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1.
Molecules ; 24(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731472

RESUMO

To discover new pharmacologically active natural products, here, we performed the phytochemical analysis of a Korean medicinal plant. Euonymus alatus (Thunb.) Sieb. is a traditional medicinal plant that has been used as a remedy for various diseases in Asian countries. In particular, the cork cambium on the twigs of E. alatus has been used to treat dysmenorrhea, tumors, diabetes, and wound. Phytochemical analysis of the methanolic extract of E. alatus twigs led to the isolation of a sterol, which was identified as (3ß,16α)-3,16-dihydroxypregn-5-en-20-one (1) by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionization mass spectrometry. The stereochemistry of 1 was established with nuclear Overhauser effect spectroscopy (NOESY) analysis and comparison of electronic circular dichroism (ECD) data. To the best of our knowledge, the isolation of compound 1 from nature is first reported here, as well as the complete and revised NMR data assignment of 1. In lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, compound 1 significantly inhibited nitric oxide (NO) production at an IC50 value of 12.54 ± 0.05 µM as well as the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, the pre-treatment with compound 1 attenuated the LPS-induced phosphorylation of nuclear factor kappa B (NF-κB) p65 through the inhibition of the phosphorylation of IκB kinase alpha (IKKα), IKKß, and inhibitor of kappa B alpha (IκBα). Compound 1 also inhibited the LPS-induced phosphorylation of p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Taken together, compound 1 may serve as an anti-inflammatory constituent of E. alatus twigs and its anti-inflammatory property is thought to be associated with the inhibition of NO production via suppression of iNOS and COX-2 expression through inhibition of IKKα/ß, I-κBα and NF-κB p65 activation and downregulation of p38, JNK, and ERK mitogen-activated protein kinase signal pathways in RAW 264.7 macrophages. These findings also provide experimental evidence that compound 1 identified from E. alatus twigs could be a candidate for an anti-inflammatory agent.


Assuntos
Anti-Inflamatórios/farmacologia , Euonymus/química , Inflamação/tratamento farmacológico , Pregnadienodiois/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Dicroísmo Circular , Ciclo-Oxigenase 2/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Quinase I-kappa B/genética , Inflamação/induzido quimicamente , Inflamação/genética , Lipopolissacarídeos/toxicidade , Espectroscopia de Ressonância Magnética , Camundongos , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Pregnadienodiois/química , Pregnadienodiois/isolamento & purificação , Células RAW 264.7 , Proteínas Quinases p38 Ativadas por Mitógeno/genética
2.
Life Sci Alliance ; 2(1)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30745312

RESUMO

Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.


Assuntos
Anti-Inflamatórios/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocardite/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Receptores de Glucocorticoides/efeitos dos fármacos , Receptores de Mineralocorticoides/efeitos dos fármacos , Aldosterona/química , Aldosterona/farmacologia , Aldosterona/uso terapêutico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Proteína 9 Associada à CRISPR/genética , Simulação por Computador , Modelos Animais de Doenças , Eplerenona/química , Eplerenona/farmacologia , Eplerenona/uso terapêutico , Técnicas de Inativação de Genes , Ligação de Hidrogênio , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/química , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Miocardite/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Prednisolona/química , Prednisolona/farmacologia , Prednisolona/uso terapêutico , Pregnadienodiois/química , Pregnadienodiois/farmacologia , Células RAW 264.7 , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/agonistas , Receptores de Mineralocorticoides/química
3.
Pharmacol Res ; 136: 140-150, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30219580

RESUMO

We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.


