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1.
Drug Discov Ther ; 16(5): 225-232, 2022 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-36288939

RESUMO

The aim of this study was to determine the efficacy and safety of ciclesonide in the treatment of novel coronavirus disease 2019 (COVID-19) as gauged by pneumonia progression. This multi-center, open-label randomized trial was conducted with patients recruited from 22 hospitals across Japan. Participants were patients admitted with mild or asymptomatic COVID-19 without signs of pneumonia on chest X-rays. Asymptomatic participants were diagnosed after identification through contact tracing. Trial participants were randomized to either the ciclesonide or control arm. Participants in the treatment arm were administered 400 µg of ciclesonide three times a day over seven consecutive days. The primary endpoint was exacerbated pneumonia within seven days. Secondary outcomes were changes in clinical findings, laboratory findings, and changes over time in the amount of the viral genome. In the treatment group, 16 patients (39.0%) were classified as having exacerbated pneumonia compared to 9 (18.8%) in the control group. The risk ratio (RR) was 2.08 (95% confidence interval (CI): 1.15-3.75), indicating a worsening of pneumonia in the ciclesonide group. Significant differences were noted in participants with a fever on admission (RR: 2.62, 90% CI: 1.17-5.85, 95% CI: 1.00-6.82) and individuals 60 years of age or older (RR: 8.80, 90% CI: 1.76-44.06, 95% CI: 1.29-59.99). The current results indicated that ciclesonide exacerbates signs of pneumonia on images in individuals with mild or asymptomatic symptoms of COVID-19 without worsening clinical symptoms.


Assuntos
Pregnenodionas , Humanos , SARS-CoV-2 , Pregnenodionas/efeitos adversos , Hospitalização , Resultado do Tratamento
2.
BMC Pulm Med ; 22(1): 368, 2022 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-36171597

RESUMO

BACKGROUND: The successful management of patients infected with coronavirus disease 2019 (COVID-19) with inhaled ciclesonide has been reported, however few studies have investigated its application among hospitalized patients. METHODS: This retrospective cohort study enrolled all adult patients admitted to our hospital with confirmed COVID-19 infection from May to June 2021. Critical patients who received mechanical ventilation within 24 h after admission and those who started ciclesonide more than 14 days after symptom onset were excluded. The in-hospital mortality rate was compared between those who did and did not receive inhaled ciclesonide. RESULTS: A total of 269 patients were enrolled, of whom 184 received inhaled ciclesonide and 85 did not. The use of ciclesonide was associated with lower in-hospital mortality (7.6% vs. 23.5%, p = 0.0003) and a trend of shorter hospital stay (12.0 (10.0-18.0) days vs. 13.0 (10.0-25.3) days, p = 0.0577). In subgroup analysis, the use of inhaled ciclesonide significantly reduced mortality in the patients with severe COVID-19 infection (6.8% vs. 50.0%, p < 0.0001) and in those with a high risk of mortality (16.4% vs. 43.2%, p = 0.0037). The use of inhaled ciclesonide also reduced the likelihood of receiving mechanical ventilation in the patients with severe COVID-19 infection. After multivariate analysis, inhaled ciclesonide remained positively correlated with a lower risk of in-hospital mortality (odds ratio: 0.2724, 95% confidence interval: 0.087-0.8763, p = 0.0291). CONCLUSIONS: The use of inhaled ciclesonide in hospitalized patients with COVID-19 infection can reduce in-hospital mortality. Further randomized studies in patients with moderate to severe COVID-19 infection are urgently needed.


