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1.
Int J Mol Sci ; 22(20)2021 Oct 15.
Article in English | MEDLINE | ID: covidwho-1470891

ABSTRACT

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.


Subject(s)
Antiviral Agents/chemistry , Enzyme Inhibitors/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/enzymology , Viral Proteins/antagonists & inhibitors , Amides/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Catalytic Domain , Databases, Chemical , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Guanidine/chemistry , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/isolation & purification , Structure-Activity Relationship , Sulfides/chemistry , Thermodynamics , Viral Proteins/metabolism
2.
Rheumatology (Oxford) ; 60(1): 399-407, 2021 01 05.
Article in English | MEDLINE | ID: covidwho-1388014

ABSTRACT

OBJECTIVES: The Janus kinase (JAK) inhibitor baricitinib may block viral entry into pneumocytes and prevent cytokine storm in patients with SARS-CoV-2 pneumonia. We aimed to assess whether baricitinib improved pulmonary function in patients treated with high-dose corticosteroids for moderate to severe SARS-CoV-2 pneumonia. METHODS: This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) <200 mmHg] who received lopinavir/ritonavir and HCQ plus either corticosteroids (CS group, n = 50) or corticosteroids and baricitinib (BCT-CS group, n = 62). The primary end point was the change in oxygen saturation as measured by pulse oximetry (SpO2)/FiO2 from hospitalization to discharge. Secondary end points included the proportion of patients requiring supplemental oxygen at discharge and 1 month later. Statistics were adjusted by the inverse propensity score weighting (IPSW). RESULTS: A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the BCT-CS vs CS group (mean differences adjusted for IPSW, 49; 95% CI: 22, 77; P < 0.001). A higher proportion of patients required supplemental oxygen both at discharge (62.0% vs 25.8%; reduction of the risk by 82%, OR adjusted for IPSW, 0.18; 95% CI: 0.08, 0.43; P < 0.001) and 1 month later (28.0% vs 12.9%, reduction of the risk by 69%, OR adjusted for IPSW, 0.31; 95% CI: 0.11, 0.86; P = 0.024) in the CS vs BCT-CS group. CONCLUSIONS: . In patients with moderate to severe SARS-CoV-2 pneumonia a combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function when compared with corticosteroids alone. TRIAL REGISTRATION: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, ENCEPP (EUPAS34966, http://www.encepp.eu/encepp/viewResource.htm? id = 34967).


Subject(s)
Azetidines/therapeutic use , COVID-19/drug therapy , Glucocorticoids/therapeutic use , Hypoxia/therapy , Janus Kinase Inhibitors/therapeutic use , Methylprednisolone/therapeutic use , Oxygen Inhalation Therapy/statistics & numerical data , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Aged , Antiviral Agents/therapeutic use , COVID-19/metabolism , COVID-19/physiopathology , Cohort Studies , Drug Combinations , Drug Therapy, Combination , Endothelium, Vascular , Enzyme Inhibitors/therapeutic use , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Hydroxychloroquine/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Interferon beta-1b/therapeutic use , Lopinavir/therapeutic use , Lung/blood supply , Male , Middle Aged , Oximetry , Prospective Studies , Ritonavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index
4.
JAMA Netw Open ; 4(8): e2119151, 2021 08 02.
Article in English | MEDLINE | ID: covidwho-1355856

