Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30.439
Filtrar
1.
J Biosci ; 452020.
Artículo en Inglés | MEDLINE | ID: mdl-32661214

RESUMEN

The current global pandemic COVID-19 caused by the SARS-CoV-2 virus has already inflicted insurmountable damage both to the human lives and global economy. There is an immediate need for identification of effective drugs to contain the disastrous virus outbreak. Global efforts are already underway at a war footing to identify the best drug combination to address the disease. In this review, an attempt has been made to understand the SARS-CoV-2 life cycle, and based on this information potential druggable targets against SARS-CoV-2 are summarized. Also, the strategies for ongoing and future drug discovery against the SARSCoV- 2 virus are outlined. Given the urgency to find a definitive cure, ongoing drug repurposing efforts being carried out by various organizations are also described. The unprecedented crisis requires extraordinary efforts from the scientific community to effectively address the issue and prevent further loss of human lives and health.


Asunto(s)
Corticoesteroides/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos , Factores Inmunológicos/uso terapéutico , Pandemias , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Progresión de la Enfermedad , Descubrimiento de Drogas , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Hidroxicloroquina/uso terapéutico , Simulación del Acoplamiento Molecular , Terapia Molecular Dirigida/métodos , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/inmunología , Neumonía Viral/epidemiología , Neumonía Viral/inmunología , Neumonía Viral/virología , Transducción de Señal/genética , Transducción de Señal/inmunología , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología
2.
Molecules ; 25(12)2020 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-32604797

RESUMEN

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Asunto(s)
Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/metabolismo , Minería de Datos/métodos , Infecciones por VIH/epidemiología , Infecciones por VIH/metabolismo , Interacciones Huésped-Patógeno/inmunología , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/metabolismo , Antiinflamatorios/uso terapéutico , Antígenos de Diferenciación/genética , Antígenos de Diferenciación/inmunología , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Proteínas del Sistema Complemento/genética , Proteínas del Sistema Complemento/inmunología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Bases de Datos Genéticas , Regulación de la Expresión Génica , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , VIH-1/inmunología , VIH-1/patogenicidad , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/genética , Humanos , Inmunidad Innata/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Inflamación , Interferones/genética , Interferones/inmunología , Interleucinas/genética , Interleucinas/inmunología , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/inmunología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Transducción de Señal , Receptores Toll-Like/genética , Receptores Toll-Like/inmunología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología
4.
Cardiovasc Diabetol ; 19(1): 114, 2020 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-32690029

RESUMEN

In the pandemic "Corona Virus Disease 2019" (COVID-19) people with diabetes have a high risk to require ICU admission. The management of diabetes in Intensive Care Unit is always challenging, however, when diabetes is present in COVID-19 the situation seems even more complicated. An optimal glycemic control, avoiding acute hyperglycemia, hypoglycemia and glycemic variability may significantly improve the outcome. In this case, intravenous insulin infusion with continuous glucose monitoring should be the choice. No evidence suggests stopping angiotensin-converting-enzyme inhibitors, angiotensin-renin-blockers or statins, even it has been suggested that they may increase the expression of Angiotensin-Converting-Enzyme-2 (ACE2) receptor, which is used by "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to penetrate into the cells. A real issue is the usefulness of several biomarkers, which have been suggested to be measured during the COVID-19. N-Terminal-pro-Brain Natriuretic-Peptide, D-dimer and hs-Troponin are often increased in diabetes. Their meaning in the case of diabetes and COVID-19 should be therefore very carefully evaluated. Even though we understand that in such a critical situation some of these requests are not so easy to implement, we believe that the best possible action to prevent a worse outcome is essential in any medical act.