Assuntos
Pregnenodionas , Adulto , Hospitalização , Humanos , Pregnenodionas/uso terapêutico , Estudos Retrospectivos
3.
EBioMedicine ; 83: 104204, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35952494

RESUMO

BACKGROUND: Multiple sclerosis is characterised by inflammation, oligodendrocyte loss and axonal demyelination and shows an additional impact on astrocytes, and their polarization. Although a certain degree of spontaneous myelin repair can be observed, disease progression, and aging impair regeneration efforts highlighting the need to better understand glial cell dynamics to establish specific regenerative treatments. METHODS: Applying a chronic demyelination model, we here analysed demyelination and remyelination related effects on astrocytes and stem cell niches and studied the consequences of medrysone application on myelin repair, and astrocyte polarization. FINDINGS: Medrysone induced recovery of mature oligodendrocytes, myelin expression and node formation. In addition, C3d/S100a10 co-expression in astrocytes was enhanced. Moreover, Timp1 expression in C3d positive astrocytes revealed another astrocytic phenotype with a myelination promoting character. INTERPRETATION: Based on these findings, specific astrocyte subpopulations are suggested to act in a myelin regenerative way and manner the regulation of which can be positively modulated by this corticosteroid. FUNDING: This work was supported by the Jürgen Manchot Stiftung, the Research Commission of the medical faculty of the Heinrich-Heine-University of Düsseldorf, the Christiane and Claudia Hempel Foundation for clinical stem cell research and the James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung.


Assuntos
Doenças Desmielinizantes , Bainha de Mielina , Corticosteroides , Animais , Astrócitos/metabolismo , Cuprizona/metabolismo , Cuprizona/farmacologia , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Oligodendroglia/metabolismo , Pregnenodionas
4.
Molecules ; 27(16)2022 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-36014345

RESUMO

An ancient saffron-based polyherbal formulation, Dawa-ul-Kurkum (DuK), has been used to treat liver ailments and other diseases and was recently evaluated for its anticancer potential against hepatocellular carcinoma (HCC) by our research team. To gain further insight into the lead molecule of DuK, we selected ten active constituents belonging to its seven herbal constituents (crocin, crocetin, safranal, jatamansone, isovaleric acid, cinnamaldehyde, coumaric acid, citral, guggulsterone and dehydrocostus lactone). We docked them with 32 prominent proteins that play important roles in the development, progression and suppression of HCC and those involved in endoplasmic reticulum (ER) stress to identify the binding interactions between them. Three reference drugs for HCC (sorafenib, regorafenib, and nivolumab) were also examined for comparison. The in silico studies revealed that, out of the ten compounds, three of them-viz., Z-guggulsterone, dehydrocostus lactone and crocin-showed good binding efficiency with the HCC and ER stress proteins. Comparison of binding affinity with standard drugs was followed by preliminary in vitro screening of these selected compounds in human liver cancer cell lines. The results provided the basis for selecting Z-guggulsterone as the best-acting phytoconstituent amongst the 10 studied. Further validation of the binding efficiency of Z-guggulsterone was undertaking using molecular dynamics (MD) simulation studies. The effects of Z-guggulsterone on clone formation and cell cycle progression were also assessed. The anti-oxidant potential of Z-guggulsterone was analyzed through DPPH and FRAP assays. qRTPCR was utilized to check the results at the in vitro level. These results indicate that Z-guggulsterone should be considered as the main constituent of DuK instead of the crocin in saffron, as previously hypothesized.


Assuntos
Carcinoma Hepatocelular , Crocus , Neoplasias Hepáticas , Pregnenodionas , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Pregnenodionas/farmacologia
5.
J Neuromuscul Dis ; 9(4): 463-476, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35723111

RESUMO

Deflazacort and prednisone/prednisolone are the current standard of care for patients with Duchenne muscular dystrophy (DMD) based on evidence that they improve muscle strength, improve timed motor function, delay loss of ambulation, improve pulmonary function, reduce the need for scoliosis surgery, delay onset of cardiomyopathy, and increase survival. Both have been used off-label for many years (choice dependent on patient preference, cost, and geographic location) before FDA approval of deflazacort for DMD in 2017. In this review, we compare deflazacort and prednisone/prednisolone in terms of their key pharmacological features, relative efficacy, and safety profiles in patients with DMD. Differentiating features include lipid solubility, pharmacokinetics, changes in gene expression profiles, affinity for the mineralocorticoid receptor, and impact on glucose metabolism. Evidence from randomized clinical trials, prospective studies, meta-analyses, and post-hoc analyses suggests that patients receiving deflazacort experience similar or slower rates of functional decline compared with those receiving prednisone/prednisolone. Regarding side effects, weight gain and behavior side effects appear to be greater with prednisone/prednisolone than with deflazacort, whereas bone health, growth parameters, and cataracts appear worse with deflazacort.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/tratamento farmacológico , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Pregnenodionas , Estudos Prospectivos
6.
J Comp Eff Res ; 11(11): 779-786, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35713895

