@article{Eastman_2020_32483554, type="Journal Article", author={Richard T RT Eastman and Jacob S JS Roth and Kyle R KR Brimacombe and Anton A Simeonov and Min M Shen and Samarjit S Patnaik and Matthew D MD Hall}, title={Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19.}, abstract={The global pandemic of SARS-CoV-2, the causative viral pathogen of COVID-19, has driven the biomedical community to action-to uncover and develop antiviral interventions. One potential therapeutic approach currently being evaluated in numerous clinical trials is the agent remdesivir, which has endured a long and winding developmental path. Remdesivir is a nucleotide analogue prodrug that perturbs viral replication, originally evaluated in clinical trials to thwart the Ebola outbreak in 2014. Subsequent evaluation by numerous virology laboratories demonstrated the ability of remdesivir to inhibit coronavirus replication, including SARS-CoV-2. Here, we provide an overview of remdesivir's discovery, mechanism of action, and the current studies exploring its clinical effectiveness.}, year={2020}, date={27 May 2020}, volume={6}, issue={5}, number={5}, pages={672-683}, journal={ACS central science}, url={https://pubmed.ncbi.nlm.nih.gov/32483554/}, language={eng}, doi={10.1021/acscentsci.0c00489}, source={PubMed}, id={32483554}, issn={2374-7943}, } @article{Wang_2020_32448345, type="Journal Article", author={Yeming Y Wang and Fei F Zhou and Dingyu D Zhang and Jianping J Zhao and Ronghui R Du and Yi Y Hu and Zhenshun Z Cheng and Ling L Gao and Yang Y Jin and Guangwei G Luo and Shouzhi S Fu and Qiaofa Q Lu and Guanhua G Du and Ke K Wang and Yang Y Lu and Guohui G Fan and Yi Y Zhang and Ying Y Liu and Shunan S Ruan and Wen W Liu and Thomas T Jaki and Frederick G FG Hayden and Peter W PW Horby and Bin B Cao and Chen C Wang}, title={Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial.}, abstract={BACKGROUND Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30 January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6 February 2020. TRIAL REGISTRATION ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.}, year={2020}, date={24 May 2020}, volume={21}, issue={1}, number={1}, pages={422}, journal={Trials}, url={https://pubmed.ncbi.nlm.nih.gov/32448345/}, language={eng}, doi={10.1186/s13063-020-04352-9}, source={PubMed}, id={32448345}, issn={1745-6215}, } @article{Singh_2020_32428865, type="Journal Article", author={Awadhesh Kumar AK Singh and Akriti A Singh and Ritu R Singh and Anoop A Misra}, title={Remdesivir in COVID-19: A critical review of pharmacology, pre-clinical and clinical studies.}, abstract={BACKGROUND & AIMS Remdesivir is a broad spectrum anti-viral drug that has shown to inhibit SARS-CoV-2, in vitro and in vivo. In absence of any effective treatment for SARS-CoV-2 infection (COVID-19), remdesivir has been tried for a compassionate use in severe COVID-19. Newer randomized controlled studies that have recently become available, showed a mixed result. We aimed to systematically search the literature to understand the pharmacology and clinical effects of remdesivir in patients with COVID-19. METHODS We systematically searched the PubMed, ClinicalTrial.Org and MedRxiv database up till May 5, 2020 using specific key words such as "Remdesivir" or 'GS-5734″ AND "COVID-19" or "SARS-CoV-2" and retrieved all the article published in English language, that have reported the pharmacology and the clinical outcomes of remdesivir in patients with COVID-19. RESULTS Initial compassionate use of remdesivir has shown a fairly good result, but difficult to quantify, in the absence of control arm. While the very first double-blind, placebo-controlled, randomized trial conducted in Wuhan, did not find any significant benefit compared to the control, the preliminary result of another similar multi-country trial has shown a significant faster time to recovery but without any difference in mortality. CONCLUSIONS Remdesivir has shown a mixed result in patients with COVID-19 with an acceptable side effect. However, jury is still out while awaiting the results from the forthcoming trials.