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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 64
| Issue : 6 | Page : 112-116 |
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Potential pharmacological agents for COVID-19
Anita Kotwani1, Sumanth Gandra2
1 Professor, Department of Pharmacology, V. P. Chest Institute, University of Delhi, Delhi, India
2 Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, Missouri, USA
| Date of Web Publication | 2-Jun-2020 |
Correspondence Address:
Anita Kotwani
Department of Pharmacology, V. P. Chest Institute, University of Delhi, Delhi - 110 007
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijph.IJPH_456_20
 Abstract | | |
A novel coronavirus disease 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) first emerged in December 2019 in Wuhan, China, has become a global pandemic. Currently, the management of COVID-19 infection is mainly supportive. Several clinical trials worldwide are evaluating several drugs approved for other indications, as well as multiple investigational agents for the treatment and prevention of COVID-19. Here, we give a brief overview of pharmacological agents and other therapies which are under investigation as treatment options or adjunctive agents for patients infected with COVID-19 and for chemoprophylaxis for the prevention of COVID-19 infection. At the time of writing this commentary, there is no peer-reviewed published evidence from randomized clinical trials of any pharmacological agents improving outcomes in COVID-19 patients. However, it was reported that remdesivir an investigational antiviral agent hastens clinical recovery, but a study is yet to be published in peer-reviewed medical journal.
Keywords: Adjunctive therapy, coronavirus disease 2019, investigational antiviral agents, potential pharmacological agents, severe acute respiratory syndrome coronavirus 2
How to cite this article:
Kotwani A, Gandra S. Potential pharmacological agents for COVID-19. Indian J Public Health 2020;64, Suppl S2:112-6 |
| Introduction | |  |
A novel coronavirus disease 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) first emerged in December 2019 in Wuhan, China, has become a global pandemic.[1] Management of COVID-19 infection consists of supportive care; however, several clinical trials worldwide are evaluating drugs approved for other indications, as well as multiple investigational agents for the treatment and prevention of COVID-19. Here, we give a brief overview of pharmacological agents and other therapies which are under investigation as treatment options or adjunctive agents for patients infected with COVID-19.
| Severe Acute Respiratory Syndrome Coronavirus 2 Life Cycle | | |
SARS-CoV-2 is a single-stranded RNA-enveloped virus which binds to the angiotensin-converting enzyme 2 receptor of the target cells using its structural spike protein (S).[2],[3] Inside the host cell, the RNA is released and translated into viral polymerase proteins. Then, viral RNA is synthesized using the RNA polymerase. Subsequently, viral structural proteins (S, M, and E) are synthesized which are then assembled with genome RNA and released from the host cell.[2] The various steps in lifecycle provide targets for investigational drugs.
| Investigational Antiviral Drugs for Coronavirus Disease 2019 | | |
Chloroquine or Hydroxychloroquine
Chloroquine, an antimalarial agent, and its derivative hydroxychloroquine, used for the treatment of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, have shown to be active against COVID-19 in vitro.[4]
Mechanism of action
It prevents fusion of the SARS-CoV-2 to host cell membrane[4] and blocks the release of SARS-CoV-2 viral genome.[5]
Randomized clinical trial data
Only few randomized clinical trials (RCTs) are reported so far which included patients with mild or moderate COVID-19 infection. All studies are limited by small number of patients, short follow-up, and relatively healthy young patients, or the results were not statistically significant between the two groups.[6] In one study in China involving 62 patients, hydroxychloroquine plus standard of care was compared to standard of care alone.[7] None of the hydroxychloroquine-treated patients (0/31) had progression of infection, whereas 13% of patients (4/31) who received standard care had progressed onto have severe infection. One study involving 30 patients in China showed no difference in time for clearance of virus from upper respiratory tract (primary outcome) in hydroxychloroquine group compared to control group.[8] Currently, there are insufficient data to recommend for or against the use of chloroquine or hydroxychloroquine for the treatment of COVID-19 infection; however, several RCTs are ongoing.[9] There are no studies reporting on chemoprophylaxis for COVID-19 infection using chloroquine or hydroxychloroquine; however, RCTs are ongoing.[9]
Major adverse effects
Although hydroxychloroquine has less toxic potential than chloroquine, both can cause QT prolongation leading to life-threatening arrhythmias. Others include hypoglycemia and rash. Long-term use could lead to bone marrow suppression and retinopathy.
