RESUMO
BACKGROUND: Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity. METHODS: SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir's dose and schedule to maximize the probability of success for COVID-19. RESULTS: Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 µM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. CONCLUSIONS: Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.
Assuntos
COVID-19 , Preparações Farmacêuticas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Carbamatos , Chlorocebus aethiops , Humanos , Imidazóis , Pirrolidinas , RNA Viral , SARS-CoV-2 , Sofosbuvir/farmacologia , Valina/análogos & derivados , Células VeroRESUMO
INTRODUCTION AND OBJECTIVES: The incidence of liver injury (LI) in hospitalized COVID-19 patients ranged from 14% to 53% based on sole or multiple elevated indexes for LI. The aims of our study were to investigate the changes of parameters (ALT, AST) in LI and determine the risk factors for LI in a cohort of 830 COVID-19 patients. METHODS: Demographic information, clinical features, and laboratory testing outcomes on admission were compared between patients with and without liver biochemistry abnormality (LBA). The same comparisons were performed between the LBA and LI groups. The updated RUCAM was used to determine the causality between drugs application and LI. Univariable and multivariable logistic regression analyses were used to explore the potential risk factors associated with LBA and LI. RESULTS: A total of 227 (27.3%) patients exhibited LBA and 32 (3.9%) patients were categorized as having LI based on the diagnostic criteria. 32.6% (74/227) of the LBA patients had RUCAM score >3, whereas the non-LBA patients had a slight lower at rate of 24.2% (146/603) (P?=?0.047). Multivariable regression showed that a higher incidence of LBA was associated with hepatic hypoattenuation on computed tomography (CT) (odds ratio: 2.243, 95% confidence interval: 1.410-3.592, p?=?0.001), lymphocyte proportion <20% (2.088, 1.476-2.954, p?1?mg/dL (2.650, 1.845-3.806, p?1 (2.558, 1.820-3.596, p?1.0?mg/dL, lymphocyte proportion <20%, AST/ALT ratio <1, and triglyceride levels >1.7?mol/L are potential risk factors for LI.
Assuntos
COVID-19/complicações , Hepatopatias/etiologia , Fígado/metabolismo , SARS-CoV-2 , Adulto , Idoso , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , COVID-19/epidemiologia , Feminino , Humanos , Hepatopatias/diagnóstico , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
La Candida haemulonii forma parte de la especie Candida no albicans. La candidemia por C. haemulonii es sumamente infrecuente, pero mortal, en los recién nacidos. Se informa sobre los dos primeros recién nacidos con candidemia por C. haemulonii en China tratados con fluconazol y se revisan dos artículos informados con anterioridad. Nuestro informe incrementa la sensibilización sobre la candidemia por C. haemulonii en recién nacidos críticos y resalta la importancia de un diagnóstico y un tratamiento tempranos de esta infección mortal.
Candida haemulonii forms part of the non-albicans Candida species. The candidemia caused by C. haemulonii is extremely rare but fatal in neonates. We reported the first two neonates with C. haemulonii candidemia in China which were treated with fluconazole and reviewed two papers previously reported. Our report adds further awareness on C. haemulonii candidemia in critical neonates and points out the importance of an early diagnosis and treatment of this fatal infection.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Fluconazol/uso terapêutico , Infecções Relacionadas a Cateter/tratamento farmacológico , Candidemia/tratamento farmacológico , Candida/isolamento & purificação , China , Resultado do Tratamento , Infecções Relacionadas a Cateter/microbiologia , Candidemia/etiologia , Candidemia/microbiologia , Antifúngicos/uso terapêuticoRESUMO
Candida haemulonii forms part of the non-albicans Candida species. The candidemia caused by C. haemulonii is extremely rare but fatal in neonates. We reported the first two neonates with C. haemulonii candidemia in China which were treated with fluconazole and reviewed two papers previously reported. Our report adds further awareness on C. haemulonii candidemia in critical neonates and points out the importance of an early diagnosis and treatment of this fatal infection.
La Candida haemulonii forma parte de la especie Candida no albicans. La candidemia por C. haemulonii es sumamente infrecuente, pero mortal, en los recién nacidos. Se informa sobre los dos primeros recién nacidos con candidemia por C. haemulonii en China tratados con fluconazol y se revisan dos artículos informados con anterioridad. Nuestro informe incrementa la sensibilización sobre la candidemia por C. haemulonii en recién nacidos críticos y resalta la importancia de un diagnóstico y un tratamiento tempranos de esta infección mortal.
Assuntos
Antifúngicos/uso terapêutico , Candidemia/tratamento farmacológico , Infecções Relacionadas a Cateter/tratamento farmacológico , Fluconazol/uso terapêutico , Candida/isolamento & purificação , Candidemia/etiologia , Candidemia/microbiologia , Infecções Relacionadas a Cateter/microbiologia , China , Humanos , Recém-Nascido , Masculino , Resultado do TratamentoRESUMO
Caesalpinia sappan has been shown to have interesting immunosuppressive properties. Its heartwood has long been used in Chinese medicines for treating a variety of immune-mediated pathology and inflammatory disease. The purpose of this work was to evaluate the immunocompetence effects of brazilein on mice lymphocytes in vitro and in vivo. The results showed that brazilein and Caesalpinia sappan ethanol extract (SME) could distinctly inhibit the proliferation of T lymphocyte stimulated by Concanavalin A (Con A) and the proliferation of B lymphocyte stimulated by lipopolysaccharides (LPS), and brazilein could suppress mice humoral immune response by plaque forming cell (PFC) test. In addition, immune organs (thymus and spleen) in mice treated with brazilein were notably atrophied and weight loss in vivo (intraperitoneal injection, i.p.). In attempting to investigate the mechanisms of the immunosuppressive activity of brazilein, we discovered that brazilein can induce apoptosis in mice spleen lymphocytes by flow cytometry analysis and DNA fragmentation assay, which may be one of the pathways that brazilein inhibited immunocompetence of mice lymphocytes.