}, year={2020}, date={12 May 2020}, volume={14}, issue={4}, number={4}, pages={641-648}, journal={Diabetes & metabolic syndrome}, url={https://pubmed.ncbi.nlm.nih.gov/32428865/}, language={eng}, doi={10.1016/j.dsx.2020.05.018}, source={PubMed}, id={32428865}, issn={1878-0334}, } @article{Jan_2020_32377559, type="Journal Article", author={Hasnain H Jan and Shah S Faisal and Ayyaz A Khan and Shahzar S Khan and Hazrat H Usman and Rabia R Liaqat and Sajjad Ali SA Shah}, title={COVID-19: Review of Epidemiology and Potential Treatments Against 2019 Novel Coronavirus.}, abstract={An epidemic of extreme respiratory deterrence, pneumonia and shortness of breath, the SARS-CoV-2 viral infection began in Wuhan, Hubei Province, China in December 2019, and rapidly spread across China and beyond, with human to human transmission. On February 12, 2020, World Health Organization officially named the new coronavirus disease as coronavirus disease 19 (COVID-19). Most COVID-19 patients were diagnosed with pneumonia and many were treated using Chinese medicines and other secondary therapies. As of April 22, 2020, the total figure of infected patients has crossed 2.6 million people worldwide with over 180,000 deaths and 700,000 patients that have recovered. Preliminary reports suggest that certain drugs, such as chloroquine and antiviral nucleotide analogues such as remdesivir, which inhibit viral replication, can target the new coronavirus, although their usefulness in the clinic is still under debate. An expert US committee developed the US NIH guidelines for COVID-19 treatment, which was just released and will be regularly updated. This manuscript reviews the epidemiology, etiology, mortality, COVID-19 clinical symptoms, and potential therapeutic drugs, while highlighting the seriousness and damage-induced by SARS-CoV-2.}, year={2020}, date={26 Apr 2020}, volume={8}, issue={2}, number={2}, pages={e108}, journal={Discoveries (Craiova, Romania)}, url={https://pubmed.ncbi.nlm.nih.gov/32377559/}, language={eng}, doi={10.15190/d.2020.5}, source={PubMed}, id={32377559}, issn={2359-7232}, } @article{Augustin_2020_32333086, type="Journal Article", author={M M Augustin and M M Hallek and S S Nitschmann}, title={[Remdesivir for patients with severe COVID-19].}, abstract={}, year={2020}, date={Jun 2020}, volume={61}, issue={6}, number={6}, pages={644-645}, journal={Der Internist}, url={https://pubmed.ncbi.nlm.nih.gov/32333086/}, language={ger}, doi={10.1007/s00108-020-00800-5}, source={PubMed}, id={32333086}, issn={1432-1289}, } @article{Yuan_2020_32473310, type="Journal Article", author={Shuofeng S Yuan and Jasper F W JFW Chan and Kenn K H KKH Chik and Chris C Y CCY Chan and Jessica O L JOL Tsang and Ronghui R Liang and Jianli J Cao and Kaiming K Tang and Lin-Lei LL Chen and Kun K Wen and Jian-Piao JP Cai and Zi-Wei ZW Ye and Gang G Lu and Hin H Chu and Dong-Yan DY Jin and Kwok-Yung KY Yuen}, title={Discovery of the FDA-approved drugs bexarotene, cetilistat, diiodohydroxyquinoline, and abiraterone as potential COVID-19 treatments with a robust two-tier screening system.}, abstract={Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50 % maximal effective concentrations (EC) that exceeded their achievable peak serum concentrations (Cmax), side effects, and/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC 1.13-2.01 μM). Bexarotene demonstrated the highest Cmax:EC ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.}, year={2020}, date={28 May 2020}, volume={159}, issue={}, number={}, pages={104960}, journal={Pharmacological research}, url={https://pubmed.ncbi.nlm.nih.gov/32473310/}, language={eng}, doi={10.1016/j.phrs.2020.104960}, source={PubMed}, id={32473310}, issn={1096-1186}, } @article{Eckhardt_2020_32513308, type="Letter", author={Christina M CM Eckhardt and Matthew J MJ Cummings and Kartik N KN Rajagopalan and Sarah S Borden and Zachary C ZC Bitan and Allison A Wolf and Alex A Kantor and Thomas T Briese and Benjamin J BJ Meyer and Samuel D SD Jacobson and Dawn D Scotto and Nischay N Mishra and Neena M NM Philip and Brie A BA Stotler and Joseph J Schwartz and Beth B Shaz and Steven L SL Spitalnik and Andrew A Eisenberger and Eldad A EA Hod and Jessica J Justman and Ken K Cheung and W Ian WI Lipkin and Max R MR O'Donnell}, title={Evaluating the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in severely ill adults with COVID-19: A structured summary of a study protocol for a randomized controlled trial.