Treatments for COVID-19: emerging drugs against the coronavirus

Francesco Potì; Cristina Pozzoli; Maristella Adami; Enzo Poli; Lucio G. Costa

doi:10.23750/abm.v91i2.9639

Treatments for COVID-19: emerging drugs against the coronavirus

Authors

Francesco Potì Department of Medicine and Surgery – Unit of Neurosciences, University of Parma, Parma, Italy
Cristina Pozzoli Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, Parma, Italy
Maristella Adami Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, Parma, Italy
Enzo Poli Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, Parma, Italy
Lucio G. Costa Department of Medicine and Surgery - Unit of Neurosciences, University of Parma, Parma, Italy

DOI: https://doi.org/10.23750/abm.v91i2.9639

Keywords:

COVID-19, SARS-CoV-2, drugs, therapy, antivirals, inflammation

Abstract

The Coronavirus disease 19 (COVID-19) outbreak has been recognized as a global threat to public health. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and no effective therapies currently exist against this novel viral agent. Along with extensive public health measures, an unprecedented global effort in identifying effective drugs for the treatment is being implemented. Potential drug targets are emerging as the result of a fast-evolving understanding of SARS-CoV-2 virology, host response to the infection, and clinical course of the disease. This brief review focuses on the latest and most promising pharmacological treatments against COVID-19 currently under investigation and discuss their potential use based on either documented efficacy in similar viral infections, or their activity against inflammatory syndromes. Ongoing clinical trials are also emphasized.

References

Paules CI, Marston HD, Fauci AS. Coronavirus Infections-More Than Just the Common Cold. JAMA - J Am Med Assoc. 2020;323(8):707-708. doi:10.1001/jama.2020.0757

Yi Y, Lagniton PNP, Ye S, Li E, Xu RH. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int J Biol Sci. 2020;16(10):1753-1766. doi:10.7150/ijbs.45134

Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733. doi:10.1056/NEJMoa2001017

J G. Three Emerging Coronaviruses in Two Decades. Am J Clin Pathol. 2020;153(4). doi:10.1093/AJCP/AQAA029

Buonaguro FM, Puzanov I, Ascierto PA. Anti-IL6R role in treatment of COVID-19-related ARDS. J Transl Med. 2020;18(1):165. doi:10.1186/s12967-020-02333-9

WHO. Coronavirus disease (COVID-19) Outbreak situation_WHO. https://www.who.int/emergencies/diseases/novel-coronavirus-2019.

Lai CC, Liu YH, Wang CY, et al. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths. J Microbiol Immunol Infect. 2020. doi:10.1016/j.jmii.2020.02.012

Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. March 2020. doi:10.1111/jth.14817

Wadman M, Couzin-Frankel J, Kaiser J, Matacic C. A rampage through the body. Science. 2020;368(6489):356-360. doi:10.1126/science.368.6489.356

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. April 2020. doi:10.1001/jama.2020.6019

Lake MA. What we know so far: COVID-19 current clinical knowledge and research. Clin Med. 2020;20(2):124-127. doi:10.7861/clinmed.2019-coron

Millet JK, Whittaker GR. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res. 2015;202:120-134. doi:10.1016/j.virusres.2014.11.021

Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181(2). doi:10.1016/j.cell.2020.02.058

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. April 2020. doi:10.1016/j.cell.2020.02.052

Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses. 2012;4(6):1011-1033. doi:10.3390/v4061011

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

Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. March 2020. doi:10.1056/nejmoa2001282

Siddiqi HK, Mehra MR. COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. J Hear Lung Transplant. March 2020. doi:10.1016/j.healun.2020.03.012

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

Marietta M, Ageno W, Artoni A, et al. COVID-19 and haemostasis: a position paper from Italian Society on Thrombosis and Haemostasis (SISET). Blood Transfus. April 2020. doi:10.2450/2020.0083-20

Bikdeli B, Madhavan M V, Jimenez D, et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. J Am Coll Cardiol. April 2020. doi:10.1016/j.jacc.2020.04.031

Search of: COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19. Accessed April 27, 2020.