Hydroxychloroquine and azithromycin combination
RCT data for the combination of hydroxychloroquine and azithromycin are not available; however, several RCTs are ongoing.[10] Two case series were reported in France, one reporting benefit[11] and other no benefit.[12] Currently, this combination should be used only in the setting of clinical trial as routine use could lead to severe adverse events with QT prolongation.
Lopinavir/ritonavir
Lopinavir/ritonavir is an approved drug for the treatment of HIV and has been shown to be effective against other novel CoVs such as SARS CoV-1 and Middle East respiratory syndrome CoV (MERS Co-V) in vitro.[13],[14] A recent study indicatedin vitro activity of lopinavir against SARS-CoV-2.[15]
Mechanism of action
It inhibits 3-chymotrypsin-like protease enzyme, which is conserved in SARS-CoV-2.[16]
Randomized clinical trial data
One well-done RCT involving 199 patients in China compared clinical outcomes among hospitalized patients with severe COVID-19 infection with lopinavir/ritonavir and standard of care.[17] Although the mortality was lower (19.2% vs. 25%) and length of intensive care unit (ICU) stay was shorter (6 days vs. 11 days) in the lopinavir/ritonavir group compared to standard of care, it was not statistically significant. In a second study, involving 86 patients with mild or moderate COVID-19 infection in China, lopinavir/ritonavir was compared to Arbidol (also known as Umifenovir) and standard of care in 2:2:1 design.[18] The results indicated no benefit in clinical outcomes with lopinavir/ritonavir or Arbidol compared to standard of care. Additional RCTs are ongoing.[19] Currently, routine use of lopinavir/ritonavir is not recommended, and it should be only used in context of clinical trial.
Major adverse effects
Nausea, vomiting, diarrhea, and hepatotoxicity.
Remdesivir
Remdesivir is an intravenous adenosine nucleotide analog prodrug with activity against several RNA viruses including SARS CoV-1 and MERS Co-V.[20] It has demonstratedin vitro activity against SARS-CoV-2 as well.[21]
Mechanism of action
It inhibits the viral RNA-dependent RNA polymerase leading to premature termination of RNA transcription.[22]
Randomized clinical trial data
One well-conducted double-blinded RCT from China examined the outcomes in patients with severe COVID-19 disease.[23] In this study, 237 patients were enrolled and randomly assigned to a remdesivir (158 patients) or placebo (79 patients). The primary endpoint was the time to clinical improvement up to day 28. Patients who received remdesivir had a faster time to clinical improvement than those receiving placebo among patients with a duration of 10 days; however, it was not statistically significant (hazard ratio: 1.52 [0.95–2.43]).[23] Another RCT conducted by the Unites States National Institute of Health reported the results in a press release, but this study is not published in a peer-reviewed medical journal.[24] According to the press release, patients who received remdesivir had a 31% faster time to recovery than those who received placebo (median time to recovery 11 days with remdesivir vs. 15 days with placebo; P < 0.001). In addition, there was a trend for survival benefit (mortality rate of 8.0% in remdesivir group vs. 11.6% in placebo group [P = 0.059]). There are several other RCTs ongoing.[25] Considering the results of the United States National Institute of Health study, on May 1, 2020, the United States Food and Drug Administration issued an emergency use authorization for the use of remdesivir for the treatment of hospitalized COVID-19 patients.[26]
Major adverse effects
Nausea, vomiting, and elevated liver enzymes.
