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1.
Scand J Gastroenterol ; 56(6): 629-634, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33831327

RESUMO

OBJECTIVES: Topical corticosteroids are considered a cornerstone in the treatment of patients with eosinophilic esophagitis. The aim of this study was to evaluate the benefit of using mometasone furoate spray versus placebo on dysphagia and health-related quality of life in these patients. MATERIAL AND METHODS: Consecutive, newly diagnosed adult patients with eosinophilic esophagitis were randomized and treated with either 200 micrograms of orally administered topical mometasone furoate or placebo 4 times daily for 8 weeks. Symptoms and quality of life were evaluated using questionnaires including the Watson Dysphagia Scale, the European Organization for Research and Treatment of Cancer Quality of Life-Oesophageal Module 18 and the Short Form-36 before and after treatment. RESULTS: In the intention-to-treat analysis (n = 36) the Watson Dysphagia Scale score after mometasone treatment was reduced by 6.5 (median, p < .01) compared with 0 (median, ns) in the placebo group. The benefit of mometasone over placebo was significant (p < .05). In the per-protocol analysis (n = 33) the Watson Dysphagia Scale score was reduced by 5 (median, p = .01) after mometasone treatment compared with 0 (median, ns) in the placebo group. The advantage of mometasone over the placebo was significant (p < .05). The benefit of using mometasoneas evaluated by the two quality of life questionnaires was, however, insignificant. CONCLUSIONS: Our finding suggests that in adult patients with eosinophilic esophagitis, topical mometasone furoate exerts a beneficial effect compared with placebo regarding the main symptom, i.e., dysphagia. A corresponding benefit could not be verified regarding the various quality of life measurements. CLINICAL TRIAL REGISTRATION: Mometasone-furoate for Treatment of Eosinophilic Esophagitis - a Randomized Placebo Controlled Study ClinicalTrials.gov Identifier (NCT02113267).


Assuntos
Transtornos de Deglutição , Esofagite Eosinofílica , Pregnadienodiois , Adulto , Transtornos de Deglutição/tratamento farmacológico , Transtornos de Deglutição/etiologia , Método Duplo-Cego , Esofagite Eosinofílica/complicações , Esofagite Eosinofílica/tratamento farmacológico , Humanos , Furoato de Mometasona , Qualidade de Vida , Resultado do Tratamento
2.
Pulm Pharmacol Ther ; 70: 102019, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33771722

RESUMO

BACKGROUND: QMF149 is an inhaled fixed-dose combination of indacaterol acetate and mometasone furoate (MF) delivered via Breezhaler®, under development for once-daily treatment of asthma. MF delivered via Twisthaler® is approved as Asmanex® Twisthaler® for the treatment of asthma. Bridging of MF delivered via Twisthaler® to MF delivered via Breezhaler® was undertaken as part of QMF149 development to enable dose comparisons between the devices. Pharmacokinetics (PK) of MF were characterized in two studies; a single dose PK study in healthy volunteers and a pharmacokinetic/pharmacodynamic (PK/PD) study in asthma patients. OBJECTIVES: The PK study in healthy volunteers evaluated the PK of single doses of MF via Breezhaler® (50-400 µg) and compared systemic exposure of MF following administration via Breezhaler® and Twisthaler® 400 µg (2 inhalations of 200 µg). The study in patients with asthma characterized the MF PK profile following once-daily inhalation of MF via Breezhaler® and Twisthaler® devices for 4 weeks. METHODS: In the open-label, single-dose, crossover study, healthy subjects sequentially received MF via Twisthaler® (400 µg, medium-dose inhaled corticosteroid [ICS]) and escalating doses via Breezhaler® (50, 100, 200, 400 µg). PK data were obtained up to 72 h post-dose. In the double-blind, double-dummy, parallel-group study, asthma patients were randomised to receive either MF 80 µg (low-dose ICS) or 320 µg (high-dose ICS) via Breezhaler®, or 200 µg (low-dose ICS) or 800 µg (2 inhalations of 400 µg; high-dose ICS) via Twisthaler® once daily for 4 weeks. PK sampling was performed on Days 1 and 28 at pre-dose and up to 24 h post-dose. RESULTS: In the healthy volunteer PK study, 20 healthy subjects completed all treatments. Dose-normalised AUClast of MF was 1.8-1.9-fold higher when delivered via Breezhaler® versus Twisthaler®. AUC and Cmax of MF increased in a dose-proportional manner over the range of 50-400 µg via Breezhaler®. Results from this study guided dose selection of MF via Breezhaler® for the asthma study. In the asthma study, in a subset of 96 patients, mean systemic exposure (AUClast and Cmax) for MF 80 and 320 µg via Breezhaler® was comparable with MF 200 and 800 µg via Twisthaler®, respectively, on Day 28. CONCLUSION: PK characterization in a healthy volunteer PK study and subsequently an asthma study enabled selection of 80 µg (low), 160 µg (medium), and 320 µg (high) delivered via Breezhaler® as MF doses comparable to the 200 µg, 400 µg and 800 µg doses delivered by Twisthaler®, respectively, as part of QMF149 formulation development.