Asunto(s)
Betacoronavirus/patogenicidad , Glucemia/efectos de los fármacos , Infecciones por Coronavirus/terapia , Diabetes Mellitus/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Unidades de Cuidados Intensivos , Neumonía Viral/terapia , Antihipertensivos/uso terapéutico , Biomarcadores/sangre , Glucemia/metabolismo , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Diabetes Mellitus/sangre , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/mortalidad , Dislipidemias/tratamiento farmacológico , Dislipidemias/mortalidad , Interacciones Huésped-Patógeno , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/mortalidad , Hipoglucemiantes/efectos adversos , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Neumonía Viral/virología , Medición de Riesgo , Factores de Riesgo , Resultado del Tratamiento
6.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-32641705
7.
Genome Med ; 12(1): 57, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32605661

RESUMEN

BACKGROUND: COVID-19 (coronavirus disease 2019) has caused a major epidemic worldwide; however, much is yet to be known about the epidemiology and evolution of the virus partly due to the scarcity of full-length SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) genomes reported. One reason is that the challenges underneath sequencing SARS-CoV-2 directly from clinical samples have not been completely tackled, i.e., sequencing samples with low viral load often results in insufficient viral reads for analyses. METHODS: We applied a novel multiplex PCR amplicon (amplicon)-based and hybrid capture (capture)-based sequencing, as well as ultra-high-throughput metatranscriptomic (meta) sequencing in retrieving complete genomes, inter-individual and intra-individual variations of SARS-CoV-2 from serials dilutions of a cultured isolate, and eight clinical samples covering a range of sample types and viral loads. We also examined and compared the sensitivity, accuracy, and other characteristics of these approaches in a comprehensive manner. RESULTS: We demonstrated that both amplicon and capture methods efficiently enriched SARS-CoV-2 content from clinical samples, while the enrichment efficiency of amplicon outran that of capture in more challenging samples. We found that capture was not as accurate as meta and amplicon in identifying between-sample variations, whereas amplicon method was not as accurate as the other two in investigating within-sample variations, suggesting amplicon sequencing was not suitable for studying virus-host interactions and viral transmission that heavily rely on intra-host dynamics. We illustrated that meta uncovered rich genetic information in the clinical samples besides SARS-CoV-2, providing references for clinical diagnostics and therapeutics. Taken all factors above and cost-effectiveness into consideration, we proposed guidance for how to choose sequencing strategy for SARS-CoV-2 under different situations. CONCLUSIONS: This is, to the best of our knowledge, the first work systematically investigating inter- and intra-individual variations of SARS-CoV-2 using amplicon- and capture-based whole-genome sequencing, as well as the first comparative study among multiple approaches. Our work offers practical solutions for genome sequencing and analyses of SARS-CoV-2 and other emerging viruses.


Asunto(s)
Betacoronavirus/genética , Genoma Viral/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Secuenciación Completa del Genoma/métodos , Infecciones por Coronavirus , Variación Genética/genética , Interacciones Huésped-Patógeno/genética , Humanos , Reacción en Cadena de la Polimerasa Multiplex/métodos , Pandemias , Neumonía Viral , ARN Viral/genética
8.
Immunol Rev ; 296(1): 205-219, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32658335

RESUMEN

This article provides a review of studies evaluating the role of host (and viral) genetics (including variation in HLA genes) in the immune response to coronaviruses, as well as the clinical outcome of coronavirus-mediated disease. The initial sections focus on seasonal coronaviruses, SARS-CoV, and MERS-CoV. We then examine the state of the knowledge regarding genetic polymorphisms and SARS-CoV-2 and COVID-19. The article concludes by discussing research areas with current knowledge gaps and proposes several avenues for future scientific exploration in order to develop new insights into the immunology of SARS-CoV-2.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Resistencia a la Enfermedad/genética , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno/genética , Neumonía Viral/inmunología , Animales , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/genética , Neumonía Viral/virología , Virus del SRAS/inmunología , Virus del SRAS/patogenicidad , Síndrome Respiratorio Agudo Grave/genética , Síndrome Respiratorio Agudo Grave/virología
9.
Blood Adv ; 4(13): 2967-2978, 2020 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-32609845