ABSTRACT

Importance: Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2; however, questions remain about which treatment is associated with the best outcomes and fewest adverse events. Objective: To compare the efficacy and safety of neuraminidase inhibitors and the endonuclease inhibitor for the treatment of seasonal influenza among healthy adults and children. Data Sources: Medline, Embase, and the Cochrane Register of Clinical Trials were searched from inception to January 2020 (the last search was updated in October 2020). Study Selection: Included studies were randomized clinical trials conducted among patients of all ages with influenza treated with neuraminidase inhibitors (ie, oseltamivir, peramivir, zanamivir, or laninamivir) or an endonuclease inhibitor (ie, baloxavir) compared with other active agents or placebo. Data Extraction and Synthesis: Two investigators identified studies and independently abstracted data. Frequentist network meta-analyses were performed; relative ranking of agents was conducted using P-score probabilities. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Data were analyzed in October 2020. Main Outcomes and Measures: The time to alleviation of influenza symptoms (TTAS), complications of influenza, and adverse events (total adverse events, nausea, and vomiting). Results: A total of 26 trials were identified that investigated antiviral drugs at high or low doses; these trials included 11 897 participants, among whom 6294 (52.9%) were men and the mean (SD) age was 32.5 (16.9) years. Of all treatments comparing with placebo in efficacy outcomes, high-quality evidence indicated that zanamivir was associated with the shortest TTAS (hazard ratio, 0.67; 95% CI, 0.58-0.77), while baloxavir was associated with the lowest risk of influenza-related complications (risk ratio [RR], 0.51; 95% CI, 0.32-0.80) based on moderate-quality evidence. In safety outcomes, baloxavir was associated with the lowest risk of total adverse events (RR, 0.84; 95% CI, 0.74-0.96) compared with placebo based on moderate-quality evidence. There was no strong evidence of associations with risk of nausea or vomiting among all comparisons, except for 75 mg oseltamivir, which was associated with greater occurrence of nausea (RR, 1.82; 95% CI, 1.38-2.41) and vomiting (RR, 1.88; 95% CI, 1.47-2.41). Conclusions and Relevance: In this systematic review and network meta-analysis, all 4 antiviral agents assessed were associated with shortening TTAS; zanamivir was associated with the shortest TTAS, and baloxavir was associated with reduced rate of influenza-related complications.


Subject(s)
Antiviral Agents/therapeutic use , Dibenzothiepins/therapeutic use , Enzyme Inhibitors/therapeutic use , Influenza, Human/drug therapy , Morpholines/therapeutic use , Pyridones/therapeutic use , Triazines/therapeutic use , Zanamivir/therapeutic use , Adolescent , Adult , Child , Endonucleases/antagonists & inhibitors , Female , Humans , Influenza A virus/drug effects , Influenza, Human/virology , Male , Middle Aged , Network Meta-Analysis , Neuraminidase/antagonists & inhibitors , Randomized Controlled Trials as Topic , Seasons , Young Adult
6.
Eur J Pharmacol ; 906: 174233, 2021 Sep 05.
Article in English | MEDLINE | ID: covidwho-1260717

ABSTRACT

Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49 ± 8.8 µmol/L) and teriflunomide (EC50 26 µmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Crotonates/pharmacology , Enzyme Inhibitors/pharmacology , Hydroxybutyrates/pharmacology , Leflunomide/pharmacology , Nitriles/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Toluidines/pharmacology , Animals , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Crotonates/adverse effects , Crotonates/therapeutic use , Drug Repositioning , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Humans , Hydroxybutyrates/adverse effects , Hydroxybutyrates/therapeutic use , Leflunomide/adverse effects , Leflunomide/therapeutic use , Nitriles/adverse effects , Nitriles/therapeutic use , Toluidines/adverse effects , Toluidines/therapeutic use
7.
Clin Pharmacol Ther ; 110(6): 1498-1511, 2021 12.
Article in English | MEDLINE | ID: covidwho-1245382

ABSTRACT

Several medications commonly used for a number of medical conditions share a property of functional inhibition of acid sphingomyelinase (ASM), or FIASMA. Preclinical and clinical evidence suggest that the ASM/ceramide system may be central to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. We examined the potential usefulness of FIASMA use among patients hospitalized for severe coronavirus disease 2019 (COVID-19) in an observational multicenter study conducted at Greater Paris University hospitals. Of 2,846 adult patients hospitalized for severe COVID-19, 277 (9.7%) were taking an FIASMA medication at the time of their hospital admission. The primary end point was a composite of intubation and/or death. We compared this end point between patients taking vs. not taking an FIASMA medication in time-to-event analyses adjusted for sociodemographic characteristics and medical comorbidities. The primary analysis was a Cox regression model with inverse probability weighting (IPW). Over a mean follow-up of 9.2 days (SD = 12.5), the primary end point occurred in 104 patients (37.5%) receiving an FIASMA medication, and 1,060 patients (41.4%) who did not. Despite being significantly and substantially associated with older age and greater medical severity, FIASMA medication use was significantly associated with reduced likelihood of intubation or death in both crude (hazard ratio (HR) = 0.71, 95% confidence interval (CI) = 0.58-0.87, P < 0.001) and primary IPW (HR = 0.58, 95%CI = 0.46-0.72, P < 0.001) analyses. This association remained significant in multiple sensitivity analyses and was not specific to one particular FIASMA class or medication. These results show the potential importance of the ASM/ceramide system in COVID-19 and support the continuation of FIASMA medications in these patients. Double-blind controlled randomized clinical trials of these medications for COVID-19 are needed.