Assuntos
Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Pregnadienodiois/farmacologia , Pregnadienodiois/uso terapêutico , Administração Oral , Anti-Inflamatórios/sangue , Biomarcadores/sangue , Glicemia/análise , Criança , Pré-Escolar , Humanos , Hidrocortisona/sangue , Insulina/sangue , Masculino , Distrofia Muscular de Duchenne/metabolismo , Pregnadienodiois/sangue
4.
Physiol Genomics ; 50(9): 735-745, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29883261

RESUMO

Corticosteroids are highly prescribed and effective anti-inflammatory drugs but the burden of side effects with chronic use significantly detracts from patient quality of life, particularly in children. Developing safer steroids amenable to long-term use is an important goal for treatment of chronic inflammatory diseases such as Duchenne muscular dystrophy (DMD). We have developed vamorolone (VBP15), a first-in-class dissociative glucocorticoid receptor (GR) ligand that shows the anti-inflammatory efficacy of corticosteroids without key steroid side effects in animal models. miRNAs are increasingly recognized as key regulators of inflammatory responses. To define effects of prednisolone and vamorolone on the muscle miRNAome, we performed a preclinical discovery study in the mdx mouse model of DMD. miRNAs associated with inflammation were highly elevated in mdx muscle. Both vamorolone and prednisolone returned these toward wild-type levels (miR-142-5p, miR-142-3p, miR-146a, miR-301a, miR-324-3p, miR-455-5p, miR-455-3p, miR-497, miR-652). Effects of vamorolone were largely limited to reduction of proinflammatory miRNAs. In contrast, prednisolone activated a separate group of miRNAs associated with steroid side effects and a noncoding RNA cluster homologous to human chromosome 14q32. Effects were validated for inflammatory miRNAs in a second, independent preclinical study. For the anti-inflammatory miRNA signature, bioinformatic analyses showed all of these miRNAs are directly regulated by, or in turn activate, the inflammatory transcription factor NF-κB. Moving forward miR-146a and miR-142 are of particular interest as biomarkers or novel drug targets. These data validate NF-κB signaling as a target of dissociative GR-ligand efficacy in vivo and provide new insight into miRNA signaling in chronic inflammation.


Assuntos
Inflamação/genética , MicroRNAs/genética , Músculos/metabolismo , Prednisona/farmacologia , Pregnadienodiois/farmacologia , Animais , Sequência de Bases , Doença Crônica , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , MicroRNAs/metabolismo , Modelos Biológicos , Músculos/efeitos dos fármacos , Músculos/patologia , Distrofia Muscular de Duchenne/genética , NF-kappa B/metabolismo , Regiões Promotoras Genéticas/genética , Receptores de Glucocorticoides/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais
5.
Steroids ; 134: 43-52, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29524454

RESUMO

BACKGROUND: Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. PURPOSE: Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. EXPERIMENTAL APPROACH: We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1-20.0 mg/kg), and multiple ascending doses (1.0-20 mg/kg/day; 14 days treatment). KEY RESULTS: Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. CONCLUSIONS AND INTERPRETATIONS: Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.


Assuntos
Pregnadienodiois/efeitos adversos , Pregnadienodiois/farmacologia , Segurança , Adulto , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem
6.
Inflamm Res ; 65(9): 737-43, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27261270

RESUMO

OBJECTIVE AND DESIGN: The goal of this study was to assess the capacity of VBP15, a dissociative steroidal compound, to reduce pro-inflammatory cytokine expression in vitro, to reduce symptoms of colitis in the trinitrobenzene sulfonic acid-induced murine model, and to assess the effect of VBP15 on growth stunting in juvenile mice. MATERIALS: In vitro studies were performed in primary human intestinal epithelial cells. Colitis was induced in mice by administering trinitrobenzene sulfonic acid. Growth stunting studies were performed in wild type outbred mice. TREATMENT: Cells were treated with VBP15 or prednisolone (10 µM) for 24 h. Mice were subjected to 3 days of VBP15 (30 mg/kg) or prednisolone (30 mg/kg) in the colitis study. In the growth stunting study, mice were subjected to VBP15 (10, 30, 45 mg/kg) or prednisolone (10 mg/kg) for 5 weeks. METHODS: Cytokines were measured by PCR and via Luminex. Colitis symptoms were evaluated by assessing weight loss, intestinal blood, and stool consistency. Growth stunting was assessed using an electronic caliper. RESULTS: VBP15 significantly reduced the in vitro production of CCL5 (p < 0.001) IL-6 (p < 0.001), IL-8 (p < 0.05) and reduced colitis symptoms (p < 0.05). VBP15 caused less growth stunting than prednisolone (p < 0.001) in juvenile mice. CONCLUSION: VBP15 may reduce symptoms of IBD, while decreasing or avoiding detrimental side effects.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Tamanho Corporal/efeitos dos fármacos , Células Cultivadas , Colite/induzido quimicamente , Colite/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Pregnadienodiois/farmacologia , Ácido Trinitrobenzenossulfônico
7.
Pulm Pharmacol Ther ; 38: 17-26, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27133900