RESUMO

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about the Cincinnati study, which was published in the Journal of Comparative Effectiveness Research in January 2020. The Cincinnati study reviewed data from 435 males with Duchenne muscular dystrophy, also known as DMD, who were treated at the Cincinnati Children's Hospital Medical Center. DMD is a rare disease that worsens over time. People with DMD experience inflammation in their muscles and muscle loss over time. They also experience bone problems such as an abnormally bent spine, also known as scoliosis, as well as heart and lung problems. WHAT HAPPENED IN THE CINCINNATI STUDY?: Prednisone and deflazacort are steroids that help to reduce muscle inflammation and are used as treatments for DMD. The study researchers wanted to further understand the differences between using prednisone and deflazacort in males with DMD by reviewing data from past medical records of patients seen in clinics rather than in clinical studies. This is known as gathering real-world evidence. In the Cincinnati study, the researchers compared males with DMD who started taking prednisone as their first steroid treatment with males who started taking deflazacort as their first steroid treatment. WHAT WERE THE RESULTS?: Overall, the researchers found that the participants who took deflazacort were able to walk until a later age before they needed to use a wheelchair, compared with those who took prednisone. They also had a lower risk of scoliosis and developed it at a later age. WHAT DO THE RESULTS OF THE STUDY MEAN?: These results helped the researchers to learn more about the differences between how well prednisone and deflazacort work in males with DMD based on their medical records.


Assuntos
Distrofia Muscular de Duchenne , Escoliose , Criança , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Idioma , Masculino , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/tratamento farmacológico , Prednisona/uso terapêutico , Pregnenodionas , Escoliose/induzido quimicamente , Escoliose/tratamento farmacológico
7.
Biochem Pharmacol ; 202: 115149, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35714682

RESUMO

Growing evidence indicates that inflammatory damage is implicated in the pathogenesis of Alzheimer's disease (AD). Z-Guggulsterone (Z-GS) is a natural steroid, which is extracted from Commiphora mukul and has anti-inflammatory effects in vivo and in vitro. In the present study, we investigated the disease-modifying effects of chronic Z-GS administration on the cognitive and neuropathological impairments in the transgenic mouse models of AD. We found that chronic Z-GS administration prevented learning and memory deficits in the APPswe/PS1dE9 mice. In addition, Z-GS treatment significantly decreased cerebral amyloid-ß (Aß) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that Z-GS treatment markedly alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated TLR4/NF-κB signaling pathways in APPswe/PS1dE9 mice were remarkably inhibited by Z-GS treatment, which was achieved via suppressing the phosphorylation of JNK. Collectively, our data demonstrate that chronic Z-GS treatment restores cognitive defects and reverses multiple neuropathological impairments in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective effects and neurobiological mechanisms of Z-GS on AD, indicating that Z-GS is a promising disease-modifying agent for the treatment of AD.


Assuntos
Doença de Alzheimer , Receptor 4 Toll-Like , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/metabolismo , Cognição , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Doenças Neuroinflamatórias , Pregnenodionas , Presenilina-1/genética , Transdução de Sinais
8.
Säo Paulo med. j ; 140(3): 430-438, May-June 2022. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1377394

