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1.
Am J Gastroenterol ; 116(9): 1924-1928, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34465694

RESUMO

INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Falência Renal Crônica/terapia , Sofosbuvir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Esquema de Medicação , Feminino , Fluorenos/administração & dosagem , Hepatite C/complicações , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Sofosbuvir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento
2.
Viruses ; 13(8)2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34452507

RESUMO

An Emergency Use Authorization was issued in the United States and in Europe for a monoclonal antibody monotherapy to prevent severe COVID-19 in high-risk patients. This study aimed to assess the risk of emergence of mutations following treatment with a single monoclonal antibody. Bamlanivimab was administered at a single dose of 700 mg in a one-hour IV injection in a referral center for the management of COVID-19 in France. Patients were closely monitored clinically and virologically with nasopharyngeal RT-PCR and viral whole genome sequencing. Six patients were treated for a nosocomial SARS-CoV-2 infection, all males, with a median age of 65 years and multiple comorbidities. All patients were infected with a B.1.1.7 variant, which was the most frequent variant in France at the time, and no patients had E484 mutations at baseline. Bamlanivimab was infused in the six patients within 4 days of the COVID-19 diagnosis. Four patients had a favorable outcome, one died of complications unrelated to COVID-19 or bamlanivimab, and one kidney transplant patient treated with belatacept died from severe COVID-19 more than 40 days after bamlanivimab administration. Virologically, four patients cleared nasopharyngeal viral shedding within one month after infusion, while two presented prolonged viral excretion for more than 40 days. The emergence of E484K mutants was observed in five out of six patients, and the last patient presented a Q496R mutation potentially associated with resistance. CONCLUSIONS: These results show a high risk of emergence of resistance mutants in COVID-19 patients treated with monoclonal antibody monotherapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , SARS-CoV-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antivirais/administração & dosagem , COVID-19/complicações , Comorbidade , Farmacorresistência Viral/genética , França , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , SARS-CoV-2/efeitos dos fármacos , Índice de Gravidade de Doença
3.
Viruses ; 13(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34452519

RESUMO

Strategies to combat COVID-19 require multiple ways to protect vulnerable people from infection. SARS-CoV-2 is an airborne pathogen and the nasal cavity is a primary target of infection. The K18-hACE2 mouse model was used to investigate the anti-SARS-CoV-2 efficacy of astodrimer sodium formulated in a mucoadhesive nasal spray. Animals received astodrimer sodium 1% nasal spray or PBS intranasally, or intranasally and intratracheally, for 7 days, and they were infected intranasally with SARS-CoV-2 after the first product administration on Day 0. Another group was infected intranasally with SARS-CoV-2 that had been pre-incubated with astodrimer sodium 1% nasal spray or PBS for 60 min before the neutralisation of test product activity. Astodrimer sodium 1% significantly reduced the viral genome copies (>99.9%) and the infectious virus (~95%) in the lung and trachea vs. PBS. The pre-incubation of SARS-CoV-2 with astodrimer sodium 1% resulted in a significant reduction in the viral genome copies (>99.9%) and the infectious virus (>99%) in the lung and trachea, and the infectious virus was not detected in the brain or liver. Astodrimer sodium 1% resulted in a significant reduction of viral genome copies in nasal secretions vs. PBS on Day 7 post-infection. A reduction in the viral shedding from the nasal cavity may result in lower virus transmission rates. Viraemia was low or undetectable in animals treated with astodrimer sodium 1% or infected with treated virus, correlating with the lack of detectable viral replication in the liver. Similarly, low virus replication in the nasal cavity after treatment with astodrimer sodium 1% potentially protected the brain from infection. Astodrimer sodium 1% significantly reduced the pro-inflammatory cytokines IL-6, IL-1α, IL-1ß, TNFα and TGFß and the chemokine MCP-1 in the serum, lung and trachea vs. PBS. Astodrimer sodium 1% nasal spray blocked or reduced SARS-CoV-2 replication and its sequelae in K18-hACE2 mice. These data indicate a potential role for the product in preventing SARS-CoV-2 infection or for reducing the severity of COVID-19.