Subject(s)
COVID-19/enzymology , COVID-19/mortality , Hospitalization/trends , Intubation, Intratracheal/mortality , Intubation, Intratracheal/trends , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19 Testing/trends , Cohort Studies , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Humans , Male , Middle Aged , Mortality/trends , Retrospective Studies , Sphingomyelin Phosphodiesterase/metabolism , Young Adult
9.
J Clin Pharm Ther ; 46(5): 1308-1311, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1220012

ABSTRACT

WHAT IS KNOWN AND OBJECTIVE: A pandemic can strain all aspects of the healthcare system, including the ability to monitor the safety of medication use. Reviewing the adequacy of medication safety practices during the COVID-19 pandemic is critical to informing responses to future pandemics. The purpose of this study was to evaluate medication safety practices at a height of both COVID-19 cases and hydroxychloroquine use. METHODS: This was a multicentre observational point prevalence study. Adult inpatients receiving hydroxychloroquine for COVID-19 between March 22 and 28, 2020 were included. The primary outcome was the percentage of patients receiving appropriate QTc monitoring. Secondary outcomes included QTc prolongation, early discontinuation of hydroxychloroquine and ventricular arrhythmias. RESULTS AND DISCUSSION: A total of 59% (167/284) of patients treated with hydroxychloroquine received appropriate QTc monitoring. QTc prolongation occurred in 25%. Hydroxychloroquine was prematurely discontinued in 1.4% of patients, all due to QTc prolongation. Ventricular arrhythmia occurred in 1.1%. WHAT IS NEW AND CONCLUSION: Medication safety practices were suboptimal with regard to hydroxychloroquine monitoring at the height of the COVID-19 pandemic. Preparation for future pandemics should devote considerable attention to medication safety.


Subject(s)
Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/diagnosis , COVID-19/drug therapy , Electrocardiography/methods , Hydroxychloroquine/adverse effects , Patient Safety/statistics & numerical data , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/therapeutic use , Female , Humans , Hydroxychloroquine/therapeutic use , Male , Middle Aged , Pandemics , Prevalence , SARS-CoV-2
11.
J Med Virol ; 93(1): 300-310, 2021 01.
Article in English | MEDLINE | ID: covidwho-1206791

ABSTRACT

The global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), named coronavirus disease 2019, has infected more than 8.9 million people worldwide. This calls for urgent effective therapeutic measures. RNA-dependent RNA polymerase (RdRp) activity in viral transcription and replication has been recognized as an attractive target to design novel antiviral strategies. Although SARS-CoV-2 shares less genetic similarity with SARS-CoV (~79%) and Middle East respiratory syndrome coronavirus (~50%), the respective RdRps of the three coronaviruses are highly conserved, suggesting that RdRp is a good broad-spectrum antiviral target for coronaviruses. In this review, we discuss the antiviral potential of RdRp inhibitors (mainly nucleoside analogs) with an aim to provide a comprehensive account of drug discovery on SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Enzyme Inhibitors/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/enzymology , Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Nucleosides/pharmacology , Nucleosides/therapeutic use , RNA-Dependent RNA Polymerase/genetics , RNA-Dependent RNA Polymerase/metabolism , SARS-CoV-2/metabolism
12.
Biomed Pharmacother ; 138: 111544, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1163406

