PHARMACOLOGICAL TREATMENTS OF COVID-19 – A REVIEW
Now the world stands in the fight against coronavirus disease 2019 (COVID-19), with its early origin from Wuhan city in China. It has evolved into a global pandemic resulting into a significant burden to the human race. As per WHO, on July 31, 2020, there were 170 million cases reported all over the world, with 6.73 lakhs deaths. There is no effective treatment so far discovered for the severe acute respiratory syndrome-CoV2. Many pharmacological agents/therapies are being used or considered for treatment. In many countries, physicians are giving COVID-19 patients treatment that has not been approved for this disease. They are treating patients using medications outside their indicated, approved uses and without study protocols, with little scientific evidence. At present, there is no evidence from randomized clinical trials (RCTs) that any potential therapy improves outcomes in patients with COVID-19. There are no clinical trial data supporting any prophylactic therapy. Along with Solidarity trial, many active clinical treatment trials are underway. This narrative review summarizes current evidence regarding major proposed treatments, repurposed or experimental, for COVID-19 and provides a summary of current clinical experience and treatment guidance for this pandemic novel coronavirus.
2. World Health Organization. Draft Landscape of COVID-19 Candidate Vaccines. Geneva: World Health Organisation; 2020.
3. Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020;396:467-8.
4. Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, et al. An mRNA vaccine against SARS-CoV-2-preliminary report. N Engl J Med 2020;1:NEJMoa2022483.
5. COVAXINTM-India’s First Indigenous COVID-19 Vaccine. Available from: https://www.bharatbiotech.com/covaxin.html.
6. Zhu FC, Guan XH, Li YH, Huang JY, Jiang T, Hou LH, et al. Immunogenicity and safety of a recombinant adenovirus type-5- vectored COVID-19 vaccine in healthy adults aged 18 years or older: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020;396:479-88.
7. Kalil AC. Treating COVID-19-Off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020;323:1897-8.
8. Zagury-Orly I, Schwartzstein RM. Covid-19-A reminder to reason. N Engl J Med 2020;383:e12.
9. Sasmi MB, Jose M, Kuttichira P. Current therapeutic options for coronavirus disease-2019-A pharmacological review. Asian J Pharm Clin Res 2020;13:42-50.
10. Ji S, Bai Q, Wu X, Zhang DW, Wang S, Shen JL, et al. Unique synergistic antiviral effects of shufeng jiedu capsule and oseltamivir in influenza A viral-induced acute exacerbation of chronic obstructive pulmonary disease. Biomed Pharmacother 2020;121:109652.
11. Cheng DZ. Clinical effectiveness and case analysis in 54 NCP patients treated with lianhuaqingwen granules [in Chinese]. World Chin Med 2020;15:150-4.
12. Yao KT, Liu MY, Li X, Huang JH, Cai HB. Retrospective clinical analysis on treatment of novel coronavirus-infected pneumonia with traditional Chinese medicine Lianhua-Qingwen. Chin J Exp Tradit Med Form 2020;???:1-7.
13. Sanders JM, Monogue MM, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 2020;???:6019.
14. Wu R, Wang L, Kuo HD, Shannar A, Peter R, Chou PJ, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep 2020;???:1-15.
15. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, 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 2020;71:732-9.
16. Savarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006;6:67-9.
17. 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;14:72-3.
18. Zhou D, Dai SM, Tong Q. COVID-19: A recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J Antimicrob Chemother 2020;75:1667-70.
19. Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Br J Rheumatol 1997;36:799-805.
20. Schultz KR, Gilman AL. The lysosomotropic amines, chloroquine and hydroxychloroquine: A potentially novel therapy for graft-versus-host disease. Leuk Lymphoma 1997;24:201-10.
21. Mauthe M, Orhon I, Rocchi C, Zhou X, Luhr M, Hijlkema KJ, et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion. Autophagy 2018;14:1435-55.
22. Jorge A, Ung C, Young LH, Melles RB, Choi HK. Hydroxychloroquine retinopathy-Implications of research advances for rheumatology care. Nat Rev Rheumatol 2018;14:693-703.
23. Joyce E, Fabre A, Mahon N. Hydroxychloroquine cardiotoxicity presenting as a rapidly evolving biventricular cardiomyopathy: Key diagnostic features and literature review. Eur Heart J Acute Cardiovasc Care 2013;2:77-83.
24. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71.
25. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomized controlled trial. BMJ 2020;369:m1849.
26. Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, et al. Review: Hydroxychloroquine and chloroquine for treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis 2020;7:ofaa130.
27. Jun C, Danping L, Li L, Ping L, Qingnian X, Lu X, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49:215-9.
28. Thomas K, Sheikh K. Small Chloroquine Study Halted Over Risk of Fatal Heart Complications. New York: The New York Times; 2020. Available from: https://www.nytimes.com/2020/04/12/health/ chloroquine-coronavirus-trump.html.
29. Bhimraj A, Morgan RL, Shumaker AH, Lavergne V, Baden L, Cheng VC, et al. Infectious diseases society of America guidelines on the treatment and management of patients with COVID-19. Clin Infect Dis 2020;???:ciaa478.
30. Available from: https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-therandomised-evaluation-of-covid-19- therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinic¬al-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19.
31. Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med 2020;383:517-25.
32. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020;56:105949.
33. Ishaqui AA, Khan AH, Sulaiman SA, Alsultan MT, Khan I, Naqvi AA. Assessment of efficacy of oseltamivir-azithromycin combination therapy in prevention of influenza-A (H1N1)pdm09 infection complications and rapidity of symptoms relief. Expert Rev Respir Med 2020;14:533-41.
34. Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci USA. 2016;113:14408-13.
35. Bacharier LB, Guilbert TW, Mauger DT, Boehmer S, Beigelman A, Fitzpatrick AM, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: A randomized clinical trial. JAMA 2015;314:2034-44.
36. Madrid PB, Panchal RG, Warren TK, Shurtleff AC, Endsley AN, Green CE, et al. Evaluation of Ebola virus inhibitors for drug repurposing. ACS Infect Dis 2015;1:317-26.
37. Rosenberg ES, Dufort EM, Udo T, Wilberschied LA, Kumar J, Tesoriero J, et al. Association of treatment with HCQ or AZT with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020;24:2493-502.
38. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med 2012;366:1881-90.
39. World Health Organization. Coronavirus disease (COVID-19) Technical Guidance: Patient Management. Geneva: World Health Organization; 2019. Available from: https://www.who.int/emergencies/diseases/ novelcoronavirus-2019/technical-guidance/patient-management. [Last accessed on 2020 Apr 15].
40. Indian Council of Medical Research. Advisory on the Use of Hydroxy- Chloroquineas Prophylaxis forSARS- CoV-2 Infection. New Delhi: Indian Council of Medical Research; 2020.Available from: https: // www. mohfw. gov.inpdf/ Advisory on the use of hydroxychloroquine as prophylaxis for SARS COVID19 infection.pdf. [Last accessed on 2020 May 06].
41. Multicenter Collaboration Group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for Chloroquine in the Treatment of novel coronavirus Pneumonia. Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:185-8.
42. Food and Drug Administration. Fact Sheet for Health Care Providers. Emergency Use Authorization (EUA) of Hydroxyl Chloroquine Sulfate Supplied from the Strategic National Stockpile for Treatment of COVID-19 in Certain Hospitalized Patients. United States: Food and Drug Administration; 2020. Available from: https://www.fda.gov/ media/136537/download. [Last accessed on 2020 May 06].
43. Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, 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;60:1648-61.
44. Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531:381-5.
45. Jacobs M, Rodger A, Bell DJ, Bhagani S, Cropley I, Filipe A, et al. Late Ebola virus relapse causing meningoencephalitis: A case report. Lancet 2016;388:498-503.
46. Sheahan TP, Sims AC, Leist SR, Schafer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.
47. Scavone C, Brusco S, Bertini M, Sportiello L, Rafaniello C, Zoccoli A, et al. Current pharmacological treatments for COVID-19: What’s next? Br J Pharmacol 2020;???:15072.
48. de Wit E, Feldmann F, Cronin J, Jordan R, Okumura A, Thomas T, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci USA 2020;117:6771-6.
49. National Institutes of Health. Potential Antiviral Drugs under Evaluation for the Treatment of COVID-19; 2020. Available from: https://www. covid19treatmentguidelines.nih.gov/antiviral-therapy. [Last accessed on 2020 May 14].
50. Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Gotte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 2020;295:4773-9.
51. 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.