RESUMO

ABSTRACT BACKGROUND: Use of inhaled corticosteroids for managing acute asthma exacerbations has been tested since the 1990s. OBJECTIVE: To compare high doses of inhaled ciclesonide with systemic hydrocortisone for managing acute asthma exacerbations in the emergency department. DESIGN AND SETTING: Double-blind, randomized clinical trial in the public healthcare system of the city of São Paulo. METHODS: Fifty-eight patients with moderate or severe asthma with peak flow < 50% of predicted were randomized into two groups. Over the course of four hours, one group received 1440 mcg of inhaled ciclesonide plus hydrocortisone-identical placebo (ciclesonide + placebo), while the other received 500 mg of intravenous hydrocortisone plus ciclesonide-identical placebo (hydrocortisone + placebo). Both groups received short-acting bronchodilators (fenoterol hydrobromide and ipratropium bromide). The research protocol included spirometry, clinical evaluation, vital signs and electrocardiogram monitoring. Data were obtained at 30 (baseline), 60, 90, 120, 180, and 240 minutes. We compared data from baseline to hour 4, between and within groups. RESULTS: Overall, 31 patients received ciclesonide + placebo and 27 received hydrocortisone + placebo. Inhaled ciclesonide was as effective as intravenous hydrocortisone for improving clinical parameters (Borg-scored dyspnea, P = 0.95; sternocleidomastoid muscle use, P = 0.55; wheezing, P = 0.55; respiratory effort, P = 0.95); and spirometric parameters (forced vital capacity, P = 0.50; forced expiratory volume in the first second, P = 0.83; peak expiratory flow, P = 0.51). CONCLUSIONS: Inhaled ciclesonide was not inferior to systemic hydrocortisone for managing acute asthma exacerbations, and it improved both clinical and spirometric parameters. TRIAL REGISTRATION: RBR-6XWC26 - Registro Brasileiro de Ensaios Clínicos (http://www.ensaiosclinicos.gov.br/rg/RBR-6xwc26/).


Assuntos
Asma/tratamento farmacológico , Hidrocortisona/uso terapêutico , Hidrocortisona/farmacologia , Pregnenodionas , Brasil , Volume Expiratório Forçado , Método Duplo-Cego , Serviço Hospitalar de Emergência
9.
Eur J Paediatr Neurol ; 38: 77-84, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35500465

RESUMO

BACKGROUND: US food and drug administration has recently approved deflazacort for Duchenne muscular dystrophy (DMD) and recommended the dosage of 0.9 mg/kg/d for patients aged ≥5years. However, data assessing the minimal efficacious dose and need of dose-titration based on age or disease severity is limited. OBJECTIVE: To determine whether deflazacort 0.45 mg/kg/d (proposed lower dosage) is non-inferior to 0.9 mg/kg/d among newly diagnosed patients with DMD. METHOD: A double-blinded, non-inferiority, randomized trial, conducted between December 2018 and July 2020. Newly diagnosed patient aged 5-15 years with genetic or muscle biopsy confirmed DMD and baseline 6-min walk distance (6MWD) > 150 m were screened. Patients were randomly assigned (1:1), stratified to prespecified subgroups by age (≤7years and >7years), and baseline 6MWD (≤350 m and >350 m), to receive either 0.45 mg/kg/d or 0.9 mg/kg/d regimens. The primary endpoint was the change in 6MWD, from baseline to week-24 of intervention. The trial was powered with a predefined, non-inferiority margin of 30 m. The analyses were by modified intention-to-treat (mITT). RESULT: A total of 97 patients were enrolled, 40 receiving 0.45 mg/kg/d and 45 receiving 0.9 mg/kg/d deflazacort comprised of mITT population. For primary endpoint analysis the mean (SD) change in 6MWD from baseline to week-24 was 9.7 m (41.5) in deflazacort 0.45 mg/kg/d, and 34.7 m (43.5) for 0.9 mg/kg/d. The mean difference in change in 6MWD across the group was 24.8 m (95% CI 6.7 to 43, p value 0.008). The mean difference in change in 6MWD in the subgroups of boys ≤7 years of age was 21.8 m (95% CI -0.82, 44.5, p = 0.059), with baseline 6MWD of >350 m was 19.9 m (95% CI -2.4, 42.4; p = 0.08). The incidence of combined moderate to severe treatment-related adverse events was significant in the 0.9 mg/kg/d group by week 24 (odds ratio 0.36 [95% CI, 0.14 to 0.89], p = 0.03). DISCUSSION: The efficacy of proposed low dose deflazacort in comparison to the standard dose did not meet the prespecified criteria for non-inferiority. The low dose deflazacort was non-inferior in subgroup of patients with age ≤7 years and baseline 6MWD of >350 m. TRIAL REGISTRATION: Clinical Trial Registry-India Identifier: CTRI/2019/02/017388.