Assuntos
Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , Dendrímeros/administração & dosagem , Cavidade Nasal/virologia , Sprays Nasais , Polilisina/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/uso terapêutico , Encéfalo/virologia , COVID-19/prevenção & controle , COVID-19/virologia , Dendrímeros/uso terapêutico , Modelos Animais de Doenças , Feminino , Fígado/virologia , Masculino , Camundongos , Camundongos Transgênicos , Polilisina/uso terapêutico , Sistema Respiratório/virologia , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Carga Viral/efeitos dos fármacos , Viremia , Replicação Viral/efeitos dos fármacos
4.
Viruses ; 13(8)2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34452529

RESUMO

An escalating pandemic of the novel SARS-CoV-2 virus is impacting global health, and effective antivirals are needed. Umifenovir (Arbidol) is an indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It has been shown that umifenovir has broad spectrum activity against different viruses. We evaluated the sensitivity of different coronaviruses, including the novel SARS-CoV-2 virus, to umifenovir using in vitro assays. Using a plaque assay, we revealed an antiviral effect of umifenovir against seasonal HCoV-229E and HCoV-OC43 coronaviruses in Vero E6 cells, with estimated 50% effective concentrations (EC50) of 10.0 ± 0.5 µM and 9.0 ± 0.4 µM, respectively. Umifenovir at 90 µM significantly suppressed plaque formation in CMK-AH-1 cells infected with SARS-CoV. Umifenovir also inhibited the replication of SARS-CoV-2 virus, with EC50 values ranging from 15.37 ± 3.6 to 28.0 ± 1.0 µM. In addition, 21-36 µM of umifenovir significantly suppressed SARS-CoV-2 virus titers (≥2 log TCID50/mL) in the first 24 h after infection. Repurposing of antiviral drugs is very helpful in fighting COVID-19. A safe, pan-antiviral drug such as umifenovir could be extremely beneficial in combating the early stages of a viral pandemic.


Assuntos
Antivirais/farmacologia , Coronavirus Humano 229E/efeitos dos fármacos , Coronavirus Humano OC43/efeitos dos fármacos , Indóis/farmacologia , Vírus da SARS/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos , Animais , Antivirais/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Coronavirus Humano 229E/fisiologia , Coronavirus Humano OC43/fisiologia , Efeito Citopatogênico Viral/efeitos dos fármacos , Humanos , Indóis/administração & dosagem , Testes de Sensibilidade Microbiana , Vírus da SARS/fisiologia , SARS-CoV-2/fisiologia , Células Vero , Carga Viral/efeitos dos fármacos , Ensaio de Placa Viral , Replicação Viral/efeitos dos fármacos
5.
Pharmaceut Med ; 35(4): 203-213, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34453703

RESUMO

The Emergency Use Authorization (EUA) originated in 2004 because of the need for emergency medical countermeasures (MCMs) against potential bioterrorist attacks. The EUA also proved useful in dealing with subsequent pandemics and has emerged as a critical regulatory pathway for therapeutics and vaccines throughout the Coronavirus Disease 2019 (COVID-19) pandemic. With the EUA process in the USA, we witnessed emergency authorizations, their expansions, as well as withdrawal of previously authorized products, which exemplifies the dynamic nature of scientific review of EUA products. EUAs proved vital for the first group of COVID-19 vaccines, including the temporary pause of one vaccine while emergency safety issues were evaluated. Although this review on the EUA is primarily focused on the USA, distinctions were made with other jurisdictions such as Europe and Canada with respect to the emergency authorizations of the vaccines. Finally, we discuss some important differences following EUA and formal new drug/vaccine application (NDA/BLA) approvals.


Assuntos
Antivirais/normas , Vacinas contra COVID-19/normas , COVID-19/prevenção & controle , Aprovação de Drogas/legislação & jurisprudência , Emergências/história , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Bioterrorismo/história , Bioterrorismo/prevenção & controle , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Canadá/epidemiologia , Defesa Civil/história , Aprovação de Drogas/história , Emergências/epidemiologia , Europa (Continente)/epidemiologia , História do Século XXI , Humanos , Pandemias/prevenção & controle , Estados Unidos/epidemiologia
6.
Nat Microbiol ; 6(9): 1188-1198, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400835