Assuntos
Asma , Pregnadienodiois , Administração por Inalação , Asma/tratamento farmacológico , Estudos Cross-Over , Método Duplo-Cego , Inaladores de Pó Seco , Humanos , Furoato de Mometasona
3.
J Pediatr ; 234: 128-133.e1, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33711287

RESUMO

OBJECTIVES: To evaluate the impact of a payor-initiated formulary change in inhaled corticosteroid coverage on lung function in patients with asthma and on provider prescribing practices. This formulary change, undertaken in August 2016 by a Medicaid payor in Kentucky, eliminated coverage of beclomethasone dipropionate, a metered dose inhaler (MDI), in favor of mometasone furoate, available as MDI and dry powder inhaler (DPI). STUDY DESIGN: A retrospective chart review was conducted on children with asthma ages 6-18 years covered by the relevant payor from a university-based pediatric practice who were seen before the formulary change (February to July 2016) and after (February to July 2017). Spirometry data from each visit was compared using the paired Student t test. RESULTS: Fifty-eight patients were identified who were initially on beclomethasone dipropionate and had spirometry available at both visits. Those who switched from an MDI to a DPI (n = 24) saw a decline in median predicted forced expiratory volume in 1 second from 98.5% to 91% (P = .013). A decline was also seen in forced expiratory flow at 25%-75%, from 89.5% predicted to 76% predicted (P = .041). No significant changes were observed in children remaining on an MDI. Seven patients discontinued inhaled corticosteroid therapy. CONCLUSIONS: This study suggests insurance formulary changes leading to use of a different inhaler device may have a detrimental impact on pediatric lung function, which may be a surrogate measure for overall asthma control. This could be due to a lack of adequate timely educational intervention as well as the inability of some children to use DPIs.


Assuntos
Pregnadienodiois , Administração por Inalação , Adolescente , Corticosteroides , Criança , Volume Expiratório Forçado , Humanos , Pulmão , Estudos Retrospectivos
4.
PLoS One ; 16(2): e0246507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33617542

RESUMO

Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFß fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, ß-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFß cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.


Assuntos
Distrofia Muscular Animal/tratamento farmacológico , Distrofia Muscular de Duchenne/tratamento farmacológico , Ácidos Aminoisobutíricos/uso terapêutico , Animais , Biomarcadores , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Prednisolona/uso terapêutico , Pregnadienodiois/uso terapêutico , Rituximab/uso terapêutico
5.
Am J Rhinol Allergy ; 35(1): 52-58, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32551922