ABSTRACT

The RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) from SARS-CoV-2 play crucial roles in the viral life cycle and are considered the most promising targets for drug discovery against SARS-CoV-2. In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach. The number of ligands selected from the PubChem database of NCBI for screening was 1760. Ligands were energy minimized using Open Babel. The RdRp and 3CLpro protein sequences were retrieved from the NCBI database. For Homology Modeling predictions, we used the Swiss model server. Their structure was then energetically minimized using SPDB viewer software and visualized in the CHIMERA UCSF software. Molecular dockings were performed using AutoDock Vina, and candidate drugs were selected based on binding affinity (∆G). Hydrogen bonding and hydrophobic interactions between ligands and proteins were visualized using Ligplot and the Discovery Studio Visualizer v3.0 software. Our results showed 58 drugs against RdRp, which had binding energy of - 8.5 or less, and 69 drugs to inhibit the 3CLpro enzyme with a binding energy of - 8.1 or less. Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib and dihydroergotamine for 3clpro and Lapatinib, Dexasone and Relategravir for RdRp). Except for Lapatinib, other drugs-complexes were stable during MD simulation. Raltegravir, an anti-HIV drug, was observed to be the best compound against RdRp based on docking binding energy (-9.5 kcal/mole) and MD results. According to the MD results and binding energy, dihydroergotamine is a suitable candidate for 3clpro inhibition (-9.6 kcal/mol). These drugs were classified into several categories, including antiviral, antibacterial, anti-inflammatory, anti-allergic, cardiovascular, anticoagulant, BPH and impotence, antipsychotic, antimigraine, anticancer, and so on. The common prescription-indications for some of these medication categories appeared somewhat in line with manifestations of COVID-19. We hope that they can be beneficial for patients with certain specific symptoms of SARS-CoV-2 infection, but they can also probably inhibit viral enzymes. We recommend further experimental evaluations in vitro and in vivo on these FDA-approved drugs to assess their potential antiviral effect on SARS-CoV-2.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Repositioning , Enzyme Inhibitors/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Animals , Antiviral Agents/adverse effects , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Dihydroergotamine/therapeutic use , Drug Approval , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase/metabolism , Raltegravir Potassium/therapeutic use , SARS-CoV-2/enzymology , United States , United States Food and Drug Administration
13.
Exp Biol Med (Maywood) ; 246(13): 1533-1540, 2021 07.
Article in English | MEDLINE | ID: covidwho-1148197

ABSTRACT

Novel 2019 coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) and coronavirus disease 2019 (COVID-19), the respiratory syndrome it causes, have shaken the world to its core by infecting and claiming the lives of many people since originating in December 2019 in Wuhan, China. World Health Organization and several states have declared a pandemic situation and state of emergency, respectively. As there is no treatment for COVID-19, several research institutes and pharmaceutical companies are racing to find a cure. Advances in computational approaches have allowed the screening of massive antiviral compound libraries to identify those that may potentially work against SARS-CoV-2. Antiviral agents developed in the past to combat other viruses are being repurposed. At the same time, new vaccine candidates are being developed and tested in preclinical/clinical settings. This review provides a detailed overview of select repurposed drugs, their mechanism of action, associated toxicities, and major clinical trials involving these agents.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Development , Enzyme Inhibitors/therapeutic use , Angiotensin Receptor Antagonists/therapeutic use , Clinical Trials as Topic , Humans
15.
Indian J Tuberc ; 67(4S): S147-S154, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1124988

ABSTRACT

COVID 19 infection is unarguably the worst pandemic of this century. Till date there is no promising drug and vaccine available to treat this deadly viral infection. In the early phase chloroquine phosphate and hydroxychloroquine sulphate have been used to fight this illness on the basis of handful observational and small randomized and small-randomized studies. The paucity of clinical evidences of an unequivocal beneficial effect of chloroquine and hydroxychloroquine on COVID-19 has resulted in the passionate use of the drug for moderate to severe cases only and stimulated the need for large clinical trials for this and other molecules. In this review, we describe in brief the mechanism of action, the clinical studies, factors for cardiac toxicity, guidelines and future directions for hydroxychloroquine use in management of COVID-19 infection.