RESUMO

SARS-CoV-2 variants of interest and concern will continue to emerge for the duration of the COVID-19 pandemic. To map mutations in the receptor-binding domain (RBD) of the spike protein that affect binding to angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2, we applied in vitro evolution to affinity-mature the RBD. Multiple rounds of random mutagenic libraries of the RBD were sorted against decreasing concentrations of ACE2, resulting in the selection of higher affinity RBD binders. We found that mutations present in more transmissible viruses (S477N, E484K and N501Y) were preferentially selected in our high-throughput screen. Evolved RBD mutants include prominently the amino acid substitutions found in the RBDs of B.1.620, B.1.1.7 (Alpha), B1.351 (Beta) and P.1 (Gamma) variants. Moreover, the incidence of RBD mutations in the population as presented in the GISAID database (April 2021) is positively correlated with increased binding affinity to ACE2. Further in vitro evolution increased binding by 1,000-fold and identified mutations that may be more infectious if they evolve in the circulating viral population, for example, Q498R is epistatic to N501Y. We show that our high-affinity variant RBD-62 can be used as a drug to inhibit infection with SARS-CoV-2 and variants Alpha, Beta and Gamma in vitro. In a model of SARS-CoV-2 challenge in hamster, RBD-62 significantly reduced clinical disease when administered before or after infection. A 2.9 Å cryo-electron microscopy structure of the high-affinity complex of RBD-62 and ACE2, including all rapidly spreading mutations, provides a structural basis for future drug and vaccine development and for in silico evaluation of known antibodies.


Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/administração & dosagem , COVID-19/virologia , SARS-CoV-2/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/genética , Animais , Antivirais/química , COVID-19/tratamento farmacológico , COVID-19/genética , COVID-19/metabolismo , Cricetinae , Desenho de Fármacos , Evolução Molecular , Feminino , Humanos , Masculino , Mesocricetus , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Receptores Virais/genética , Receptores Virais/metabolismo , SARS-CoV-2/química , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Internalização do Vírus/efeitos dos fármacos
7.
Front Immunol ; 12: 716407, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34394121

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new strain of coronavirus and the causative agent of the current global pandemic of coronavirus disease 2019 (COVID-19). There are currently no FDA-approved antiviral drugs for COVID-19 and there is an urgent need to develop treatment strategies that can effectively suppress SARS-CoV-2 infection. Numerous approaches have been researched so far, with one of them being the emerging exosome-based therapies. Exosomes are nano-sized, lipid bilayer-enclosed structures, share structural similarities with viruses secreted from all types of cells, including those lining the respiratory tract. Importantly, the interplay between exosomes and viruses could be potentially exploited for antiviral drug and vaccine development. Exosomes are produced by virus-infected cells and play crucial roles in mediating communication between infected and uninfected cells. SARS-CoV-2 modulates the production and composition of exosomes, and can exploit exosome formation, secretion, and release pathways to promote infection, transmission, and intercellular spread. Exosomes have been exploited for therapeutic benefits in patients afflicted with various diseases including COVID-19. Furthermore, the administration of exosomes loaded with immunomodulatory cargo in combination with antiviral drugs represents a novel intervention for the treatment of diseases such as COVID-19. In particular, exosomes derived from mesenchymal stem cells (MSCs) are used as cell-free therapeutic agents. Mesenchymal stem cell derived exosomes reduces the cytokine storm and reverse the inhibition of host anti-viral defenses associated with COVID-19 and also enhances mitochondrial function repair lung injuries. We discuss the role of exosomes in relation to transmission, infection, diagnosis, treatment, therapeutics, drug delivery, and vaccines, and present some future perspectives regarding their use for combating COVID-19.


Assuntos
Antivirais/administração & dosagem , Antivirais/uso terapêutico , COVID-19/terapia , Portadores de Fármacos/uso terapêutico , Exossomos/metabolismo , Imunomodulação/imunologia , Biomarcadores/metabolismo , COVID-19/patologia , COVID-19/transmissão , Síndrome da Liberação de Citocina/terapia , Humanos , Células-Tronco Mesenquimais/imunologia , SARS-CoV-2/imunologia
8.
Int J Med Mushrooms ; 23(5): 1-11, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34347990

RESUMO

Since December 2019, a de novo pattern of pneumonia, later named coronavirus disease 2019 (COVID-19), has caused grave upset throughout the global population. COVID-19 is associated with several comorbidities; thus, preventive and therapeutic strategies targeting those comorbidities along with the causative agent, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), seem imperative. In this state-of-the-art review, edible and medicinal mushrooms are featured in the treatment of SARS-CoV-2, COVID-19 pathomanifestations, and comorbid issues. Because this is not an original research article, we admit our shortcomings in inferences. Yet we are hopeful that mushroom-based therapeutic approaches can be used to achieve a COVID-free world. Among various mushroom species, reishi or lingzhi (Ganoderma lucidum) seem most suitable as anti-COVID agents for the global population.