Sperimentazioni cliniche - COVID-19 | Agenzia Italiana del Farmaco. https://www.aifa.gov.it/sperimentazioni-cliniche-covid-19. Accessed April 26, 2020.

Cvetkovic RS, Goa KL. Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs. 2003;63(8):769-802. doi:10.2165/00003495-200363080-00004

Kaletra | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/kaletra. Accessed April 24, 2020.

Barrila J, Bacha U, Freire E. Long-range cooperative interactions modulate dimerization in SARS 3CL pro. Biochemistry. 2006;45(50):14908-14916. doi:10.1021/bi0616302

Kim Y, Liu H, Galasiti Kankanamalage AC, et al. Reversal of the Progression of Fatal Coronavirus Infection in Cats by a Broad-Spectrum Coronavirus Protease Inhibitor. PLoS Pathog. 2016;12(3). doi:10.1371/journal.ppat.1005531

Choy K-T, Yin-Lam Wong A, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786. doi:10.1016/j.antiviral.2020.104786

Chu CM, Cheng VCC, Hung IFN, et al. 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

Chan JF-W, Yao Y, Yeung M-L, et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J Infect Dis. 2015;212(12):1904-1913. doi:10.1093/infdis/jiv392

Kim UJ, Won EJ, Kee SJ, Jung SI, Jang HC. Combination therapy with lopinavir/ritonavir, ribavirin and interferon-a for Middle East respiratory syndrome. Antivir Ther. 2016;21(5):455-459. doi:10.3851/IMP3002

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.

Jin YH, Cai L, Cheng ZS, et al. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version). Mil Med Res. 2020;7(1). doi:10.1186/s40779-020-0233-6

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. March 2020. doi:10.1001/jamainternmed.2020.0994

Navarro J, Curran A. Profile of once-daily darunavir/cobicistat fixeddose combination for the treatment of HIV/AIDS. HIV/AIDS - Res Palliat Care. 2016;8:175-182. doi:10.2147/HIV.S56158

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

Efficacy and Safety of Darunavir and Cobicistat for Treatment of COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04252274. Accessed April 24, 2020.

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

Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. 2020. doi:10.1016/j.tmaid.2020.101615

Gordon CJ, Tchesnokov EP, Woolner E, et al. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem. 2020. doi:10.1074/jbc.RA120.013679

EMA provides recommendations on compassionate use of remdesivir for COVID-19 | European Medicines Agency. https://www.ema.europa.eu/en/news/ema-provides-recommendations-compassionate-use-remdesivir-covid-19. Accessed April 24, 2020.

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

Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med. 2020;382(10):929-936. doi:10.1056/NEJMoa2001191

Kujawski SA, Wong KK, Collins JP, et al. First 12 patients with coronavirus disease 2019 (COVID-19) in the United States. medRxiv. 2020:2020.03.09.20032896. doi:10.1101/2020.03.09.20032896

Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04292730. Accessed April 24, 2020.

Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734TM) in Participants With Severe Coronavirus Disease (COVID-19) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04292899. Accessed April 24, 2020.

AIFA e Gilead annunciano che l’Italia è tra i Paesi che testeranno l’antivirale remdesivir per il trattamento del COVID-19. https://www.aifa.gov.it/web/guest/-/aifa-e-gilead-annunciano-che-l-italia-e-tra-i-paesi-che-testeranno-l-antivirale-remdesivir-per-il-trattamento-del-covid-19. Accessed April 24, 2020.

notizia | Agenzia Italiana del Farmaco. https://www.aifa.gov.it/web/guest/-/covid-19-aifa-autorizza-lo-studio-solidarity-promosso-dall-oms. Accessed April 24, 2020.

Programmi di uso compassionevole – COVID-19 | Agenzia Italiana del Farmaco. https://www.aifa.gov.it/programmi-di-uso-compassionevole-covid-19. Accessed April 24, 2020.