RESUMO

Overproduction of secretory mucins contributes to morbidity/mortality in inflammatory lung diseases. Inflammatory mediators directly increase expression of mucin genes, but few drugs have been shown to directly repress mucin gene expression. IL-1ß upregulates the MUC5AC mucin gene in part via the transcription factors NFκB while the glucocorticoid Dexamethasone (Dex) transcriptionally represses MUC5AC expression by Dex-activated GR binding to two GRE cis-sites in the MUC5AC promoter in lung epithelial cells. VBP compounds (ReveraGen BioPharma) maintain anti-inflammatory activity through inhibition of NFκB but exhibit reduced GRE-mediated transcriptional properties associated with adverse side-effects and thus have potential to minimize harmful side effects of long-term steroid therapy in inflammatory lung diseases. We investigated VBP15 efficacy as an anti-mucin agent in two types of airway epithelial cells and analyzed the transcription factor activity and promoter binding associated with VBP15-induced MUC5AC repression. VBP15 reduced MUC5AC mRNA abundance in a dose- and time-dependent manner similar to Dex in the presence or absence of IL-1ß in A549 and differentiated human bronchial epithelial cells. Repression was abrogated in the presence of RU486, demonstrating a requirement for GR in the VBP15-induced repression of MUC5AC. Inhibition of NFκB activity resulted in reduced baseline expression of MUC5AC indicating that constitutive activity maintains MUC5AC production. Chromatin immunoprecipitation analysis demonstrated lack of GR and of p65 (NFκB) binding to composite GRE domains in the MUC5AC promoter following VBP15 exposure of cells, in contrast to Dex. These data demonstrate that VBP15 is a novel anti-mucin agent that mediates the reduction of MUC5AC gene expression differently than the classical glucocorticoid, Dex.


Assuntos
Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Mucina-5AC/genética , Pregnadienodiois/farmacologia , Células A549 , Anti-Inflamatórios/administração & dosagem , Brônquios/citologia , Brônquios/efeitos dos fármacos , Linhagem Celular , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Mucinas/antagonistas & inibidores , Mucinas/metabolismo , Pregnadienodiois/administração & dosagem , RNA Mensageiro/metabolismo , Fatores de Tempo
8.
Respir Res ; 16: 132, 2015 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-26511361

RESUMO

BACKGROUND: Mitotic synchrony is the synchronous progression of a population of cells through the cell cycle and is characteristic of non-diseased airway epithelial cells. However, we previously showed that asthmatic airway epithelial cells are characterized by mitotic asynchrony and are pro-inflammatory as a result. Glucocorticoids can induce mitotic synchrony that in turn suppresses the pro-inflammatory state of diseased cells, suggesting a novel anti-inflammatory mechanism of action. Herein, we benchmarked traditional glucocorticoids against the ability of a new clinical-stage dissociative steroidal drug, VBP15, for mitotic resynchronization and associated anti-inflammatory activity in asthmatic airway epithelial cells. METHODS: Primary airway epithelial cells differentiated at air-liquid interface were exposed to VBP15, dexamethasone or vehicle following in vitro mechanical injury. Basolateral cytokine secretions (TGF-ß1, IL-6, IL-10, IL-13, and IL-1ß) were analyzed at different time points using cytometric bead assays and mitosis was examined by flow cytometry. RESULTS: VBP15 improved mitotic synchrony of proliferating asthmatic cells in air-liquid interface cultures compared to vehicle-exposed cultures. VBP15 also significantly reduced the basolateral secretion of pro-inflammatory (i.e. IL-1ß) and pro-fibrogenic cytokines (i.e. TGF-ß1) in air-liquid interface-differentiated asthmatic epithelial cultures following mechanical injury. CONCLUSION: VBP15 improves mitotic asynchrony and injury-induced pro-inflammatory and fibrogenic responses in asthmatic airway epithelial cultures with efficacy comparable to traditional glucocorticoids. As it is predicted to show superior side effect profiles compared to traditional glucocorticoids, VBP15 holds potential for treatment of asthma and other respiratory conditions.