Assuntos
Distrofia Muscular de Duchenne , Pregnenodionas , Criança , Método Duplo-Cego , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Pregnenodionas/efeitos adversos , Resultado do Tratamento , Caminhada/fisiologia
10.
J Pharmacol Sci ; 149(3): 81-84, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35641031

RESUMO

Ciclesonide (Cic) is approved as an inhalant for asthma and was clinically tested as a candidate therapy for coronavirus disease 2019 (COVID-19). Its active metabolite Cic2 was recently reported to suppress genomic RNA replication of severe acute respiratory syndrome coronavirus 2. In this study, we designed and synthesized a set of ciclesonide-acetal (Cic-acetal) derivatives. Among designated compounds, some Cic-acetal derivatives with a linear alkyl chain exhibited strong viral copy-number reduction activities compared with Cic2. These compounds might serve as lead compounds for developing novel anti-COVID-19 agents.


Assuntos
Antivirais , Acetais/farmacologia , Antivirais/farmacologia , Humanos , Pregnenodionas , RNA Viral/genética , RNA Viral/farmacologia , SARS-CoV-2 , Replicação Viral/genética
11.
Sao Paulo Med J ; 140(3): 430-438, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35508008

RESUMO

BACKGROUND: Use of inhaled corticosteroids for managing acute asthma exacerbations has been tested since the 1990s. OBJECTIVE: To compare high doses of inhaled ciclesonide with systemic hydrocortisone for managing acute asthma exacerbations in the emergency department. DESIGN AND SETTING: Double-blind, randomized clinical trial in the public healthcare system of the city of São Paulo. METHODS: Fifty-eight patients with moderate or severe asthma with peak flow < 50% of predicted were randomized into two groups. Over the course of four hours, one group received 1440 mcg of inhaled ciclesonide plus hydrocortisone-identical placebo (ciclesonide + placebo), while the other received 500 mg of intravenous hydrocortisone plus ciclesonide-identical placebo (hydrocortisone + placebo). Both groups received short-acting bronchodilators (fenoterol hydrobromide and ipratropium bromide). The research protocol included spirometry, clinical evaluation, vital signs and electrocardiogram monitoring. Data were obtained at 30 (baseline), 60, 90, 120, 180, and 240 minutes. We compared data from baseline to hour 4, between and within groups. RESULTS: Overall, 31 patients received ciclesonide + placebo and 27 received hydrocortisone + placebo. Inhaled ciclesonide was as effective as intravenous hydrocortisone for improving clinical parameters (Borg-scored dyspnea, P = 0.95; sternocleidomastoid muscle use, P = 0.55; wheezing, P = 0.55; respiratory effort, P = 0.95); and spirometric parameters (forced vital capacity, P = 0.50; forced expiratory volume in the first second, P = 0.83; peak expiratory flow, P = 0.51). CONCLUSIONS: Inhaled ciclesonide was not inferior to systemic hydrocortisone for managing acute asthma exacerbations, and it improved both clinical and spirometric parameters. TRIAL REGISTRATION: RBR-6XWC26 - Registro Brasileiro de Ensaios Clínicos (http://www.ensaiosclinicos.gov.br/rg/RBR-6xwc26/).


Assuntos
Asma , Hidrocortisona , Asma/tratamento farmacológico , Brasil , Método Duplo-Cego , Serviço Hospitalar de Emergência , Volume Expiratório Forçado , Humanos , Hidrocortisona/farmacologia , Hidrocortisona/uso terapêutico , Pregnenodionas
12.
JAMA ; 327(15): 1456-1468, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35381069

RESUMO

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.


