Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review | Clinical Pharmacy and Pharmacology | JAMA | JAMA Network
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1.
Zhu  N, Zhang  D, Wang  W,  et al; China Novel Coronavirus Investigating and Research Team.  A novel coronavirus from patients with pneumonia in China, 2019.   N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017 PubMedGoogle ScholarCrossref
2.
Chinese Clinical Trials. http://www/chictr.org/enindex.aspx. Accessed March 31, 2020.
3.
Hoffmann  M, Kleine-Weber  H, Schroeder  S,  et al.  SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.   Cell. Published online March 4, 2020. doi:10.1016/j.cell.2020.02.052 PubMedGoogle Scholar
4.
Chen  Y, Liu  Q, Guo  D.  Emerging coronaviruses: genome structure, replication, and pathogenesis.   J Med Virol. 2020;92(4):418-423. doi:10.1002/jmv.25681 PubMedGoogle ScholarCrossref
5.
Fehr  AR, Perlman  S.  Coronaviruses: an overview of their replication and pathogenesis.   Methods Mol Biol. 2015;1282:1-23. doi:10.1007/978-1-4939-2438-7_1 PubMedGoogle ScholarCrossref
6.
Fung  TS, Liu  DX.  Coronavirus infection, ER stress, apoptosis and innate immunity.   Front Microbiol. 2014;5:296. doi:10.3389/fmicb.2014.00296 PubMedGoogle ScholarCrossref
7.
Savarino  A, Boelaert  JR, Cassone  A, Majori  G, Cauda  R.  Effects of chloroquine on viral infections: an old drug against today’s diseases?   Lancet Infect Dis. 2003;3(11):722-727. doi:10.1016/S1473-3099(03)00806-5 PubMedGoogle ScholarCrossref
8.
Al-Bari  MAA.  Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases.   Pharmacol Res Perspect. 2017;5(1):e00293. doi:10.1002/prp2.293 PubMedGoogle Scholar
9.
Zhou  D, Dai  SM, Tong  Q.  COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.  [published online March 20, 2020].  J Antimicrob Chemother. 2020;dkaa114. doi:10.1093/jac/dkaa114 PubMedGoogle Scholar
10.
Devaux  CA, Rolain  JM, Colson  P, Raoult  D.  New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?   Int J Antimicrob Agents. Published online March 11, 2020. doi:10.1016/j.ijantimicag.2020.105938 PubMedGoogle Scholar
11.
Colson  P, Rolain  JM, Lagier  JC, Brouqui  P, Raoult  D.  Chloroquine and hydroxychloroquine as available weapons to fight COVID-19.   Int J Antimicrob Agents. Published online March 4, 2020. doi:10.1016/j.ijantimicag.2020.105932 PubMedGoogle Scholar
12.
National Health Commission and State Administration of Traditional Chinese Medicine. Diagnosis and treatment protocol for novel coronavirus pneumonia. Accessed March 18, 2020. https://www.chinalawtranslate.com/wp-content/uploads/2020/03/Who-translation.pdf
13.
Chloroquine [database online]. Hudson, OH: Lexicomp Inc; 2016. Accessed March 17, 2020. http://online.lexi.com
14.
Aralen (chloroquine phosphate) [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2008. Accessed March 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/006002s045lbl.pdf
15.
Yao  X, Ye  F, Zhang  M,  et al.  In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).   Clin Infect Dis. Published online March 9, 2020. doi:10.1093/cid/ciaa237 PubMedGoogle Scholar
16.
Gautret  P, Lagier  JC, Parola  P,  et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial.   Int J Antimicrob Agents. Published online March 20, 2020. doi:10.1016/j.ijantimicag.2020.105949 PubMedGoogle Scholar
17.
Chen  J, Liu  D, Liu  L,  et al.  A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19).   J Zhejiang Univ (Med Sci). Published online March 6, 2020. doi:10.3785/j.issn.1008-9292.2020.03.03Google Scholar
18.
Hydroxychloroquine [database online]. Hudson, OH: Lexicomp Inc; 2016. Accessed March 17, 2020. http://online.lexi.com
19.
Plaquenil (Hydroxychloroquine sulfate) [package insert]. St Michael, Barbados: Concordia Pharmaceuticals Inc; 2018. Accessed March 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/009768Orig1s051lbl.pdf
20.
Lim  HS, Im  JS, Cho  JY,  et al.  Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax.   Antimicrob Agents Chemother. 2009;53(4):1468-1475. doi:10.1128/AAC.00339-08 PubMedGoogle ScholarCrossref
21.
Chu  CM, Cheng  VC, Hung  IF,  et al; HKU/UCH SARS Study Group.  Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings.   Thorax. 2004;59(3):252-256. doi:10.1136/thorax.2003.012658 PubMedGoogle ScholarCrossref
22.
de Wilde  AH, Jochmans  D, Posthuma  CC,  et al.  Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.   Antimicrob Agents Chemother. 2014;58(8):4875-4884. doi:10.1128/AAC.03011-14 PubMedGoogle ScholarCrossref
23.
Cao  B, Wang  Y, Wen  D,  et al.  A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19.   N Engl J Med. Published online March 18, 2020. doi:10.1056/NEJMoa2001282 PubMedGoogle Scholar
24.
Lopinavir/ritonavir [database online]. Hudson (OH): Lexicomp Inc; 2016. Accessed March 17, 2020. http://online.lexi.com
25.
Kaletra (Lopinavir and ritonavir) [package insert]. North Chicago, IL: Abbvie; 2019. Accessed March 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021226s048lbl.pdf
26.
Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Accessed March 17, 2020. http://www.aidsinfo.nih.gov/ContentFiles/ AdultandAdolescentGL.pdf
27.
Kadam  RU, Wilson  IA.  Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol.   Proc Natl Acad Sci U S A. 2017;114(2):206-214. doi:10.1073/pnas.1617020114 PubMedGoogle ScholarCrossref
28.
Khamitov  RA, Loginova  SIa, Shchukina  VN, Borisevich  SV, Maksimov  VA, Shuster  AM.  Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures [in Russian].   Vopr Virusol. 2008;53(4):9-13.PubMedGoogle Scholar
29.
Wang  Z, Yang  B, Li  Q, Wen  L, Zhang  R.  Clinical Features of 69 cases with coronavirus disease 2019 in Wuhan, China.   Clin Infect Dis. Published online March 16, 2020. doi:10.1093/cid/ciaa272 PubMedGoogle Scholar
30.
Siegel  D, Hui  HC, Doerffler  E,  et al.  Discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[2,1-f][triazin-4-amino] adenine C-nucleoside (GS-5734) for the treatment of Ebola and emerging viruses.   J Med Chem. 2017;60(5):1648-1661. doi:10.1021/acs.jmedchem.6b01594 PubMedGoogle ScholarCrossref
31.
Al-Tawfiq  JA, Al-Homoud  AH, Memish  ZA.  Remdesivir as a possible therapeutic option for the COVID-19.   Travel Med Infect Dis. Published online March 5, 2020. doi:10.1016/j.tmaid.2020.101615 PubMedGoogle Scholar
32.
Sheahan  TP, Sims  AC, Leist  SR,  et al.  Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV.   Nat Commun. 2020;11(1):222. doi:10.1038/s41467-019-13940-6 PubMedGoogle ScholarCrossref
33.
Hayden  FG, Shindo  N.  Influenza virus polymerase inhibitors in clinical development.   Curr Opin Infect Dis. 2019;32(2):176-186. doi:10.1097/QCO.0000000000000532 PubMedGoogle ScholarCrossref
34.
Avigan (favipiravir) [package insert]. Tokyo, Japan: Taisho Toyama Pharmaceutical Co Ltd; 2017, 4th version. Accessed March 25, 2020.
35.
Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. chinaXiv. Preprint posted March 5, 2020. doi:10.12074/202003.00026
36.
Actemra (tocilizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2019. Accessed March 17, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125276s127,125472s040lbl.pdf
37.