}, abstract={OBJECTIVES The aim of this study is to evaluate the efficacy and safety of human anti-SARS-CoV-2 convalescent plasma in hospitalized adults with severe SARS-CoV-2 infection. TRIAL DESIGN This is a prospective, single-center, phase 2, randomized, controlled trial that is blinded to participants and clinical outcome assessor. PARTICIPANTS Eligible participants include adults (≥ 18 years) with evidence of SARS-CoV-2 infection by PCR test of nasopharyngeal or oropharyngeal swab within 14 days of randomization, evidence of infiltrates on chest radiography, peripheral capillary oxygen saturation (SpO2) ≤ 94% on room air, and/or need for supplemental oxygen, non-invasive mechanical ventilation, or invasive mechanical ventilation, who are willing and able to provide written informed consent prior to performing study procedures or who have a legally authorized representative available to do so. Exclusion criteria include participation in another clinical trial of anti-viral agent(s)* for coronavirus disease-2019 (COVID-19), receipt of any anti-viral agent(s)* with possible activity against SARS-CoV-2 <24 hours prior to plasma infusion, mechanical ventilation (including extracorporeal membrane oxygenation [ECMO]) for ≥ 5 days, severe multi-organ failure, history of allergic reactions to transfused blood products per NHSN/CDC criteria, known IgA deficiency, and pregnancy. Included participants will be hospitalized at the time of randomization and plasma infusion. *Use of remdesivir as treatment for COVID-19 is permitted. The study will be undertaken at Columbia University Irving Medical Center in New York, USA. INTERVENTION AND COMPARATOR The investigational treatment is anti-SARS-CoV-2 human convalescent plasma. To procure the investigational treatment, volunteers who recovered from COVID-19 will undergo testing to confirm the presence of anti-SARS-CoV-2 antibody to the spike trimer at a 1:400 dilution. Donors will also be screened for transfusion-transmitted infections (e.g. HIV, HBV, HCV, WNV, HTLV-I/II, T. cruzi, ZIKV). If donors have experienced COVID-19 symptoms within 28 days, they will be screened with a nasopharyngeal swab to confirm they are SARS-CoV-2 PCR-negative. Plasma will be collected using standard apheresis technology by the New York Blood Center. Study participants will be randomized in a 2:1 ratio to receive one unit (200 - 250 mL) of anti-SARS-CoV-2 plasma versus one unit (200 - 250 mL) of the earliest available control plasma. The control plasma cannot be tested for presence of anti-SARS-CoV-2 antibody prior to the transfusion, but will be tested for anti- SARS-CoV-2 antibody after the transfusion to allow for a retrospective per-protocol analysis. MAIN OUTCOMES The primary endpoint is time to clinical improvement. This is defined as time from randomization to either discharge from the hospital or improvement by one point on the following seven-point ordinal scale, whichever occurs first. 1. Not hospitalized with resumption of normal activities 2. Not hospitalized, but unable to resume normal activities 3. Hospitalized, not requiring supplemental oxygen 4. Hospitalized, requiring supplemental oxygen 5. Hospitalized, requiring high-flow oxygen therapy or non-invasive mechanical ventilation 6. Hospitalized, requiring ECMO, invasive mechanical ventilation, or both 7. Death This scale, designed to assess clinical status over time, was based on that recommended by the World Health Organization for use in determining efficacy end-points in clinical trials in hospitalized patients with COVID-19. A recent clinical trial evaluating the efficacy and safety of lopinavir- ritonavir for patients hospitalized with severe COVID-19 used a similar ordinal