Assuntos
Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Dexametasona/farmacologia , Células Epiteliais/efeitos dos fármacos , Glucocorticoides/farmacologia , Pulmão/efeitos dos fármacos , Mitose/efeitos dos fármacos , Pregnadienodiois/farmacologia , Asma/metabolismo , Asma/patologia , Estudos de Casos e Controles , Células Cultivadas , Citocinas/metabolismo , Células Epiteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/prevenção & controle , Fatores de Tempo
9.
Otolaryngol Head Neck Surg ; 153(2): 298-301, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26084823

RESUMO

OBJECTIVE: In this study, we aimed to experimentally investigate the effects of nasal corticosteroids on the levels of secretory immunoglobulin A (sIgA) in nasal mucosa in rats. STUDY DESIGN: Prospective, randomized control trial. SETTING: Research laboratory. SUBJECT AND METHODS: Twenty-four male Sprague Dawley rats were included in our study. The rats were randomized into 3 groups. In group 1, nasal mometasone furoate was applied to the rats for 30 days. Saline was applied to group 2 for 30 days. Group 3 was the control group and received no treatment throughout the study period. Nasal lavage was conducted on both nasal openings of all rats in the 3 groups at the beginning of the study and on days 15 and 30, and the lavage solution (distilled water) was collected by aspiration. RESULTS: In group 1, the sIgA value was significantly higher at day 15 than at baseline. No significant difference was found between the sIgA values on day 15 and day 30. In groups 2 and 3, there were no significant differences in sIgA values at baseline, day 15, and day 30. The sIgA value of group 1 on day 15 was significantly higher than the values of groups 2 and 3. The sIgA value of group 1 on day 30 was significantly higher than the values of groups 2 and 3. CONCLUSION: Topical corticosteroids (mometasone furoate) applied to the nasal mucosa significantly increase nasal sIgA levels.


Assuntos
Corticosteroides/administração & dosagem , Imunoglobulina A Secretora/análise , Pregnadienodiois/administração & dosagem , Pregnadienodiois/farmacologia , Administração Intranasal , Animais , Masculino , Furoato de Mometasona , Lavagem Nasal , Ratos , Ratos Sprague-Dawley
10.
BMJ Open ; 5(2): e006131, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25649209

