológico , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos
7.
United European Gastroenterol J ; 8(10): 1186-1195, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33028169

RESUMO

BACKGROUND: In patients with mesalazine-refractory ulcerative colitis, systemic corticosteroids are the treatment of choice. OBJECTIVE: To evaluate the efficacy and safety of prolonged release budesonide granules for the induction of remission in patients with mesalazine-refractory ulcerative colitis. METHODS: Patients with mesalazine-refractory ulcerative colitis discontinued mesalazine at baseline and received 9 mg prolonged release budesonide granules daily for 8 weeks in this open-label, phase IIa study, followed by a 2-week follow-up phase wherein patients continued treatment on alternate days (EudraCT number 2014-005635-14; ClinicalTrials.gov identifier NCT02550418). The primary endpoint was clinical remission (Clinical Activity Index ≤4; stool frequency <18 per week; absence of rectal bleeding) at Week 8. Secondary endpoints included clinical, endoscopic and histological measures of disease at Week 8. A post hoc analysis assessed histo-endoscopic mucosal healing. Treatment-emergent adverse events and morning cortisol levels were assessed throughout the treatment and follow-up phases. RESULTS: A total of 61 patients were included in the intention-to-treat population; 50 were included in the follow-up analysis set. Clinical remission was achieved in 29 patients (47.5%; 95% confidence interval: 34.6-60.7%) by Week 8. Mean stool and bloody stool frequency decreased significantly from 32.5 to 22.9 per week (p<0.0001) and from 17.6 to 8.1 per week (p<0.0001), respectively. Rates of mucosal healing, endoscopic remission and histological remission were 58.0%, 54.0% and 36.0%, respectively. Histo-endoscopic mucosal healing was achieved by 34.0% of patients. Twenty-four patients (39.3%) experienced treatment-emergent adverse events, of which gastrointestinal disorders (16.4%) were the most common. Mean morning cortisol levels were not significantly suppressed by Week 8. CONCLUSIONS: Treatment with prolonged release budesonide granules for 8 weeks was associated with clinical, endoscopic and histological remission and demonstrated a favourable safety profile in patients with mesalazine-refractory ulcerative colitis. These results warrant further investigation into the potential of prolonged release budesonide granules as an alternative treatment for this patient population.


Assuntos
Anti-Inflamatórios/administração & dosagem , Budesonida/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Mesalamina/farmacologia , Administração Oral , Adolescente , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios não Esteroides , Budesonida/efeitos adversos , Budesonida/farmacologia , Budesonida/uso terapêutico , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colo/diagnóstico por imagem , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Colonoscopia , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/efeitos adversos , Esquema de Medicação , Resistência a Medicamentos , Feminino , Humanos , Mucosa Intestinal/diagnóstico por imagem , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Indução de Remissão/métodos , Resultado do Tratamento , Adulto Jovem
8.
Am J Physiol Lung Cell Mol Physiol ; 319(6): L949-L956, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32903026

RESUMO

Recent clinical trials have shown improvements in neonatal outcomes after intratracheal administration of a combination of budesonide/surfactant (ITBS) in infants at risk of bronchopulmonary dysplasia. However, the effect of ITBS on lung function and alveolar structure is not known. We aimed to determine the effect of ITBS on lung function, parenchymal structure, and inflammatory cytokine expression in a relevant preterm animal model for bronchopulmonary dysplasia. Premature neonatal rabbits were administered a single dose of ITBS on the day of delivery and exposed to 95% oxygen. Following 7 days of hyperoxia, in vivo forced oscillation and pressure-volume maneuvers were performed to examine pulmonary function. Histological and molecular analysis was performed to assess alveolar and extracellular matrix (ECM) morphology, along with gene expression of connective tissue growth factor (CTGF), IL-8, and CCL-2. ITBS attenuated the functional effect of hyperoxia-induced lung injury and limited the change to respiratory system impedance, measured using the forced oscillation technique. Treatment effects were most obvious in the small airways, with significant effects on small airway resistance and small airway reactance. In addition, ITBS mitigated the decrease in inspiratory capacity and static compliance. ITBS restricted alveolar septal thickening without altering the mean linear intercept and mitigated hyperoxia-induced remodeling of the ECM. These structural changes were associated with improved inspiratory capacity and lung compliance. Gene expression of CTGF, IL-8, and CCL-2 was significantly downregulated in the lung. Treatment with ITBS shortly after delivery attenuated the functional and structural consequences of hyperoxia-induced lung injury to day 7 of life in the preterm rabbit.