Assuntos
Agaricales/química , Antivirais/uso terapêutico , Produtos Biológicos/uso terapêutico , COVID-19/prevenção & controle , COVID-19/terapia , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Antivirais/administração & dosagem , Produtos Biológicos/administração & dosagem , COVID-19/imunologia , COVID-19/fisiopatologia , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/terapia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Camundongos , Reishi/química , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
9.
Drug Des Devel Ther ; 15: 3313-3330, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34366663

RESUMO

The acute respiratory syndrome coronavirus (SARS-CoV-2) has spread across the world, resulting in a pandemic COVID-19 which is a human zoonotic disease that is caused by a novel coronavirus (CoV) strain thought to have originated in wild or captive bats in the initial COVID outbreak region. The global COVID-19 outbreak started in Guangdong Province, China's southernmost province. The global response to the COVID-19 pandemic has been hampered by the sheer number of infected people, many of whom need intensive care before succumbing to the disease. The epidemic is being handled by a combination of disease control by public health interventions and compassionate treatment for those who have been impacted. There is no clear anti-COVID-19 medication available at this time. However, the need to find medications that can turn the tide has led to the development of a number of investigational drugs as potential candidates for improving outcomes, especially in the severely and critically ill. Although many of these adjunctive medications are still being studied in clinical trials, professional organizations have attempted to define the circumstances in which their use is deemed off-label or compassionate. It is important to remind readers that new information about COVID-19's clinical features, treatment options, and outcomes is released on a regular basis. The mainstay of treatment remains optimized supportive care, and the therapeutic effectiveness of the subsequent agents is still being studied.


Assuntos
Antivirais/administração & dosagem , Vacinas contra COVID-19/administração & dosagem , COVID-19/tratamento farmacológico , Portadores de Fármacos , Reposicionamento de Medicamentos , Modelos Moleculares , Animais , Antivirais/química , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/virologia , Vacinas contra COVID-19/química , Composição de Medicamentos , Interações Hospedeiro-Patógeno , Humanos , Nanopartículas , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Vacinação
10.
Int J Mol Sci ; 22(15)2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34360721

RESUMO

Host lipid metabolism reprogramming is essential for hepatitis C virus (HCV) infection and progression to severe liver disease. Direct-acting antivirals (DAAs) achieve a sustained virological response (SVR) in most patients, but virus eradication does not always protect against hepatocellular carcinoma (HCC). Angiopoietin-like protein-3 (ANGPTL-3) and angiopoietin-like protein-4 (ANGPTL-4) regulate the clearance of plasma lipids by inhibiting cellular lipase activity and possess emerging roles in tumourigenesis. We used ELISA and RT-qPCR to investigate ANGPTL-3 and ANGPTL-4 expression in HCV patients with characterised fibrosis throughout the natural history of hepatitis C and in long-term HCV infection in vitro, before and after DAA treatment. ANGPTL-3 was decreased in patients with advanced fibrosis compared to other disease stages, while ANGPTL-4 was progressively increased from acute infection to cirrhosis and HCC, peaking at the advanced fibrosis stage. Only ANGPTL-3 mRNA was down-regulated during early infection in vitro, although both ANGPTLs were increased later. DAA treatment did not alter ANGPTL-3 levels in advanced fibrosis/cirrhosis and in HCV infection in vitro, in contrast to ANGPTL-4. The association between ANGPTLs and fibrosis in HCV infection was underlined by an inverse correlation between the levels of ANGPTLs and serum transforming growth factor- ß (TGF-ß). Collectively, we demonstrate the pivotal role of advanced fibrosis in defining the expression fate of ANGPTLs in HCV infection and after treatment and propose a role for ANGPTL-3 as a contributor to post-treatment deregulation of lipid metabolism that could predispose certain individuals to HCC development.