Trial of Treatments for COVID-19 in Hospitalized Adults - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04315948?term=NCT04315948&draw=2&rank=1. Accessed April 24, 2020.

Adaptive COVID-19 Treatment Trial (ACTT) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04280705?term=NCT04280705&draw=2&rank=1. Accessed April 24, 2020.

A Trial of Remdesivir in Adults With Mild and Moderate COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04252664?term=NCT04252664&draw=2&rank=1. Accessed April 24, 2020.

A Trial of Remdesivir in Adults With Severe COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04257656?term=NCT04257656&draw=2&rank=1. Accessed April 24, 2020.

Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. April 2020. doi:10.1056/NEJMoa2007016

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

Schrezenmeier E, Dörner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020;16(3):155-166. doi:10.1038/s41584-020-0372-x

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). doi:10.1002/prp2.293

Devaux CA, Rolain J-M, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. March 2020:105938. doi:10.1016/j.ijantimicag.2020.105938

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 an Off Publ Infect Dis Soc Am. March 2020. doi:10.1093/cid/ciaa237

Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020. doi:10.1016/j.ijantimicag.2020.105932

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). doi:10.5582/BST.2020.01047

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). 2020;49(February):1-10. doi:10.3785/j.issn.1008-9292.2020.03.03

Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv. April 2020:2020.04.16.20065920. doi:10.1101/2020.04.16.20065920

Chloroquine/ Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19) in the Healthcare Setting - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04303507?term=nct04303507&draw=2&rank=1. Accessed April 25, 2020.

Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04308668?term=nct04308668&draw=2&rank=1. Accessed April 25, 2020.

COVID-19: reminder of risk of serious side effects with chloroquine and hydroxychloroquine | European Medicines Agency. https://www.ema.europa.eu/en/news/covid-19-reminder-risk-serious-side-effects-chloroquine-hydroxychloroquine. Accessed April 24, 2020.

McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med. 1983;75(1 PART 1):11-18. doi:10.1016/0002-9343(83)91265-2

Bergholz R, Schroeter J, Rüther K. Evaluation of risk factors for retinal damage due to chloroquine and hydroxychloroquine. Br J Ophthalmol. 2010;94(12):1637-1642. doi:10.1136/bjo.2009.174458

Khamitov RA, Loginova SI, Shchukina VN, Borisevich S V, Maksimov VA, Shuster AM. [Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures]. Vopr Virusol. 2008;53(4):9-13.

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

Search of: umifenovir | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=umifenovir&cntry=&state=&city=&dist=&Search=Search. Accessed April 25, 2020.

Clinical Study of Arbidol Hydrochloride Tablets in the Treatment of Pneumonia Caused by Novel Coronavirus - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04260594?term=umifenovir&cond=COVID-19&draw=2&rank=3. Accessed April 25, 2020.

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. March 2020. doi:10.1093/cid/ciaa272

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

Furuta Y, Komeno T, Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Japan Acad Ser B Phys Biol Sci. 2017;93(7):449-463. doi:10.2183/pjab.93.027

Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res. 2013;100(2):446-454. doi:10.1016/j.antiviral.2013.09.015

Sissoko D, Laouenan C, Folkesson E, et al. Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea. PLoS Med. 2016;13(3). doi:10.1371/journal.pmed.1001967

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

McKimm-Breschkin JL, Fry AM. Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses. Antiviral Res. 2016;129:21-38. doi:10.1016/j.antiviral.2016.01.012

McKimm-Breschkin JL, Jiang S, Hui DS, Beigel JH, Govorkova EA, Lee N. Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference. In: Antiviral Research. Vol 149. Elsevier B.V.; 2018:118-142. doi:10.1016/j.antiviral.2017.11.013

Madelain V, Nguyen THT, Olivo A, et al. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials. Clin Pharmacokinet. 2016;55(8):907-923. doi:10.1007/s40262-015-0364-1