Assuntos
Budesonida/farmacologia , Hiperóxia/metabolismo , Lesão Pulmonar/tratamento farmacológico , Tensoativos/farmacologia , Animais , Modelos Animais de Doenças , Humanos , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Surfactantes Pulmonares/farmacologia , Coelhos
9.
Medicina (Kaunas) ; 56(7)2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32674447

RESUMO

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.


Assuntos
Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Corticosteroides/uso terapêutico , Budesonida/administração & dosagem , Budesonida/farmacologia , Budesonida/uso terapêutico , Clobetasol/administração & dosagem , Clobetasol/farmacologia , Clobetasol/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Doença Enxerto-Hospedeiro/fisiopatologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos
10.
J Int Med Res ; 48(6): 300060520929179, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32589857

RESUMO

OBJECTIVE: To investigate the relationship between therapeutic efficacy in children with asthma and interleukin-13 (IL-13) rs20541 polymorphisms. METHODS: Fifty children with moderate-to-severe asthma were assigned to the GG, GA, and AA groups according to the IL-13 gene locus rs20541 polymorphism. The patients received budesonide inhalation suspension 1 mg twice daily combined with fluticasone propionate 80 µg/inhalation. The improvement of clinical symptoms (gasping, coughing, and wheezing), improvement of lung function, and adverse reactions were observed. RESULTS: Lung function did not significantly differ among three groups before treatment. After treatment, the time to symptom relief was significantly shorter in the GG group than that in the other two groups. The forced expiratory volume in one second and percent predicted peak expiratory flow were also significantly better in the GG group than in the other two groups. CONCLUSION: Budesonide inhalation suspension combined with fluticasone propionate is an effective treatment regimen for moderate-to-severe asthma. Polymorphism of the IL-13 rs20541 locus may be correlated with therapeutic efficacy. Patients carrying the GG allele were more responsive than their counterparts with the GA or AA allele.


Assuntos
Asma , Interleucina-13 , Administração por Inalação , Androstadienos/farmacologia , Androstadienos/uso terapêutico , Asma/tratamento farmacológico , Asma/genética , Broncodilatadores/uso terapêutico , Budesonida/farmacologia , Budesonida/uso terapêutico , Criança , Método Duplo-Cego , Volume Expiratório Forçado , Humanos , Interleucina-13/genética , Interleucina-13/farmacologia , Interleucina-13/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética
12.
Clin Transl Gastroenterol ; 11(4): e00164, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32352681

RESUMO

INTRODUCTION: Eosinophilic esophagitis (EoE) is a T-helper 2 (Th2), eosinophilic disease associated with pathologic tissue remodeling that leads to end-organ dysfunction. During early-stage disease, inflammation and subepithelial fibrosis are coupled and reversible, but in late-stage or therapy-resistant disease, there can be uncoupling of these features with progressive esophageal rigidity and strictures contributing to clinical dysphagia and food impactions. No current pharmacotherapeutic interventions directly target esophageal fibrosis. Based on the ability of the thiazolidinediones (TZD) to regulate intestinal and hepatic fibrosis, we tested the antifibrotic effects of the TZDs, rosiglitazone and pioglitazone, in preclinical studies using primary human esophageal fibroblasts. METHODS: Primary fibroblasts isolated from normal or EoE esophagi were treated with transforming growth factor (TGF)-ß1 in the absence or presence of TZDs and, in some experiments, without or with budesonide and analyzed by quantitative real-time PCR and immunoblotting. Immunohistochemical analysis of human esophageal biopsies was performed. RESULTS: EoE esophageal biopsies and esophageal fibroblasts expressed higher levels of the TZD receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), than normal controls. PPAR-γ was inducible by the Th2 cytokine, interleukin 4 (IL-4). TZD significantly reduced TGF-ß1-induced myofibroblast and fibrotic gene and protein expression preferentially in EoE, but not normal esophageal fibroblasts. In esophageal fibroblasts, TGF-ß1 increased phosphorylated Smad2/3 and p38, but TZDs preferentially inhibited p38 phosphorylation, suggesting signaling pathway-specific effects. The TZDs were more potent than budesonide at decreasing collagen-1α1 expression. DISCUSSION: The TZDs preferentially exert antifibrotic effects in TGF-ß1-activated EoE fibroblasts and provide a preclinical foundation for further investigation of the potential of the TZDs in EoE pathologic remodeling.