52. National Library of Medicine-National Institutes of Health. Mild/ Moderate 2019-nCoV Remdesivir RCT. United States: NIH; 2020. Available from: https://www.clinicaltrials.gov/ct2/show/ NCT04252664.
53. National Library of Medicine-National Institutes of Health. Severe 2019-nCoV Remdesivir RCT. United States: NIH; 2020. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04257656.
54. Grein J, Ohmagari N, Shin D, Diaz G, Asperges E, Castagna A, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020;382:2327-36.
55. Wang Y, Zhang D, Du G, Du R, Zhou J, Jin Y, et al. Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-78.
56. US Food and Drug Administration. Letter of Emergency Use Authorization (EUA) for Emergency Use of Remdesivir for the Treatment of Hospitalized 2019 Coronavirus Disease (COVID-19) Patients, to Gilead Sciences, Inc.; 2020. Available from: https://www. fda.gov/media/137564/download. [Last accessed on 2020 May 06].
57. National Institutes of Health. Covid-19 Treatment Guidelines: Remdesivir; 2020. Available from: https://www. covid19treatmentguidelines.nih.gov/antiviral-therapy/remdesivir.
58. Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the treatment of Covid-19-Preliminary report. N Engl J Med 2020;1:NEJMoa2007764.
59. Clinical Management Protocol Covid 19. Government of India Ministry of Health and Family welfare. Version 5; 2020. Available from: https://www.mohfw.gov.in/pdf/ UpdatedClinicalManagementProtocolforCOVID19dated03072020.pdf.
60. Du YX, Chen XP. Favipiravir: Pharmacokinetics and concerns about clinical trials for 2019-nCoV infections. Clin Pharmacol Ther 2020;108:242-7.
61. Furuta Y, Gowen BB, Takahashi K, Shiraki K, Smee DF, Barnard DL. Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antiviral Res 2013;100:446-54.
62. De Clercq E. New nucleoside analogues for the treatment of hemorrhagic fever virus infections. Chem Asian J 2019;14:3962-8.
63. Shiraki K, Daikoku T. Favipiravir, an anti-influenza drug against life-threatening RNA virus infections. Pharmacol Ther 2020;209:107512.
64. 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;93:449-63.
65. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, et al. Favipiravir Versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv; 2020.
66. Kalantri SP, Thakur D. The DCGI has Granted Approval for Use of the Drug to Treat Mild COVID-19 Patients, But on What Basis? Available from: https://www.thehindu.com/opinion/op-ed/the-many-questions-about-favipiravir/article31908725.ece.
67. Glenmark Gets Regulatory Approval for Favipiravir to Treat Covid-19. Available from: https://www.pharmaceutical-technology.com/news/ glenmark-favipiravir-covid-nod.
68. Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med 2020;18:164.
69. Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 2020;117:10970-5.
70. Genentech. Actemra (Tocilizumab). South San Francisco, CA: Genentech, Inc.; 2019. Available from: https://www.accessdata.fda. gov/drugsatfda_docs/label/2019/125276s127,125472s040lbl.pdf. [Last accessed on 2020 Mar 17].
71. Luo P, LiuY, Qiu L, Liu X, Liu D, Li J, et al. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92:814-8.
72. Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020;38:529-32.
73. Toniati O, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, et al. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmune Rev 2020;19:102568.
74. Guaraldi G, Meschiari M, Cozzi-Lepri A, Milic J, Tonelli R, Menozzi M, et al. Tocilizumab in patients with severe COVID-19: A retrospective cohort study. Lancet Rheumatol 2020;2:E474-84.
75. Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis 2020;???:ciaa954.
76. The Hindu. Tocilizumab Fails to Address COVID-19 Pneumonia. Chennai, Tamil Nadu: The Hindu; 2020. Available from: https://www. thehindu.com/sci-tech/health/tocilizumab-fails-to-address-covid-19- pneumonia/article32224050.ece.
77. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395:10223:473-5.
78. Villar J, Belda J, Anon JM, Blanco J, Perez-Mendez L, Ferrando C, et al. Evaluating the efficacy of dexamethasone in the treatment of patients with persistent acute respiratory distress syndrome: Study protocol for a randomized controlled trial. Trials 2016;17:342.
79. Alhazzani W, Meller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al.Surviving sepsis campaign: Guidelines on the management of critically ill adults with coronavirus disease 2019(COVID-19). Crit Care Med 2020;48:6:440.