Assuntos
Glucocorticoides , Distrofia Muscular de Duchenne , Prednisona , Criança , Pré-Escolar , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Glucocorticoides/uso terapêutico , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Pregnenodionas/efeitos adversos
13.
Clin Microbiol Infect ; 28(7): 1010-1016, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35304280

RESUMO

OBJECTIVES: To assess the efficacy of inhaled ciclesonide in reducing the risk of adverse outcomes in COVID-19 outpatients at risk of developing severe illness. METHODS: COVERAGE is an open-label, randomized controlled trial. Outpatients with documented COVID-19, risk factors for aggravation, symptoms for ≤7 days, and absence of criteria for hospitalization are randomly allocated to either a control arm or one of several experimental arms, including inhaled ciclesonide. The primary efficacy endpoint is COVID-19 worsening (hospitalization, oxygen therapy at home, or death) by Day 14. Other endpoints are adverse events, maximal follow-up score on the WHO Ordinal Scale for Clinical Improvement, sustained alleviation of symptoms, cure, and RT-PCR and blood parameter evolution at Day 7. The trial's Safety Monitoring Board reviewed the first interim analysis of the ciclesonide arm and recommended halting it for futility. The results of this analysis are reported here. RESULTS: The analysis involved 217 participants (control 107, ciclesonide 110), including 111 women and 106 men. Their median age was 63 years (interquartile range 59-68), and 157 of 217 (72.4%) had at least one comorbidity. The median time since first symptom was 4 days (interquartile range 3-5). During the 28-day follow-up, 2 participants died (control 2/107 [1.9%], ciclesonide 0), 4 received oxygen therapy at home and were not hospitalized (control 2/107 [1.9%], ciclesonide 2/110 [1.8%]), and 24 were hospitalized (control 10/107 [9.3%], ciclesonide 14/110 [12.7%]). In intent-to-treat analysis of observed data, 26 participants reached the composite primary endpoint by Day 14, including 12 of 106 (11.3%, 95% CI: 6.0%-18.9%) in the control arm and 14 of 106 (13.2%; 95% CI: 7.4-21.2%) in the ciclesonide arm. Secondary outcomes were similar for both arms. DISCUSSION: Our findings are consistent with the European Medicines Agency's COVID-19 task force statement that there is currently insufficient evidence that inhaled corticosteroids are beneficial for patients with COVID-19.


Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Oxigênio , Pregnenodionas , SARS-CoV-2 , Resultado do Tratamento
16.
Molecules ; 27(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164154

RESUMO

Autism spectrum disorder is a neurodevelopmental disorder marked by repetitive behaviour, challenges in verbal and non-verbal communication, poor socio-emotional health, and cognitive impairment. An increased level of signal transducer and activator of transcription 3 (STAT3) and a decreased level of peroxisome proliferator-activated receptor (PPAR) gamma have been linked to autism pathogenesis. Guggulsterone (GST) has a neuroprotective effect on autistic conditions by modulating these signalling pathways. Consequently, the primary objective of this study was to examine potential neuroprotective properties of GST by modulating JAK/STAT and PPAR-gamma levels in intracerebroventricular propionic acid (ICV PPA) induced experimental model of autism in adult rats. In this study, the first 11 days of ICV-PPA injections in rats resulted in autism-like behavioural, neurochemical, morphological, and histopathological changes. The above modifications were also observed in various biological samples, including brain homogenate, CSF, and blood plasma. GST was also observed to improve autism-like behavioural impairments in autistic rats treated with PPA, including locomotion, neuromuscular coordination, depression-like behaviour, spatial memory, cognition, and body weight. Prolonged GST treatment also restored neurochemical deficits in a dose-dependent manner. Chronic PPA administration increased STAT3 and decreased PPAR gamma in autistic rat brain, CSF, and blood plasma samples, which were reversed by GST. GST also restored the gross and histopathological alterations in PPA-treated rat brains. Our results indicate the neuroprotective effects of GST in preventing autism-related behavioural and neurochemical alterations.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Pregnenodionas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Modelos Animais de Doenças , Feminino , Janus Quinases/metabolismo , Masculino , PPAR gama/metabolismo , Propionatos , Ratos Wistar , Fatores de Transcrição STAT/metabolismo
17.
Aktuelle Urol ; 53(5): 454-460, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-31537025