RESUMO

INTRODUCTION: The purpose of this study is to determine the post-treatment levels of total oxidant status (TOS) and total antioxidant status (TAS), that are increased due to pathophysiology, and to compare those with pre-treatment levels in allergic rhinitis patients.Material-Methods: Among 84 patients clinically diagnosed with allergic rhinitis, 31 patients were started only on nasal steroid treatment (mometasone furoate), and 53 patients were started on nasal steroid and oral antihistamine treatment (mometasone furoate + rupatadine fumarate 10 mg). Blood samples were taken from the patients at the first examination and at post-treatment month 1.TAS and TOS were measured from the blood samples. RESULTS: While no significant change was determined in mean TAS levels with treatment, a statistically significant decrease was determined in TOS values in post-treatment period (P < .01). There was no significant change in TAS and TOS values of patients only using nasal steroids, while a significant decrease was determined in post-treatment TOS values of patients using both nasal steroids and oral antihistamines (P < .001). It was determined that TOS values of women were significantly lower compared to men, and it was also reduced in seasonal allergic rhinitis compared to perennial allergic rhinitis (P < .05 for both). CONCLUSION: In allergic rhinitis patients, concomitant use of nasal steroids and antihistamines significantly decreases total oxidative stress. It may be stated that the addition of antihistamines to allergic rhinitis treatment positively affects treatment.


Assuntos
Antialérgicos , Pregnadienodiois , Rinite Alérgica , Administração Intranasal , Antialérgicos/uso terapêutico , Antioxidantes/uso terapêutico , Feminino , Antagonistas dos Receptores Histamínicos H1 , Humanos , Masculino , Furoato de Mometasona/uso terapêutico , Estresse Oxidativo , Rinite Alérgica/tratamento farmacológico , Esteroides
6.
J Nepal Health Res Counc ; 18(2): 268-270, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32969391

RESUMO

BACKGROUND: Allergic rhinitis is a common ailment with rising trend and worldwide prevalence of some 400 million. METHODS: This prospective randomized crosssectional study was done at the Department of Otorhinolaryngology and Head and Neck Surgery, Tribhuvan University, Teaching Hospital, Kathmandu, Nepal from June 2016 to August 2017. They were randomly assigned to two groups by lottery method. Group A received mometasone furoate intranasal spray and Group B received oral montelukast for a total duration of one month. Prior to starting medication and one month after medications, total nasal symptom score was documented. Statistical analysis was done using SPSS version 18. RESULTS: Total of 126 patients between 16 to 52 years were enrolled in the study. The mean duration of symptoms was 3.93 years. The mean value of serum total IgE was 833.49 IU/ml. The mean pre and post medication score for mometasone furoate intranasal spray group was 16.32 and 5.44 respectively, which was significant. Similarly, the mean pre and post medication score for oral montelukast group was 15.24 and 7.87 respectively which was also found to be significant. Comparing the means of scores for both the groups, mometasone furoate was found to be more effective than oral montelukast. CONCLUSIONS: Both mometasone furoate intranasal spray and oral montelukast were effective in the treatment of patient with allergic rhinitis. Oral montelukast can therefore be used as a first line treatment for patients with allergic rhinitis.


Assuntos
Antialérgicos , Pregnadienodiois , Rinite Alérgica , Acetatos , Ciclopropanos , Humanos , Furoato de Mometasona , Nepal , Estudos Prospectivos , Quinolinas , Rinite Alérgica/tratamento farmacológico , Sulfetos , Resultado do Tratamento
7.
PLoS Med ; 17(9): e1003222, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956407

RESUMO

BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].