80. National Institute of Health Research. Published 2020 June 16. Available from: https://www.nihr.ac.uk/news/first-drug-to-reduce-mortality-in-hospitalised-patients-with-respiratory-complications-of-covid-19-found/25061.
81. Villar J, Ferrando C, Martinez D, Ambros A, Munoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: A multicentre, randomised controlled trial. Lancet Respir Med 2020;8:3:267-76.
82. Zha L, Li S, Pan L, Tefsen B, Li Y, French N, et al. Corticosteroid treatment of patients with coronavirus disease 2019(COVID-19). Med J Aust 2020;212:9:416-20.
83. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, 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 2020;1:e200994.
84. Villar J, Confalonieeri M, Pastores M, Meduri GU. Rationale for prolonged corticosteroid treatment in the acute respiratory distress syndrome caused by coronavirus disease 2019. Crit Care Explor 2020;2:4:e0111.
85. RECOVERY. Randomized Evaluation of Covid 19 Therapy. Low-cost Dexamethasone Reduces Death by up to One Third in Hospitalised Patients with Severe Respiratory Complications of COVID-19. Available from: https://www.recoverytrial.net/news.
86. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Available from: https:// www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management. [Last accessed on 2020 Jun 25].
87. Important to Use Dexamethasone Only for Serious COVID Cases WHO. Available from: https://www.reuters.com/article/us-health-coronavirus-who-dexamethasone/important-to-use-dexamethasone-only-for-serious-covid-cases-who-idUSKBN23O2MT. [Last accessed on 2020 Jul 08].
88. World Health Organization. Director General’s Opening Remarks at the Media Briefing on COVID-19. Available from: https://www.who. int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19. [Last accessed on 2020 Jun 22].
89. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med 2020;382:1787-99.
90. Ye XT, Luo Y, Xia S, Sun Q, Ding J, Zhou Y. Clinical efficacy of lopinavir/ritonavir in the treatment of Coronavirus disease 2019. Eur Rev Med Pharmacol Sci 2020;24:3390-6.
91. Kim JW, Kim EJ, Kwon HH, Jung CY, Kim KC, Choe JY. Lopinavir-ritonavir versus hydroxychloroquine for viral clearance and clinical improvement in patients with mild to moderate coronavirus disease 2019. Korean J Intern Med 2020;1:224.
92. Osborne V, Davies M, Lane S, Evans A, Denyer J, Dhanda S, et al. Lopinavir-ritonavir in the treatment of COVID-19: A dynamic systematic benefit-risk assessment. Drug Saf 2020;43:809-21.
93. RECOVERY Randomized Evaluation of Covid 19 Therapy. Available from: https://www.recoverytrial.net/news/no-clinical-benefit-from-use-of-lopinavir-ritonavir-in-hospitalised-covid-19-patients-studied-in-recovery. [Last accessed on 2020 Jul 08].
94. On behalf of the Oxford Covid-19 Evidence Service Team. Centre for Evidence Based Medicine, Nuffield Department of Primary Care Health Sciences. Available from: https://www.cebm.net/covid-19/ lopinavir-ritonavir-a-rapid-review-of-the-evidence-for-effectiveness-in-treating-covid. [Last accessed on 2020 Jul 14].
95. World Health Organization. Geneva. Available from: https:// www.who.int/news-room/detail/04-07-2020-who-discontinues-hydroxychloroquine-and-lopinavir-ritonavir-treatment-arms-for-covid-19.
96. Markowitz CE. Interferon beta: Mechanism of action and dosing issues. Neurology 2007;68:s8-11.
97. Pereda R, Gonzalez D, Rivero H, Rivero J, Perez A, del Rosario Lopez L, et al. Therapeutic effectiveness of interferon-alpha2b against COVID-19: The Cuban experience. Available from: https://www. medrxiv.org/content/10.1101/2020.05.29.20109199v1.
98. Zhou Q, Chen V, Shannon CP, Shan X, Xiang X, Wang X. Interferon- ?2b treatment for COVID-19. Front Immunol 2020;11:1061.
99. World Health Organization. Geneva. Available from: https://www.who. int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19- treatments.
100.Toumi M, Liang S, Dabbous M, Wang Y, Qiu T, Han R. COVID-19: Why SOLIDARITY and DisCoVeRy Trials may Fail to Bring Informative and Timely Results. medRxiv; 2020.
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.