RESUMEN

Thrombocytopenia is a common complication of influenza virus infection, and its severity predicts the clinical outcome of critically ill patients. The underlying cause(s) remain incompletely understood. In this study, in patients with an influenza A/H1N1 virus infection, viral load and platelet count correlated inversely during the acute infection phase. We confirmed this finding in a ferret model of influenza virus infection. In these animals, platelet count decreased with the degree of virus pathogenicity varying from 0% in animals infected with the influenza A/H3N2 virus, to 22% in those with the pandemic influenza A/H1N1 virus, up to 62% in animals with a highly pathogenic A/H5N1 virus infection. This thrombocytopenia is associated with virus-containing platelets that circulate in the blood. Uptake of influenza virus particles by platelets requires binding to sialoglycans and results in the removal of sialic acids by the virus neuraminidase, a trigger for hepatic clearance of platelets. We propose the clearance of influenza virus by platelets as a paradigm. These insights clarify the pathophysiology of influenza virus infection and show how severe respiratory infections, including COVID-19, may propagate thrombocytopenia and/or thromboembolic complications.


Asunto(s)
Plaquetas/virología , Virus de la Influenza A/patogenicidad , Gripe Humana/complicaciones , Ácido N-Acetilneuramínico/metabolismo , Polisacáridos/metabolismo , Trombocitopenia/etiología , Animales , Plaquetas/metabolismo , Plaquetas/patología , Modelos Animales de Enfermedad , Hurones , Interacciones Huésped-Patógeno , Humanos , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Subtipo H1N1 del Virus de la Influenza A/fisiología , Subtipo H3N2 del Virus de la Influenza A/patogenicidad , Subtipo H3N2 del Virus de la Influenza A/fisiología , Subtipo H5N1 del Virus de la Influenza A/patogenicidad , Subtipo H5N1 del Virus de la Influenza A/fisiología , Virus de la Influenza A/fisiología , Gripe Humana/metabolismo , Gripe Humana/patología , Gripe Humana/virología , Infecciones por Orthomyxoviridae/complicaciones , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Trombocitopenia/metabolismo , Trombocitopenia/patología , Trombocitopenia/virología , Internalización del Virus
10.
BMC Infect Dis ; 20(1): 480, 2020 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-32631335

RESUMEN

BACKGROUND: Influenza A virus (IAV) infection is a serious public health problem not only in South East Asia but also in European and African countries. Scientists are using network biology to dig deep into the essential host factors responsible for regulation of virus infections. Researchers can explore the virus invasion into the host cells by studying the virus-host relationship based on their protein-protein interaction network. METHODS: In this study, we present a comprehensive IAV-host protein-protein interaction network that is obtained based on the literature-curated protein interaction datasets and some important interaction databases. The network is constructed in Cytoscape and analyzed with its plugins including CytoHubba, CytoCluster, MCODE, ClusterViz and ClusterOne. In addition, Gene Ontology and KEGG enrichment analyses are performed on the highly IAV-associated human proteins. We also compare the current results with those from our previous study on Hepatitis C Virus (HCV)-host protein-protein interaction network in order to find out valuable information. RESULTS: We found out 1027 interactions among 829 proteins of which 14 are viral proteins and 815 belong to human proteins. The viral protein NS1 has the highest number of associations with human proteins followed by NP, PB2 and so on. Among human proteins, LNX2, MEOX2, TFCP2, PRKRA and DVL2 have the most interactions with viral proteins. Based on KEGG pathway enrichment analysis of the highly IAV-associated human proteins, we found out that they are enriched in the KEGG pathway of basal cell carcinoma. Similarly, the result of KEGG analysis of the common host factors involved in IAV and HCV infections shows that these factors are enriched in the infection pathways of Hepatitis B Virus (HBV), Viral Carcinoma, measles and certain other viruses. CONCLUSION: It is concluded that the list of proteins we identified might be used as potential drug targets for the drug design against the infectious diseases caused by Influenza A Virus and other viruses.