Nguyen THT, Guedj J, Anglaret X, et al. Favipiravir pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted. PLoS Negl Trop Dis. 2017;11(2). doi:10.1371/journal.pntd.0005389

Favié LMA, Murk JL, Meijer A, Laura Nijstad A, Van Maarseveen EM, Sikma MA. Pharmacokinetics of favipiravir during continuous venovenous haemofiltration in a critically ill patient with influenza. Antivir Ther. 2018;23(5):457-461. doi:10.3851/IMP3210

Phase 3 Efficacy and Safety Study of Favipiravir for Treatment of Uncomplicated Influenza in Adults - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02008344?term=NCT02008344&draw=2&rank=1. Accessed April 25, 2020.

Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. 2020:2020.03.17.20037432. doi:10.1101/2020.03.17.20037432

Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering. March 2020. doi:10.1016/j.eng.2020.03.007

Search of: favipiravir | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=favipiravir&cntry=&state=&city=&dist=&Search=Search. Accessed April 25, 2020.

Clinical Study To Evaluate The Performance And Safety Of Favipiravir in COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04336904?term=NCT04336904&draw=2&rank=1. Accessed April 25, 2020.

Maeurer M, Rao M, Zumla A. Host-directed therapies for antimicrobial resistant respiratory tract infections. Curr Opin Pulm Med. 2016;22(3):203-211. doi:10.1097/MCP.0000000000000271

Salvatore M, Satlin MJ, Jacobs SE, et al. DAS181 for Treatment of Parainfluenza Virus Infections in Hematopoietic Stem Cell Transplant Recipients at a Single Center. Biol Blood Marrow Transplant. 2016;22(5):965-970. doi:10.1016/j.bbmt.2016.02.011

Dhakal B, D’Souza A, Pasquini M, et al. DAS181 Treatment of Severe Parainfluenza Virus 3 Pneumonia in Allogeneic Hematopoietic Stem Cell Transplant Recipients Requiring Mechanical Ventilation. Case Rep Med. 2016;2016:8503275. doi:10.1155/2016/8503275

Search of: das181 | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=das181&cntry=&state=&city=&dist=&Search=Search. Accessed April 25, 2020.

DAS181 for STOP COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04354389?term=das181&cond=COVID-19&draw=2&rank=2. Accessed April 25, 2020.

Jin Z, Du X, Xu Y, et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature. April 2020. doi:10.1038/s41586-020-2223-y

Parnham MJ, Sies H. The early research and development of ebselen. Biochem Pharmacol. 2013;86(9):1248-1253. doi:10.1016/j.bcp.2013.08.028

Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375-3383. doi:10.1172/JCI57158

Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. Cytokine release syndrome. J Immunother Cancer. 2018;6(1). doi:10.1186/s40425-018-0343-9

Oved JH, Barrett DM, Teachey DT. Cellular therapy: Immune-related complications. Immunol Rev. 2019;290(1):114-126. doi:10.1111/imr.12768

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. doi:10.1016/S0140-6736(20)30566-3

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033-1034. doi:10.1016/S0140-6736(20)30628-0

Xu, Xiaoling, Han, Mingfeng, Li, Tiantian, Sun, Wei, Wang, Dongsheng, Fu, Binqing, Zhou, Yonggang, Zheng, Xiaohu, Yang, Yun, Li, Xiuyong, Zhang, Xiaohua, Pan, Aijun, Wei H. Effective treatment of severe COVID-19 patients with tocilizumab. ChinaXiv. 2020. doi:10.12074/202003.00026

Search of: tocilizumab | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=tocilizumab&cntry=&state=&city=&dist=&Search=Search. Accessed April 26, 2020.

Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04317092?term=tocilizumab&cond=COVID-19&draw=2&rank=1. Accessed April 26, 2020.

Efficacy of Early Administration of Tocilizumab in COVID-19 Patients - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04346355?term=parma&cond=COVID-19&draw=2&rank=5. Accessed April 26, 2020.