Assuntos
Esofagite Eosinofílica/tratamento farmacológico , Esôfago/patologia , Miofibroblastos/efeitos dos fármacos , Pioglitazona/farmacologia , Rosiglitazona/farmacologia , Biópsia , Budesonida/farmacologia , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/patologia , Esôfago/citologia , Esôfago/efeitos dos fármacos , Esôfago/imunologia , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-4/metabolismo , Miofibroblastos/imunologia , Miofibroblastos/metabolismo , PPAR gama/metabolismo , Pioglitazona/uso terapêutico , Cultura Primária de Células , Rosiglitazona/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
13.
Eur J Pharm Biopharm ; 151: 61-72, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32283213

RESUMO

Inflammatory bowel disease (IBD) affects a confined area of the intestine and, therefore, administration of drugs via oral route is preferable. However, obstacles such as changes in the pH along gastrointestinal tract (GIT), enzymatic activity, and intraluminal pressure may cause low drug availability in the target tissue when delivered orally. Previous studies have pointed out the benefits of using micron-sized particles for targeting inflamed intestinal mucosa and nanoparticles for delivery of anti-inflammatory agents to the affected epithelial cells. We hypothesized that by combining the benefits of micro- and nano- particles, we could create a more efficient delivery system for budesonide, a glucocorticosteroid commonly used for anti-inflammatory IBD therapy. The aim of this study was to develop a novel multistage system for oral delivery designed to increase concentrations budesonidein the inflamed intestinal tissue. The multistage system consists of Stage 1 mesoporous silicon microparticles (S1MP) loaded with stage 2 poly-lactic-glycolic acid (PLGA) budesonide-encapsulating nanoparticles (BNP). BNP were efficiently loaded into S1MP (loading efficiency of 45.9 ± 14.8%) due to the large pore volume and high surface area of S1MP and exhibited controlled release profiles with enhanced drug dissolution rate in biologically relevant pHs. Due to the robustness in acidic pH and their geometry, S1MP protected the loaded budesonide in the acidic (gastric) pH with only 20% release. This allowed for the prolonged release of the BNP in the higher pH conditions (intestinal pH). The sustained release of BNP could facilitate accumulation in the inflamed tissue, enabling BNP to penetrate inflamed mucosa and release active budesonide to the target site. The multistage systems of S1MP and BNP were further evaluated in three-dimensional (3D) in vitro model of IBD and were found to (1) increase accumulation of BNP in the inflamed areas, (2) restore the barrier function of Caco-2 inflamed monolayer, and (3) significantly reduce pro-inflammatory cytokine release almost to the level of the healthy control.


Assuntos
Budesonida/química , Budesonida/farmacologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Silício/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Células CACO-2 , Linhagem Celular Tumoral , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Mucosa Intestinal/metabolismo , Nanopartículas/química , Tamanho da Partícula , Solubilidade
14.
Medicina (Kaunas) ; 56(3)2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32120846

RESUMO

BACKGROUND: Viral infection is the main cause of asthma and COPD (chronic obstructive pulmonary disease) exacerbation and accumulate inflammatory cells to airway tissue. We have reported poly I:C, a mimic product of the virus and ligand of toll-like receptor 3 (TLR3), induced inflammatory chemokines from airway epithelial cells and found prior incubation with corticosteroids diminishes the effect of TLR3 activation. In clinical practice, mild asthma is recommended as-needed budesonide (BUD) when symptoms occur following a viral infection, etc. However, many questions still surround BUD's usefulness if taken after a virus has already infected airway tissue. OBJECTIVE: The aim of this study was to investigate the inhibitory effects of BUD on inflammatory cytokines induced by viral infection. Methods: Normal human bronchial epithelial (NHBE) cells were stimulated with poly I:C or infected with human rhinovirus-16 (HRV16) and BUD was added after the initial stimulation. Expression of both thymic stromal lymphopoietin (TSLP) and CCL26/eotaxin-3 was quantified by real-time RT-PCR and enzyme-linked immunosorbent assay (ELISA), respectively. Knockdown study was performed. Results: Pre-or post-incubation with BUD inhibited both poly I:C- and HRV16-induced mRNAs and proteins of both thymic stromal lymphopoietin (TSLP) and CCL26 with significance. Knockdown of the glucocorticoid receptor diminished these effects of BUD. Under the same conditions of BUD's experiment, post-incubation with neither fluticasone propionate nor dexamethasone suppressed expression of both TSLP and CCL26, which induced by poly I:C. CONCLUSION: Post-addition of BUD inhibited the virus-induced TSLP and CCL26 from the airway epithelial cells. These results suggest that inhalation of BUD after viral infection has beneficial effects on asthma. CONCLUSION: Late addition of BUD may benefit among patient with viral infection and type 2 allergic airway disease such as asthma.