RESUMO

OBJECTIVE: To investigate the safety and efficacy of QMF149, a once-daily, fixed-dose combination of the long-acting ß2-agonist (LABA) indacaterol maleate and inhaled corticosteroid (ICS) mometasone furoate (MF) for the treatment of persistent asthma. The hypothesis was that QMF149 would not increase the risk of serious asthma exacerbations. SETTING: 174 research centres in nine countries. PARTICIPANTS: 1519 adolescents and adults with persistent asthma who were treated or qualified for treatment with combination LABA/ICS were randomised, and 1508 were included in the intention-to-treat analysis. INTERVENTION: Patients were randomised to QMF149 (indacaterol maleate 500 µg/MF 400 µg) or MF (400 µg) once daily via Twisthaler inhalation device in a double-blind, parallel-group study for 6-21 months. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary end point was time to first serious asthma exacerbation (resulting in hospitalisation, intubation or death). The key secondary end point was annual rate of exacerbations requiring systemic corticosteroids. RESULTS: Treatment with QMF149 resulted in no significant difference in time to first serious exacerbation compared to MF (2 (0.3%) vs 6 events (0.8%); difference -0.52 percentage point; 95% CI -1.25 to 0.21, p=0.160, HR=0.31; 95% CI 0.06 to 1.54, p=0.151). QMF149 significantly reduced the annual rate of exacerbations requiring systemic corticosteroids (rate ratio=0.71; 95% CI 0.55 to 0.90, p=0.005). Proportions of patients experiencing adverse events were similar across groups (74.0% in the QMF149 group and 73.4% in the MF group). Serious adverse events occurred in 4% and 5.8% of patients in the QMF149 and MF groups, respectively. CONCLUSIONS: No significant difference was observed in the primary outcome of time to first serious asthma exacerbation in patients treated with QMF149 compared with patients treated with MF. Long-term treatment with QMF149 once daily had a favourable safety/efficacy profile in adolescent and adult patients with persistent asthma. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT00941798.


Assuntos
Corticosteroides/uso terapêutico , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Progressão da Doença , Indanos/uso terapêutico , Maleatos/uso terapêutico , Pregnadienodiois/uso terapêutico , Quinolonas/uso terapêutico , Administração por Inalação , Adolescente , Corticosteroides/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Agonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Antialérgicos/farmacologia , Antialérgicos/uso terapêutico , Antiasmáticos/farmacologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Indanos/farmacologia , Masculino , Maleatos/farmacologia , Pessoa de Meia-Idade , Furoato de Mometasona , Pregnadienodiois/farmacologia , Quinolonas/farmacologia , Adulto Jovem
11.
Cell Mol Neurobiol ; 35(3): 377-387, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25392236

RESUMO

Multiple sclerosis is a chronic disease of the central nervous system characterized by an autoimmune inflammatory reaction that leads to axonal demyelination and tissue damage. Glucocorticoids, such as prednisolone, are effective in the treatment of multiple sclerosis in large part due to their ability to inhibit pro-inflammatory pathways (e.g., NFκB). However, despite their effectiveness, long-term treatment is limited by adverse side effects. VBP15 is a recently described compound synthesized based on the lazeroid steroidal backbone that shows activity in acute and chronic inflammatory conditions, yet displays a much-reduced side effect profile compared to traditional glucocorticoids. The purpose of this study was to determine the effectiveness of VBP15 in inhibiting inflammation and disease progression in experimental autoimmune encephalomyelitis (EAE), a widely used mouse model of multiple sclerosis. Our data show that VBP15 is effective at reducing both disease onset and severity. In parallel studies, we observed that VBP15 was able to inhibit the production of NFκB-regulated pro-inflammatory transcripts in human macrophages. Furthermore, treatment with prednisolone-but not VBP15-increased expression of genes associated with bone loss and muscle atrophy, suggesting lack of side effects of VBP15. These findings suggest that VBP15 may represent a potentially safer alternative to traditional glucocorticoids in the treatment of multiple sclerosis and other inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Índice de Gravidade de Doença , Animais , Anti-Inflamatórios/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/patologia , Pregnadienodiois/farmacologia , Gravidez , Resultado do Tratamento
12.
J Cell Biol ; 207(1): 139-58, 2014 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-25313409

RESUMO

We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor ß-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues.