scale, as have recent clinical trials of novel therapeutics for severe influenza, including a post-hoc analysis of a trial evaluating immune plasma. The primary safety endpoints are cumulative incidence of grade 3 and 4 adverse events and cumulative incidence of serious adverse events during the study period. RANDOMIZATION Study participants will be randomized in a 2:1 ratio to receive anti-SARS-CoV-2 plasma versus control plasma using a web-based randomization platform. Treatment assignments will be generated using randomly permuted blocks of different sizes to minimize imbalance while also minimizing predictability. BLINDING (MASKING) The study participants and the clinicians who will evaluate post-treatment outcomes will be blinded to group assignment. The blood bank and the clinical research team will not be blinded to group assignment. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE) We plan to enroll 129 participants, with 86 in the anti-SARS-CoV-2 arm, and 43 in the control arm. Among the participants, we expect ~70% or n = 72 will achieve clinical improvement. This will yield an 80% power for a one-sided Wald test at 0.15 level of significance under the proportional hazards model with a hazard ratio of 1.5. TRIAL STATUS Protocol AAAS9924, Version 17APR2020, 4/17/2020 Start of recruitment: April 20, 2020 Recruitment is ongoing. TRIAL REGISTRATION ClinicalTrials.gov: NCT04359810 Date of trial registration: April 24, 2020 Retrospectively registered 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.}, year={2020}, date={06 Aug 2020}, volume={21}, issue={1}, number={1}, pages={499}, journal={Trials}, url={https://pubmed.ncbi.nlm.nih.gov/32513308/}, language={eng}, doi={10.1186/s13063-020-04422-y}, source={PubMed}, id={32513308}, issn={1745-6215}, } @article{Abouhashem_2020_32323565, type="News, Research Support, N.I.H., Extramural", author={Ahmed S AS Abouhashem and Kanhaiya K Singh and Hassan M E HME Azzazy and Chandan K CK Sen}, title={Is Low Alveolar Type II Cell in the Lungs of Elderly Linked to the Observed Severity of COVID-19?}, abstract={Human lungs single-cell RNA sequencing data from healthy donors (elderly and young; GEO accession no. GSE122960) were analyzed to isolate and specifically study gene expression in alveolar type II cells. Colocalization of angiotensin-converting enzyme 2 () and enables severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) to enter the cells. Expression levels of these genes in the alveolar type II cells of elderly and young patients were comparable and, therefore, do not seem to be responsible for worse outcomes observed in coronavirus disease 2019 (COVID-19) affected elderly. In cells from the elderly, 263 genes were downregulated and 95 upregulated. Superoxide dismutase 3 () was identified as the top-ranked gene that was most downregulated in the elderly. Other redox-active genes that were also downregulated in cells from the elderly included activating transcription factor 4 () and metallothionein 2A (). is an endoplasmic reticulum stress sensor that defends lungs induction of heme oxygenase 1. The study of downstream factors known to be induced by , according to Ingenuity Pathway Analysis™, identified 24 candidates. Twenty-one of these were significantly downregulated in the cells from the elderly. These downregulated candidates were subjected to enrichment using the Reactome Database identifying that in the elderly, the ability to respond to heme deficiency and the -dependent ability to respond to endoplasmic reticulum stress is significantly compromised. -based therapeutic strategies have provided beneficial results in treating lung disorders including fibrosis. The findings of this study propose the hypotheses that lung-specific delivery of /-related antioxidants will work in synergy with promising antiviral drugs such as remdesivir to further improve COVID-19 outcomes in the elderly.