A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04320615?term=tocilizumab&cond=COVID-19&draw=2&rank=7. Accessed April 26, 2020.

Kim S, Östör AJK, Nisar MK. Interleukin-6 and cytochrome-P450, reason for concern? Rheumatol Int. 2012;32(9):2601-2604. doi:10.1007/s00296-012-2423-3

Zhang X, Peck R. Clinical pharmacology of tocilizumab for the treatment of patients with rheumatoid arthritis. Expert Rev Clin Pharmacol. 2011;4(5):539-558. doi:10.1586/ecp.11.33

Search of: sarilumab | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=sarilumab&cntry=&state=&city=&dist=&Search=Search&flds=abkuy. Accessed April 26, 2020.

Sarilumab COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04327388?term=sarilumab&cond=COVID-19&draw=2&rank=7. Accessed April 26, 2020.

Dinarello CA, Simon A, Van Der Meer JWM. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633-652. doi:10.1038/nrd3800

Kineret | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/kineret. Accessed April 26, 2020.

Al-Salama ZT. Emapalumab: First Global Approval. Drugs. 2019;79(1):99-103. doi:10.1007/s40265-018-1046-8

Lounder DT, Bin Q, De Min C, Jordan MB. Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections. Blood Adv. 2019;3(1):47-50. doi:10.1182/bloodadvances.2018025858

Schoenborn JR, Wilson CB. Regulation of Interferon-γ During Innate and Adaptive Immune Responses. Adv Immunol. 2007;96:41-101. doi:10.1016/S0065-2776(07)96002-2

Ye L, Schnepf D, Staeheli P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat Rev Immunol. 2019;19(10):614-625. doi:10.1038/s41577-019-0182-z

EU/3/10/749 | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu310749. Accessed April 26, 2020.

Search of: anakinra | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=anakinra&cntry=&state=&city=&dist=&Search=Search. Accessed April 26, 2020.

Efficacy and Safety of Emapalumab and Anakinra in Reducing Hyperinflammation and Respiratory Distress in Patients With COVID-19 Infection. - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04324021?term=emapalumab&cond=COVID-19&draw=2&rank=1. Accessed April 26, 2020.

Panda D, Daijo JE, Jordan MA, Wilson L. Kinetic Stabilization of Microtubule Dynamics at Steady State in Vitro by Substoichiometric Concentrations of Tubulin-Colchicine Complex. Biochemistry. 1995;34(31):9921-9929. doi:10.1021/bi00031a014

Ravelli RBG, Gigant B, Curmi PA, et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004;428(6979):198-202. doi:10.1038/nature02393

Perico N, Ostermann D, Bontempeill M, et al. Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation. J Am Soc Nephrol. 1996;7(4).

Stack J, Ryan J, McCarthy G. Colchicine: New Insights to an Old Drug. Am J Ther. 2015;22(5):e151-e157. doi:10.1097/01.mjt.0000433937.07244.e1

Martínez GJ, Celermajer DS, Patel S. The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation. Atherosclerosis. 2018;269:262-271. doi:10.1016/j.atherosclerosis.2017.12.027

Biswas K, Das Sarma J, Perlman S. Effect of Microtubule Disruption on Neuronal Spread and Replication of Demyelinating and Nondemyelinating Strains of Mouse Hepatitis Virus In Vitro. J Virol. 2014;88(5):3043-3047. doi:10.1128/jvi.02545-13

Lu N, Yang Y, Liu H, et al. Inhibition of respiratory syncytial virus replication and suppression of RSV-induced airway inflammation in neonatal rats by colchicine. 3 Biotech. 2019;9(11). doi:10.1007/s13205-019-1917-z

Angelini MM, Akhlaghpour M, Neuman BW, Buchmeier MJ. Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. MBio. 2013;4(4). doi:10.1128/mBio.00524-13

Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, et al. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology. 2015;485:330-339. doi:10.1016/j.virol.2015.08.010

Yue Y, Nabar NR, Shi CS, et al. SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death. Cell Death Dis. 2018;9(9). doi:10.1038/s41419-018-0917-y

COVID-19 - AIFA autorizza sperimentazione clinica con colchicina. https://www.aifa.gov.it/web/guest/-/covid-19-aifa-autorizza-sperimentazione-clinica-con-colchicina. Accessed April 26, 2020.

