Mechanisms of action and adverse effects of the major therapeutic agents in trial for COVID-19 therapeutics: Review of literature

Submitted: 3 November 2020
Accepted: 26 May 2021
Published: 5 July 2021
Abstract Views: 421
PDF: 171
Appendix: 36
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

The race to find an effective cure for COVID-19 is on. Most of the candidate drugs in various clinical trials are being re-purposed but none has been approved as at date. It is pertinent for the bedside physicians to understand the mechanisms of action of these agents and their peculiar adverse effects so they are properly guided on the risk/benefit of the drugs they choose in managing COVID-19 patients. Clinicaltrials.gov, the international clinical trials platform of the WHO, the EU clinical trials register and the Cochrane Central Register of Controlled Trials were searched for registered clinical trials. Studies in therapeutic trials were considered eligible for the work. Frequency table was made for the most common trialled drugs and the mechanisms of actions and adverse effects of the selected drugs were reviewed. Ten studies were selected for review in a descending order of their frequency in different therapeutic trials and these are ritonavir, lopinavir, chloroquine/ hydroxychloroquine, interferon, remdesvir, favipravir, umifenovir, darunavir, tocilizumab and methylprednisolone. The bedside physicians need to understand the mechanisms of action of these agents and their peculiar adverse effects for proper guidance on the risk/benefit of the drugs they choose in managing COVID- 19 patients.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