Asunto(s)
Interacciones Huésped-Patógeno/genética , Virus de la Influenza A/metabolismo , Gripe Humana/metabolismo , Mapas de Interacción de Proteínas/genética , Biología de Sistemas/métodos , Proteínas Portadoras/genética , Proteínas de Unión al ADN/genética , Hepacivirus/metabolismo , Hepatitis C/metabolismo , Hepatitis C/virología , Humanos , Gripe Humana/virología , Factores de Transcripción/genética , Proteínas del Núcleo Viral/genética , Proteínas no Estructurales Virales/genética , Replicación Viral
11.
Trials ; 21(1): 635, 2020 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-32650818

RESUMEN

OBJECTIVES: The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64. TRIAL DESIGN: Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial. PARTICIPANTS: Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate <20, mental state alert, no signs of septic shock. Cardiac risk is minimised by requiring a Tisdale score ≤ 6. Patients are recruited in the two german cities of Ulm and Tübingen in various ambulatory care settings. INTERVENTION AND COMPARATOR: Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2nd day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g. MAIN OUTCOMES: Rate of hospitalization or death at day 7 after study inclusion RANDOMISATION: All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list. BLINDING (MASKING): Patients and investigators, as well as treating physicians are blinded to the treatment- allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients. TRIAL STATUS: Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 TRIAL REGISTRATION: ClinicalTrials.gov: NCT04351516 , date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Atención Ambulatoria , Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/administración & dosificación , Neumonía Viral/tratamiento farmacológico , Factores de Edad , Anciano , Envejecimiento , Antivirales/efectos adversos , Betacoronavirus/patogenicidad , Causas de Muerte , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Método Doble Ciego , Esquema de Medicación , Femenino , Alemania , Hospitalización , Interacciones Huésped-Patógeno , Humanos , Hidroxicloroquina/efectos adversos , Masculino , Estudios Multicéntricos como Asunto , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Neumonía Viral/virología , Valor Predictivo de las Pruebas , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento
12.
Trials ; 21(1): 604, 2020 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-32616067