Assuntos
Fibrose/patologia , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/patologia , Regeneração/fisiologia , Animais , Anti-Inflamatórios/farmacologia , Diferenciação Celular , Células Cultivadas , Distrofina/genética , Humanos , Inflamação/patologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/metabolismo , Músculo Esquelético/citologia , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular do Cíngulo dos Membros/patologia , Distrofia Muscular Animal/patologia , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/patologia , Prednisona/farmacologia , Pregnadienodiois/farmacologia , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Estrutura Terciária de Proteína , RNA Mensageiro/genética , Células-Tronco/citologia , Fator de Crescimento Transformador beta
14.
Kulak Burun Bogaz Ihtis Derg ; 24(1): 1-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24798432

RESUMO

OBJECTIVES: This study aims to examine the effect of topical mometasone furoate nasal spray on nasal Staphylococcus aureus (S. aureus) colonization in the treatment of allergic rhinitis. PATIENTS AND METHODS: Between January 2012 and February 2013, 53 patients having perennial allergic rhinitis symptoms (37 females, 16 males) and 53 healthy controls (36 females, 17 males) were included in the study. Nasal cultures were obtained and evaluated before and after the treatment in allergic rhinitis patients who were admitted to the ear, nose and throat (ENT) outpatient clinic and receiving a mometasone furoate nasal spray treatment (200 mcg/day) once a day for one-month. In healthy controls, nasal cultures were obtained and evaluated once. RESULTS: In allergic rhinitis patients, five cultures were positive for S. aureus before the treatment while the number of cultures positive for S. aureus was six after the treatment. There was no significant difference in the pre-treatment and post-treatment S. aureus colonization between the patient group and controls (p>0.05). CONCLUSION: Mometasone furoate nasal spray used in the treatment of allergic rhinitis appears to be ineffective for nasal S. aureus colonization.


Assuntos
Antialérgicos/farmacologia , Portador Sadio/tratamento farmacológico , Pregnadienodiois/farmacologia , Rinite Alérgica Perene/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Administração Intranasal , Adolescente , Adulto , Idoso , Antialérgicos/administração & dosagem , Portador Sadio/microbiologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Sprays Nasais , Pregnadienodiois/administração & dosagem , Rinite Alérgica Perene/microbiologia , Infecções Estafilocócicas/microbiologia , Adulto Jovem
15.
PLoS One ; 9(4): e93754, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24710117

RESUMO

BACKGROUND: Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse. OBJECTIVE: To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa. METHODS: We used an ex-vivo human nasal mucosal tissue model and employed pre- and post- Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use. RESULTS: At a fixed concentration of 10-10 M, FF had significantly higher suppressive effects on interferon (IFN)-γ, interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-α, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-α after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF. CONCLUSION: The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre- and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use.


Assuntos
Androstadienos/farmacologia , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Mucosa Nasal/metabolismo , Pregnadienodiois/farmacologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adulto , Idoso , Citocinas/imunologia , Enterotoxinas/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Furoato de Mometasona , Mucosa Nasal/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Tempo
16.
Int Immunopharmacol ; 19(1): 153-60, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24434372

RESUMO

Fluticasone furoate (FF) and mometasone furoate (MF) are potent glucocorticoids recommended for the treatment of allergic rhinitis and other inflammatory diseases. However, whether these drugs render any anti-inflammatory effects in Chronic Obstructive Pulmonary Disease (COPD) is unclear. Emerging data on suppressors of cytokine signaling-3 (SOCS-3) activation in the lungs during inflammation suggests that SOCS3 can be potential targets for regulating pulmonary inflammatory responses in COPD. In this study, we compared the effect of FF with MF on SOCS-3 expression in tobacco smoke (TS) exposed BAEpCs in vitro and in a mouse model of COPD in vivo. BAEpCs were exposed to TS or room air and later were treated with either FF (1nmol-100nmol) or MF (10-500nmol) inhibitors in the presence and absence of Jak1 and Stat-3 inhibitors. C57BL/6 mice were exposed to TS for 6 months, and treated with either FF, MF for 2 and 4 weeks. FF induced 7 fold increases in SOCS-3 expression in BAEpCs whereas MF induced a three fold increase when compared to control. Jak1 and Stat-3 inhibitors significantly inhibited the FF and MF induced SOCS-3 expression in BAEpCs. In addition, FF and MF restored TS inhibited SOCS-3 expression in the airway epithelium of COPD mice. FF and MF treatments significantly reduced leukocyte infiltration in airways and inhibited lung inflammation. Our study elucidates a novel mechanism for the anti-inflammatory action of FF in COPD. The superior efficacy of FF may be in part due to the increased expression of SOCS-3 in BAEpCs.