Subject(s)
COVID-19/drug therapy , Enzyme Inhibitors/pharmacology , Hydroxychloroquine/pharmacology , SARS-CoV-2 , Enzyme Inhibitors/therapeutic use , Humans , Hydroxychloroquine/therapeutic use
16.
Orphanet J Rare Dis ; 16(1): 114, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1112440

ABSTRACT

BACKGROUND: Hydroxyurea is one of the earliest drugs that showed promise in the management of haemoglobinopathies that include ß-thalassaemia and sickle cell disease. Despite this, many aspects of hydroxyurea are either unknown or understudied; specifically, its usefulness in ß-thalassaemia major and haemoglobin E ß-thalassaemia is unclear. However, during COVID-19 pandemic, it has become a valuable adjunct to transfusion therapy in patients with ß-haemoglobinopathies. In this review, we aim to explore the available in vitro and in vivo mechanistic data and the clinical utility of hydroxyurea in ß-haemoglobinopathies with a special emphasis on its usefulness during the COVID-19 pandemic. MAIN BODY: Hydroxyurea is an S-phase-specific drug that reversibly inhibits ribonucleoside diphosphate reductase enzyme which catalyses an essential step in the DNA biosynthesis. In human erythroid cells, it induces the expression of γ-globin, a fetal globin gene that is suppressed after birth. Through several molecular pathways described in this review, hydroxyurea exerts many favourable effects on the haemoglobin content, red blood cell indices, ineffective erythropoiesis, and blood rheology in patients with ß-haemoglobinopathies. Currently, it is recommended for sickle cell disease and non-transfusion dependent ß-thalassaemia. A number of clinical trials are ongoing to evaluate its usefulness in transfusion dependent ß-thalassaemia. During the COVID-19 pandemic, it was widely used as an adjunct to transfusion therapy due to limitations in the availability of blood and logistical disturbances. Thus, it has become clear that hydroxyurea could play a remarkable role in reducing transfusion requirements of patients with haemoglobinopathies, especially when donor blood is a limited resource. CONCLUSION: Hydroxyurea is a well-tolerated oral drug which has been in use for many decades. Through its actions of reversible inhibition of ribonucleoside diphosphate reductase enzyme and fetal haemoglobin induction, it exerts many favourable effects on patients with ß-haemoglobinopathies. It is currently approved for the treatment of sickle cell disease and non-transfusion dependent ß-thalassaemia. Also, there are various observations to suggest that hydroxyurea is an important adjunct in the treatment of transfusion dependent ß-thalassaemia which should be confirmed by randomised clinical trials.


Subject(s)
COVID-19/drug therapy , Hemoglobinopathies/drug therapy , Hydroxyurea/therapeutic use , Bloodless Medical and Surgical Procedures , Enzyme Inhibitors/therapeutic use , Humans , Ribonucleoside Diphosphate Reductase/antagonists & inhibitors
17.
Inflamm Res ; 70(4): 389-405, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1092089

ABSTRACT

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a world-wide pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, treatment of severe COVID-19 is far from clear. Therefore, it is urgent to develop an effective option for the treatment of patients with COVID-19. Most patients with severe COVID-19 exhibit markedly increased serum levels of pro-inflammatory cytokines, including interferon (IFN)-α, IFN-γ, and interleukin (IL)-1ß. Immunotherapeutic strategies have an important role in the suppression of cytokine storm and respiratory failure in patients with COVID-19. METHODS: A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar preprint database using all available MeSH terms for Coronavirus, SARS-CoV-2, anti-rheumatoid agents, COVID-19, cytokine storm, immunotherapeutic drugs, IFN, interleukin, JAK/STAT inhibitors, MCP, MIP, TNF. RESULTS: Here, we first review common complications of COVID-19 patients, particularly neurological symptoms. We next explain host immune responses against COVID-19 particles. Finally, we summarize the existing experimental and clinical immunotherapeutic strategies, particularly anti-rheumatoid agents and also plasma (with a high level of gamma globulin) therapy for severe COVID-19 patients. We discuss both their therapeutic effects and side effects that should be taken into consideration for their clinical application. CONCLUSION: It is suggested that immunosuppressants, such as anti-rheumatoid drugs, could be considered as a potential approach for the treatment of cytokine storm in severe cases of COVID-19. One possible limitation of immunosuppressant therapy is their inhibitory effects on host anti-viral immune response. So, the appropriate timing of administration should be carefully considered.