Assuntos
Broncodilatadores/farmacologia , Budesonida/farmacologia , Citocinas/efeitos dos fármacos , Infecções por Picornaviridae/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Rhinovirus , Técnicas de Cultura de Células , Quimiocina CCL26/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Humanos , Infecções por Picornaviridae/virologia , Mucosa Respiratória/citologia , Mucosa Respiratória/virologia , Infecções Respiratórias/virologia
15.
Front Immunol ; 11: 143, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158443

RESUMO

Mesenchymal stromal cells (MSCs) are administered locally to treat sites of inflammation. Local delivery is known to cause MSCs to aggregate into "spheroids," which alters gene expression and phenotype. While adherent MSCs are highly efficient in their inhibition of T cells, whether or not this property is altered upon MSC aggregation has not been thoroughly determined. In this study, we discovered that aggregation of MSCs into spheroids causes them to lose their T cell-suppressive abilities. Interestingly, adding budesonide, a topical glucocorticoid steroid, alongside spheroids partially restored MSC suppression of T cell proliferation. Through a series of inhibition and add-back studies, we determined budesonide acts synergistically with spheroid MSC-produced PGE2 to suppress T cell proliferation through the PGE2 receptors EP2 and EP4. These findings highlight critical differences between adherent and spheroid MSC interactions with human immune cells that have significant translational consequences. In addition, we uncovered a mechanism through which spheroid MSC suppression of T cells can be partly restored. By understanding the phenotypic changes that occur upon MSC aggregation and the impact of MSC drug interactions, improved immunosuppressive MSC therapies for localized delivery can be designed.


Assuntos
Imunomodulação/imunologia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/metabolismo , Esferoides Celulares/imunologia , Esferoides Celulares/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células da Medula Óssea/metabolismo , Budesonida/farmacologia , Agregação Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Humanos , Fatores Imunológicos/metabolismo , Ativação Linfocitária , Transdução de Sinais/efeitos dos fármacos , Doadores de Tecidos , Cordão Umbilical/citologia
16.
Sci Rep ; 10(1): 5363, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210313

RESUMO

Muscle resident fibro-adipogenic progenitors (FAPs), support muscle regeneration by releasing cytokines that stimulate the differentiation of myogenic stem cells. However, in non-physiological contexts (myopathies, atrophy, aging) FAPs cause fibrotic and fat infiltrations that impair muscle function. We set out to perform a fluorescence microscopy-based screening to identify compounds that perturb the differentiation trajectories of these multipotent stem cells. From a primary screen of 1,120 FDA/EMA approved drugs, we identified 34 compounds as potential inhibitors of adipogenic differentiation of FAPs isolated from the murine model (mdx) of Duchenne muscular dystrophy (DMD). The hit list from this screen was surprisingly enriched with compounds from the glucocorticoid (GCs) chemical class, drugs that are known to promote adipogenesis in vitro and in vivo. To shed light on these data, three GCs identified in our screening efforts were characterized by different approaches. We found that like dexamethasone, budesonide inhibits adipogenesis induced by insulin in sub-confluent FAPs. However, both drugs have a pro-adipogenic impact when the adipogenic mix contains factors that increase the concentration of cAMP. Gene expression analysis demonstrated that treatment with glucocorticoids induces the transcription of Gilz/Tsc22d3, an inhibitor of the adipogenic master regulator PPARγ, only in anti-adipogenic conditions. Additionally, alongside their anti-adipogenic effect, GCs are shown to promote terminal differentiation of satellite cells. Both the anti-adipogenic and pro-myogenic effects are mediated by the glucocorticoid receptor and are not observed in the presence of receptor inhibitors. Steroid administration currently represents the standard treatment for DMD patients, the rationale being based on their anti-inflammatory effects. The findings presented here offer new insights on additional glucocorticoid effects on muscle stem cells that may affect muscle homeostasis and physiology.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Glucocorticoides/farmacologia , Desenvolvimento Muscular/efeitos dos fármacos , Músculo Esquelético/citologia , Adipogenia/efeitos dos fármacos , Animais , Budesonida/administração & dosagem , Budesonida/farmacologia , Diferenciação Celular/fisiologia , Células Cultivadas , AMP Cíclico/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Microscopia de Fluorescência , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/patologia , PPAR gama/metabolismo , Receptores de Glucocorticoides/metabolismo , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Células Satélites de Músculo Esquelético/patologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/patologia , Fatores de Transcrição/metabolismo
17.
J Crohns Colitis ; 14(7): 962-973, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32016376