Stockman  LJ, Bellamy  R, Garner  P.  SARS: systematic review of treatment effects.   PLoS Med. 2006;3(9):e343. doi:10.1371/journal.pmed.0030343 PubMedGoogle Scholar
38.
Morra  ME, Van Thanh  L, Kamel  MG,  et al.  Clinical outcomes of current medical approaches for Middle East respiratory syndrome: a systematic review and meta-analysis.   Rev Med Virol. 2018;28(3):e1977. doi:10.1002/rmv.1977 PubMedGoogle Scholar
39.
Gao  J, Tian  Z, Yang  X.  Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.   Biosci Trends. 2020;14(1):72-73. doi:10.5582/bst.2020.01047 PubMedGoogle ScholarCrossref
40.
ClinicalTrials.gov. Accessed March 18, 2020. https://clinicaltrials.gov/
41.
Kalil  AC.  Treating COVID-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics.   JAMA. Published March 24, 2020. doi:10.1001/jama.2020.4742 PubMedGoogle Scholar
42.
Interview with David Juurlink.  Coronavirus (COVID-19) update: chloroquine/hydroxychloroquine and azithromycin.   JAMA. March 24, 2020. Accessed April 3, 2020. https://edhub.ama-assn.org/jn-learning/audio-player/18337225Google Scholar
43.
Osadchy  A, Ratnapalan  T, Koren  G.  Ocular toxicity in children exposed in utero to antimalarial drugs: review of the literature.   J Rheumatol. 2011;38(12):2504-2508. doi:10.3899/jrheum.110686 PubMedGoogle ScholarCrossref
44.
Dong  L, Hu  S, Gao  J.  Discovering drugs to treat coronavirus disease 2019 (COVID-19).   Drug Discov Ther. 2020;14(1):58-60. doi:10.5582/ddt.2020.01012 PubMedGoogle ScholarCrossref
45.
Yao  TT, Qian  JD, Zhu  WY, Wang  Y, Wang  GQ.  A systematic review of lopinavir therapy for SARS coronavirus and MERS coronavirus-A possible reference for coronavirus disease-19 treatment option.  [published online February 27, 2020].  J Med Virol. 2020. doi:10.1002/jmv.25729 PubMedGoogle Scholar
46.
Chan  KS, Lai  ST, Chu  CM,  et al.  Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study.   Hong Kong Med J. 2003;9(6):399-406.PubMedGoogle Scholar
47.
Wu  C, Chen  X, Cai  Y,  et al.  Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.   JAMA Intern Med. Published online March 13, 2020. PubMedGoogle Scholar
48.
Foolad  F, Aitken  SL, Shigle  TL,  et al.  Oral versus aerosolized ribavirin for the treatment of respiratory syncytial virus infections in hematopoietic cell transplant recipients.   Clin Infect Dis. 2019;68(10):1641-1649. doi:10.1093/cid/ciy760 PubMedGoogle ScholarCrossref
49.
Arabi  YM, Shalhoub  S, Mandourah  Y,  et al.  Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study.  Clin Infect Dis. Published online June 25, 2019. doi:10.1093/cid/ciz544 PubMedGoogle Scholar
50.
Altınbas  S, Holmes  JA, Altınbas  A.  Hepatitis C virus infection in pregnancy: an update.   Gastroenterol Nurs. 2020;43(1):12-21. doi:10.1097/SGA.0000000000000404 PubMedGoogle ScholarCrossref
51.
Wang  D, Hu  B, Hu  C,  et al.  Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.   JAMA. Published online February 7, 2020. doi:10.1001/jama.2020.1585 PubMedGoogle Scholar
52.
Totura  AL, Bavari  S.  Broad-spectrum coronavirus antiviral drug discovery.   Expert Opin Drug Discov. 2019;14(4):397-412. doi:10.1080/17460441.2019.1581171 PubMedGoogle ScholarCrossref
53.
Li  G, De Clercq  E.  Therapeutic options for the 2019 novel coronavirus (2019-nCoV).   Nat Rev Drug Discov. 2020;19(3):149-150. doi:10.1038/d41573-020-00016-0 PubMedGoogle ScholarCrossref
54.
Coleman  CM, Sisk  JM, Mingo  RM, Nelson  EA, White  JM, Frieman  MB.  Abelson kinase inhibitors are potent inhibitors of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus fusion.   J Virol. 2016;90(19):8924-8933. doi:10.1128/JVI.01429-16 PubMedGoogle ScholarCrossref
55.
Dyall  J, Gross  R, Kindrachuk  J,  et al.  Middle East respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies.   Drugs. 2017;77(18):1935-1966. doi:10.1007/s40265-017-0830-1 PubMedGoogle ScholarCrossref
56.
Pfefferle  S, Schöpf  J, Kögl  M,  et al.  The SARS-coronavirus-host interactome: identification of cyclophilins as target for pan-coronavirus inhibitors.   PLoS Pathog. 2011;7(10):e1002331. doi:10.1371/journal.ppat.1002331 PubMedGoogle Scholar
57.
de Wilde  AH, Zevenhoven-Dobbe  JC, van der Meer  Y,  et al.  Cyclosporin A inhibits the replication of diverse coronaviruses.   J Gen Virol. 2011;92(pt 11):2542-2548. doi:10.1099/vir.0.034983-0 PubMedGoogle ScholarCrossref
58.
Wang  M, Cao  R, Zhang  L,  et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.   Cell Res. 2020;30(3):269-271. doi:10.1038/s41422-020-0282-0 PubMedGoogle ScholarCrossref
59.
Rossignol  JF.  Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus.   J Infect Public Health. 2016;9(3):227-230. doi:10.1016/j.jiph.2016.04.001 PubMedGoogle ScholarCrossref
60.
Gurwitz  D.  Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.   Drug Dev Res. Published online March 4, 2020. doi:10.1002/ddr.21656 PubMedGoogle Scholar
61.
American Heart Association. Patients taking angiotensin converting enzyme inhibitors (ACE-i) or angiotensin receptor blocker (ARB) medications should continue therapy as prescribed [news release]. Published March 17, 2020. Accessed March 18, 2020. https://newsroom.heart.org/news/patients-taking-ace-i-and-arbs-who-contract-covid-19-should-continue-treatment-unless-otherwise-advised-by-their-physician
62.
European Society for Cardiology. Position statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. Published March 13, 2020. Accessed March 18, 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
63.
World Health Organization. WHO R&D blueprint: ad-hoc expert consultation on clinical trials for Ebola therapeutics. Published October 2018. Accessed March 20, 2020. https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf
64.
Jacobs  M, Rodger  A, Bell  DJ,  et al.  Late Ebola virus relapse causing meningoencephalitis: a case report.   Lancet. 2016;388(10043):498-503. doi:10.1016/S0140-6736(16)30386-5 PubMedGoogle ScholarCrossref
65.
Holshue  ML, DeBolt  C, Lindquist  S,  et al; Washington State 2019-nCoV Case Investigation Team.  First case of 2019 novel coronavirus in the United States.   N Engl J Med. 2020;382(10):929-936. doi:10.1056/NEJMoa2001191 PubMedGoogle ScholarCrossref
66.
Kujawski  SA, Wong  K, Collins  JP,  et al. First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. medRxiv. Preprint posted March 9, 2020. doi:10.1101/2020.03.09.20032896
67.
Furuta  Y, Komeno  T, Nakamura  T.  Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase.   Proc Jpn Acad Ser B Phys Biol Sci. 2017;93(7):449-463. doi:10.2183/pjab.93.027 PubMedGoogle ScholarCrossref
68.
Mentré  F, Taburet  AM, Guedj  J,  et al.  Dose regimen of favipiravir for Ebola virus disease.   Lancet Infect Dis. 2015;15(2):150-151. doi:10.1016/S1473-3099(14)71047-3 PubMedGoogle ScholarCrossref
69.
Sissoko  D, Laouenan  C, Folkesson  E,  et al; JIKI Study Group.  Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea  [published correction appears in PLoS Med. 2016;13(4):e1002009].  PLoS Med. 2016;13(3):e1001967. doi:10.1371/journal.pmed.1001967 PubMedGoogle Scholar
70.
Shiraki  K, Daikoku  T.  Favipiravir, an anti-influenza drug against life-threatening RNA virus infections.  [published online February 22, 2020].  Pharmacol Ther. 2020;107512. doi:10.1016/j.pharmthera.2020.107512 PubMedGoogle Scholar