Assuntos
Atividade Motora/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Corticosteroides/efeitos adversos , Criança , Pré-Escolar , Progressão da Doença , Glucocorticoides/efeitos adversos , Humanos , Masculino , Prednisona/uso terapêutico , Pregnadienodiois/metabolismo , Resultado do Tratamento , Caminhada/fisiologia
8.
Proc Natl Acad Sci U S A ; 117(39): 24285-24293, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32917814

RESUMO

Duchenne muscular dystrophy is a genetic disorder that shows chronic and progressive damage to skeletal and cardiac muscle leading to premature death. Antiinflammatory corticosteroids targeting the glucocorticoid receptor (GR) are the current standard of care but drive adverse side effects such as deleterious bone loss. Through subtle modification to a steroidal backbone, a recently developed drug, vamorolone, appears to preserve beneficial efficacy but with significantly reduced side effects. We use combined structural, biophysical, and biochemical approaches to show that loss of a receptor-ligand hydrogen bond drives these remarkable therapeutic effects. Moreover, vamorolone uniformly weakens coactivator associations but not corepressor associations, implicating partial agonism as the main driver of its dissociative properties. Additionally, we identify a critical and evolutionarily conserved intramolecular network connecting the ligand to the coregulator binding surface. Interruption of this allosteric network by vamorolone selectively reduces GR-driven transactivation while leaving transrepression intact. Our results establish a mechanistic understanding of how vamorolone reduces side effects, guiding the future design of partial agonists as selective GR modulators with an improved therapeutic index.


Assuntos
Distrofia Muscular de Duchenne/tratamento farmacológico , Pregnadienodiois/administração & dosagem , Pregnadienodiois/química , Humanos , Ligação de Hidrogênio , Ligantes , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Ligação Proteica , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
9.
Hum Mol Genet ; 29(15): 2481-2495, 2020 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-32592467

RESUMO

Duchenne muscular dystrophy (DMD) is caused by loss of dystrophin in muscle, and while all patients share the primary gene and biochemical defect, there is considerable patient-patient variability in clinical symptoms. We sought to develop multivariate models of serum protein biomarkers that explained observed variation, using functional outcome measures as proxies for severity. Serum samples from 39 steroid-naïve DMD boys 4 to <7 years enrolled into a clinical trial of vamorolone were studied (NCT02760264). Four assessments of gross motor function were carried out for each participant over a 6-week interval, and their mean was used as response for biomarker models. Weighted correlation network analysis was used for unsupervised clustering of 1305 proteins quantified using SOMAscan® aptamer profiling to define highly representative and connected proteins. Multivariate models of biomarkers were obtained for time to stand performance (strength phenotype; 17 proteins) and 6 min walk performance (endurance phenotype; 17 proteins) including some shared proteins. Identified proteins were tested with associations of mRNA expression with histological severity of muscle from dystrophinopathy patients (n = 28) and normal controls (n = 6). Strong associations predictive of both clinical and histological severity were found for ERBB4 (reductions in both blood and muscle with increasing severity), SOD1 (reductions in muscle and increases in blood with increasing severity) and CNTF (decreased levels in blood and muscle with increasing severity). We show that performance of DMD boys was effectively modeled with serum proteins, proximal strength associated with growth and remodeling pathways and muscle endurance centered on TGFß and fibrosis pathways in muscle.


Assuntos
Biomarcadores/sangue , Distrofina/sangue , Distrofia Muscular de Duchenne/sangue , Criança , Pré-Escolar , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/patologia , Oligonucleotídeos , Fenótipo , Pregnadienodiois/administração & dosagem , Índice de Gravidade de Doença , Esteroides/metabolismo
10.
J Clin Pharmacol ; 60(10): 1385-1396, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32434278

RESUMO

Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax ), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50  = 186 ng·h/mL), followed by time to climb 4 stairs (E50  = 478 ng·h/mL), time to run/walk 10 m (E50  = 1220 ng·h/mL), and 6-minute walk test (E50  = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/ß2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Distrofia Muscular de Duchenne/tratamento farmacológico , Pregnadienodiois/administração & dosagem , Pregnadienodiois/farmacocinética , Administração Oral , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/uso terapêutico , Área Sob a Curva , Biomarcadores/sangue , Criança , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Sistema de Condução Cardíaco/efeitos dos fármacos , Humanos , Masculino , Pregnadienodiois/efeitos adversos , Pregnadienodiois/uso terapêutico , Resultado do Tratamento
11.
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
12.
Inflamm Res ; 68(11): 969-980, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446438