}, year={2020}, date={07 Oct 2020}, volume={33}, issue={2}, number={2}, pages={59-65}, journal={Antioxidants & redox signaling}, url={https://pubmed.ncbi.nlm.nih.gov/32323565/}, language={eng}, doi={10.1089/ars.2020.8111}, source={PubMed}, id={32323565}, issn={1557-7716}, } @article{Lu_2020_31996494, type="Journal Article", author={Hongzhou H Lu}, title={Drug treatment options for the 2019-new coronavirus (2019-nCoV).}, abstract={As of January 22, 2020, a total of 571 cases of the 2019-new coronavirus (2019-nCoV) have been reported in 25 provinces (districts and cities) in China. At present, there is no vaccine or antiviral treatment for human and animal coronavirus, so that identifying the drug treatment options as soon as possible is critical for the response to the 2019-nCoV outbreak. Three general methods, which include existing broad-spectrum antiviral drugs using standard assays, screening of a chemical library containing many existing compounds or databases, and the redevelopment of new specific drugs based on the genome and biophysical understanding of individual coronaviruses, are used to discover the potential antiviral treatment of human pathogen coronavirus. Lopinavir /Ritonavir, Nucleoside analogues, Neuraminidase inhibitors, Remdesivir, peptide (EK1), abidol, RNA synthesis inhibitors (such as TDF, 3TC), anti-inflammatory drugs (such as hormones and other molecules), Chinese traditional medicine, such ShuFengJieDu Capsules and Lianhuaqingwen Capsule, could be the drug treatment options for 2019-nCoV. However, the efficacy and safety of these drugs for 2019- nCoV still need to be further confirmed by clinical experiments.}, year={2020}, date={16 Mar 2020}, volume={14}, issue={1}, number={1}, pages={69-71}, journal={Bioscience trends}, url={https://pubmed.ncbi.nlm.nih.gov/31996494/}, language={eng}, doi={10.5582/bst.2020.01020}, source={PubMed}, id={31996494}, issn={1881-7823}, } @article{Li_2020_32223926, type="Journal Article", author={Yan-Ni YN Li and Ya Y Su}, title={Remdesivir attenuates high fat diet (HFD)-induced NAFLD by regulating hepatocyte dyslipidemia and inflammation via the suppression of STING.}, abstract={High-fat diet (HFD) is a predisposing factor for metabolic syndrome-related systemic inflammation and non-alcoholic fatty liver disease (NAFLD). However, there is still no effective therapeutic treatment for NAFLD. Here, we showed that remdesivir (RDV, GS-5734), as a broad-spectrum antiviral nucleotide prodrug with anti-inflammatory effects, was effective for attenuating HFD-induced metabolic disorder and insulin resistance. Results revealed that the liver weight, hepatic dysfunction and lipid accumulation were markedly increased compared with that of the Control group, while that of the RDV group exhibited significant reduction, accompanied by the improved signaling pathway regulating fatty acid metabolism. In agreement with reduced lipid deposition, RDV supplementation suppressed the systematic and hepatic inflammation, as evidenced by reduction of inflammatory cytokines and the blockage of nuclear factor κB (NF-κB) signaling. In addition, stimulator of interferon genes (STING) and its down-streaming factor interferon regulatory factor 3 (IRF3) were greatly increased in livers of HFD-fed mice, which were considerably restrained by RDV treatment. The in vitro analysis suggested that RDV functioned as an inhibitor of STING, contributing to the suppression of dyslipidemia and inflammation induced by palmitate (PA). However, PA-triggered lipid deposition and inflammatory response was further accelerated in hepatocytes with STING over-expression. Notably, RDV-attenuated lipid disorder and inflammation were significantly abrogated by the over-expression of STING in PA-stimulated hepatocytes. Taken together, these findings indicated that RDV exhibited protective effects against NAFLD development mainly through repressing STING signaling, and thus could be considered as a potential therapeutic strategy.}, year={2020}, date={28 May 2020}, volume={526}, issue={2}, number={2}, pages={381-388}, journal={Biochemical and biophysical research communications}, url={https://pubmed.ncbi.nlm.nih.gov/32223926/}, language={eng}, doi={10.1016/j.bbrc.2020.03.034}, source={PubMed}, id={32223926}, issn={1090-2104}, }