71.
Chinello  P, Petrosillo  N, Pittalis  S, Biava  G, Ippolito  G, Nicastri  E; INMI Ebola Team.  QTc interval prolongation during favipiravir therapy in an Ebolavirus-infected patient.   PLoS Negl Trop Dis. 2017;11(12):e0006034. doi:10.1371/journal.pntd.0006034 PubMedGoogle Scholar
72.
Kumagai  Y, Murakawa  Y, Hasunuma  T,  et al.  Lack of effect of favipiravir, a novel antiviral agent, on QT interval in healthy Japanese adults.   Int J Clin Pharmacol Ther. 2015;53(10):866-874. doi:10.5414/CP202388 PubMedGoogle ScholarCrossref
73.
Chen  C, Huang  J, Cheng  Z,  et al. Favipiravir versus Arbidol for COVID-19: a randomized clinical trial. medRxiv. Preprint posted March 27, 2020. doi:10.1101/2020.03.17.20037432
74.
Liu  C, Zhou  Q, Li  Y,  et al.  Research and development of therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases.   ACS Cent Sci. 2020;6(3):315-331. doi:10.1021/acscentsci.0c00272 PubMedGoogle ScholarCrossref
75.
Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing. bioRxiv. Preprint posted March 22, 2020. doi:10.1101/2020.03.22.002386
76.
Russell  CD, Millar  JE, Baillie  JK.  Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury.   Lancet. 2020;395(10223):473-475. doi:10.1016/S0140-6736(20)30317-2 PubMedGoogle ScholarCrossref
77.
Arabi  YM, Mandourah  Y, Al-Hameed  F,  et al; Saudi Critical Care Trial Group.  Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome.   Am J Respir Crit Care Med. 2018;197(6):757-767. doi:10.1164/rccm.201706-1172OC PubMedGoogle ScholarCrossref
78.
Ni  YN, Chen  G, Sun  J, Liang  BM, Liang  ZA.  The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis.   Crit Care. 2019;23(1):99. doi:10.1186/s13054-019-2395-8 PubMedGoogle ScholarCrossref
79.
Mehta  P, McAuley  DF, Brown  M, Sanchez  E, Tattersall  RS, Manson  JJ; HLH Across Speciality Collaboration, UK.  COVID-19: consider cytokine storm syndromes and immunosuppression.   Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0 PubMedGoogle ScholarCrossref
80.
Zhou  F, Yu  T, Du  R,  et al.  Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.   Lancet. 2020;395(10229):1054-1062. doi:10.1016/S0140-6736(20)30566-3 PubMedGoogle ScholarCrossref
81.
Sanofi. Sanofi and Regeneron begin global Kevzara (sarilumab) clinical trial program in patients with severe COVID-19 [news release]. Published March 16, 2020. Accessed March 18, 2020. http://www.news.sanofi.us/2020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19
82.
Chen  L, Xiong  J, Bao  L, Shi  Y.  Convalescent plasma as a potential therapy for COVID-19.   Lancet Infect Dis. 2020;20(4):398-400. doi:10.1016/S1473-3099(20)30141-9 PubMedGoogle ScholarCrossref
83.
Soo  YO, Cheng  Y, Wong  R,  et al.  Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients.   Clin Microbiol Infect. 2004;10(7):676-678. doi:10.1111/j.1469-0691.2004.00956.x PubMedGoogle ScholarCrossref
84.
Arabi  Y, Balkhy  H, Hajeer  AH,  et al.  Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol.   Springerplus. 2015;4:709. doi:10.1186/s40064-015-1490-9 PubMedGoogle ScholarCrossref
85.
Hung  IF, To  KK, Lee  CK,  et al.  Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection.   Clin Infect Dis. 2011;52(4):447-456. doi:10.1093/cid/ciq106 PubMedGoogle ScholarCrossref
86.
Mair-Jenkins  J, Saavedra-Campos  M, Baillie  JK,  et al; Convalescent Plasma Study Group.  The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis.   J Infect Dis. 2015;211(1):80-90. doi:10.1093/infdis/jiu396 PubMedGoogle ScholarCrossref
87.
Shen  C, Wang  Z, Zhao  F,  et al.  Treatment of 5 critically ill patients with COVID-19 with convalescent plasma.   JAMA. 2020. Published online March 27, 2020. doi:10.1001/jama.2020.4783PubMedGoogle Scholar
88.
Cao  W, Liu  X, Bai  T,  et al.  High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019.   Open Forum Infect Dis. Published online March 21, 2020. doi:10.1093/ofid/ofaa102 Google Scholar
89.
US Food and Drug Administration. Investigational COVID-19 Convalescent plasma: emergency INDs. Updated April 3, 2020. Accessed March 26, 2020. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/investigational-covid-19-convalescent-plasma-emergency-inds
90.
Wang C, Li W, Drabek D, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. bioRxiv. Preprint posted March 11, 2020. doi:10.1101/2020.03.11.987958.2020
91.
Huang  C, Wang  Y, Li  X,  et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.   Lancet. 2020;395(10223):497-506. doi:10.1016/S0140-6736(20)30183-5 PubMedGoogle ScholarCrossref
92.
Chen  N, Zhou  M, Dong  X,  et al.  Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.   Lancet. 2020;395(10223):507-513. doi:10.1016/S0140-6736(20)30211-7 PubMedGoogle ScholarCrossref
93.
Yang  X, Yu  Y, Xu  J,  et al.  Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study.   Lancet Respir Med. Published online February 24, 2020. doi:10.1016/S2213-2600(20)30079-5 PubMedGoogle Scholar
94.
Young  BE, Ong  SWX, Kalimuddin  S,  et al; Singapore 2019 Novel Coronavirus Outbreak Research Team.  Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore.   JAMA. Published online March 3, 2020. doi:10.1001/jama.2020.3204 PubMedGoogle Scholar
95.
Guan  WJ, Ni  ZY, Hu  Y,  et al; China Medical Treatment Expert Group for Covid-19.  Clinical Characteristics of Coronavirus Disease 2019 in China.   N Engl J Med. Published online February 28, 2020. doi:10.1056/NEJMoa2002032 PubMedGoogle Scholar
96.
Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19) clinical care. Updated March 30, 2020. Accessed March 18, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
97.
World Health Organization. Clinical management of severe acute respiratory infection when COVID-19 is suspected. Updated March 13, 2020. Accessed March 18, 2020. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
98.
Kupferschmidt  K, Cohen  J. WHO launches global megatrial of the four most promising coronavirus treatments. Science. Published March 22, 2020. Accessed March 23, 2020. https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments#
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    19 Comments for this article
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    Naproxen
    Richard Brown, MA (Cantab) MSc (Edin) | Farm Veterinarian Scotland
    I am surprised there is no mention of naproxen. The French may be about to start a trial with naproxen as a component of therapy (NCT04325633). Even if an RCT is not performed for Naproxen as a component, an epidemiological study should be performed to follow those who take naproxen long term (and who have been advised to continue to use it, ie some rheumatoid arthritis sufferers) and see if through this pandemic they have ( paradoxically) been less at risk.
    CONFLICT OF INTEREST: None Reported
    COVID-19 Angiotensin Paradigm can also be addressed
    Andrew Ashworth, MbChB | Bonhard Medical, Scotland
    This review of some pharmacological interventions (1) is a helpful summary but it restricts itself, perhaps based on the methodology, to interventions directed toward SARS-COV-2 virus itself and so does not include potential interventions to mitigate the clinical effects of COVID-19.