RESUMEN

OBJECTIVES: PRIMARY OBJECTIVE: To determine whether chemoprophylaxis with hydroxychloroquine versus placebo increases time to contracting coronavirus disease 2019 (COVID-19) in frontline healthcare workers. SECONDARY OBJECTIVES: 1) To determine whether chemoprophylaxis with daily versus weekly dosing of hydroxychloroquine increases time to contracting COVID-19 disease in frontline healthcare workers. 2) To compare the number of COVID-19 cases between each trial arm on the basis of positive tests (as per current clinical testing methods and/or serology) 3) To compare the percentage of COVID-19 positive individuals with current testing methods versus serologically-proven COVID-19 in each trial arm 4) To compare COVID-19 disease severity in each trial arm 5) To compare recovery time from COVID-19 infection in each trial arm EXPLORATORY OBJECTIVES: 1) To determine compliance (as measured by trough pharmacokinetic hydroxychloroquine levels) on COVID-19 positive tests 2) To determine if genetic factors determine susceptibility to COVID-19 disease or response to treatment 3) To determine if blood group determines susceptibility to COVID-19 disease 4) To compare serum biomarkers of COVID-19 disease in each arm TRIAL DESIGN: Double-blind, multi-centre, 2-arm (3:3:2 ratio) randomised placebo-controlled trial PARTICIPANTS: National Health Service (NHS) workers who have direct patient contact delivering care to patients with COVID-19. Participants in the trial will be recruited from a number of NHS hospitals directly caring for patients with COVID-19. INCLUSION CRITERIA: To be included in the trial the participant MUST: 1) Have given written informed consent to participate 2) Be aged 18 years to 70 years 3) Not previously have been diagnosed with COVID-19 4) Work in a high-risk secondary or tertiary healthcare setting (hospitals accepting COVID-19 patients) with direct patient-facing care EXCLUSION CRITERIA: The presence of any of the following will mean participants are ineligible: 1) Known COVID-19 positive test at baseline (if available) 2) Symptomatic for possible COVID-19 at baseline 3) Known hypersensitivity reaction to hydroxychloroquine, chloroquine or 4-aminoquinolines 4) Known retinal disease 5) Known porphyria 6) Known chronic kidney disease (CKD; eGFR<30ml/min) 7) Known epilepsy 8) Known heart failure or conduction problems 9) Known significant liver disease (Gilbert's syndrome is permitted) 10) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency 11) Currently taking any of the following contraindicated medications: Digoxin, Chloroquine, Halofantrine, Amiodarone, Moxifloxacin, Cyclosporin, Mefloquine, Praziquantel, Ciprofloxacin, Clarithromycin, Prochlorperazine, Fluconazole 12) Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine 13) Currently breastfeeding 14) Unable to be followed-up during the trial 15) Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit 16) Not able to use or have access to a modern phone device/web-based technology 17) Any other clinical reason which may preclude entry in the opinion of the investigator INTERVENTION AND COMPARATOR: Interventions being evaluated are: A) Daily hydroxychloroquine or B) Weekly hydroxychloroquine or C) Placebo The maximum treatment period is approximately 13 weeks per participant. Hydroxychloroquine-identical matched placebo tablets will ensure that all participants are taking the same number and dosing regimen of tablets across the three trial arms. There is no variation in the dose of hydroxychloroquine by weight. The dosing regimen for the three arms of the study (A, B, C) are described in further detail below. Arm A: Active Hydroxychloroquine (- daily dosing and placebo-matched hydroxychloroquine - weekly dosing). Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading phase - 400mg (2 x 200mg tablets) taken twice a day for 2 days Days 3 onwards: Maintenance Phase - 200mg (1 x 200mg tablet) taken once daily, every day for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Arm B: Active Hydroxychloroquine (- weekly dosing and placebo matched hydroxychloroquine - daily dosing.) Form: Tablets Route: Oral. Dose and Frequency: Active hydroxychloroquine: Days 1-2: Loading Phase - 400mg (2 x 200mg tablets) taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg tablets) taken once a week on the same day each week (every 7th day) for 90 days (~3 months) Matched Placebo hydroxychloroquine: Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Arm C: Matched placebo Hydroxychloroquine (- daily dosing and matched placebo hydroxychloroquine - weekly dosing.) Form: Table. Route: Oral. Frequency: Matched placebo hydroxychloroquine - daily dosing: Days 1-2: Loading Phase - 2 tablets taken twice daily for 2 days Days 3 onwards: Maintenance Phase - 1 tablet taken once daily for 90 days (~3 months) Matched placebo hydroxychloroquine - weekly dosing: Days 3 onwards: Maintenance Phase - 2 tablets taken once a week on the same day each week (every 7th day) for 90 days (~3 months) A schematic of the dosing schedule can be found in the full study protocol (Additional File 1). MAIN OUTCOMES: Time to diagnosis of positive COVID-19 disease (defined by record of date of symptoms onset and confirmed by laboratory test) RANDOMISATION: Participants will be randomised to either hydroxychloroquine dosed daily with weekly placebo, HCQ dosed weekly with daily placebo, or placebo dosed daily and weekly. Randomisation will be in a 3:3:2 ratio [hydroxychloroquine-(daily), hydroxychloroquine-(weekly), placebo], using stratified block randomisation. Random block sizes will be used, and stratification will be by study site. BLINDING (MASKING): Participants and trial investigators consenting participants, delivering trial assessments and procedures will be blinded to intervention. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A sufficient number of participants will be enrolled so that approximately 1000 participants in total will have data suitable for the primary statistical analysis. It is anticipated that approximately 1,200 participants will need to be enrolled in total, to allow for a 20% dropout over the period of the trial. This would result in approximately 450:450:300 participants randomised to hydroxychloroquine daily, hydroxychloroquine weekly+daily matched placebo or matched-placebo daily and weekly. TRIAL STATUS: V 1.0, 7th April 2020 EU Clinical Trials Register EudraCT Number: 2020-001331-26 Date of registration: 14th April 2020 Trial registered before first participant enrolment. Trial site is Cambridge University Hospitals NHS Foundation Trust. Recruitment started on 11th May 2020. It is anticipated that the trial will run for 12 months. The recruitment end date cannot yet be accurately predicted. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Asunto(s)
Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Quimioprevención , Infecciones por Coronavirus/prevención & control , Personal de Salud , Hidroxicloroquina/administración & dosificación , Salud Laboral , Pandemias/prevención & control , Neumonía Viral/prevención & control , Adolescente , Adulto , Anciano , Antivirales/efectos adversos , Antivirales/farmacocinética , Betacoronavirus/patogenicidad , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Esquema de Medicación , Inglaterra , Femenino , Interacciones Huésped-Patógeno , Humanos , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/farmacocinética , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Neumonía Viral/diagnóstico , Neumonía Viral/transmisión , Neumonía Viral/virología , Factores Protectores , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
13.
Viruses ; 12(6)2020 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-32599823