Citations

Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020;395:565-74. DOI: https://doi.org/10.1016/S0140-6736(20)30251-8
WHO. Rolling updates on coronavirus disease (COVID-19). Geneve: WHO; 2020. Accessed: 31st July 2020. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen
WHO. Coronavirus disease (COVID-19) Situation Report -118. Geneve: WHO; 2020. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200517-covid-19-sitrep-118.pdf?sfvrsn=21c0dafe_10
Crosby JC, Heimann MA, Burleson SL, et al. COVID-19: A review of therapeutics under investigation. J Am Coll Emerg Physicians Open 2020;1:231-7. DOI: https://doi.org/10.1002/emp2.12081
Yan Y, Shin WI, Pang YX, et al. The first 75 days of novel coronavirus (SARS-CoV-2) outbreak: recent advances, prevention, and treatment. Int J Environ Res Public Health 2020;17:30. DOI: https://doi.org/10.3390/ijerph17072323
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9. DOI: https://doi.org/10.1001/jama.2020.1585
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. DOI: https://doi.org/10.1016/S0140-6736(20)30183-5
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;395:507-13. DOI: https://doi.org/10.1016/S0140-6736(20)30211-7
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 2020;8:475-81. DOI: https://doi.org/10.1016/S2213-2600(20)30079-5
Ashburn TT, Thor KB. Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 2004;3:673-83. DOI: https://doi.org/10.1038/nrd1468
Lythgoe MP, Middleton P. Ongoing clinical trials for the management of the COVID-19 pandemic. Trends Pharmacol Sci 2020;41:363-82. DOI: https://doi.org/10.1016/j.tips.2020.03.006
Dionne B. Key principles of antiretroviral pharmacology. Infect Dis Clin North Am 2019;33:787-805. DOI: https://doi.org/10.1016/j.idc.2019.05.006
Paintsil E, Cheng YC. Antiviral Agents. In: Encyclopedia of Microbiology. Eds: Thomas M. Schmidt. Michigan: Elsevier; 2019: pp. 176-225.
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;11:222. DOI: https://doi.org/10.1038/s41467-019-13940-6
Tobaiqy M, Qashqary M, Al-Dahery S, et al. Therapeutic management of patients with COVID-19: a systematic review. Infect Prev Pract 2020;2:17. DOI: https://doi.org/10.1101/2020.04.02.20051029
Jespersen S, Hønge BL, Krarup H, et al. Protease inhibitors or NNRTIs as first-line HIV-1 treatment in West Africa (PIONA): A randomized controlled trial. J Acquir Immune Defic Syndr 2018;79:386-93. DOI: https://doi.org/10.1097/QAI.0000000000001820
Silva B, Peixoto G, da Luz S, et al. Adverse effects of chronic treatment with the Main subclasses of highly active antiretroviral therapy: a systematic review. HIV Med 2019;20:429-38. DOI: https://doi.org/10.1111/hiv.12733
Su B, Wang Y, Zhou R, et al. Efficacy and tolerability of lopinavir/ritonavir- and efavirenz-based initial antiretroviral therapy in HIV-1-infected patients in a tertiary care hospital in Beijing, China. Front Pharmacol 2019;10:1472. DOI: https://doi.org/10.3389/fphar.2019.01472
Amirian ES, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health 2020;9:100128. DOI: https://doi.org/10.1016/j.onehlt.2020.100128
Brown AJ, Won JJ, Graham RL, et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res 2019;169:104541. DOI: https://doi.org/10.1016/j.antiviral.2019.104541
Jordan PC, Liu C, Raynaud P, et al. Initiation, extension, and termination of RNA synthesis by a paramyxovirus polymerase. PLoS Pathog 2018;14:e1006889. DOI: https://doi.org/10.1371/journal.ppat.1006889
Tchesnokov EP, Feng JY, Porter DP, Götte M. Mechanism of inhibition of Ebola virus RNA-dependent RNA polymerase by remdesivir. Viruses 2019;11:326. DOI: https://doi.org/10.3390/v11040326
Ledford H. Hopes rise for coronavirus drug remdesvir. Nature 2020. doi: https://doi.org/10.1038/d41586-020-01295-8 DOI: https://doi.org/10.1038/d41586-020-01295-8
Hayden FG, Shindo N. Influenza virus polymerase inhibitors in clinical development. Curr Opin Infect Dis 2019;32:176-86. DOI: https://doi.org/10.1097/QCO.0000000000000532
Beigel JH, Nam HH, Adams PL, et al. Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res 2019;167:45-67. DOI: https://doi.org/10.1016/j.antiviral.2019.04.006
Furuta Y, Gowen BB, Takahashi K, et al. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 2013;100:446-54. DOI: https://doi.org/10.1016/j.antiviral.2013.09.015
Madelain V, Nguyen TH, 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;55:907-23. DOI: https://doi.org/10.1007/s40262-015-0364-1
Principi N, Camilloni B, Alunno A, et al. Drugs for influenza treatment: is there significant news? Front Med (Lausanne) 2019;6:109. DOI: https://doi.org/10.3389/fmed.2019.00109
Aoki M, Das D, Hayashi H, et al. Mechanism of darunavir (DRV)'s high genetic barrier to HIV-1 resistance: A key V32I substitution in protease rarely occurs, but once it occurs, it predisposes HIV-1 to develop DRV resistance. mBio 2018;9:e02425-17. DOI: https://doi.org/10.1128/mBio.02425-17
Antoniou T, Szadkowski L, Walmsley S, et al. Comparison of atazanavir/ritonavir and darunavir/ritonavir based antiretroviral therapy for antiretroviral naïve patients. BMC Infect Dis 2017:17:266. DOI: https://doi.org/10.1186/s12879-017-2379-8