    SARS-COV-2 targets ACE2 and, while reduced expression of ACE2 has not been shown, the assumption of such a reduction is consistent with clinical findings. ACE2 converts inactivates Angiotensin II to Angiotensin 1-7.(3). Without ACE2, Angiotensin II causes contraction of smooth muscle via the phosphodiesterase 5 (PDE5) pathway (4) with vasoconstriction and cough.

    This ‘COVID-19 Angiotensin Paradigm”
    is consistent with clinical effects mediated by vasoconstriction:
    • Reduced gas exchange and therefore reduced oxygen supply to the systemic circulation
    • Reduced blood-borne immune response to the viral particles
    • Increased pressure in the Pulmonary artery with shunting of deoxygenated pulmonary arterial blood to the systemic circulation.
    - Bronchiolar smooth muscle-mediated cough

    Current pharmacological interventions appear to be focussed on antivirals. Current therapy relies on increasing alveolar oxygen concentration. If ACE2 fails to protect distal pulmonary vessels from Angiotensin II, then mitigating its effects has the immediate potential significantly to alter the progress of the disease. PDE-5 inhibitors are widely available and appear to have significant promise in addressing the increased exposure of pulmonary smooth muscle to Angiotensin II in COVID-19. There is an anecdotal report of a PDE5 inhibitor being used effectively in a similar historical case (5).

    PDE5 inhibitors in COVID-19 offer a means of treatment in poorer countries where ventilatory support is less available. A clinical trial is required.

    REFERENCES

    1. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. Published online April 13, 2020. doi:10.1001/jama.2020.6019(2)
    2. Hoffmann et al., 2020, Cell 181, 1–10 April 16, 2020 a 2020 Elsevier Inc. https://doi.org/10.1016/j.cell.2020.02.052,
    3. Tikellis, C.,Thomas, M.C. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease International Journal of Peptides Volume 2012, Article ID 256294, doi:10.1155/2012/256294
    4. Dongsoo Kima, Toru Aizawab, Heng Weic, et al. Angiotensin II increases phosphodiesterase 5A expression in vascular smooth muscle cells: A mechanism by which angiotensin II antagonizes cGMP signaling J Mol Cell Cardiol. 2005 January ; 38(1): 175–184. doi:10.1016/j.yjmcc.2004.10.013
    5. Ashworth AJ. Enhanced recovery from respiratory infection following treatment with a PDE-5 inhibitor: a single case study Prim Care Respir J 2012; 21(1): 17-18 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547895/
    CONFLICT OF INTEREST: None Reported
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    Pulmonary Delivery of Possible Therapeutic Agents for COVID-19
    Hasham Shafi, PhD Pharmaceutics | CSIR-Central drug research institute, University of Kashmir
    The review is well articulated and all therapeutic agents in trials or being used are discused. I would have expected researchers around the globe to give prime consideration to the route of drug delivery, It's well established that pulmonary delivery as a dry powder inhalation of some of the drug candidates can target these drugs directly to the site of infection and can reduce the drug dose especially in drugs with toxicity issues.
    CONFLICT OF INTEREST: None Reported
    Darunavir Has No Activity Against SARS-CoV-2
    Marcelo Radisic, MD | d.Institute, Instituto de Trasplante y Alta Complejidad / Sanatorio Finochietto. Buenos Aires, Argentina.
    Although darunavir is an effective inhibitor of the HIV-dimeric aspartyl protease, it has no demonstrated activity against SARS-CoV-2 protease, which is a cysteine protease. Darunavir has low affinity with the catalytic center of the SARS-CoV-2 protease active site.

    Janssen, the manufacturer of darunavir, has reported that results from a single center, open label, randomised controlled trial conducted at Shanghai Public Health Clinical Center (SPHCC) testing darunavir and cobicistat (DRV/c) in treating 30 COVID-19 patients showed that DRV/c was not effective (1). In addition, the in-vitro antiviral activity of darunavir against SARS-CoV-2 was assessed and darunavir showed no activity
    against SARS-CoV-2 at clinically relevant concentrations (EC50>100 μM).

    These data do not support the use of darunavir for the treatment of COVID-19

    REFERENCES

    1. https://www.janssen.com/ireland/lack-evidence-support-use-darunavir-based-treatments-sars-cov-2, accessed April 4th, 2020
    CONFLICT OF INTEREST: None Reported
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    Is Remdesivir the Answer for COVID-19?
    Sarosh Ahmed Khan, MBBS; MD; FACP; FRCP Edin | Naseem Medical Center, Baghe Mehtab, Srinagar, Kashmir 190019
    The anti-viral drug remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, had until now shown only in vitro activity against SARS-CoV-2. It had also been tried in non-clinical models in ebola and other coronaviruses (SARS-CoV and MERSCoV) (1,2). It was investigated in Ebola virus infection & found to have a favorable clinical safety profile, as reported on the basis of experience in about 500 persons (volunteers and patients) (3,4).