RESUMEN

The respiratory Influenza A Viruses (IAVs) and emerging zoonotic viruses such as Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pose a significant threat to human health. To accelerate our understanding of the host-pathogen response to respiratory viruses, the use of more complex in vitro systems such as normal human bronchial epithelial (NHBE) cell culture models has gained prominence as an alternative to animal models. NHBE cells were differentiated under air-liquid interface (ALI) conditions to form an in vitro pseudostratified epithelium. The responses of well-differentiated (wd) NHBE cells were examined following infection with the 2009 pandemic Influenza A/H1N1pdm09 strain or following challenge with the dsRNA mimic, poly(I:C). At 30 h postinfection with H1N1pdm09, the integrity of the airway epithelium was severely impaired and apical junction complex damage was exhibited by the disassembly of zona occludens-1 (ZO-1) from the cell cytoskeleton. wdNHBE cells produced an innate immune response to IAV-infection with increased transcription of pro- and anti-inflammatory cytokines and chemokines and the antiviral viperin but reduced expression of the mucin-encoding MUC5B, which may impair mucociliary clearance. Poly(I:C) produced similar responses to IAV, with the exception of MUC5B expression which was more than 3-fold higher than for control cells. This study demonstrates that wdNHBE cells are an appropriate ex-vivo model system to investigate the pathogenesis of respiratory viruses.


Asunto(s)
Subtipo H1N1 del Virus de la Influenza A/fisiología , Gripe Humana/virología , Mucosa Respiratoria/citología , Mucosa Respiratoria/virología , Animales , Bronquios/citología , Bronquios/virología , Células Cultivadas , Quimiocinas/metabolismo , Citocinas/metabolismo , Perros , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/epidemiología , Uniones Intercelulares , Células de Riñón Canino Madin Darby , Modelos Biológicos , Mucina 5AC/metabolismo , Pandemias , Cultivo de Virus
14.
Pharmacol Res Perspect ; 8(4): e00623, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32658389

RESUMEN

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 novel coronavirus, has spread worldwide causing high fatality rates. Neither a vaccine nor specific therapeutic approaches are available, hindering the fight against this disease and making better understanding of its pathogenesis essential. Despite similarities between SARS-CoV-2 and SARS-CoV, the former has unique characteristics which represent a great challenge to physicians. The mechanism of COVID-19 infection and pathogenesis is still poorly understood. In the present review, we highlight possible pathways involved in the pathogenesis of COVID-19 and potential therapeutic targets, focusing on the role of the renin-angiotensin-aldosterone system.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/virología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Sistema Renina-Angiotensina , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Medicina Basada en la Evidencia , Interacciones Huésped-Patógeno , Humanos , Pandemias , Peptidil-Dipeptidasa A/uso terapéutico , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos
15.
Physiol Res ; 69(3): 511-514, 2020 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-32682363

RESUMEN

Knowledge of genomic interindividual variability could help us to explain why different manifestation of clinical severity of Covid-19 infection as well as modified pharmacogenetic relations can be expected during this pandemic condition.