RESUMO

OBJECTIVE AND DESIGN: The objective of this study was to assess the effect of vamorolone, a first-in-class dissociative steroidal compound, to inhibit inflammation when administered after disease onset in the murine collagen antibody-induced arthritis model of arthritis. ANIMALS: 84 DBA1/J mice were used in this study (n = 12 per treatment group). TREATMENT: Vamorolone or prednisolone was administered orally after disease onset for a duration of 7 days. METHODS: Disease score and bone erosion were assessed using previously described scoring systems. Cytokines were measured in joints via immunoassay, and joint cathepsin B activity (marker of inflammation) was assessed using optical imaging of joints on live mice. RESULTS: We found that vamorolone treatment led to a reduction of several disease parameters including disease score, joint inflammation, and the presence of pro-inflammatory mediators to a degree similar of that observed with prednisolone treatment. More importantly, histopathological analysis of affected joints showed that vamorolone treatment significantly reduced the degree of bone erosion while this bone-sparing property was not observed with prednisolone treatment at any of the tested doses. CONCLUSIONS: While many intervention regimens in other studies are administered prior to disease onset in animal models, the current study involves delivery of the potential therapeutic after disease onset. Based on the findings, vamorolone may offer an efficacious, yet safer alternative to conventional steroidal compounds in the treatment of rheumatoid arthritis and other inflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Animais , Anticorpos Monoclonais/imunologia , Artrite Experimental/imunologia , Artrite Experimental/patologia , Colágeno Tipo II/imunologia , Citocinas/imunologia , Articulações/efeitos dos fármacos , Articulações/imunologia , Articulações/patologia , Lipopolissacarídeos , Masculino , Camundongos Endogâmicos DBA
13.
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
14.
J Clin Pharmacol ; 59(7): 979-988, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30742306

RESUMO

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder occurring in boys and caused by mutations in the dystrophin gene. Vamorolone is a first-generation delta-9,11 compound that has favorable efficacy and side effect profiles relative to classical glucocorticoids. The pharmacokinetics (PK) of oral vamorolone were assessed in parallel-group studies in healthy men (phase 1, n = 86) and boys with DMD (phase 2a, n = 48) during 14 days of once-daily dosing with a range of doses. Vamorolone exhibited moderate variability in PK, with the maximum plasma concentration usually occurring at 2-4 hours and a half-life of approximately 2 hours for all doses and days examined. Population PK modeling of all data together indicated that the PK of vamorolone can be well described by a 1-compartment model with zero-order absorption. Both men and boys showed a dose-linearity of PK parameters for the doses examined, with no accumulation of the drug during daily dosing. Ingestion with food resulted in markedly enhanced absorption of the drug, as tested in healthy men. There were similar PK of vamorolone in healthy men and DMD boys with apparent clearance averaging 2.0 L/h/kg in men and 1.7 L/h/kg in boys. Overall, vamorolone exhibited well-behaved linear PK, with similar profiles in healthy men and boys with DMD, moderate variability in PK parameters, and absorption and disposition profiles similar to those of classical glucocorticoids.


Assuntos
Anti-Inflamatórios/farmacocinética , Distrofia Muscular de Duchenne/tratamento farmacológico , Pregnadienodiois/farmacocinética , Adulto , Anti-Inflamatórios/uso terapêutico , Área Sob a Curva , Humanos , Masculino , Pessoa de Meia-Idade , Pregnadienodiois/uso terapêutico , Adulto Jovem
15.
Acta Physiol (Oxf) ; 225(2): e13172, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30120816