    But a recent small industry-conducted (Gilead Sciences) study appeared to show efficacy in seriously ill COVID-19 patients (5) . About 2/3rd of patients given the drug on compassionate-use
    basis showed signs of clinical improvement. Patients had confirmed COVID-19 with an O2-sat of =< 94% while they were breathing ambient air or were receiving O2 support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered IV on day 1, followed by 100 mg daily for the remaining 9 days. Of the 61 patients who received at least one dose of Remdesivir, data from 8 was not analyzed. At baseline, 57% were receiving mechanical ventilation(MV) and 8% were receiving ECMO. During a median follow-up of 18 days, 68% patients had an improvement in O2-support class, including 57% receiving MV who were extubated. A total of 25 patients were discharged, & 7 died; mortality was 18% among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

    The downsides:
    1. Small size of the cohort
    2. Viral load data to confirm the antiviral effects of remdesivir or any association between baseline viral load & viral suppression were not collected
    3. The duration of remdesivir therapy was not uniform
    4. Shorter duration of therapy (e.g., 5 vs 10 days) was not studied 
    5. 60% reported adverse events including raised liver enzymes, diarrhea, rash, renal impairment, & hypotension. AEs were more common in patients receiving invasive ventilation. Of 23% who had serious AEs, common ones were multi-organ dysfunction syndrome, septic shock, acute kidney injury, & hypotension. 4 patients had to stop treatment because of these
    6. The study did not have a control arm so we don't know the contribution of other factors like type of supportive care (concomitant medications or variations in ventilatory practices) & differences in institutional treatment protocols & thresholds for hospitalization

    Pharma companies seeing the desperate need of a drug have come up with a new name for “off-label use”: compassionate-use

    We may not be able to draw definitive conclusions, but if these caveats are taken care of, it seems that remdesivir may have clinical benefit in patients with severe Covid-19

    References

    1. de Wit E et al. Prophylactic & therapeutic Remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A 2020; 117: 6771-6
    2. Sheahan TP et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic & zoonotic coronaviruses. Sci Tran Med 2017; 9(396): eaal3653
    3. Mulangu S et al. A randomized, controlled trial of Ebola virus disease therapeutics. NEJM 2019; 381: 2293-303
    4. EMA. Summary on compassionate use: Remdesivir Gilead. April 3 2020
    5. Grein J et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM April 10 2020 DOI: 10.1056/NEJMoa2007016
    CONFLICT OF INTEREST: None Reported
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    Novel CoViD Impairment of hypoxic pulmonary vasoconstriction hypothesis
    Darren Emerick, MBBS | University of Queensland
    Working on the hypothesis that novel CoViD unusually causes impairment of hypoxic pulmonary vasoconstriction, COVID-19 would be a hyperaemic pneumonia, resulting in major ventilation-perfusion mismatch.

    Therapies that may modulate hypoxic pulmonary vasoconstriction include:

    Buffered L-lactic acid infusion [+R shift ODC]
    Angiotensin II infusion
    Beta 2 agonist infusion
    TASK-1 channel blockers eg doxapram, almitrine, 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives [Bayer phase 1 trials]
    Desferrioxamine infusion
    Hyperthermia [+R shift ODC]
    Methanandamide/Anandamide infusion
    Bupivacaine infusion

    [ET-1 infusion seems unlikely to represent a therapeutic strategy for enhancing HPV during acute (<4 h) hypoxia]
    CONFLICT OF INTEREST: None Reported
    What Does "Most Promising" Mean?
    Marlowe Fox, JD, MS | None
    This meta-analysis seems to be an important splash of cold water on potential treatments. In particular, the HCQ/CQ trials that resulted in statistically significant p-values but failed to control/adjust for several confounding variables (1,2). However, the description of remdesivir as the "most promising treatment” seems to have even less empirical support.

    It also begs the question of what constitutes the “most promising treatment.” Does it mean:

    1. Best in-vitro effects (best mechanistic explanation/identification of mediator)
    2. Highest probability of similar in-vivo effects
    3. Robust empirical support (sample size; sufficiently articulated methods/evaluation procedures; controlling for comorbidities, symptom
    onset, prescriptions i.e. RAAS inhibitors; statistical significance)
    4. Probability of non-toxic, low side effect dosing
    5. Availability, cost-effectiveness, other pragmatic concerns
    6. Potential for prophylactic use as well
    7. Reducing the contagious phase of the infected

    And if this was the case, why did the article not articulate as much in its methods? This would obviate any concern of an ad hoc conclusion or any other potential bias.

    Remdesivir’s “promise” seems to be based on its “potent” in vitro effects against SARS-CoV-2 as well as two studies in which a total of four patients received remdesivir (3,4). In one study, a 35 y/o healthy male, after progressively worsening symptoms, received treatment on day 7 of hospital admission (day 11 of symptom onset). Within 24 hours, the patient’s oxygen saturation went from 90% to 96%, and he was taken off supplemental oxygen (3). In the other study 12 patients were examined, of which 3 received the treatment. The study was plagued by confounding variables. Not to mention, all 12 patients recovered (4). It should be noted that these studies are only footnoted in the article.

    Whatever the HCQ trials were lacking, they offered at least some scientific rigor (1,2). The article criticizes the French study (2) for “a small sample size…the removal of 6 patients in the hydroxychloroquine group...” Similarly, it critiques the Wuhan study: “At day 7, virologic clearance was similar, with 86.7% vs 93.3% clearance for the hydroxychloroquine plus standard of care group and standard care group, respectively (P > .05).” However, the Wuhan study’s most noteworthy findings may have been the average reduction of about 1 day in fever and coughing, both of which were supported by p-values of 0.0008 and .0016 respectively (1). Assuming these results are accurate, cutting a day off symptoms could substantially decrease the infection rate as well as increase the availability of hospital resources. There are certainly concerns with the Wuhan study—p-hacking or HARKING could very well have been involved—but the same problems exist with the remdesivir reports.

    With no clinical trials that sufficiently control for confounding variables, the most promising treatment would likely be the one with the most empirically supported mechanism (mediator). I would be interested in a meta-analysis that surveyed all the potential causal mechanisms, whether they be anti-viral or inhibition/blocking somewhere along the RAAS-pathway (5).

    References

    1. https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3
    2. https://www.medrxiv.org/content/10.1101/2020.03.16.20037135v1
    3. https://www.nejm.org/doi/10.1056/NEJMoa2001191
    4. https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1
    5. https://jamanetwork.com/journals/jama/fullarticle/2763803
    CONFLICT OF INTEREST: None Reported
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    Androgen Pathway Targets and Incomplete TMPRSS2 Inhibitors list
    Carlos Wambier, MD, PhD | Warren Alpert Medical School, Brown University
    This article mentions Transmembrane Protease Serine 2 (TMPRSS2) but fails to address the pivotal role of androgen receptor (RA) activation for transcription of the TMPRSS2 gene. The androgen pathway is key to individual vulnerability, since androgen-promoted proteins are increasingly expressed after puberty (1).

    Clinical signs of androgen expression such as androgenic alopecia (2) could be strictly linked to vulnerability.

    Thus, targeting any step of the androgen pathway with the following agents may theoretically increase host resistance:

    LH (GnRH) analogues: Degarelix, Goserelin, Leuprolide, Leuprorelin, Nafarelin 
    Testosterone (steroidogenesis) inhibitors: Ketoconazole, Fluconazole, Itraconazole 
    5-alpha reductase inhibitors: Dutasteride, Finasteride 
    RA inhibitors:
    Spironolactone, Bicalutamide, Darolutamide, Enzalutamide, Flutamide, Nilutamide: 

    All of which are used for androgenic suppression.

    Finally, the first TMPRSS2 inhibitor described was bromhexine, a common cough medication (3), to add to camostat, a new drug.

    The list above indexes the main medications that might be used to target the androgen pathway of viral entry in cells (through TMPRSS2 priming of both viral spike and ACE2) (1).