Assuntos
Proteína 4 Semelhante a Angiopoietina/biossíntese , Proteínas Semelhantes a Angiopoietina/biossíntese , Antivirais/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Hepacivirus/metabolismo , Hepatite C Crônica , Cirrose Hepática , Linhagem Celular Tumoral , Feminino , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/metabolismo , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino
11.
J Clin Lab Anal ; 35(9): e23923, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34390043

RESUMO

BACKGROUND: The dynamic alteration and comparative study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding pattern during treatment are limited. This study explores the potential risk factors influencing prolonged viral shedding in COVID-19. METHODS: A total of 126 COVID-19 patients were enrolled in this retrospective longitudinal study. A multivariate logistic regression analysis was carried out to estimate the potential risk factors. RESULTS: 38.1% (48/126) cases presented prolonged respiratory tract viral shedding, and 30 (23.8%) cases presented prolonged rectal swab viral shedding. Obesity (OR, 3.31; 95% CI, 1.08-10.09), positive rectal swab (OR, 3.43; 95% CI, 1.53-7.7), treatment by lopinavir/ritonavir with chloroquine phosphate (OR, 2.5; 95% CI, 1.04-6.03), the interval from onset to antiviral treatment more than 7 days (OR, 2.26; 95% CI, 1.04-4.93), lower CD4+ T cell (OR, 0.92; 95% CI, 0.86-0.99) and higher NK cells (OR, 1.11; 95% CI, 1.02-1.20) were significantly associated with prolonged respiratory tract viral shedding. CD3-CD56+ NK cells (OR, 0.87; 95% CI, 0.76-0.99) were related with prolonged fecal shedding. CONCLUSIONS: Obesity, delayed antiviral treatment, and positive SARS-CoV-2 for stool were independent risk factors for prolonged SARS-CoV-2 RNA shedding of the respiratory tract. A combination of LPV/r and abidol as the initial antiviral regimen was effective in shortening the duration of viral shedding compared with LPV/r combined with chloroquine phosphate. CD4+ T cell and NK cells were significantly associated with prolonged viral shedding, and further studies are to be warranted to determine the mechanism of immunomodulatory response in virus clearance.


Assuntos
COVID-19/virologia , Fezes/virologia , SARS-CoV-2/fisiologia , Eliminação de Partículas Virais/fisiologia , Adulto , Animais , Antivirais/administração & dosagem , Contagem de Linfócito CD4 , COVID-19/epidemiologia , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Cloroquina/análogos & derivados , Feminino , Humanos , Células Matadoras Naturais , Estudos Longitudinais , Lopinavir/administração & dosagem , Lynx , Masculino , Obesidade/epidemiologia , Sistema Respiratório/virologia , Estudos Retrospectivos , Fatores de Risco , Ritonavir/administração & dosagem , Fatores de Tempo , Eliminação de Partículas Virais/efeitos dos fármacos
12.
Viruses ; 13(7)2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34372520

RESUMO

The 2019 novel coronavirus (COVID-19) pandemic has placed a significant strain on hepatitis programs and interventions (screening, diagnosis, and treatment) at a critical moment in the context of hepatitis C virus (HCV) elimination. We sought to quantify changes in Direct Acting Antiviral (DAA) utilization among different countries during the pandemic. We conducted a cross-sectional time series analysis between 1 September 2018 and 31 August 2020, using the IQVIA MIDAS database, which contains DAA purchase data for 54 countries. We examined the percent change in DAA units dispensed (e.g., pills and capsules) from March to August 2019 to the same period of time in 2020 across the 54 countries. Interrupted time-series analysis was used to examine the impact of COVID-19 on monthly rates of DAA utilization across each of the major developed economies (G7 nations). Overall, 46 of 54 (85%) jurisdictions experienced a decline in DAA utilization during the pandemic, with an average of -43% (range: -1% in Finland to -93% in Brazil). All high HCV prevalence (HCV prevalence > 2%) countries in the database experienced a decline in utilization, average -49% (range: -17% in Kazakhstan to -90% in Egypt). Across the G7 nations, we also observed a decreased trend in DAA utilization during the early months of the pandemic, with significant declines (p < 0.01) for Canada, Germany, the United Kingdom, and the United States of America. The global response to COVID-19 led to a large decrease in DAA utilization globally. Deliberate efforts to counteract the impact of COVID-19 on treatment delivery are needed to support the goal of HCV elimination.