RESUMO

INTRODUCTION: To evaluate the efficacy of tamsulosin and deflazacort in the spontaneous expulsion of distal ureteral stones when applied in an independent or combined manner. METHODS: 134 patients with distal ureteral stones (4 - 10 mm) were included in tothe study. All patients were randomized into four groups: group 1 (n = 37) patients receiving tamsulosin (0.4 mg/day); group 2 (n = 26) patients receiving deflazacort (30 mg/day); group 3 (n = 37) patients receiving combined treatment (tamsulosin and deflazacort) with the same dosages; and group 4, control group cases (n = 34), receiving paracetamol on demand. Although deflazacort treatment was limited to 10 days due to the possible associated side effects, α-blocker and paracetamol lasted up to four weeks. Patients were followed up on a weekly basis and at the end of four weeks all groups were compared primarily with respect to the stone expulsion rates. RESULTS: No statistically significant difference was noted between all groups regarding the age, sex, or stone burden (p > 0.05). Spontaneous stone expulsion rates after 4 weeks were 64.8 %, 69.2 %, 75.7 %, and 26.4 % in group 1, 2, 3, and 4 respectively. Spontaneous passage rates were statistically higher in all treatment groups when compared with the control group. Despite the highest spontaneous stone expulsion rate noted in group 3; this difference was not statistically significant when compared with the group 1 and 2. No major side effect related to the medications was observed. CONCLUSIONS: Tamsulosin facilitated the spontaneous passage of distal ureteral stones < 10 mm in size in an effective manner particularly when applied in combination with an oral corticosteroid.


Assuntos
Acetaminofen , Cálculos Ureterais , Acetaminofen/uso terapêutico , Humanos , Pregnenodionas , Estudos Prospectivos , Sulfonamidas/uso terapêutico , Tansulosina/uso terapêutico , Resultado do Tratamento , Cálculos Ureterais/tratamento farmacológico
18.
Drug Test Anal ; 14(2): 252-261, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34634175

RESUMO

Ciclesonide (CIC) is the first inhaled highly potent corticosteroid that does not cause any cortisol suppression. It has been developed for the treatment of asthma in human and more recently in equine. CIC is the active compound of Aservo® EquiHaler® (Boehringer Ingelheim Vetmedica GmbH), the pre-filled inhaler generating a medicated mist based on Soft Mist™ technology. This prodrug is rapidly converted to desisobutyryl-ciclesonide (des-CIC), the main pharmacologically active compound. Due to its anti-inflammatory properties, CIC is prohibited for use in horse competitions. To set up an appropriate control, the determination of detection times and screening limits are required. Therefore, a highly sensitive analytical method based on supported liquid extraction (SLE) combined with liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS) was developed to detect CIC and its active metabolite des-CIC in plasma. The lower limit of detection of CIC and des-CIC was approximately 1 pg/ml in plasma. After a pilot study conducted on a single horse at the recommended dose (eight actuations twice daily corresponding to 5.5 mg/day for the first 5 days, followed by 12 actuations once daily corresponding to 4.1 mg/day in the last 5 days), the same protocol was applied in the main study using six horses. In all horses, CIC and des-CIC levels were less than 5 and 10 pg/ml, respectively, at 36 h after the end of the administration. The outcome of this risk assessment study should be useful to draw any recommendations for horse competitions.