Antinori A, Rusconi S, Gianotti N, et al. Cardiovascular adverse events during treatment with darunavir-based regimens in an Italian observational study. Drug Des Devel Ther 2019;13:1667-85. DOI: https://doi.org/10.2147/DDDT.S180981
Delicio AM, Lajos GJ, Amaral E, et al. Adverse effects of antiretroviral therapy in pregnant women infected with HIV in Brazil from 2000 to 2015: a cohort study. BMC Infect Dis 2018;18:485. DOI: https://doi.org/10.1186/s12879-018-3397-x
Fink SL, Vojtech L, Wagoner J, et al. The antiviral drug arbidol inhibits zika virus. Sci Rep 2018;8:8989. DOI: https://doi.org/10.1038/s41598-018-27224-4
Pshenichnaya NY, Bulgakova VA, Lvov NI, et al. Clinical efficacy of umifenovir in influenza and ARVI (study ARBITR). Ter Arkh 2019;91:56-63. DOI: https://doi.org/10.26442/00403660.2019.03.000127
Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, et al. Arbidol and other low-molecular-weight drugs that inhibit lassa and ebola viruses. J Virol 2019;93:e02185-18. DOI: https://doi.org/10.1128/JVI.02185-18
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 2020;55:105938. DOI: https://doi.org/10.1016/j.ijantimicag.2020.105938
Al-Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother 2015;70:1608-21. DOI: https://doi.org/10.1093/jac/dkv018
D'Alessandro S, Scaccabarozzi D, Signorini L, et al. The use of antimalarial drugs against viral infection. Microorganisms 2020;8:85. DOI: https://doi.org/10.3390/microorganisms8010085
Haładyj E, Sikora M, Felis-Giemza A, M. Olesińska. Antimalarials - are they effective and safe in rheumatic diseases? Reumatologia 2018;56:164-73. DOI: https://doi.org/10.5114/reum.2018.76904
Savarino A, Boelaert JR, Cassone A, et al. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis 2003;3:722-7. DOI: https://doi.org/10.1016/S1473-3099(03)00806-5
Sharma A. Chloroquine paradox may cause more damage than help fight COVID-19. Microbes Infect 2020;22:154-6. DOI: https://doi.org/10.1016/j.micinf.2020.04.004
Ozato K, Tailor P, Kubota T. The interferon regulatory factor family in host defense: mechanism of action. J Biol Chem 2007;282:20065-9. DOI: https://doi.org/10.1074/jbc.R700003200
O'Brien TR, Thomas DL, Jackson SS, et al. Weak induction of interferon expression by severe acute respiratory syndrome coronavirus 2 supports clinical trials of interferon-λ to treat early coronavirus disease 2019. Clin Infect Dis 2020;71:1410-2. DOI: https://doi.org/10.1093/cid/ciaa453
Subramanian G, Kuzmanovic T, Zhang Y, et al. A new mechanism of interferon's antiviral action: Induction of autophagy, essential for paramyxovirus replication, is inhibited by the interferon stimulated gene, TDRD7. PLoS Pathog 2018;14:e1006877. DOI: https://doi.org/10.1371/journal.ppat.1006877
George PM, Badiger R, Alazawi W, et al. Pharmacology and therapeutic potential of interferons. Pharmacol Therapeutics 2012;135:44-53. DOI: https://doi.org/10.1016/j.pharmthera.2012.03.006
Prokunina-Olsson L, Alphonse N, Dickenson RE, et al. COVID-19 and emerging viral infections: The case for interferon lambda. J Exp Med 2020;217:e20200653. DOI: https://doi.org/10.1084/jem.20200653
Ferrara G, Petrillo MG, Giani T, et al. Clinical use and molecular action of corticosteroids in the pediatric age. Int J Mol Sci 2019;20:444. DOI: https://doi.org/10.3390/ijms20020444
Ponticelli C, Locatelli F. Glucocorticoids in the treatment of glomerular diseases: pitfalls and pearls. Clin J Am Soc Nephrol 2018;13:815-22. DOI: https://doi.org/10.2215/CJN.12991117
Williams DM. Clinical pharmacology of corticosteroids. Respiratory Care 2018;63:655-70. DOI: https://doi.org/10.4187/respcare.06314
Ocejo A, Correa R. Methylprednisolone. 2021 May 7. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.
Wang Y, Jiang W, He Q, et al. A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduct Target Ther 2020;5:57. DOI: https://doi.org/10.1038/s41392-020-0158-2
Zhou W, Liu Y, Tian D, et al. Potential benefits of precise corticosteroids therapy for severe 2019-nCoV pneumonia. Signal Transduct Target Ther 2020;5:18. DOI: https://doi.org/10.1038/s41392-020-0127-9
Karkhur S, Hasanreisoglu M, Vigil E, et al. Interleukin-6 inhibition in the management of non-infectious uveitis and beyond. J Ophthalmic Inflamm Infect 2019;9:17. DOI: https://doi.org/10.1186/s12348-019-0182-y
Luo P, Liu Y, Qiu L, et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92:814-8. DOI: https://doi.org/10.1002/jmv.25801
Oldfield V, Dhillon S, Plosker GL. Tocilizumab: a review of its use in the management of rheumatoid arthritis. Drugs 2009;69:609-32. DOI: https://doi.org/10.2165/00003495-200969050-00007
Emeka Donald Ogiji, Department of Pharmacology/Therapeutics, Ebonyi State University, Abakaliki, Ebonyi State

Department of Pharmacology/Therapeutics, Ebonyi State University, Abakaliki, Nigeria.

How to Cite

Ogiji, E. D. ., Ezeanosike, O. B., Ofor, C. C., Ezeanosike, E., Maduba, C. C., & Ghasi, S. (2021). Mechanisms of action and adverse effects of the major therapeutic agents in trial for COVID-19 therapeutics: Review of literature. Annals of Clinical and Biomedical Research, 2(2). https://doi.org/10.4081/acbr.2021.118