    Studies for male prophylaxis with medications that have a favorable side-effect profile (5-alpha reductase inhibitors), and in life-threatening circumstances, chemical castration, as done in metastatic prostate cancer, could also be tested in clinical trials.

    Some patients present with increased risk of thrombosis from androgen blockade. A phytochemical compound, quercetin-3-β-O-D-glucoside (isoquercetin), with antiviral activity against Zika and Ebola virus(4,5), inhibits the androgen receptor (6) and targets extracellular protein disulfide isomerase (PDI), improving markers of coagulation in advanced cancer patients (7). PDI is a thiol isomerase secreted by vascular cells, that is required for thrombus formation.

    REFERENCES:
    1. Wambier CG, Goren A. SARS-COV-2 infection is likely to be androgen mediated. J Am Acad Dermatol. April 2020. doi:10.1016/j.jaad.2020.04.032
    2. Goren A, McCoy J, Wambier CG, et al. What does androgenetic alopecia have to do with COVID-19? An insight into a potential new therapy. Dermatol Ther. April 2020:e13365. doi:10.1111/dth.13365
    3. Lucas JM, Heinlein C, Kim T, et al. The Androgen-Regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discov. 2014;4(11):1310-1325. doi:10.1158/2159-8290.CD-13-1010
    4. Qiu X, Kroeker A, He S, et al. Prophylactic efficacy of quercetin 3-β-O-D-glucoside against Ebola virus infection. Antimicrob Agents Chemother. 2016;60(9):5182-5188. doi:10.1128/AAC.00307-16
    5. Wong G, He S, Siragam V, et al. Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection. Virol Sin. 2017;32(6):545-547. doi:10.1007/s12250-017-4057-9
    6. Xing N. Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Carcinogenesis. 2001. doi:10.1093/carcin/22.3.409
    7. Zwicker JI, Schlechter BL, Stopa JD, et al. Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer. JCI insight. 2019;4(4):1-12. doi:10.1172/jci.insight.125851
    CONFLICT OF INTEREST: None Reported
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    Reconsider Corticosteroids
    Lei Zhang, M.D. | Tianjin Cancer Institution and Hospital
    People have a negative attitude towards use of corticosteroids for COVID-19 (1) for several reasons. First is that the original protocol in SARS used large doses (2) with potential for serious complications, including femoral head necrosis, secondary infections, etc. (3) with outcomes attributed to SARS rather than the treatment. Secondly, no potential effective antiviral drugs such as remdesivir were developed at the time when SARS broke out, (4) so large doses undoubtedly caused an increase in viral replication and delay in viral clearance (5).

    Postmortem analysis of COVID-19 patients has confirmed the lung tissue injury caused by cytokine storms
    and the formation of acute respiratory distress syndrome (ARDS) (6), which is a problem that antiviral drugs cannot solve. Twenty years ago, methylprednisolone therapy was proven effective for improving lung injury and reducing mortality in ARDS (7). Recently, in treatment of COVID-19, it has also been reported that the use of steroids, especially low-dose therapy, can effectively reverse the condition of severe patients and reduce death. (8) (9) If we could change the traditional usage pattern, adopt early low-dose corticosteroids therapy, and use them with effective antiviral drugs, the mortality rate of severe COVID-19 patients might be reduced .

    REFERENCE
    1, Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review [published online ahead of print, 2020 Apr 13]. JAMA. 2020;10.1001/jama.2020.6019. doi:10.1001/jama.2020.6019
    2, Sung JJ, Wu A, Joynt GM, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax.2004;59(5):414–420.
    3, Hong N, Du XK. Avascular necrosis of bone in severe acute respiratory syndrome. Clin Radiol. 2004;59(7):602–608. doi:10.1016/j.crad.2003.12.008
    4, Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19 [published online ahead of print, 2020 Apr 10]. N Engl J Med. 2020;10.1056/NEJMoa2007016.doi:10.1056/NEJMoa2007016
    5, Lee N, Allen Chan KC, Hui DS, Ng EK, Wu A, et al. (2004) Effects of early corticosteroid treatment on plasma SARS-associated coronavirus RNA concentrations in adult patients. J Clin Virol 31: 304–309.
    6, Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020 Feb 18 [Epub ahead of print].
    7, Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998;280(2):159–165. doi:10.1001/jama.280.2.159
    8, Zheng C, Wang J, Guo H, et al. Risk-adapted Treatment Strategy For COVID-19 Patients [published online ahead of print, 2020 Mar 27]. Int J Infect Dis. 2020;S1201-9712(20)30179-X. doi:10.1016/j.ijid.2020.03.047
    9, Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. Published online March 13,
    CONFLICT OF INTEREST: None Reported
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    The Social Life of SARS-Cov-2 With Therapeutic Implications
    Arturo Tozzi, Pediatrician | University of North Texas
    Viruses may spread not just as single particles, but also as collective aggregates (Segredo-Otero and Sanjuán, 2019; Andreu-Moreno and Sanjuán, 2020). These assemblies stand for “viral communities” with enhanced infectious capacity and improved spread compared with “free” viral particles (Cuevas et al., 2020). It is well known that coronavirus particles are able to stick together through virion-virion binding and to form aggregates. In particular, their particles tightly adhere with their projections sticking into each other, forming a mosaic patch that leads virions to squeeze and lose their spherical shape (Lin et al., 2004; Groneberg et al., 2005). It has been shown that, when SARS-Cov-2 grows in supernatants of infected cells, virions tend to aggregate in small globular assemblies that progressively give rise to larger net-like aggregates (Peter Doherty Institute for Infection and Immunity, https://www.youtube.com/watch?v=qTt3P5V8M1A&feature=youtu.be).

    The ability to build particles assemblies and achieve collective dynamical behavior may provide invaluable advantages to SARS-Cov-2. The squeezing in their spherical shape allows particles to achieve a best package, increasing their number in a given amount of host fluids and maximizing viral load. SARS-CoV-2 positive patients with few/no symptoms and modest levels of detectable viral RNA in the oropharynx have been described (Zou et al., 2020). This finding, together with the observation that SARS-CoV-2 displays a well-known decay rate both in aerosols and various surfaces (van Doremalen et al., 2020), suggests the possibility that reduced viral loads could be correlated with decreased viral ability to build particles clustering. The globular-like arrangement of multiple SARS-CoV-2 virions may provide another advantage against host immunity and environmental offenses: even if immune systems or environmental factors engage the external core of the viral assembly, an inner viral sanctuary might be spared from further damages. It is noteworthy that, while VSV multi-virion complexes occur unfrequently in standard cell cultures, they are abundant in other fluids such as saliva (Cuevas et al., 2020). Further, it might be hypothesized that the lower symptomatic response in children to COVID-19 (Huang et al., 2020; Bi et al., 2020) could be correlated with local factors endowed in the pediatric respiratory airways that are able to scatter the viral assemblies responsible for symptoms severity. In sum, clustered SARS-Cov-2 dissemination stands for a potential target leading to novel antiviral strategies able to mechanically disrupt virionic assemblies.