Favipiravir
Favipiravir is an approved drug for the treatment of influenza A in Japan[3] and China[27] with activity against several RNA viruses with pandemic potential.[28]
Mechanism of action
It inhibits the viral RNA-dependent RNA polymerase halting viral replication.[27]
Randomized clinical trial data
Limited RCT data is available. In one RCT in China, 240 hospitalized patients with moderate-to-severe COVID-19 were randomized to favipiravir or Arbidol.[29] There was no significant difference in the primary outcome which was clinical recovery rate at 7 days (61% in favipiravir vs. 52% in Arbidol; P = 0.14).[29] There are currently insufficient data to recommend either for or against the use of favipiravir for the treatment of COVID-19. Currently, an RCT using favipiravir is planned in India.[30]
Major adverse effects
Nausea, vomiting, elevated serum uric acid levels, and elevated liver enzymes.
Other antivirals
Arbidol (Umifenovir) is an antiviral agent currently approved in Russia and China for the treatment and prophylaxis of influenza.[3],[27] In RCTs which included Arbidol, it did not show benefit over standard of care[18] or with other agent such as favipiravir;[18],[29] however, other trials are ongoing.
Ribavirin has known antiviral activity and has been proposed as one of the potential agents against SARS-CoV-2 and several RCTs are ongoing.[31] However, the major limitation with it is the adverse effects (hepatotoxicity, hemolytic anemia, and teratogenicity).[3]
Oseltamivir which is currently approved for the treatment of influenza has limited role in the treatment of SARS-CoV-2.[3]
| Adjunctive Therapies for Coronavirus Disease 2019 | | |
Some adjunctive therapies for supportive care are currently under investigations or are used off-label. These agents may target the virus (e.g., convalescent plasma [CP]) or modulate the immune response (e.g., interleukin (IL)-1 or IL-6 inhibitors) or anti-inflammatory agents (corticosteroids).
Immunoglobulin therapy or convalescent plasma
CP is plasma collected from patients fully recovered from SARS-CoV-2 infection.[32] CP contains antibodies that could help clearing the free virus and the virus from the infected cells. A previous meta-analysis of observational studies showed reduction in mortality with convalescent plasma or hyperimmune immunoglobulin among SARS-CoV-1 and severe influenza infection.[33]
Mechanism of action
CP-derived antibodies can neutralize a virus by preventing replication or by binding without interfering with replication.[32]
Randomized clinical trial data
RCT data are not available at present. In case series of two studies with 5[34] and 10,[35] severely ill COVID-19 patients showed promising results. The clinical status of all patients had improved approximately 1 week after transfusion. In addition, the patients' neutralizing antibody titers increased after respiratory samples tested negative after transfusion. Many RCTs of CP for COVID-19 infections are underway in various countries.[36] Currently, routine use of CP therapy is not recommended for the treatment of COVID-19 outside the clinical trial setting.
Major adverse effects
Potential antibody-dependent enhancement of infection, transfusion-associated acute lung injury, and allergic transfusion reactions.[37]
| Anticytokine Agents | | |
A good amount of data from various studies indicate that cytokine storm plays an important role in severe cases of COVID-19. Therefore, monoclonal antibodies directed against key inflammatory cytokines represent other potential class of adjunctive therapy for COVID-19 infection.[38]
Interleukin-1 and Interleukin-6 inhibitors
SARS-Cov-2 infects the upper and lower respiratory tract and cause mild or highly acute respiratory syndrome with a release of preinflammatory cytokines, including IL-1 β and IL-6.[39] Similarly, the Janus kinase (JAK) family of enzymes regulate signal transduction in immune cells, and thus, JAK inhibitors could block the cytokine release. Therefore, IL-1, IL-6, and JAK inhibitors could overcome the systemic inflammation associated with severe COVID-19 illness.[40]
Mechanism of action
It inhibits the amplified immune response and cytokine release.[40]
Randomized clinical trial data
Currently, there is no RCT data examining the impact of IL-1, IL-6, and JAK inhibitors on COVID-19-infected patients. RCTs are underway for COVID-19 infection using Anakinra (recombinant human IL-1 receptor antagonist), recombinant humanized anti-IL-6 receptor monoclonal antibodies (tocilizumab, sarilumab), and siltuximab (recombinant human-mouse chimeric monoclonal antibody that binds IL-6).[41],[42] Currently, routine use of these agents is not recommended for the treatment of COVID-19 outside the clinical trial setting.