RESUMO

BACKGROUND AND AIMS: Diarrhoea is a common, debilitating symptom of gastrointestinal disorders. Pathomechanisms probably involve defects in trans-epithelial water transport, but the role of aquaporin [AQP] family water channels in diarrhoea-predominant diseases is unknown. We investigated the involvement of AQPs in the pathobiology of collagenous colitis [CC], which features chronic, watery diarrhoea despite overtly normal intestinal epithelial cells [IECs]. METHODS: We assessed the expression of all AQP family members in mucosal samples of CC patients before and during treatment with the corticosteroid drug budesonide, steroid-refractory CC patients and healthy controls. Samples were analysed by genome-wide mRNA sequencing [RNA-seq] and quantitative real-time PCR [qPCR]. In some patients, we performed tissue microdissection followed by RNA-seq to explore the IEC-specific CC transcriptome. We determined changes in the protein levels of the lead candidates in IEC by confocal microscopy. Finally, we investigated the regulation of AQP expression by corticosteroids in model cell lines. RESULTS: Using qPCR and RNA-seq, we identified loss of AQP8 expression as a hallmark of active CC, which was reverted by budesonide treatment in steroid-responsive but not refractory patients. Consistently, decreased AQP8 mRNA and protein levels were observed in IECs of patients with active CC, and steroid drugs increased AQP8 expression in model IECs. Moreover, low APQ8 expression was strongly associated with higher stool frequency in CC patients. CONCLUSION: Down-regulation of epithelial AQP8 may impair water resorption in active CC, resulting in watery diarrhoea. Our results suggest that AQP8 is a potential drug target for the treatment of diarrhoeal disorders.


Assuntos
Aquaporinas/genética , Aquaporinas/metabolismo , Colite Colagenosa/genética , Colite Colagenosa/metabolismo , Diarreia/genética , Diarreia/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Aquaporina 1/genética , Budesonida/farmacologia , Budesonida/uso terapêutico , Células CACO-2 , Colite Colagenosa/complicações , Colite Colagenosa/tratamento farmacológico , Dexametasona/farmacologia , Diarreia/etiologia , Regulação para Baixo/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Células HT29 , Homeostase , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Água/metabolismo
18.
Respir Investig ; 58(3): 155-168, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32094077

RESUMO

BACKGROUND: Coronavirus 229E (HCoV-229E), one of the causes of the common cold, exacerbates chronic obstructive pulmonary disease (COPD) and bronchial asthma. Long-acting muscarinic antagonists and ß2-agonists and inhaled corticosteroids inhibit the exacerbation of COPD and bronchial asthma caused by infection with viruses, including HCoV-229E. However, the effects of these drugs on HCoV-229E replication and infection-induced inflammation in the human airway are unknown. METHODS: Primary human nasal (HNE) and tracheal (HTE) epithelial cell cultures were infected with HCoV-229E. RESULTS: Pretreatment of HNE and HTE cells with glycopyrronium or formoterol decreased viral RNA levels and/or titers, the expression of the HCoV-229E receptor CD13, the number and fluorescence intensity of acidic endosomes where HCoV-229E RNA enters the cytoplasm, and the infection-induced production of cytokines, including IL-6, IL-8, and IFN-ß. Treatment of the cells with the CD13 inhibitor 2'2'-dipyridyl decreased viral titers. Pretreatment of the cells with a combination of three drugs (glycopyrronium, formoterol, and budesonide) exerted additive inhibitory effects on viral titers and cytokine production. Pretreatment of HNE cells with glycopyrronium or formoterol reduced the susceptibility to infection, and pretreatment with the three drugs inhibited activation of nuclear factor-kappa B p50 and p65 proteins. Pretreatment with formoterol increased cAMP levels and treatment with cAMP decreased viral titers, CD13 expression, and the fluorescence intensity of acidic endosomes. CONCLUSIONS: These findings suggest that glycopyrronium, formoterol, and a combination of glycopyrronium, formoterol, and budesonide inhibit HCoV-229E replication partly by inhibiting receptor expression and/or endosomal function and that these drugs modulate infection-induced inflammation in the airway.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Budesonida/farmacologia , Coronavirus/fisiologia , Citocinas/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Fumarato de Formoterol/farmacologia , Glicopirrolato/farmacologia , Antagonistas Muscarínicos/farmacologia , Mucosa Nasal/citologia , Traqueia/citologia , Replicação Viral/efeitos dos fármacos , Antígenos CD13/metabolismo , Células Cultivadas , Humanos
19.
Dig Dis Sci ; 65(11): 3297-3304, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974913