Colchicine Counteracting Inflammation in COVID-19 Pneumonia - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/study/NCT04322565?term=NCT04322565&cond=COVID-19&draw=2&rank=1#contacts. Accessed April 23, 2020.

Mukherjee D, Topol EJ. The role of low-molecular-weight heparin in cardiovascular diseases. Prog Cardiovasc Dis. 2002;45(2):139-156. doi:10.1053/pcad.2002.127679

Yan AT, Goodman SG. Low-molecular-weight heparins in ischemic heart disease. Curr Opin Cardiol. 2004;19(4):309-316. doi:10.1097/01.hco.0000129665.55707.f6

Hirsh J, Anand SS, Halperin JL, Fuster V. Guide to Anticoagulant Therapy: Heparin. Circulation. 2001;103(24):2994-3018. doi:10.1161/01.CIR.103.24.2994

Li T, Lu H, Zhang W. Clinical observation and management of COVID-19 patients. Emerg Microbes Infect. 2020;9(1):687-690. doi:10.1080/22221751.2020.1741327

SHI C, WANG C, WANG H, et al. Clinical observations of low molecular weight heparin in relieving inflammation in COVID-19 patients: A retrospective cohort study. medRxiv. April 2020:2020.03.28.20046144. doi:10.1101/2020.03.28.20046144

Shukla D, Spear PG. Herpesviruses and heparan sulfate: an intimate relationship in aid of viral entry. J Clin Invest. 2001;108(4):503-510. doi:10.1172/jci13799

Ghezzi S, Cooper L, Rubio A, et al. Heparin prevents Zika virus induced-cytopathic effects in human neural progenitor cells. Antiviral Res. 2017;140:13-17. doi:10.1016/j.antiviral.2016.12.023

Vicenzi E, Canducci F, Pinna D, et al. Coronaviridae and SARS-associated Coronavirus Strain HSR1. Emerg Infect Dis. 2004;10(3):413-418. doi:10.3201/eid1003.030683

Thachil J. The versatile heparin in COVID-19. J Thromb Haemost. April 2020. doi:10.1111/jth.14821

Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. March 2020. doi:10.1111/jth.14810

CD B, HB M, MB Y, EE M. ISTH Interim Guidance on Recognition and Management of Coagulopathy in COVID-19: A Comment. J Thromb Haemost. 2020. doi:10.1111/JTH.14860

Lythgoe MP, Middleton P. Ongoing Clinical Trials for the Management of the COVID-19 Pandemic. Trends Pharmacol Sci. April 2020. doi:10.1016/j.tips.2020.03.006

Olumiant | European Medicines Agency. https://www.ema.europa.eu/en/medicines/human/EPAR/olumiant. Accessed April 27, 2020.

Drug Approval Package: Olumiant (baricitinib). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/207924Orig1s000TOC.cfm. Accessed April 27, 2020.

Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30-e31. doi:10.1016/S0140-6736(20)30304-4

Stebbing J, Phelan A, Griffin I, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020;20(4):400-402. doi:10.1016/S1473-3099(20)30132-8

Search of: baricitinib | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=baricitinib&cntry=&state=&city=&dist=&Search=Search. Accessed April 27, 2020.