Assuntos
Pregnenodionas , Pró-Fármacos , Animais , Cromatografia Líquida/métodos , Cavalos , Projetos Piloto , Pregnenodionas/análise
19.
JAMA Intern Med ; 182(1): 42-49, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34807241

RESUMO

Importance: Systemic corticosteroids are commonly used in treating severe COVID-19. However, the role of inhaled corticosteroids in the treatment of patients with mild to moderate disease is less clear. Objective: To determine the efficacy of the inhaled steroid ciclesonide in reducing the time to alleviation of all COVID-19-related symptoms among nonhospitalized participants with symptomatic COVID-19 infection. Design, Setting, and Participants: This phase 3, multicenter, double-blind, randomized clinical trial was conducted at 10 centers throughout the US and assessed the safety and efficacy of a ciclesonide metered-dose inhaler (MDI) for treating nonhospitalized participants with symptomatic COVID-19 infection who were screened from June 11, 2020, to November 3, 2020. Interventions: Participants were randomly assigned to receive ciclesonide MDI, 160 µg per actuation, for a total of 2 actuations twice a day (total daily dose, 640 µg) or placebo for 30 days. Main Outcomes and Measures: The primary end point was time to alleviation of all COVID-19-related symptoms (cough, dyspnea, chills, feeling feverish, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell) by day 30. Secondary end points included subsequent emergency department visits or hospital admissions for reasons attributable to COVID-19. Results: A total of 413 participants were screened and 400 (96.9%) were enrolled and randomized (197 [49.3%] in the ciclesonide arm and 203 [50.7%] in the placebo arm; mean [SD] age, 43.3 [16.9] years; 221 [55.3%] female; 2 [0.5%] Asian, 47 [11.8%] Black or African American, 3 [0.8%] Native Hawaiian or other Pacific Islander, 345 [86.3%] White, and 1 multiracial individuals [0.3%]; 172 Hispanic or Latino individuals [43.0%]). The median time to alleviation of all COVID-19-related symptoms was 19.0 days (95% CI, 14.0-21.0) in the ciclesonide arm and 19.0 days (95% CI, 16.0-23.0) in the placebo arm. There was no difference in resolution of all symptoms by day 30 (odds ratio, 1.28; 95% CI, 0.84-1.97). Participants who were treated with ciclesonide had fewer subsequent emergency department visits or hospital admissions for reasons related to COVID-19 (odds ratio, 0.18; 95% CI, 0.04-0.85). No participants died during the study. Conclusions and Relevance: The results of this randomized clinical trial demonstrated that ciclesonide did not achieve the primary efficacy end point of reduced time to alleviation of all COVID-19-related symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04377711.


Assuntos
Pregnenodionas/normas , Administração por Inalação , Adolescente , Adulto , Instituições de Assistência Ambulatorial/organização & administração , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Instituições de Assistência Ambulatorial/tendências , COVID-19/epidemiologia , Método Duplo-Cego , Feminino , Glucocorticoides/normas , Glucocorticoides/uso terapêutico , Humanos , Masculino , Inaladores Dosimetrados , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Pregnenodionas/uso terapêutico
20.
Bioorg Med Chem ; 54: 116563, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34942553

RESUMO

Pancreatic cancer is one of the deadliest types of malignancies. A new intervention aiming to combat pancreatic cancer is targeting its extra-ordinary ability to tolerate nutrition starvation, a phenomenon known as "Austerity". As a part of a research program aiming to develop a new-generation of anticancer agents, known as "anti-austerity agents", guggulsterone derivatives (GSDs) were identified as unique anti-austerity agents in terms of potency and selectivity. These agents are able to exert preferential cytotoxic activity only under nutrient-deprived conditions with little or no toxicity under normal conditions. In the present study, a library of 14 GSDs was synthesized and screened against PANC-1 human pancreatic cells. Among tested compounds, GSD-11 showed the most potent activity with PC50 a value of 0.72 µM. It also inhibited pancreatic cancer cell migration and colony formation in a concentration-dependent manner. A mechanistic study revealed that this compound can inhibit the activation of the Akt/mTOR signaling pathway. Therefore, GSD-11 could be a promising lead compound for the anticancer drug discovery against pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Pancreáticas/tratamento farmacológico , Pregnenodionas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Pregnenodionas/síntese química , Pregnenodionas/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Células Tumorais Cultivadas
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