Major adverse effects
Risk of serious bacterial infections including tuberculosis.
| Interferons | | |
Interferons belong to the family of cytokines and have antiviral properties. However, significant toxicities (hematological toxicities, elevated liver enzymes, nausea, vomiting, and psychiatric problems) of interferons outweigh the potential benefit and thus are not recommended for treatment or as adjuvant therapy for COVID-19.[3] Currently, no RCT data as monotherapy are available.
| Corticosteroids | | |
Corticosteroids are currently not recommended as adjunctive therapy in patients with COVID-19, except in case of RCT.[21] The rationale for such recommendation is based on observational studies in patients with SARS CoV-1 and MERS Co-V that the benefit of decreasing the host inflammatory response in the lungs is outweighed by corticosteroids adverse effects, including delayed viral clearance, and increased risk of secondary infections, hyperglycemia, psychosis, and avascular necrosis.[3],[43],[44] However, patients with chronic diseases (such as primary or secondary adrenal insufficiency, rheumatological diseases, asthma, and chronic obstructive pulmonary disease) on chronic corticosteroid therapy (oral or inhalational) should not discontinue the therapy.[21]
| India Situation | | |
The Ministry of Health and Family Welfare (MoH&FW), Government of India, released their revised guidelines on clinical management of COVID-19 on March 31, 2020. Considering the available data at that time, it is suggested that for patients with severe disease and requiring ICU management, the combination of hydroxychloroquine and azithromycin may be considered as an off-label indication. The guidelines suggest that these drugs should be administered under close medical supervision with monitoring for side effects including QTc interval. This therapy is not recommended for children <12 years, pregnant, and lactating mothers.[45] The MoH&FW released an advisory (March 22, 2020) on the use of hydroxychloroquine as prophylaxis for SARS-CoV-2 infection based on the recommendation by the National Task Force for COVID-19 constituted by the Indian Council of Medical Research. The advisory provides for placing the following high-risk population under chemoprophylaxis with hydroxychloroquine for (i) asymptomatic health-care workers involved in the care of suspected or confirmed cases of COVID and (ii) asymptomatic household contacts of laboratory confirmed cases.[46]
Many centers in different states of India are engaged in RCTs evaluating treatment, prevention, and adjunctive therapies for the management of COVID-19.[47] These clinical trials are mainly evaluating hydroxychloroquine and chloroquine in the prevention of new infection and adverse outcomes and effect of chloroquine in addition to standard therapy in COVID-19 patients. The World Health Organization's Solidarity trial involving four treatment options (remdesivir, chloroquine or hydroxychloroquine, lopinavir with ritonavir, and lopinavir with ritonavir plus interferon) comparing standard of care for hospitalized patients with COVID-19 infection is also ongoing.[47],[48] Some other clinical trials include evaluating the effect of Ayurveda and homeopathy agents on the prevention of COVID-19, the efficacy of recombinant Bacillus Calmette–Guerin vaccine in reducing infection incidence and disease severity of COVID-19 and the efficacy and safety of convalescent plasma therapy in severely sick COVID-19 patients at many centers.[47]
| Conclusion | | |
The COVID-19 pandemic is an ongoing public health crisis for which effective therapeutic agents are urgently needed. At the time of writing this commentary, there is no peer-reviewed published evidence from randomized clinical trials of any pharmacological agents improving outcomes in COVID-19 patients. Globally, several clinical trials involving repurposed and novel pharmacological agents for the treatment of COVID-19 are ongoing and thus recommendations may change with new evidence. The positive results of remdesivir against COVID-19 are encouraging; however, the findings from other ongoing remdesivir trials will be critical in establishing its therapeutic efficacy against COVID-19 infection.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed 2020;91:157-60.  |