Assuntos
Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , Antivirais/normas , Brasil/epidemiologia , COVID-19/epidemiologia , Canadá/epidemiologia , Estudos Transversais , Egito/epidemiologia , Finlândia/epidemiologia , Alemanha/epidemiologia , Hepacivirus/isolamento & purificação , Hepatite C , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Cazaquistão/epidemiologia , Pandemias , Prevalência , SARS-CoV-2/isolamento & purificação , Reino Unido/epidemiologia , Estados Unidos
13.
Viruses ; 13(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34372616

RESUMO

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


Assuntos
Antivirais/farmacologia , Budesonida/farmacologia , COVID-19/tratamento farmacológico , SARS-CoV-2/efeitos dos fármacos , Corticosteroides/farmacologia , Animais , Antivirais/administração & dosagem , Budesonida/administração & dosagem , COVID-19/virologia , Chlorocebus aethiops , Glucocorticoides/farmacologia , Humanos , Células Vero , Replicação Viral/efeitos dos fármacos
14.
Eur J Med Res ; 26(1): 92, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34384499

RESUMO

PURPOSE: Herpes zoster (HZ), or shingles, is a clinical syndrome resulting from the reactivation of latent varicella zoster virus (VZV) within the sensory ganglia. We evaluated the safety and tolerability of ES16001 (ethanol extract of Elaeocarpus sylvestris var. ellipticus), a novel inhibitor of varicella zoster virus reactivation in healthy adults. METHOD: Single-center, randomized, double-blind, placebo-controlled, single and multiple ascending dose (SAD and MAD, respectively) studies were conducted in 20- to 45-year-old healthy adults without chronic disease. In the SAD study (n = 32), subjects randomly received a single oral dose of 240, 480, 960, or 1440 mg ES16001 or a placebo. In the MAD study (n = 16), subjects randomly received once daily doses of 480 or 960 mg ES16001 or a placebo for 5 days. The safety and tolerability of the drug were evaluated by monitoring participants' treatment emergent adverse events (TEAEs) and vital signs, electrocardiograms (ECGs), physical examinations, and clinical laboratory tests. RESULTS: In the SAD study, 11 adverse reactions were seen in 5 subjects, and in the MAD study, 8 adverse reactions were seen in 6 subjects. All adverse reactions were mild, and no serious adverse reactions occurred. The most common adverse reaction was an increase in alanine aminotransferase (ALT), but all test values were in the clinically non-significant range, and their clinical significance was judged to be small considering the fact that most of the test values returned to normal immediately after the end of drug administration. CONCLUSION: ES16001 has good safety and tolerability when administered both once and repeatedly to healthy subjects. Further research is needed to identify any possible drug-induced hepatotoxicity, which appears infrequently. Our findings provide a rationale for further clinical investigations of ES16001 for the prevention of HZ. TRIAL REGISTRATION: CRIS, KCT0006066. Registered 7 April 2021-Retrospectively registered, https://cris.nih.go.kr/cris/search/detailSearch.do/19071 ).


Assuntos
Antivirais/efeitos adversos , Elaeocarpaceae/química , Herpes Zoster/tratamento farmacológico , Extratos Vegetais/efeitos adversos , Adulto , Alanina Transaminase/sangue , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Tolerância a Medicamentos , Feminino , Herpes Zoster/prevenção & controle , Humanos , Masculino , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Ativação Viral/efeitos dos fármacos
15.
Front Immunol ; 12: 695972, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34341659

RESUMO

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.


Assuntos
COVID-19/imunologia , Granulócitos/imunologia , Células Supressoras Mieloides/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/administração & dosagem , Arginase/antagonistas & inibidores , Arginase/metabolismo , Arginina/administração & dosagem , Arginina/sangue , Arginina/metabolismo , Infecções Assintomáticas , COVID-19/sangue , COVID-19/diagnóstico , COVID-19/tratamento farmacológico , Estudos de Casos e Controles , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/administração & dosagem , Feminino , Granulócitos/metabolismo , Voluntários Saudáveis , Humanos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Linfócitos T/imunologia
16.
PLoS Pathog ; 17(8): e1009427, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34370799

RESUMO

Impaired type I interferons (IFNs) production or signaling have been associated with severe COVID-19, further promoting the evaluation of recombinant type I IFNs as therapeutics against SARS-CoV-2 infection. In the Syrian hamster model, we show that intranasal administration of IFN-α starting one day pre-infection or one day post-infection limited weight loss and decreased viral lung titers. By contrast, intranasal administration of IFN-α starting at the onset of symptoms three days post-infection had no impact on the clinical course of SARS-CoV-2 infection. Our results provide evidence that early type I IFN treatment is beneficial, while late interventions are ineffective, although not associated with signs of enhanced disease.