Assuntos
Androstadienos/farmacologia , Anti-Inflamatórios/farmacologia , Pregnadienodiois/farmacologia , Proteínas Supressoras da Sinalização de Citocina/genética , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Brônquios/citologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glucocorticoides/farmacologia , Humanos , Janus Quinase 1/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Furoato de Mometasona , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/antagonistas & inibidores
17.
Steroids ; 79: 1-6, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24184487

RESUMO

Two new unusual cholestane derivatives, pentacyclic steroid 16,22-epoxy-20ß,23S-dihydroxycholest-1-ene-3-one (1) and 20ß,23S-dihydroxycholest-1-ene-3,22-dione (2), along with two new pregnane derivatives, 15ß,17α-dihydroxypregna-4,6-diene-3,20-dione (3) and 11α-hydroxypregna-4-ene-3,6,20-trione (4), were isolated from the South China Sea gorgonian coral Subergorgia suberosa. Their structures were established based on the extensive analyses of 2D NMR, IR, and HRMS. Antifouling tests against Balanus amphitrite larvae settlement indicated that 1 and 2 exhibited inhibitory effect with EC50 values of 5.3, and 14.5 µg/mL, respectively.


Assuntos
Antozoários/química , Incrustação Biológica/prevenção & controle , Esteroides/química , Esteroides/farmacologia , Animais , Colestanos/química , Colestanos/farmacologia , Colestenonas/química , Colestenonas/farmacologia , Relação Dose-Resposta a Droga , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas , Estrutura Molecular , Oceanos e Mares , Prednisona/análogos & derivados , Prednisona/química , Prednisona/farmacologia , Pregnadienodiois/química , Pregnadienodiois/farmacologia , Pregnanos/química , Pregnanos/farmacologia , Espectrofotometria , Estereoisomerismo , Thoracica/efeitos dos fármacos , Thoracica/crescimento & desenvolvimento
18.
Laryngoscope ; 124(3): 602-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23878015

RESUMO

OBJECTIVES/HYPOTHESIS: Clinical improvement in patients with chronic rhinosinusitis (CRS) treated with steroids alone has previously been ascribed to the steroids' anti-inflammatory properties rather than any direct effect on the bacteria. The aim of this study was to determine if commonly used intranasal steroids directly reduce bacterial biofilm production in vitro. STUDY DESIGN: In vitro comparative controlled trial. METHODS: Staphylococcus aureus biofilms were grown on minimum biofilm eradication concentration device pegs and treated with the commonly prescribed CRS topical steroids fluticasone, mometasone, or budesonide. These were dissolved in vehicle solvents and added to cerebrospinal fluid (CSF) broth. Concentrations (including therapeutic doses) tested for fluticasone and mometasone ranged from 25 µg/200 µL to 400 µg/200 µL, and from 16 µg/200 µL to 2000 µg/200 µL for budesonide. Control pegs were exposed to equivalent volumes of the appropriate solvent/CSF broth. Confocal scanning laser microscopy and COMSTAT software were used to quantify biofilms at 24 hours after treatment. RESULTS: Significant differences from control were found for fluticasone at 400 µg/200 µL (difference = -0.3065 µm(3)/µm(2), P = .007), mometasone at 300 µg/200 µL and 400 µg/200 µL (difference = -0.15 µm(3)/µm(2), P = .006, and difference = -0.9193 µm(3)/µm(2), P = .034, respectively), and budesonide at 750 µg/200 µL, 1000 µg/200 µL and 2000 µg/200 µL (difference = -1.0137 µm(3)/µm(2), P = .038, difference = -0.6164, P = .009, and difference = -0.1906 µm(3)/µm(2), P = .029, respectively). CONCLUSIONS: The concentrations of 400 µg/200 µL of fluticasone, 300 µg and 400 µg/200 µL of mometasone, and 750 µg, 1,000 µg, and 2,000 µg/200 µL of budesonide directly reduce biofilm production in vitro, outside of the inflammatory milieu.