RESUMO

AIM: Critical illness myopathy (CIM) is a consequence of modern critical care, leading to skeletal muscle atrophy/paralysis with negative consequences for mortality/morbidity and health care costs. Glucocorticoids (GCs) have been proposed to trigger CIM. Here, we compare outcomes of two GCs, the commonly used prednisolone and the newly developed dissociative vamorolone in response to the intensive care unit (ICU) condition for 5 days, ie, sedation, immobilization, and mechanical ventilation. METHODS: Rats were divided into a 0-day sham-operated control group, and three groups exposed to 5 days ICU condition during treatment with prednisolone (PRED) or vamorolone (VAM) or none of these GCs (ICU-group). Survival, body and muscle weights, cytokine concentrations, regulation of muscle contraction in single fast- and slow-twitch muscle fibres, myofibrillar protein expression and protein degradation pathways were studied. RESULTS: Critical illness myopathy geno- and pheno-types were confirmed in the ICU group. However, VAM and PRED groups showed reduced atrophy/weakness than the ICU group, and muscle specific differences with more severe negative effects on fast-twitch muscle fibres in the PRED than the other groups. CONCLUSION: These results show that vamorolone provides a GC intervention superior to typical GCs in improving CIM outcomes. Further, the findings do not support the notion that moderate-dose GC treatment represents a factor triggering CIM.


Assuntos
Anti-Inflamatórios/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Animais , Proteínas Contráteis/metabolismo , Estado Terminal , Citocinas/sangue , Modelos Animais de Doenças , Feminino , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Doenças Musculares/fisiopatologia , Prednisolona/uso terapêutico , Ratos , Ratos Sprague-Dawley
16.
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
17.
Mol Ther ; 26(9): 2231-2242, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30166241

RESUMO

Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice-findings that correlate with reports of prednisolone worsening symptoms of LGMD2B patients. Our findings showing improved cellular and pre-clinical efficacy of vamorolone compared to prednisolone and better safety profile of vamorolone indicates the suitability of vamorolone for clinical trials in LGMD2B.


Assuntos
Disferlina/deficiência , Distrofias Musculares/tratamento farmacológico , Esteroides/uso terapêutico , Adolescente , Animais , Células Cultivadas , Disferlina/metabolismo , Humanos , Masculino , Camundongos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Prednisolona/uso terapêutico , Pregnadienodiois/uso terapêutico
18.
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
19.
Sci Rep ; 8(1): 6081, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29666400

RESUMO

Clinicians often hesitate prescribing corticosteroids to treat corticosteroid-responsive conditions in sickle cell disease (SCD) patients because their use can be associated with complications (increased hospital readmission, rebound pain, strokes, avascular necrosis, acute chest syndrome). Consequently, SCD patients may receive suboptimal treatment for corticosteroid-responsive conditions. We conducted a preclinical trial of dissociative (vamorolone) and conventional (prednisolone) corticosteroid compounds to evaluate their effects on nociception phenotype, inflammation, and organ dysfunction in SCD mice. Prednisolone and vamorolone had no significant effects on nociception phenotype or anemia in homozygous mice. Conversely, prednisolone and vamorolone significantly decreased white blood cell counts and hepatic inflammation. Interestingly, the effects of vamorolone were milder than those of prednisolone, as vamorolone yielded less attenuation of hepatic inflammation compared to prednisolone. Compared to controls and heterozygotes, homozygotes had significant liver necrosis, which was significantly exacerbated by prednisolone and vamorolone despite decreased hepatic inflammation. These hepatic histopathologic changes were associated with increases in transaminases and alkaline phosphatase. Together, these results suggest that, even in the setting of decreasing hepatic inflammation, prednisolone and vamorolone were associated with significant hepatic toxicity in SCD mice. These findings raise the possibility that hepatic function deterioration could occur with the use of corticosteroids (conventional and dissociative) in SCD.


Assuntos
Anemia Falciforme/complicações , Anti-Inflamatórios/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Glucocorticoides/efeitos adversos , Nociceptividade/efeitos dos fármacos , Prednisolona/efeitos adversos , Pregnadienodiois/efeitos adversos , Animais , Anti-Inflamatórios/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Inflamação/complicações , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Prednisolona/uso terapêutico , Pregnadienodiois/uso terapêutico
20.
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
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