Kawase M, Shirato K, van der Hoek L, Taguchi F, Matsuyama S. Simultaneous Treatment of Human Bronchial Epithelial Cells with Serine and Cysteine Protease Inhibitors Prevents Severe Acute Respiratory Syndrome Coronavirus Entry. J Virol. 2012;86(12):6537-6545. doi:10.1128/jvi.00094-12

Maggio R, Corsini GU. Repurposing the mucolytic cough suppressant and TMPRSS2 protease inhibitor bromhexine for the prevention and management of SARS-CoV-2 infection. Pharmacol Res. April 2020:104837. doi:10.1016/j.phrs.2020.104837

Search of: camostat | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=camostat&cntry=&state=&city=&dist=&Search=Search. Accessed April 27, 2020.

Search of: bromhexine | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=bromhexine&cntry=&state=&city=&dist=&Search=Search. Accessed April 27, 2020.

Yuksel M, Okajima K, Uchiba M, Okabe H. Gabexate mesilate, a synthetic protease inhibitor, inhibits lipopolysaccharide-induced tumor necrosis factor-α production by inhibiting activation of both nuclear factor-κB and activator protein-1 in human monocytes. J Pharmacol Exp Ther. 2003;305(1):298-305. doi:10.1124/jpet.102.041988

Brandi G, Tavolari S, De Rosa F, et al. Antitumoral efficacy of the protease inhibitor gabexate mesilate in colon cancer cells harbouring KRAS, BRAF and PIK3CA mutations. PLoS One. 2012;7(7). doi:10.1371/journal.pone.0041347

Xie LB, Zeng DY, Wang XD, Lin T, Li YP, Lu YP. Preconditioning with gabexate is superior to inosine for ameliorating acute renal ischemia-reperfusion injury in rats. Transplant Proc. 2014;46(1):40-45. doi:10.1016/j.transproceed.2013.10.037

Kim SC, Yang HR. Clinical efficacy of gabexate mesilate for acute pancreatitis in children. Eur J Pediatr. 2013;172(11):1483-1490. doi:10.1007/s00431-013-2068-6

Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S. Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r, and C1 esterase. BBA - Enzymol. 1977;484(2):417-422. doi:10.1016/0005-2744(77)90097-3

Yamamoto M, Kiso M, Sakai-Tagawa Y, et al. The anticoagulant nafamostat potently inhibits SARS-CoV-2 infection in vitro: an existing drug with multiple possible therapeutic effects. bioRxiv. April 2020:2020.04.22.054981. doi:10.1101/2020.04.22.054981

Yamamoto M, Matsuyama S, Li X, et al. Identification of nafamostat as a potent inhibitor of middle east respiratory syndrome Coronavirus s protein-mediated membrane fusion using the split-protein-based cell-cell fusion assay. Antimicrob Agents Chemother. 2016;60(11):6532-6539. doi:10.1128/AAC.01043-16

Efficacy of Nafamostat in Covid-19 Patients (RACONA Study) - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04352400?term=nafamostat&cond=COVID-19&draw=2&rank=1. Accessed April 27, 2020.

Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020. doi:10.1002/ddr.21656

Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang. Accessed April 27, 2020.

EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic | European Medicines Agency. https://www.ema.europa.eu/en/news/ema-advises-continued-use-medicines-hypertension-heart-kidney-disease-during-covid-19-pandemic. Accessed April 27, 2020.

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

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

Search of: convalescent Plasma | COVID-19 - List Results - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/results?cond=COVID-19&term=convalescent+Plasma&cntry=&state=&city=&dist=&Search=Search. Accessed April 28, 2020.

Hyperimmune Plasma for Critical Patients With COVID-19 - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04321421?term=hyperimmune+Plasma&cond=COVID-19&draw=2&rank=1. Accessed April 28, 2020.

Convalescent Antibodies Infusion in Critically Ill COVID 19 Patients - Full Text View - ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04346589?term=convalescent+Plasma&cond=COVID-19&draw=2&rank=42. Accessed April 28, 2020.

WHO Solidarity Trial – Accelerating a safe and effective COVID-19 vaccine. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-trial-accelerating-a-safe-and-effective-covid-19-vaccine. Accessed April 27, 2020.