Asunto(s)
Infecciones por Coronavirus/genética , Neumonía Viral/genética , Betacoronavirus/fisiología , Predisposición Genética a la Enfermedad , Interacciones Huésped-Patógeno/genética , Humanos , Pandemias , Peptidil-Dipeptidasa A/genética
16.
Trials ; 21(1): 607, 2020 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-32616063

RESUMEN

OBJECTIVES: The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group. 6. To determine the risk of vertical transmission (intra-utero and intra-partum) of SARS-CoV-2. TRIAL DESIGN: Randomized double-blind placebo-controlled two-arm multicentre clinical trial to evaluate the safety and efficacy of HCQ to prevent and/or minimize SARS-CoV-2 infection during pregnancy. Participants will be randomized to receive a 14-day oral treatment course of HCQ or placebo, ratio 1:1. PARTICIPANTS: Study population: pregnant women undergoing routine prenatal follow up or attending emergency units at the participating hospitals who report either symptoms/signs suggestive of COVID-19 disease or close contact with a suspected or confirmed COVID-19 case. Inclusion criteria Women will be invited to participate in the trial and sign an informed consent if they meet the following inclusion criteria. • Presenting with fever (≥37.5°C) and/or one mild symptom suggestive of COVID-19 disease (cough, dyspnoea, chills, odynophagia, diarrhoea, muscle pain, anosmia, dysgeusia, headache) OR being contact* of a SARS-CoV-2 confirmed or suspected case in the past 14 days • More than 12 weeks of gestation (dated by ultrasonography) • Agreement to deliver in the study hospitals Exclusion criteria • Known hypersensitivity to HCQ or other 4-amonoquinoline compounds • History of retinopathy of any aetiology • Concomitant use of digoxin, cyclosporine, cimetidine • Known liver disease • Clinical history of cardiac pathology including known long QT syndrome • Unable to cooperate with the requirements of the study • Participating in other intervention studies • Delivery onset (characterized by painful uterine contractions and variable changes of the cervix, including some degree of effacement and slower progression of dilatation up to 5 cm for first and subsequent labours) The study participants will be stratified by clinical presentation and SARS-CoV-2 PCR results. Assignment of participants to study groups will be as follows: • SARS-CoV-2-PCR confirmed, infected pregnant women: a. symptomatic (n=100) b. asymptomatic (n=100) • SARS-CoV-2 PCR negative pregnant women in contact* with a SARS-CoV-2-infected confirmed or suspected case (n=514). *The ECDC definition of close contact will be followed. The trial will be conducted in five hospitals in Spain: Hospital Clínic of Barcelona, Hospital Sant Joan de Déu and Hospital de la Santa Creu i Sant Pau, in Barcelona, and HM Puerta del Sur and Hospital Universitario de Torrejón, in Madrid. INTERVENTION AND COMPARATOR: Participants will be randomized to HCQ (400 mg/day for three days, followed by 200 mg/day for 11 days) or placebo (2 tablets for three days, followed by one tablet for 11 days). MAIN OUTCOMES: The primary outcome is the number of PCR-confirmed infected pregnant women assessed from collected nasopharyngeal and oropharyngeal swabs at day 21 after treatment start (one week after treatment is completed). RANDOMISATION: Allocation of participants to study arms will be done centrally by the trial's Sponsor (the Barcelona Institute for Global Health, ISGlobal) by block randomization. This method will ensure balanced allocation to both arms. The electronic CRF will automatically assign a study number to each participant, depending on her study group and recruitment site. Each number will be related to a treatment number, which assigns them to one of the study arms. BLINDING (MASKING): Participants, caregivers, investigators and those assessing the outcomes will be blinded to group assignment. Study tablets (HCQ and placebo) will be identically packaged in small opaque bottles. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. TRIAL STATUS: Protocol version 1.0, from May 8th, 2020. Recruitment is ongoing (first patient recruited the 19th May 2020 and recruitment end anticipated by December 2020). TRIAL REGISTRATION: EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562 , retrospectively registered 1 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Antivirales/administración & dosificación , Betacoronavirus/efectos de los fármacos , Quimioprevención , Infecciones por Coronavirus/prevención & control , Hidroxicloroquina/administración & dosificación , Pandemias/prevención & control , Neumonía Viral/prevención & control , Complicaciones Infecciosas del Embarazo/prevención & control , Antivirales/efectos adversos , Antivirales/farmacocinética , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Método Doble Ciego , Esquema de Medicación , Femenino , Interacciones Huésped-Patógeno , Humanos , Hidroxicloroquina/efectos adversos , Hidroxicloroquina/farmacocinética , Estudios Multicéntricos como Asunto , Neumonía Viral/diagnóstico , Neumonía Viral/mortalidad , Neumonía Viral/virología , Embarazo , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/mortalidad , Complicaciones Infecciosas del Embarazo/virología , Factores Protectores , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , España , Factores de Tiempo , Resultado del Tratamiento , Esparcimiento de Virus/efectos de los fármacos
19.
J Biosci ; 452020.
Artículo en Inglés | MEDLINE | ID: mdl-32713862