    Arturo Tozzi
    Center for Nonlinear Science, Department of Physics, University of North Texas, Denton, Texas, USA
    tozziarturo@libero.it
    Arturo.Tozzi@unt.edu

    James F. Peters
    Department of Electrical and Computer Engineering, University of Manitoba
    Department of Mathematics, Adıyaman University, 02040 Adıyaman, Turkey
    james.peters3@umanitoba.ca

    Isabella Annesi-Maesano
    French NIH (INSERM), EPAR Department, IPLESP, INSERM
    Sorbonne University, Paris, France.
    isabella.annesi-maesano@inserm.fr

    Gennaro D'Amato
    Division of Respiratory and Allergic Diseases, Department of Chest Diseases, High Specialty A. Cardarelli Hospital, Napoli, Italy
    Medical School of Specialization in Respiratory Diseases, University on Naples Federico II.
    gdamatomail@gmail.com
    CONFLICT OF INTEREST: None Reported
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    Clarification on Angiotensin Receptor Blockers' Proposed Role in SARS-CoV-2
    James Cutrell, MD | UT Southwestern Medical Center, Dallas, Texas
    We would like to clarify a statement in our current review on page E7 which reads, “In contrast, angiotensin receptor blockers could theoretically provide clinical benefit via blockade of ACE2 receptors.”

    One proposed mechanism for angiotensin receptor blockers' (ARBs') amelioration of SARS-CoV-2 lung injury stems from ARB inhibition of the angiotensin receptor 1 (AT1R), not direct inhibition of the ACE2 receptor. This blockade in theory dampens angiotensin II mediated AT1R activation and downstream signaling that underlies SARS-CoV-2 mediated lung injury. An additional purported ARB mechanism of lung protection is ACE2 upregulation and subsequent increased conversion of angiotensin II
    to angiotensin 1-7, a known vasodilator. These clinical benefits of ARBs have not been established but are being studied in ongoing clinical trials.

    This clarification does not affect the clinical recommendations in our review which are concordant with major clinical societies and practice guidelines recommending continued therapy with ACE inhibitors or ARBs in patients already on these agents.

    1. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. Published online March, 4, 2020. doi:10.1002/ddr.21656

    2. Patel AB, Verma A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What is the Evidence? JAMA. Published online March 24, 2020. doi:10.1001/jama.2020.4812
    CONFLICT OF INTEREST: Dr. Cutrell received non-financial support from Regeneron and Gilead outside the submitted work.
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    Absence of Effective Treatment
    Eduardo Quinteros, MD. Board IM Cardio | Internal Medicine and Critical care, Clinica Mayo Bell Ville, Argentina
    After reading this review I thought the title might better be "Absence of Probable Treatments for COVID19." People are desperate for an oseltamivir for SARS-CoV-2, and medical journals become repositories of letters and reviews with 70-patient studies that are too limited to provide a solution. Some comments are at the level of what you hear in a supermarket line, spreading more confusion. We'd do well to remember the first principle of medicine: first, do no harm.
    CONFLICT OF INTEREST: None Reported
    Is There Evidence for Treatment with Hydroxychloroquine & Azithromycin?
    John Baer, M.D. |
    Regarding the hydroxychloroquine-azithromycin study cited (ref 16), I have concerns. I recommend having a look at the methods & the detailed patient data present at the end of the draft of the paper (Supplementary Table 1: https://www.medrxiv.org/content/10.1101/2020.03.16.20037135v1.full.pdf). This table is not included in the final publication. Method of testing was cell culture cytotoxicity, then PCR of the supernatant. Lots of room for false positive and negatives, e.g. some patients in both the control and treatment groups oscillated between positive and negative; is "POS" a patient with cytotoxicity alone, without PCR confirmation? There is lots of missing and heterogeneous data in the control group. The methods and detailed patient data raise significant questions about whether there was a treatment effect.
    CONFLICT OF INTEREST: None Reported
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    Statins and COVID-19
    Timo Strandberg, MD, PhD | Universities of Helsinki and Oulu, and Helsinki University Hospital
    Sanders et al present various pharmacologic possibilities to prevent and treat COVID-19 (1). They do not mention statin treatment, which is a potential way to improve host resistance without directly attacking the virus (2).

    Statins have favorable effects on endothelium dysfunction and may also prevent thromboembolic complications (3). Although statins have anti-inflammatory and immunomodulatory properties and their use has been associated with less complications during infections (2), I don’t believe that statins would act as direct antimicrobial agents in COVID-19. But a considerable portion of patients have cardiovascular diseases or diabetes, and statins are evidence-based treatment to reduce
    morbidity and mortality in those individuals (4). Statin treatment is also associated with mortality benefit among older, frail patients (5), a considerable group of COVID-19 victims.

    That low cholesterol is associated with worse prognosis in many acute diseases and in frailty is no argument to avoid statin treatment, because the mechanisms of ‘endogenous’ (due to acute conditions, frailty) and ‘exogenous’ (caused by statins) cholesterol reduction are different (6).

    Statins are well-known, generally safe, cheap, and effective drugs. However, adherence is frequently not optimal due to, for example, fake information on the internet and social media. I think appropriate use of statins among patients with cardiovascular risk should be actively promoted during the COVID-19 pandemia.

    REFERENCES

    1. Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic treatments for coronavirus disease 2019 (COVID-19)A Review. JAMA. Published online April 13, 2020. doi:10.1001/jama.2020.6019
    2. Fedson DS. Treating the host response to emerging virus disease: lessons learned from sepsis, pneumonia, influenza and Ebola. Ann Transl Med 2016;4:421
    3. Kunutsor SK, Seidu S, Khunti K. Statins and primary prevention of venous thromboembolism: a systematic review and meta-analysis. Lancet Haematol. 2017 Feb;4(2):e83-e93. doi: 10.1016/S2352-3026(16)30184-3.
    4. Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407-415
    5. Strandberg TE. Deprescribing statins-Is it ethical? J Am Geriatr Soc. 2016;64(9):1926-7.
    6. Gnanenthiran SR, Ng ACC, Cumming R, et al. Low total cholesterol is associated with increased major adverse cardiovascular events in men aged ≥70 years not taking statins. Heart. 2019 Oct 13. pii: heartjnl-2019-315449. doi: 10.1136/heartjnl-2019-315449
    CONFLICT OF INTEREST: Collaborations (research, consultative, educational) with companies (including Amgen, Merck, Orion, Sanofi, Servier) and other entities interested in cholesterol-lowering. I take a statin daily.
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    Vitamin C
    Harri Hemila, MD,PhD | University of Helsinki
    The literature summarizing a possible role for vitamin C in COVID-19 is briefly summarized at https://pubpeer.com/publications/61151FA38F4AC67A54273EDC4C1C6E
    CONFLICT OF INTEREST: None Reported
    Disappointing Review
    Todd Clark, MD | ER Physician in Private Hospital System with Academic Affiliations
    Disappointing review mostly in its overemphasis of certain weak therapies (remdesivir for one), and complete omission of other promising therapies (vitamin C (Dr. Marik’s critical care protocol) and heparin (DIC prevention), to name a few).

    Remdesivir study patients were cherry-picked and would have gotten better without the drug.

    Only 15 comments after over 700,000 views of this article is alarming as well. Hoping people aren’t just taking what is written here as gospel.
    CONFLICT OF INTEREST: None Reported
    Biased Review
    Dinesh Ranjan, MD, FACS | PRAN Philanthropic Clinic
    Sanders and colleagues have published a detailed review of pharmacologic treatment options for Covid-19 in JAMA (1). Two drugs, hydroxychloroquine (HCQ) and remdesivir, have garnered most attention by medical journals and public media lately. While the French study touting HCQ with azithromycin had several shortcomings (2), it was hailed by President Trump regardless. The academic medicine, medical journals and main-stream media have condemned HCQ. In contrast however, remdesivir seems to have caught the fancy of the same group who seem to be willing to ignore the shortcomings of remdesivir data. This double standard is evident in this review.