| 2. | Jiang S, Hillyer C, Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol 2020;41:355-9. |
| 3. | Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. JAMA 2020;323:1824-36. |
| 4. | 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. |
| 5. | Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6:16. |
| 6. | Huang M, Tang T, Pang P, Pang P, Li M, Ma R, et al. Treating COVID-19 with chloroquine. J Mol Cell Biol 2020;12:322-5. |
| 7. | Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv 2020. (Preprint) doi: https://doi.org/10.1101/2020.03.22.20040758. |
| 8. | Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Uni Med Sci 2020;49:215-9. |
| 9. | |
| 10. | |
| 11. | Gautret P, Lagier JC, Parola P, Hoong VT, Neddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020;34:101663. |
| 12. | Molina JM, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection. Med Mal Infect 2020;50:384. pii: S0399-077X (20) 30085-8. |
| 13. | Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH, Chan KS, et al. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax 2004;59:252-6. |
| 14. | de Wilde AH, Jochmans D, Posthuma CC, Zevenhoven-Dobbe JC, van Nieuwkoop S, Bestebroer TM, 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;58:4875-84. |
| 15. | Choy KT, Wong AY, Kaewpreedee P, Sia SF, Chen D, Hui KPY, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 2020;178:104786. |
| 16. | Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines. J Genet Genomics 2020;47:119-21. |
| 17. | 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. |
| 18. | Li Y, Xie Z, Lin W, Cai W, Wen C, Guan Y, et al. An Exploratory Randomized, Controlled Study on the Efficacy and Safety of Lopinavir/Ritonavir or Arbidol Treating Adult Patients Hospitalized with Mild/Moderate COVID-19 (ELACOI). MedRxiv; 2020. |
| 19. | |
| 20. | Ko WC, Rolain JM, Lee NY, Chen PL, Huang CT, Lee PI, et al. Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 2020;55:105933. |
| 21. | |
| 22. | Liu W, Morse JS, Lalonde T, Xu S. Learning from the past: Possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. Chembiochem 2020;21:730-8. |
| 23. | Wang Y, Zhang D, Du G, Du R, Zhao 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. |
| 24. | |
| 25. | |
| 26. | |
| 27. | Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther 2020;14:58-60. |
| 28. | Delang L, Abdelnabi R, Neyts J. Favipiravir as a potential countermeasure against neglected and emerging RNA viruses. Antiviral Res 2018;153:85-94. |
| 29. | Chen C, Huang J, Cheng Z, Yin P, Cheng Z, Wu J, et al. Favipiravir Versus Arbidol for COVID-19: A Randomized Clinical Trial. MedRxiv; 2020. |
| 30. | |
| 31. | Khalili JS, Zhu H, Mak A, Yan Y, Zhu Y. Novel coronavirus treatment with ribavirin: Groundwork for evaluation concerning COVID-19. J Med Virol 2020;1-7 (online). doi: 10.1002/jmv.25798. |
| 32. | Bloch EM, Shoham S, Casadevall A, Sachais BS, Shaz B, Winters JL, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Inv 2020. (In press). https://doi:org/10.1172/JCI 138745. |
| 33. | Mair-Jenkins J, Saavedra-Campos M, Baillie JK, Cleary P, Khaw FM, Lim WS, et al. 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;211:80-90. |
| 34. | Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA 2020;323:1582-9. |
| 35. | Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020;117:9490-6. |
| 36. | |
| 37. | Narick C, Triulzi DJ, Yazer MH. Transfusion-associated circulatory overload after plasma transfusion. Transfusion 2012;52:160-5. |
| 38. | Zhang C, Wu Z, Li J-W, Zhao H, Wang G-Q. The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J Antimicrob Agents 2020:105954. (pre-proof). |
| 39. | Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34. pii: 1. |
| 40. | Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4. |
| 41. | |
| 42. | |
| 43. | Arabi YM, Mandourah Y, Al-Hameed F, Sindi AA, Almekhlafi GA, Hussein MA, et al. Corticosteroid therapy for critically ill patients with Middle East respiratory syndrome. Am J Respir Crit Care Med 2018;197:757-67. |
| 44. | Stockman LJ, Bellamy R, Garner P. SARS: Systematic review of treatment effects. PLoS Med 2006;3:e343. |
| 45. | |
| 46. | |
| 47. | |
| 48. | |
|