RESUMEN

The two biological evidences to endorse the antiviral activity of RNA interference (RNAi) are biogenesis of viral-siRNA (v-siRNA) by the host and encoding of RNAi-suppressor protein by viral genome. It has been recently established that mammals and mammalian cell lines mount antiviral RNAi to defend themselves against the invading viruses. The large part of viral pathogenicity is also due to the RNAi suppressor proteins. In this context it is only natural to ask what kinds of RNAi suppressors are encoded by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the central character of the present pandemic. The following mini review addresses this question.


Asunto(s)
Betacoronavirus/genética , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Interferencia de ARN/fisiología , ARN Interferente Pequeño/genética , Proteínas Virales/genética , Animales , Línea Celular , Chlorocebus aethiops , Interacciones Huésped-Patógeno/fisiología , Humanos , Inmunidad Innata/inmunología , Pandemias , Células Vero
20.
Signal Transduct Target Ther ; 5(1): 125, 2020 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-32661235

RESUMEN

Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson's diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.


Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Proteínas de Choque Térmico/genética , Ribonucleoproteínas Nucleares Heterogéneas/genética , Interacciones Huésped-Patógeno/efectos de los fármacos , Neumonía Viral/tratamiento farmacológico , Antivirales/síntesis química , Betacoronavirus/genética , Betacoronavirus/patogenicidad , Ensamble y Desensamble de Cromatina/efectos de los fármacos , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Regulación de la Expresión Génica , Proteínas de Choque Térmico/agonistas , Proteínas de Choque Térmico/antagonistas & inhibidores , Proteínas de Choque Térmico/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/agonistas , Ribonucleoproteínas Nucleares Heterogéneas/antagonistas & inhibidores , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Interacciones Huésped-Patógeno/genética , Humanos , Terapia Molecular Dirigida/métodos , Pandemias , Neumonía Viral/genética , Neumonía Viral/patología , Neumonía Viral/virología , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Precursores del ARN/genética , Precursores del ARN/metabolismo , Índice de Severidad de la Enfermedad , Transducción de Señal , Transcripción Genética/efectos de los fármacos , Replicación Viral/efectos de los fármacos
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA