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1.
Medicine (Baltimore) ; 100(35): e27139, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34477166

RESUMEN

INTRODUCTION: Acute liver failure (ALF) is a life-threatening condition that remains challenging for physicians despite several advances in supportive care. Etiologies vary worldwide, with herpes simplex virus (HSV) hepatitis representing less than 1% of cases. Despite its low incidence, ALF is a lethal cause of acute necrotizing hepatitis and has a high mortality. Early antiviral treatment is beneficial for survival and decreased liver transplantation necessity. However, plasmapheresis, despite its theoretical potential benefit, is scarcely reported. PATIENT CONCERNS: A 25-year-old woman with no known disease presented with painful pharynx ulcers, increased transaminases and impaired liver function. DIAGNOSIS: ALF due to a disseminated HSV-2 primary infection was diagnosed with a positive polymerase chain reaction for HSV-2 in the biopsied liver tissue and blood. INTERVENTIONS: Empiric antiviral treatment was initiated. After clinical deterioration, plasmapheresis was also initiated. OUTCOMES: After 6 cycles of plasmapheresis and supportive care, the patient's condition improved without undergoing liver transplantation. CONCLUSIONS: ALF is a life-threatening condition, and HSV as an etiology must be suspected based on background, clinical manifestation, and laboratory information. The potential role of plasmapheresis in HSV hepatitis should be considered.


Asunto(s)
Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Herpes Simple/complicaciones , Fallo Hepático Agudo/virología , Plasmaféresis , Adulto , Femenino , Herpesvirus Humano 2/aislamiento & purificación , Humanos , Fallo Hepático Agudo/diagnóstico por imagen , Fallo Hepático Agudo/terapia , Tomografía Computarizada por Rayos X
2.
PLoS One ; 16(9): e0256903, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34520465

RESUMEN

INTRODUCTION: During COVID-19 pandemic, the use of several drugs has represented the worldwide clinical practice. However, though the current increase of knowledge about the disease, there is still no effective treatment for the usage of drugs. Thus, we retrospectively assessed use and effects of therapeutic regimens in hospitalized patients on in-hospital mortality. METHODS: COVOCA is a retrospective observational cohort study on 18 COVID centres throughout Campania Region Hospitals. We included adult patients with confirmed SARS-CoV-2 infection, discharged/dead between March/June 2020. RESULTS: 618 patients were included, with an overall in-hospital cumulative mortality incidence of 23.1%. Most prescribed early treatments were antivirals (72%), antibiotics (65%) and hydroxychloroquine/anticoagulants (≈50%). Tocilizumab, indeed, was largely prescribed late during hospitalization. Multivariable models, with a cut-off at day 2 for early COVID-19 therapy administration, did not disclose any significant association of a single drug administration on the clinical outcome. DISCUSSION: COVOCA represents the first multicenter database in Campania region. None drug class used during the pandemic significantly modified the outcome, regardless of therapy beginning, both overall and net of those already in non-invasive ventilation (NIV)/ orotracheal intubation (OTI) at hospitalization. Our cumulative incidence of mortality seems lower than other described during the same period, particularly in Northern Italy.


Asunto(s)
Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , COVID-19/mortalidad , Anciano , COVID-19/epidemiología , Femenino , Mortalidad Hospitalaria , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Pandemias , Terapia Respiratoria , Estudios Retrospectivos
3.
Washington; Pan American Health Organization; 26 ed; Sept. 13, 2021. 357 p.
No convencional en Inglés | PIE | ID: biblio-1291221

RESUMEN

The vast amount of data generated by clinical studies of potential therapeutic options for COVID-19 presents important challenges. The new data must be interpreted quickly so that prescribers can make optimal treatment decisions with as little harm to patients as possible, and so that medicines manufacturers can scale up production rapidly and bolster their supply chains. Rapid interpretation of fresh data will save lives by ensuring that successful drugs can be administered to as many patients as possible as quickly as possible. This publication, the 25th edition of the database of evidence on potential therapeutic options for COVID-19, examines 137 therapeutic options. This information will help investigators, policymakers, and prescribers navigate the flood of relevant data to ensure that management of COVID-19, at both individual and population levels, is based on the best available knowledge. This resource will be continually updated as more research is released into the public space.


Asunto(s)
Humanos , Antivirales/uso terapéutico , SARS-CoV-2/efectos de los fármacos , COVID-19/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Ensayos Clínicos como Asunto
4.
BMJ Case Rep ; 14(9)2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34479903

RESUMEN

Remdesivir is an antiviral used for the treatment of COVID-19 requiring hospitalisation. Information on its cardiovascular safety profile is scarce. We report the case of a 37-year-old man with COVID-19 who developed bradycardia after receiving remdesivir. We recommend a baseline ECG for all patients prior to receiving remdesivir and continuous cardiac monitoring during treatment, especially among those with underlying cardiovascular disease, elderly and using ß-blockers.


Asunto(s)
Bradicardia , COVID-19 , Adenosina Monofosfato/análogos & derivados , Adulto , Anciano , Alanina/análogos & derivados , Antivirales/uso terapéutico , Bradicardia/inducido químicamente , Bradicardia/tratamiento farmacológico , COVID-19/tratamiento farmacológico , Humanos , Masculino , SARS-CoV-2
6.
Mem Inst Oswaldo Cruz ; 116: e200603, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34495083

RESUMEN

BACKGROUND: In March 2020, the World Health Organization (WHO) launched the Solidarity Program, probably the largest global initiative to encourage and support research in four promising drugs, named Remdesivir, Hydroxychloroquine, ß Interferon and the combination Lopinavir / Ritonavir, to reduce the mortality of Coronavirus disease 2019 (COVID-19). OBJECTIVES: Considering the potential impact of Solidarity Program to restrain the current pandemic, the present study aims to investigate whether it was designed upon indicators of scientific productivity, defined as the level of the production of new scientific knowledge and of the institutional capabilities, estimated in terms of scientific publications and technological agreements. METHODS: The scientific documents on Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Coronavirus were retrieved from Scopus database while the technological agreements on coronavirus were obtained through Cortellis. As for the institutions and countries, we have considered the data on author's affiliations in both set of data. For comparison, we included the analysis of documents related with other drugs or therapies, such as vaccines and antibodies, which were listed in a Clarivate's report on coronaviruses research. FINDINGS: Most of the analysis refers to documents on Coronavirus, the largest group. The number of documents related to WHO's drugs are almost five times higher than in the other groups. This subset of documents involves the largest and most diverse number of institutions and countries. As for agreements, we observed a smaller number of institutions involved in it, suggesting differences between countries in terms of technical and human capabilities to develop basic and/or clinical research on coronavirus and to develop new forms or products to treat or to prevent the disease. MAIN CONCLUSIONS: Hence, the results shown in this study illustrate that decisions taken by an international scientific body, as WHO, were mainly based in scientific knowledge and institutional competencies.


Asunto(s)
Antivirales , COVID-19 , Antivirales/uso terapéutico , Combinación de Medicamentos , Humanos , SARS-CoV-2 , Organización Mundial de la Salud
7.
World J Gastroenterol ; 27(31): 5219-5231, 2021 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-34497446

RESUMEN

BACKGROUND: Hepatitis C virus (HCV) infection is a major global public health problem. In the Republic of Cyprus, the estimated prevalence of chronic hepatitis C (CHC) among the general population is 0.6%, while the CHC prevalence among people who inject drugs (PWID) is estimated at 46%. Direct-acting antivirals that can eliminate HCV are not yet widely available in the Republic of Cyprus. However, when direct-acting antivirals become available, a long-term strategic plan to guide elimination efforts will be needed to maximize the effect of treatment. AIM: To determine the programmatic targets to eliminate HCV in the Republic of Cyprus. METHODS: A dynamic, stochastic, individual-based model of HCV transmission, disease progression, and cascade of care was calibrated to data from Cyprus. The model stratifies the population into the infected general population and the PWID population. A variety of test, prevention, and treatment strategies concerning the general population, PWID, or both were examined. The time horizon of the analysis was until 2034. RESULTS: Under the status quo scenario, the model predicted that 75 (95% confidence interval (CI): 60, 91) and 575 (95%CI: 535, 615) liver-related deaths and new infections would occur by 2034, respectively. Launching an expanded treatment program, without screening interventions, would cause modest outcomes regarding CHC prevalence (16.6% reduction in 2034 compared to 2020) and liver-related deaths (10 deaths would be prevented compared to the status quo scenario by 2034). Implementing a test and treat strategy among the general population but without any intervention in the PWID population would suffice to meet the mortality target but not the incidence target. To achieve HCV elimination in Cyprus, 3080 (95%CI: 3000, 3200) HCV patients need to be diagnosed and treated by 2034 (2680 from the general population and 400 from PWID), and harm reduction coverage among PWID should be increased by 3% per year (from 25% in 2020 to 67% in 2034). CONCLUSION: Elimination of HCV is a demanding public health strategy, which requires significant interventions both among the general population and high-risk groups.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Abuso de Sustancias por Vía Intravenosa , Antivirales/uso terapéutico , Chipre/epidemiología , Hepacivirus , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Humanos , Prevalencia , Abuso de Sustancias por Vía Intravenosa/epidemiología
8.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-34502335

RESUMEN

A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been identified as the pathogen responsible for the outbreak of a severe, rapidly developing pneumonia (Coronavirus disease 2019, COVID-19). The virus enzyme, called 3CLpro or main protease (Mpro), is essential for viral replication, making it a most promising target for antiviral drug development. Recently, we adopted the drug repurposing as appropriate strategy to give fast response to global COVID-19 epidemic, by demonstrating that the zonulin octapeptide inhibitor AT1001 (Larazotide acetate) binds Mpro catalytic domain. Thus, in the present study we tried to investigate the antiviral activity of AT1001, along with five derivatives, by cell-based assays. Our results provide with the identification of AT1001 peptide molecular framework for lead optimization step to develop new generations of antiviral agents of SARS-CoV-2 with an improved biological activity, expanding the chance for success in clinical trials.


Asunto(s)
Antivirales/farmacología , Simulación del Acoplamiento Molecular , Oligopéptidos/química , Péptidos/metabolismo , SARS-CoV-2/efectos de los fármacos , Antivirales/química , Antivirales/metabolismo , Antivirales/uso terapéutico , Sitios de Unión , COVID-19/tratamiento farmacológico , COVID-19/virología , Dominio Catalítico , Línea Celular , Citomegalovirus/efectos de los fármacos , Reposicionamiento de Medicamentos , Herpesvirus Humano 3/efectos de los fármacos , Humanos , Simulación de Dinámica Molecular , Péptidos/síntesis química , Péptidos/farmacología , Péptidos/uso terapéutico , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/metabolismo
9.
Front Immunol ; 12: 729776, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34504502

RESUMEN

Coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus that has spread rapidly around the world, leading to high mortality because of multiple organ dysfunction; however, its underlying molecular mechanism is unknown. To determine the molecular mechanism of multiple organ dysfunction, a bioinformatics analysis method based on a time-order gene co-expression network (TO-GCN) was performed. First, gene expression profiles were downloaded from the gene expression omnibus database (GSE161200), and a TO-GCN was constructed using the breadth-first search (BFS) algorithm to infer the pattern of changes in the different organs over time. Second, Gene Ontology enrichment analysis was used to analyze the main biological processes related to COVID-19. The initial gene modules for the immune response of different organs were defined as the research object. The STRING database was used to construct a protein-protein interaction network of immune genes in different organs. The PageRank algorithm was used to identify five hub genes in each organ. Finally, the Comparative Toxicogenomics Database played an important role in exploring the potential compounds that target the hub genes. The results showed that there were two types of biological processes: the body's stress response and cell-mediated immune response involving the lung, trachea, and olfactory bulb (olf) after being infected by COVID-19. However, a unique biological process related to the stress response is the regulation of neuronal signals in the brain. The stress response was heterogeneous among different organs. In the lung, the regulation of DNA morphology, angiogenesis, and mitochondrial-related energy metabolism are specific biological processes related to the stress response. In particular, an effect on tracheal stress response was made by the regulation of protein metabolism and rRNA metabolism-related biological processes, as biological processes. In the olf, the distinctive stress responses consist of neural signal transmission and brain behavior. In addition, myeloid leukocyte activation and myeloid leukocyte-mediated immunity in response to COVID-19 can lead to a cytokine storm. Immune genes such as SRC, RHOA, CD40LG, CSF1, TNFRSF1A, FCER1G, ICAM1, LAT, LCN2, PLAU, CXCL10, ICAM1, CD40, IRF7, and B2M were predicted to be the hub genes in the cytokine storm. Furthermore, we inferred that resveratrol, acetaminophen, dexamethasone, estradiol, statins, curcumin, and other compounds are potential target drugs in the treatment of COVID-19.


Asunto(s)
COVID-19/complicaciones , Insuficiencia Multiorgánica/genética , Antivirales/uso terapéutico , Encéfalo/metabolismo , Encéfalo/virología , COVID-19/tratamiento farmacológico , COVID-19/genética , COVID-19/virología , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Pulmón/metabolismo , Pulmón/virología , Insuficiencia Multiorgánica/tratamiento farmacológico , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/metabolismo , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/virología , Mapas de Interacción de Proteínas , SARS-CoV-2/fisiología , Tráquea/metabolismo , Tráquea/virología , Transcriptoma
10.
PLoS One ; 16(9): e0256977, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34473766

RESUMEN

INTRODUCTION: Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. Although most patients with COVID-19 develop asymptomatic or mild disease, some patients develop severe disease. The effectiveness of various therapeutic agents, including antiviral drugs, steroids, and anti-inflammatories for COVID-19, have been being confirmed. The effect of administering steroids in early disease is unclear. This study therefore aimed to evaluate the effectiveness and risk of exacerbation of steroids administered preceding antiviral drugs in patients with COVID-19 pneumonia. METHODS: This retrospective, single-center, observational study included consecutive patients with COVID-19 between March 2020 and March 2021. Patients were divided into a steroids-first group and antiviral-drugs-first group. Mortality, duration of hospitalization, incidence rate and duration of intensive care unit (ICU) admission, intubation, and extracorporeal membrane oxygenation (ECMO) induction of the two groups were compared. RESULTS: A total of 258 patients were admitted during the study period. After excluding patients who received symptomatic treatment only, who were taking immunosuppressive drugs, or who were administered antiviral drugs only, 68 patients were included in the analysis, 16 in the steroids-first group and 52 in the antiviral-drugs-first group. The rate of intubation, ICU admission and ECMO induction were significantly higher in the steroids-first group than in the antiviral-drugs-first group (81.3% vs. 33.3, p<0.001, 75.0% vs. 29.4%, p = 0.001, and 31.3% vs. 7.8%, p = 0.017, respectively). Furthermore, patients who received steroids within ten days after starting antiviral drugs had significantly lower rates of ICU admission, intubation, and ECMO induction. (81.3% vs. 42.9% p = 0.011, 75.0% vs. 37.1% p = 0.012, and 31.3% vs. 8.6% p = 0.039, respectively). CONCLUSIONS: Administering steroids prior to antiviral drugs soon after symptom onset can aggravate disease severity. When administration of steroids is considered soon after symptom onset, it may be safer to initiate antiviral drugs first.


Asunto(s)
Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , Dexametasona/uso terapéutico , Hospitalización/estadística & datos numéricos , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , SARS-CoV-2/efectos de los fármacos , Anciano , Antivirales/administración & dosificación , COVID-19/fisiopatología , COVID-19/virología , Dexametasona/administración & dosificación , Esquema de Medicación , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Síndrome de Dificultad Respiratoria/fisiopatología , Estudios Retrospectivos , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
11.
Sci Rep ; 11(1): 17810, 2021 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-34497279

RESUMEN

Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.


Asunto(s)
Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/metabolismo , Antivirales/farmacología , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Hígado/efectos de los fármacos , Proteínas de Transporte de Catión Orgánico/metabolismo , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/antagonistas & inhibidores , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/química , Adenosina Monofosfato/metabolismo , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/análogos & derivados , Alanina/química , Alanina/metabolismo , Alanina/farmacología , Alanina/uso terapéutico , Antivirales/química , Antivirales/metabolismo , Antivirales/uso terapéutico , COVID-19/tratamiento farmacológico , Comorbilidad , Reposicionamiento de Medicamentos , Humanos , Hígado/metabolismo , Hígado/patología , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Lopinavir/química , Lopinavir/metabolismo , Lopinavir/farmacología , Lopinavir/uso terapéutico , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Ritonavir/química , Ritonavir/metabolismo , Ritonavir/farmacología , Ritonavir/uso terapéutico , SARS-CoV-2/aislamiento & purificación , Especificidad por Sustrato
12.
BMC Ophthalmol ; 21(1): 337, 2021 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-34530769

RESUMEN

BACKGROUND: Acute retinal necrosis is considered a rare infectious uveitis. This condition is usually caused by varicella-zoster virus or herpes simplex virus. Acute retinal necrosis caused by co-infection with multiple viruses is extremely rare. Herein, we report a case of acute retinal necrosis caused by co-infection with herpes simplex virus (type I and II) and varicella-zoster virus (VZV) in a natalizumab-treated patient due to multiple sclerosis. CASE PRESENTATION: An adult man presented with a complaint of decreased vision of the right eye from 12 days ago. He was a known case of multiple sclerosis receiving natalizumab. Examination of the right eye revealed severe conjunctival injection, fine diffuse keratic precipitates, 3 + anterior chamber and vitreous cells, elevated intraocular pressure (26 mmHg), a blurred optic disk with hemorrhagic patches, and occlusive vasculitis plus confluent necrotizing patches in the peripheral retina compatible with diagnosis of acute retinal necrosis. He underwent anterior chamber and vitreous tap, and real-time PCR detected HSV I & II and VZV on the vitreous specimen. A second PCR showed the same result. After neurological consultation, natalizumab was discontinued and intravenous acyclovir was started followed by oral acyclovir and oral prednisolone to control the disease, which was successful. CONCLUSIONS: Although rare, multiple-viral infection should be considered in the physiopathology of acute retinal necrosis, especially in immunosuppressed patients.


Asunto(s)
Coinfección , Síndrome de Necrosis Retiniana Aguda , Aciclovir/uso terapéutico , Antivirales/uso terapéutico , Herpesvirus Humano 3 , Humanos , Masculino , Natalizumab/efectos adversos , Síndrome de Necrosis Retiniana Aguda/inducido químicamente , Síndrome de Necrosis Retiniana Aguda/diagnóstico , Síndrome de Necrosis Retiniana Aguda/tratamiento farmacológico
14.
Trials ; 22(1): 584, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34479601

RESUMEN

OBJECTIVES: The primary objective of the study is to demonstrate the efficacy of low-dose IFN-ß in reducing the risk of SARS-CoV-2 recently infected elderly patients to progress towards severe COVID-19 versus control group within 28 days. Secondary objectives are: 1) To assess the reduction in Intensive Care Unit (ICU) admission in patients treated with IFN-ß versus control group within 28 days of randomization 2) To assess the reduction in number of deaths in IFN- ß compared to control group (day 28) 3) To evaluate the increase in proportion of participants returning to negative SARS-CoV-2 RT-PCR in IFN-ß -treated versus control group at Day 14 and Day 28 4) To assess the increase in SARS-CoV-2-specific binding antibody titers in IFN-ß compared to control group (day 28) 5) To assess the safety of IFN-ß -treated patients versus control group TRIAL DESIGN: Randomized, Open-Label, Controlled, Superiority Phase II Study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the two treatment groups in a ratio 2:1 (IFN-treated versus control patients). Randomization will be stratified by gender. Stratified randomization will balance the presence of male and female in both study arms. PARTICIPANTS: Male and female adults aged 65 years or older with newly diagnosed SARS-CoV-2 infection and mild COVID-19 symptoms are eligible for the study. The trial is being conducted in Rome. Participants will be either hospitalized or home isolated. A group of physicians belonging to the Special Unit for Regional Continued Care (USCAR), specifically trained for the study and under the supervision of the National Institute for Infectious Diseases "Lazzaro Spallanzani", will be responsible for the screening, enrolment, treatment and clinical monitoring of patients, thus acting as a bridge between clinical centers and territorial health management. Inclusion criteria are as follows: ≥ 65 years of age at time of enrolment; Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, in any specimen < 72 hours prior to randomization; Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures; Understands and agrees to comply with planned study procedures; Agrees to the collection of nasopharyngeal swabs and venous blood samples per protocol; Being symptomatic for less than 7 days before starting therapy; NEWS2 score ≤2. Exclusion criteria are as follows: Hospitalized patients with illness of any duration, and at least one of the following: Clinical assessment (evidence of rales/crackles on exam) and SpO2 ≤ 94% on room air at rest or after walking test, OR Acute respiratory failure requiring mechanical ventilation and/or supplemental oxygen; Patients currently using IFN-ß (e.g., multiple sclerosis patients); Patients undergoing chemotherapy or other immunosuppressive treatments; Patients with chronic kidney diseases; Known allergy or hypersensitivity to IFN (including asthma); Any autoimmune disease (resulting from patient anamnesis); Patients with signs of dementia or neurocognitive disorders; Patients with current severe depression and/or suicidal ideations; Being concurrently involved in another clinical trial; HIV infection (based on the anamnesis); Use of any antiretroviral medication; Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min); Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition); Any physical or psychological impediment in a patient that could let the investigator to suspect his/her poor compliance; Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: Control arm: No specific antiviral treatment besides standard of care. Treatment arm: 11µg (3MIU) of IFN-ß1a will be injected subcutaneously at day 1, 3, 7, and 10 in addition to standard of care. The drug solution, contained in a pre-filled cartridge, will be injected by means of the RebiSmart® electronic injection device. Interferon ß1a (Rebif®, Merck KGaA, Darmstadt, Germany) is a disease-modifying drug used to treat relapsing forms of multiple sclerosis (MS). The dose selected for this study is expected to exploit the antiviral and immunomodulatory properties of the cytokine without causing relevant toxicity or inducing refractoriness phenomena sometimes observed after high-dose and/or chronic IFNß treatments. MAIN OUTCOMES: Primary endpoint of the study is the proportion of patients experiencing a disease progression, during at least 5 days, according to the National Early Warning Score (NEWS2). The NEWS2 score is a standardized approach aimed at promptly detecting signs of clinical deterioration in acutely ill patients and establishing the potential need for higher level of care. It is based on the evaluation of vital signs, including respiratory rate, oxygen saturation, temperature, blood pressure, pulse/heart rate, AVPU response. The resulting observations, compared to a normal range, are combined in a single composite "alarm" score. Any other clinical sign clearly indicating a disease worsening will be considered as disease progression. RANDOMIZATION: Sixty patients will be randomized 2:1 to receive IFN-ß1a plus the standard of care or the standard of care only. Eligible patients will be randomized (no later than 36 h after enrolment) by means of a computerized central randomization system. All patients will receive a unique patient identification number at enrolling visit when signing the informed consent and before any study procedure is performed. This number remains constant throughout the entire study. The randomization of patients will be closed when 60 patients have been enrolled. The randomization will be stratified by sex; for each stratum a sequence of treatments randomly permuted in blocks of variable length (3 or 6) will be generated. BLINDING (MASKING): This is an open-label study. After the randomization, patients will be notified whether they will be in the experimental arm or in the control arm. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The study plans to enrol 60 patients: 40 in the IFN-ß1a arm, 20 in the control arm, according to a 2:1 - treated: untreated ratio. TRIAL STATUS: Protocol Version: 3.0 Version Date: 18/03/2021 The study is open for recruitment since 16/04/2021.Recruitment is expected to l be completed before 15/08/2021. TRIAL REGISTRATION: EudraCT N°: 2020-003872-42, registration date: 19/10/2020. 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/uso terapéutico , COVID-19 , Infecciones por VIH , Interferón beta/uso terapéutico , Anciano , Ensayos Clínicos Fase II como Asunto , Femenino , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
15.
Rev Med Suisse ; 17(748): 1453-1456, 2021 Sep 01.
Artículo en Francés | MEDLINE | ID: mdl-34468096

RESUMEN

Treatment of hepatitis C has known major progress thanks to direct-acting antivirals resulting in the healing, defined by a viral clearance (sustained virological response [SVR]), in the vast majority of patients. However, there is a residual risk of progressive liver damage in a minority of patients, potentially leading to complications such as liver decompensation, hepatocellular carcinoma and/or death. This article discusses the current knowledge of residual liver disease after treatment, the impact of comorbidities and the factors potentially predicting patients at risk of complications and warranting surveillance.


Asunto(s)
Carcinoma Hepatocelular , Hepatitis C Crónica , Hepatitis C , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Hepacivirus , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Humanos , Cirrosis Hepática/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología
17.
Sci Rep ; 11(1): 17748, 2021 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-34493768

RESUMEN

Based on WHO reports the new SARS-CoV-2 coronavirus is currently widespread all over the world. So far > 162 million cases have been confirmed, including > 3 million deaths. Because of the pandemic still spreading across the globe the accomplishment of computational methods to find new potential mechanisms of virus inhibitions is necessary. According to the fact that C60 fullerene (a sphere-shaped molecule consisting of carbon) has shown inhibitory activity against various protein targets, here the analysis of the potential binding mechanism between SARS-CoV-2 proteins 3CLpro and RdRp with C60 fullerene was done; it has resulted in one and two possible binding mechanisms, respectively. In the case of 3CLpro, C60 fullerene interacts in the catalytic binding pocket. And for RdRp in the first model C60 fullerene blocks RNA synthesis pore and in the second one it prevents binding with Nsp8 co-factor (without this complex formation, RdRp can't perform its initial functions). Then the molecular dynamics simulation confirmed the stability of created complexes. The obtained results might be a basis for other computational studies of 3CLPro and RdRp potential inhibition ways as well as the potential usage of C60 fullerene in the fight against COVID-19 disease.


Asunto(s)
Antivirales/farmacología , COVID-19/tratamiento farmacológico , Fulerenos/farmacología , Antivirales/uso terapéutico , COVID-19/epidemiología , COVID-19/virología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/ultraestructura , Inhibidores de Proteasa de Coronavirus/química , Inhibidores de Proteasa de Coronavirus/farmacología , Inhibidores de Proteasa de Coronavirus/uso terapéutico , ARN Polimerasa Dependiente de ARN de Coronavirus/antagonistas & inhibidores , ARN Polimerasa Dependiente de ARN de Coronavirus/ultraestructura , Cristalografía por Rayos X , Fulerenos/química , Fulerenos/uso terapéutico , Humanos , Simulación de Dinámica Molecular , Inhibidores de la Síntesis del Ácido Nucleico/química , Inhibidores de la Síntesis del Ácido Nucleico/farmacología , Inhibidores de la Síntesis del Ácido Nucleico/uso terapéutico , Pandemias/prevención & control , ARN Viral/biosíntesis , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , SARS-CoV-2/ultraestructura
18.
Molecules ; 26(17)2021 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-34500548

RESUMEN

The emergence of COVID-19 continues to pose severe threats to global public health. The pandemic has infected over 171 million people and claimed more than 3.5 million lives to date. We investigated the binding potential of antiviral cyanobacterial proteins including cyanovirin-N, scytovirin and phycocyanin with fundamental proteins involved in attachment and replication of SARS-CoV-2. Cyanovirin-N displayed the highest binding energy scores (-16.8 ± 0.02 kcal/mol, -12.3 ± 0.03 kcal/mol and -13.4 ± 0.02 kcal/mol, respectively) with the spike protein, the main protease (Mpro) and the papainlike protease (PLpro) of SARS-CoV-2. Cyanovirin-N was observed to interact with the crucial residues involved in the attachment of the human ACE2 receptor. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) approach revealed that all forms of energy, except the polar solvation energy, favourably contributed to the interactions of cyanovirin-N with the viral proteins. With particular emphasis on cyanovirin-N, the current work presents evidence for the potential inhibition of SARS-CoV-2 by cyanobacterial proteins, and offers the opportunity for in vitro and in vivo experiments to deploy the cyanobacterial proteins as valuable therapeutics against COVID-19.


Asunto(s)
Antivirales/farmacología , Proteínas Bacterianas/farmacología , COVID-19/tratamiento farmacológico , Inhibidores de Proteasa de Coronavirus/farmacología , Antivirales/uso terapéutico , Proteínas Bacterianas/uso terapéutico , Proteínas Bacterianas/ultraestructura , COVID-19/virología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Proteasas 3C de Coronavirus/ultraestructura , Proteasas Similares a la Papaína de Coronavirus/antagonistas & inhibidores , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Proteasas Similares a la Papaína de Coronavirus/ultraestructura , Inhibidores de Proteasa de Coronavirus/uso terapéutico , Inhibidores de Proteasa de Coronavirus/ultraestructura , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Unión Proteica , Mapeo de Interacción de Proteínas , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/ultraestructura , Difracción de Rayos X
19.
Int J Mol Sci ; 22(17)2021 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-34502033

RESUMEN

The novel coronavirus disease, caused by severe acute respiratory coronavirus 2 (SARS-CoV-2), rapidly spreading around the world, poses a major threat to the global public health. Herein, we demonstrated the binding mechanism of PF-07321332, α-ketoamide, lopinavir, and ritonavir to the coronavirus 3-chymotrypsin-like-protease (3CLpro) by means of docking and molecular dynamic (MD) simulations. The analysis of MD trajectories of 3CLpro with PF-07321332, α-ketoamide, lopinavir, and ritonavir revealed that 3CLpro-PF-07321332 and 3CLpro-α-ketoamide complexes remained stable compared with 3CLpro-ritonavir and 3CLpro-lopinavir. Investigating the dynamic behavior of ligand-protein interaction, ligands PF-07321332 and α-ketoamide showed stronger bonding via making interactions with catalytic dyad residues His41-Cys145 of 3CLpro. Lopinavir and ritonavir were unable to disrupt the catalytic dyad, as illustrated by increased bond length during the MD simulation. To decipher the ligand binding mode and affinity, ligand interactions with SARS-CoV-2 proteases and binding energy were calculated. The binding energy of the bespoke antiviral PF-07321332 clinical candidate was two times higher than that of α-ketoamide and three times than that of lopinavir and ritonavir. Our study elucidated in detail the binding mechanism of the potent PF-07321332 to 3CLpro along with the low potency of lopinavir and ritonavir due to weak binding affinity demonstrated by the binding energy data. This study will be helpful for the development and optimization of more specific compounds to combat coronavirus disease.


Asunto(s)
Antivirales/farmacología , COVID-19/tratamiento farmacológico , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Proteasa de Coronavirus/farmacología , Lactamas/farmacología , Leucina/farmacología , Nitrilos/farmacología , Prolina/farmacología , Antivirales/uso terapéutico , Dominio Catalítico/efectos de los fármacos , Proteasas 3C de Coronavirus/metabolismo , Inhibidores de Proteasa de Coronavirus/uso terapéutico , Humanos , Lactamas/uso terapéutico , Leucina/uso terapéutico , Lopinavir/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Nitrilos/uso terapéutico , Prolina/uso terapéutico , Ritonavir/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología
20.
JNMA J Nepal Med Assoc ; 59(238): 614-621, 2021 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-34508415

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is alarming worldwide incurring tremendous loss of life and possession. Individuals are facing a terrible pandemic condition in the absence of appropriate medicines and vaccines to combat SARS-CoV-2 infection. This review aimed to provide details on potential treatment steps that can be taken in the current pandemic-fighting situation in Nepal. A massive review was performed including 60 articles from the relevant field. Preliminary results on the efficacy of some existing anti-viral agents were found, however, promising data on effective treatment regimen for COVID 19 are yet to be obtained. This review examines various drugs and their mechanism of actions which are currently used in clinical trials or may be used to treat COVID-19 in the near future.


Asunto(s)
COVID-19 , Antivirales/uso terapéutico , Humanos , Nepal , Pandemias , SARS-CoV-2
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