Subject(s)
COVID-19/epidemiology , COVID-19/therapy , Cytokine Release Syndrome/drug therapy , Immunologic Factors/therapeutic use , Animals , Antirheumatic Agents/therapeutic use , COVID-19/immunology , Cytokines/metabolism , Enzyme Inhibitors/therapeutic use , Humans , Immunization, Passive , Immunosuppressive Agents/therapeutic use , Immunotherapy , Inflammation/drug therapy , Interferons/therapeutic use , Interleukin-1/antagonists & inhibitors , Interleukin-6/antagonists & inhibitors , Janus Kinase 1/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Respiratory Insufficiency/therapy , STAT1 Transcription Factor/antagonists & inhibitors , Signal Transduction
18.
Biophys Chem ; 272: 106564, 2021 05.
Article in English | MEDLINE | ID: covidwho-1091923

ABSTRACT

INTRODUCTION: Despite all the efforts to treat COVID-19, no particular cure has been found for this virus. Since developing antiviral drugs is a time-consuming process, the most effective approach is to evaluate the approved and under investigation drugs using in silico methods. Among the different targets within the virus structure, as a vital component in the life cycle of coronaviruses, RNA-dependent RNA polymerase (RdRP) can be a critical target for antiviral drugs. The impact of the existence of RNA in the enzyme structure on the binding affinity of anti-RdRP drugs has not been investigated so far. METHODS: In this study, the potential anti-RdRP effects of a variety of drugs from two databases (Zinc database and DrugBank) were evaluated using molecular docking. For this purpose, the newly emerged model of COVID-19 (RdRP) post-translocated catalytic complex (PDB ID: 7BZF) that consists of RNA was chosen as the target. RESULTS: The results indicated that idarubicin (IDR), a member of the anthracycline antibiotic family, and fenoterol (FNT), a known beta-2 adrenergic agonist drug, tightly bind to the target enzyme and could be used as potential anti-RdRP inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These outcomes revealed that due to the ligand-protein interactions, the presence of RNA in this structure could remarkably affect the binding affinity of inhibitor compounds. CONCLUSION: In silico approaches, such as molecular docking, could effectively address the problem of finding appropriate treatment for COVID-19. Our results showed that IDR and FNT have a significant affinity to the RdRP of SARS-CoV-2; therefore, these drugs are remarkable inhibitors of coronaviruses.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Computational Chemistry , Enzyme Inhibitors/pharmacology , RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , Antiviral Agents/therapeutic use , COVID-19/virology , Enzyme Inhibitors/therapeutic use , Humans , Molecular Docking Simulation , SARS-CoV-2/enzymology , SARS-CoV-2/isolation & purification
19.
Am J Obstet Gynecol MFM ; 2(2): 100118, 2020 05.
Article in English | MEDLINE | ID: covidwho-1064729

ABSTRACT

Novel coronavirus disease 2019 is rapidly spreading throughout the New York metropolitan area since its first reported case on March 1, 2020. The state is now the epicenter of coronavirus disease 2019 outbreak in the United States, with 84,735 cases reported as of April 2, 2020. We previously presented an early case series with 7 coronavirus disease 2019-positive pregnant patients, 2 of whom were diagnosed with coronavirus disease 2019 after an initial asymptomatic presentation. We now describe a series of 43 test-positive cases of coronavirus disease 2019 presenting to an affiliated pair of New York City hospitals for more than 2 weeks, from March 13, 2020, to March 27, 2020. A total of 14 patients (32.6%) presented without any coronavirus disease 2019-associated viral symptoms and were identified after they developed symptoms during admission or after the implementation of universal testing for all obstetric admissions on March 22. Among them, 10 patients (71.4%) developed symptoms of coronavirus disease 2019 over the course of their delivery admission or early after postpartum discharge. Of the other 29 patients (67.4%) who presented with symptomatic coronavirus disease 2019, 3 women ultimately required antenatal admission for viral symptoms, and another patient re-presented with worsening respiratory status requiring oxygen supplementation 6 days postpartum after a successful labor induction. There were no confirmed cases of coronavirus disease 2019 detected in neonates upon initial testing on the first day of life. Based on coronavirus disease 2019 disease severity characteristics by Wu and McGoogan, 37 women (86%) exhibited mild disease, 4 (9.3%) severe disease, and 2 (4.7%) critical disease; these percentages are similar to those described in nonpregnant adults with coronavirus disease 2019 (about 80% mild, 15% severe, and 5% critical disease).