Assuntos
Corticosteroides/farmacologia , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Androstadienos/farmacologia , Biofilmes/crescimento & desenvolvimento , Budesonida/farmacologia , Meios de Cultivo Condicionados , Relação Dose-Resposta a Droga , Fluticasona , Humanos , Técnicas In Vitro , Furoato de Mometasona , Pregnadienodiois/farmacologia , Valores de Referência , Sensibilidade e Especificidade , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
19.
Vestn Otorinolaringol ; (6): 57-60, 2014.
Artigo em Russo | MEDLINE | ID: mdl-25734311

RESUMO

The objective of the present study was to improve the effectiveness of medicamental therapy of exudative otitis media in the children with recurrent and chronic adenoiditis. It was shown that the use of fluifort (carbocysteine lysine salt) for the treatment of exudative otitis media in the children presenting with chronic adenoiditis is a more effective approach in comparison with the expectant management. It is concluded that the application of carbocysteine lysine salt in combination with the mometasone furoate nasal spray ensures the rapid elimination of the symptoms of adenoiditis and significantly accelerates the resolution of exudative otitis media compared with the monotherapeutic treatment.


Assuntos
Tonsila Faríngea/patologia , Anti-Infecciosos Locais/farmacologia , Anti-Inflamatórios/farmacologia , Carbocisteína/farmacologia , Nasofaringite/tratamento farmacológico , Otite Média com Derrame/tratamento farmacológico , Pregnadienodiois/farmacologia , Tonsila Faríngea/efeitos dos fármacos , Anti-Infecciosos Locais/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Carbocisteína/administração & dosagem , Criança , Pré-Escolar , Doença Crônica , Comorbidade , Quimioterapia Combinada , Humanos , Furoato de Mometasona , Nasofaringite/epidemiologia , Otite Média com Derrame/epidemiologia , Pregnadienodiois/administração & dosagem , Resultado do Tratamento
20.
Eur Arch Otorhinolaryngol ; 271(8): 2213-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24362587

RESUMO

We aimed to evaluate nasal mucosal changes and efficiency of nasal steroids and diclofenac on nasal mucosa during hyperbaric oxygen (HBO) treatment. Forty adult Albino-Wistar rats were randomized into four groups. Group 1 (control group) (n = 10) not exposed to hyperbaric or enhanced oxygen concentrations; group 2 (HBO group) (n = 10) underwent only HBO treatment; group 3 (n = 10) received HBO and intranasal mometasone furoate (10 µl/day); group 4 (n = 10) treated with HBO and diclofenac sodium (10 mg/kg/day ip). Specimens of nasal mucosa were collected after sacrificing and dissection of animals. The specimens were processed for light microscopic evaluation, and then evaluated histopathologically for fibroblastic proliferation and inflammation. Regarding the scores of inflammation, the level of inflammation in the control group was significantly less severe than the other groups (p < 0.05). Evaluation of the fibrosis scores showed that the scores of both groups 2 and 4 were significantly increased (p < 0.05). There were no statistically significant differences between groups 2, 3, and 4 as for fibrosis and inflammation (p > 0.05). Chronic HBO treatment induced mild inflammation of the nasal mucosa. These effects cannot be prevented adequately by administration of nasal steroids and diclofenac.


Assuntos
Anti-Inflamatórios/farmacologia , Diclofenaco/farmacologia , Oxigenoterapia Hiperbárica , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/patologia , Pregnadienodiois/farmacologia , Administração Intranasal , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Método Duplo-Cego , Fibrose/etiologia , Fibrose/prevenção & controle , Oxigenoterapia Hiperbárica/efeitos adversos , Inflamação/etiologia , Inflamação/prevenção & controle , Masculino , Furoato de Mometasona , Distribuição Aleatória , Ratos Wistar
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