Assuntos
Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , Interferon Tipo I/administração & dosagem , Administração Intranasal , Animais , Chlorocebus aethiops , Cricetinae , Modelos Animais de Doenças , Mesocricetus , SARS-CoV-2
17.
Transpl Immunol ; 68: 101435, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34216759

RESUMO

Acute graft-versus-host disease (aGVHD) is a rare complication after liver transplantation that characterized by high mortality. We presented a case of aGVHD after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The patient suffered from fever, oral ulcer, rashes and diarrhea and had a co-infection with Cytomegalovirus (CMV). Short tandem repeat (STR) analysis for cluster of differentiation (CD3) cells and skin biopsy indicated aGVHD. His regimens included high dose of steroids, ruxolitinib, basiliximab, local liver radiotherapy and antibiotics prophylaxis, with the withdrawal of tacrolimus and MMF. Unfortunately, he developed an acute rejection followed by cytomegalovirus infection and lung infection. Soon afterwards he was sent to "isolation ward" due to high suspicion for clinical coronavirus disease 2019 (COVID-19). Fortunately, He was excluded from COVID-19 after nucleic acid and antibody tests. Though closely contact with other COVID-19 patients for a month, the patient was not affected with COVID-19 through his careful protective measures. Finally, the patient recovered after antiviral and antifungal treatment. To our knowledge, this is the first case report of a patient recovered from aGVHD as a close contact.


Assuntos
Antifúngicos/administração & dosagem , Antivirais/administração & dosagem , Teste de Ácido Nucleico para COVID-19 , COVID-19/diagnóstico , Carcinoma Hepatocelular/terapia , Infecções por Citomegalovirus , Citomegalovirus , Doença Enxerto-Hospedeiro/tratamento farmacológico , Neoplasias Hepáticas/terapia , Transplante de Fígado , SARS-CoV-2 , Doença Aguda , Infecções por Citomegalovirus/tratamento farmacológico , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/virologia , Humanos , Masculino , Pessoa de Meia-Idade
18.
Sci Signal ; 14(690)2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230209

RESUMO

Inorganic polyphosphates (polyPs) are linear polymers composed of repeated phosphate (PO4 3-) units linked together by multiple high-energy phosphoanhydride bonds. In addition to being a source of energy, polyPs have cytoprotective and antiviral activities. Here, we investigated the antiviral activities of long-chain polyPs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In molecular docking analyses, polyPs interacted with several conserved amino acid residues in angiotensin-converting enzyme 2 (ACE2), the host receptor that facilitates virus entry, and in viral RNA-dependent RNA polymerase (RdRp). ELISA and limited proteolysis assays using nano- LC-MS/MS mapped polyP120 binding to ACE2, and site-directed mutagenesis confirmed interactions between ACE2 and SARS-CoV-2 RdRp and identified the specific amino acid residues involved. PolyP120 enhanced the proteasomal degradation of both ACE2 and RdRp, thus impairing replication of the British B.1.1.7 SARS-CoV-2 variant. We thus tested polyPs for functional interactions with the virus in SARS-CoV-2-infected Vero E6 and Caco2 cells and in primary human nasal epithelial cells. Delivery of a nebulized form of polyP120 reduced the amounts of viral positive-sense genomic and subgenomic RNAs, of RNA transcripts encoding proinflammatory cytokines, and of viral structural proteins, thereby presenting SARS-CoV-2 infection in cells in vitro.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Polifosfatos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Administração por Inalação , Sequência de Aminoácidos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Antivirais/administração & dosagem , Antivirais/química , COVID-19/metabolismo , COVID-19/virologia , Células CACO-2 , Chlorocebus aethiops , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/genética , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Citocinas/metabolismo , Células HEK293 , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Técnicas In Vitro , Modelos Biológicos , Simulação de Acoplamento Molecular , Nebulizadores e Vaporizadores , Polifosfatos/administração & dosagem , Polifosfatos/química , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios e Motivos de Interação entre Proteínas , Proteólise/efeitos dos fármacos , RNA Viral/genética , RNA Viral/metabolismo , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Homologia de Sequência de Aminoácidos , Transdução de Sinais/efeitos dos fármacos , Células Vero , Replicação Viral/efeitos dos fármacos
19.
PLoS One ; 16(7): e0254341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34242340