Subject(s)
Ambulatory Care , COVID-19/therapy , Cesarean Section , Hospitalization , Labor, Induced , Pregnancy Complications, Infectious/therapy , Adult , Anti-Bacterial Agents/therapeutic use , Asymptomatic Diseases , Azithromycin/therapeutic use , COVID-19/complications , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19 Nucleic Acid Testing , Carrier State/diagnosis , Disease Management , Enzyme Inhibitors/therapeutic use , Female , Fluid Therapy , Gestational Age , Hospitals, Community , Hospitals, University , Humans , Hydroxychloroquine/therapeutic use , Infection Control/methods , Intensive Care Units , Labor, Obstetric , Multi-Institutional Systems , New York City , Obesity, Maternal/complications , Obstetric Labor, Premature , Oxygen Inhalation Therapy , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/physiopathology , Retrospective Studies , SARS-CoV-2 , Telemedicine , Young Adult
20.
Am J Obstet Gynecol MFM ; 2(2): 100113, 2020 05.
Article in English | MEDLINE | ID: covidwho-1064728

ABSTRACT

At our institution, 2 of the initial 7 pregnant patients with confirmed coronavirus disease 2019 severe infection (28.6%; 95% CI, 8.2%-64.1%) developed cardiac dysfunction with moderately reduced left ventricular ejection fractions of 40%-45% and hypokinesis. Viral myocarditis and cardiomyopathy have also been reported in nonpregnant coronavirus disease 2019 patients. A case series of nonpregnant patients with coronavirus disease 2019 found that 33% of those in intensive care developed cardiomyopathy. More data are needed to ascertain the incidence of cardiomyopathy from coronavirus disease 2019 in pregnancy, in all pregnant women with coronavirus disease 2019, and those with severe disease (eg, pneumonia). We suggest an echocardiogram in pregnant women with coronavirus disease 2019 pneumonia, in particular those necessitating oxygen, or those who are critically ill, and we recommend the use of handheld, point-of-care devices where possible to minimize contamination of staff and traditional large echocardiogram machines.


Subject(s)
COVID-19/therapy , Cardiomyopathies/therapy , Cesarean Section , Heart Failure/therapy , Pregnancy Complications, Cardiovascular/therapy , Pregnancy Complications, Infectious/therapy , Respiration, Artificial , Adult , Anti-Arrhythmia Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Anticonvulsants/therapeutic use , Blood Gas Analysis , COVID-19/complications , COVID-19/diagnosis , COVID-19/physiopathology , COVID-19 Nucleic Acid Testing , Cardiomyopathies/diagnosis , Cardiomyopathies/etiology , Cardiomyopathies/physiopathology , Diabetes, Gestational , Diuretics/therapeutic use , Echocardiography , Enzyme Inhibitors/therapeutic use , Female , Fever , Furosemide/therapeutic use , Heart Arrest/etiology , Heart Arrest/therapy , Heart Failure/diagnosis , Heart Failure/etiology , Heart Failure/physiopathology , Humans , Hydroxychloroquine/therapeutic use , Hypoxia/etiology , Hypoxia/therapy , Intubation, Intratracheal , Magnesium Sulfate/therapeutic use , Metoprolol/therapeutic use , Middle Aged , Obesity, Maternal/complications , Oxygen Inhalation Therapy , Point-of-Care Systems , Pre-Eclampsia/drug therapy , Pre-Eclampsia/physiopathology , Pregnancy , Pregnancy Complications, Cardiovascular/diagnosis , Pregnancy Complications, Cardiovascular/physiopathology , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/physiopathology , Return of Spontaneous Circulation , SARS-CoV-2 , Severity of Illness Index , Stroke Volume , Tachycardia/drug therapy , Tachycardia/physiopathology , Tachycardia, Supraventricular/drug therapy , Tachycardia, Supraventricular/etiology
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