    The
    authors state that they reviewed English language”articles catalogued in PubMed. However, they cite a Chinese language paper not catalogued in PubMed, showing no benefit with HCQ (3). They appear to ignore other English language papers supporting HCQ. Finally, the authors conclude that they “do not support adoption” of HCQ/Azithromycin “without additional studies”.

    In contrast, when discussing remdesivir; the authors recommend that “inclusion of this agent for treatment of Covid-19 may be considered”. This recommendation is based upon “anticipated results from RCTs” and “successful case reports” in Covid-19 patients. Recommendations are based on anticipated results? And the successful case reports they state includes a study of 3 (out of 7 hospitalized) patients, without any difference in outcome. The authors, while making a case for its antiviral properties, state that remdesivir was used in clinical trials in Ebola – but they fail to mention that their cited reference did not include humans (4). They mention other single case reports of remdesivir use in Ebola. Unfortunately, they neglect to mention that the definitive study on Ebola therapeutics: a randomized trial of four therapeutic options, had not supported Remdesivir (5). Surely, a search in PubMed had brought up this NEJM paper? Why was this ignored while the authors were using single case reports to support remdesivir?

    That remdesivir has become the favorite in journals and media is obvious (6). And it may yet be the best option for our patients once we have results from trials. We just wish that the reviews and recommendations published in respected journals will use an even-handed approach and not be openly cherry-picking information to support possible preexisting biases.

    REFERENCE

    1. Sanders JM, Monogue ML, Jodlowski TZ et al. JAMA. 2020 Apr 13. doi: 10.1001/jama.2020.6019.
    2. Gautret P, Lagier JC, Parola P et al. . Int J Antimicrob Agents. 2020 Mar 20:105949. doi: 10.1016/j.ijantimicag.2020
    3. Chen J,Liu D,Liu L, etal. J Zhejiang Univ (MedSci). Published on line March 6, 2020.doi:10.3785/j
    4. https://www.who. int/ebola/drc-2018/summaries-of-evidenceexperimental-therapeutics.pdf
    5. Mulangu S, Dodd LE, Davey RT. Randomized, Controlled Trial of Ebola Virus Disease Therapeutics N Engl J Med. 2019 Dec 12;381(24):2293-2303
    6. 7. Grein J, Ohmagari N, Shin D et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. doi: 10.1056/NEJMoa2007016
    CONFLICT OF INTEREST: None Reported
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    Be Humble, Alert, and Creative!
    Bert Govig, MD, MPH | McGill University
    Thanks to Dr Sanders and his team for this clear paper and particularly for repetition of the fundamental point: there is no known treatment for COVID-19 ... RCTs are needed.

    This sober fact is humbling. In our search for treatments we should remember:

    * Graphical illustration helps us think about these drugs, but should not fool us into thinking we understand the disease. It is quite likely that the drugs we will use to treat COVID-19 will work through unknown or unanticipated mechanisms. ACE inhibitors, Beta Blockers, statins, PDE-5 inhibitors, SGLT-2 inhibitors, and even hydroxy chloroquine
    are used today for purposes that were accidentally discovered after they were in clinical use.
    * Most of the candidate drugs will either have no effect or will cause harm. That is the nature of pharmacologic research. However we have hundreds of thousands of patients that will die from COVID and outcomes (particularly hard ones like death) drive power. We have the power, and the professional and moral mandate to rapidly eliminate drugs that don’t work until solutions are found. This requires focus, discipline, coordination, and leadership.
    * We should not ignore nonpharmacologic treatment. Prone ventilation seemed foolish until it worked. Similarly, we have discovered in clinical medicine that sleep, diet, stress, smoking, body weight, and a host of other behaviours dramatically influence health and disease. As we look for pharmacologic treatments for COVID-19 patients, we should cast our scientific gaze broadly. The goal is to save patients by all means possible.
    CONFLICT OF INTEREST: None Reported
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    Sivelestat for ARDS in COVID-19
    Hiroyuki Okura, MD. | Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
    This review provides comprehensive, useful and timely information to the doctors who are currently fighting against the devastating pandemic situation all over the world. While I was reading this review article I noticed that one drug commonly used for the treatment of acute respiratory distress syndrome (ARDS) in Japan is missing. The drug is sivelestat, a selective neutrophil elastase inhibitor, which is commercially available in Japan, but not in China, USA or European countries. Based on favorable results of a phase III trial (1), this drug was approved for the treatment of acute lung injury caused by systemic inflammatory response syndrome in Japan. On the other hand, because an international randomized trial failed to demonstrate efficacy of sivelestat in patients with moderate to severe acute respiratory distress syndrome (ARDS) (2), it has not been on the global market. Therefore, it is not surprising that there are no published reports regarding the use of sivelestat during treatment of ARDS caused by COVID-19 (as of May 8, 2020). A recent retrospective analysis using a Japanese nationwide administrative database (Diagnostic Procedure Combination; DPC) in 2012 demonstrated that the early (within 7 days) use of sivelestat may improve outcome in patients with acute lung injury/ ARDS (3). Although I do not have full access to the Japanese nationwide status of the drugs used for COVID-19, I found a case report (written in Japanese) describing 2 clinical cases who were successfully recovered after intensive treatments including use of sivelestat (4). As of May, 9, Japan is one of the countries with the lowest mortality rate due to COVID-19 (case-fatality rate of 3.6 % and deaths/100k population of 0.44) (5). Although exact mechanisms for the differences in mortality due to COVID-19 is unclear, the inter-country differences in the specific drugs used for ARDS such as sevelestat may, in-part, explain the differences in mortality.

    References
    1. Tamakuma S, Shibaya T, Hirasawa H, Ogawa M, Nakashima M. A Phase Ⅲ Clinical Study of a Neutrophil Elastase lnhibitor;ONO-50460・Na in SIRS Patients. Rinsyoiyaku. 1998;14(2):289-318.
    2. Zeiher BG, Matsuoka S, Kawabata K, Repine JE. Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics. Crit Care Med. 2002;30(5 Suppl):S281-287.
    3. Kido T, Muramatsu K, Yatera K, et al. Efficacy of early sivelestat administration on acute lung injury and acute respiratory distress syndrome. Respirology. 2017;22(4):708-713.
    4. The Japanese Association for Infectious Diseases. case report (http://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_casereport_200312_4.pdf). Accessed on May 8, 2020.
    5. The Johns Hopkins Hospital. COVID-19 data analysis center. Mortality Analysis. (https://coronavirus.jhu.edu/data/mortality) Accessed on May 8, 2020.
    CONFLICT OF INTEREST: Research grant from ONO PHARMACEUTICAL CO., LTD.
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    Review
    April 13, 2020

    Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review

    Author Affiliations
    • 1Department of Pharmacy, University of Texas Southwestern Medical Center, Dallas
    • 2Division of Infectious Diseases and Geographic Medicine, Department of Medicine, University of Texas Southwestern Medical Center, Dallas
    • 3Pharmacy Service, VA North Texas Health Care System, Dallas
    JAMA. 2020;323(18):1824-1836. doi:10.1001/jama.2020.6019
    Abstract

    Importance  The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection.

    Observations  No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19.

    Conclusions and Relevance  The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.

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