RESUMO

BACKGROUND: Aerosolization of respiratory droplets is considered the main route of coronavirus disease 2019 (COVID-19). Therefore, reducing the viral load of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) shed via respiratory droplets is potentially an ideal strategy to prevent the spread of the pandemic. The in vitro virucidal activity of intranasal Povidone-Iodine (PVP-I) has been demonstrated recently to reduce SARS-CoV-2 viral titres. This study evaluated the virucidal activity of the aqueous solution of Iodine-V (a clathrate complex formed by elemental iodine and fulvic acid) as in Essential Iodine Drops (EID) with 200 µg elemental iodine/ml content against SARS-CoV-2 to ascertain whether it is a better alternative to PVP-I. METHODS: SARS-CoV-2 (USAWA1/2020 strain) virus stock was prepared by infecting Vero 76 cells (ATCC CRL-1587) until cytopathic effect (CPE). The virucidal activity of EID against SARS-CoV-2 was tested in three dilutions (1:1; 2:1 and 3:1) in triplicates by incubating at room temperature (22 ± 2°C) for either 60 or 90 seconds. The surviving viruses from each sample were quantified by a standard end-point dilution assay. RESULTS: EID (200 µg iodine/ml) after exposure for 60 and 90 seconds was compared to controls. In both cases, the viral titre was reduced by 99% (LRV 2.0). The 1:1 dilution of EID with virus reduced SARS-CoV-2 virus from 31,623 cell culture infectious dose 50% (CCID50) to 316 CCID50 within 90 seconds. CONCLUSION: Substantial reductions in LRV by Iodine-V in EID confirmed the activity of EID against SARS-CoV-2 in vitro, demonstrating that Iodine-V in EID is effective at inactivating the virus in vitro and therefore suggesting its potential application intranasally to reduce SARS-CoV-2 transmission from known or suspected COVID-19 patients.


Assuntos
Antivirais/administração & dosagem , COVID-19 , Pandemias , Povidona-Iodo/administração & dosagem , SARS-CoV-2 , Administração Intranasal , Animais , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/transmissão , Chlorocebus aethiops , Humanos , Iodo/administração & dosagem , Células Vero
20.
Folia Neuropathol ; 59(2): 113-120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34284539

RESUMO

The majority of COVID-19 cases are only mildly or moderately symptomatic, but in some patients excessive inflammatory response becomes the dominant factor of disease progression to the advanced stage, with high mortality. Treatment with anti-inflammatory drugs either does not prevent disease progression (non-steroidal anti-inflammatory drugs [NSAIDs], colchicine), or is recommended only at the advanced disease stage (dexamethasone). Fluvoxamine and amantadine are drugs used to treat neurological and psychiatric diseases. Fluvoxamine is a selective serotonin uptake inhibitor, whereas amantadine is an old antiviral variably influencing brain neurotransmitter systems, and repurposed to Parkinson's disease. Both drugs are agonists of sigma-1 receptors located in the endoplasmic reticulum, which effect seems responsible for their anti-inflammatory activity. Moreover, amantadine was found to dampen the expression of cathepsin-L, a lysosomal enzyme implicated in SARS-CoV-2 virus entry to target cells. In two small controlled clinical trials, early treatment of SARS-CoV-2-infected persons with fluvoxamine fully prevented COVID-19 symptoms. Anecdotal evidence shows that amantadine may be similarly effective. Both drugs are easily available, inexpensive and have favorable safety profiles. Clinical trials evaluating their efficacy as much-needed post-exposure prophylaxis and early treatment of COVID-19 are ongoing.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antivirais/administração & dosagem , COVID-19/tratamento farmacológico , Fármacos do Sistema Nervoso Central/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , COVID-19/diagnóstico , COVID-19/imunologia , Humanos , Resultado do Tratamento
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