RESUMO

BACKGROUND: New formulations for topical treatment of ulcerative colitis with budesonide inclusion complex (BUDHP-ß-CD) and poloxamers (PL) were developed for future clinical use. AIMS: This study evaluated the efficacy of such novel formulations in a rat model of colitis. METHODS: The PL-BUDHP-ß-CD systems were prepared by direct dispersion of the complex (BUD concentration 0.5 mg mL-1) in solutions with PL407 or PL403. Male Wistar rats underwent TNBS-induced colitis and were treated for 5 days by a rectal route, as follows: BUD 1: BUDHP-ß-CD + PL407 (18%); BUD 2: BUDHP-ß-CD + PL407 (20%); BUD 3: BUDHP-ß-CD + PL407 (18%) + PL403 (2%); BUD 4: plain BUD; BUD 5: BUDHP-ß-CD; C1: HP-ß-CD + PL407 (18%); C2: HP-ß-CD + PL407 (20%); C3: HP-ß-CD + PL407 (18%) + PL403 (2%); C4: saline. A negative control group without colitis was also used. Colitis was assessed via myeloperoxidase (MPO) activity, and macroscopic and microscopic damage score in colon tissues. Protein levels of TNF-α, IL-1ß, IL-10 and endogenous glucocorticoids were obtained using ELISA. RESULTS: BUDHP-ß-CD poloxamer formulations had similar MPO activity when compared with the negative control group. All formulations presented lower MPO activity than BUDHP-ß-CD and plain BUD (p < 0.001). BUD 2 produced lower microscopic score values than plain BUD and BUDHP-ß-CD (p < 0.01). All formulations with BUDHP-ß-CD poloxamers reduced TNF-α levels (p < 0.05). CONCLUSION: Novel budesonide inclusion complex formulations improved microscopic damage and reduced colonic MPO activity and TNF-α levels.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/farmacologia , Budesonida/farmacologia , Colite Ulcerativa/tratamento farmacológico , Hidrogéis/farmacologia , Poloxâmero/farmacologia , Animais , Modelos Animais de Doenças , Combinação de Medicamentos , Masculino , Ratos , Ratos Wistar
20.
Int J Pharm ; 577: 119034, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31991183

RESUMO

Relapse in Allergic Rhinitis (AR) is triggered by various unclear mechanisms. Xanthium strumarium L. as a traditional folk medicine can inhibit inflammatory responses through multiple mechanisms. Xanthatin (XT) is a bioactive compound derived from Xanthium strumarium L, and we developed a polymeric micelle (PM) that is dendritic cells (DCs)-specific targeting delivery system loading XT (NGR-XT-PM) based on a cyclic peptide moiety (NGR) to render DCs maturation-resistant for therapy of refractory AR. A murine model of AR was employed to investigate the in vivo therapeutic efficiency and relapse rate compared with the commercial product Budesonide. The results showed intranasal administration of NGR-XT-PM presented significant anti-allergy effect with no recurrence, in contrast, all mice treatment with Budesonide relapsed. NGR-XT-PM could effectively reverse the Th1/Th2 imbalance by depleting the serum inflammatory levels (IgE, histamine and IL-4) and DCs surface costimulatory molecules (CD80, CD86 and I-A/I-E), and promote immune tolerance by upregulating the level of Treg cells and reducing the levels of Th2, Th9 and Th17 cells. Furthermore, we appealed to virtual screening of inflammatory targets and found XT blocking the COX-2/PGE2 signaling pathway, which is a key effector in immune responses. These indicated CD13-specific NGR could facilitate XT selectively targeting DCs for efficiently ameliorating refractory rhinitis, and NGR-XT-PM should be a potential anti-AR drug.


Assuntos
Antígenos CD13/química , Células Dendríticas/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Furanos/química , Furanos/farmacologia , Oligopeptídeos/química , Rinite Alérgica/prevenção & controle , Administração Intranasal , Animais , Budesonida/farmacologia , Antígenos CD13/administração & dosagem , Células Dendríticas/imunologia , Furanos/administração & dosagem , Mediadores da Inflamação/sangue , Masculino , Camundongos , Micelas , Nanomedicina/métodos , Oligopeptídeos/administração & dosagem , Rinite Alérgica/sangue , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
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