Synthetic and Herbal Drugs Registered in Clinical Trials on COVID-19: a Review on Recent Research

Document Type : Review Article

Authors

1 Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran

2 Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

Abstract

COVID-19 emerged as a widespread worldwide ailment in 2019, with a continued breakdown of novel gamma and lambda variants. Given the high incidence of COVID-19 even in the vaccinated people, research is in progress to develop convenient used drugs to control coronavirus disease. Herein, to review the effectiveness and safety of the recent antiviral, antibacterial, and herbal medication utilized to treat COVID-19, electronic databases including Scopus, PubMed, and Cochrane Library were compiled from papers registered in clinical trials on COVID-19 from January 2021 to February 2022. Oseltamivir, remdesivir, ivermectin, casirivimab, imdevimab, sotrovimab, Tocilizumab, sarilumab, dexamethasone, methylprednisolon, paxlovid, fluvoxamine, molnupiravir, ruxolitinib, tofacitinib, baricitinib, favipiravir, molnupiravir, azithromycin, niclosamide, nitazoxanide, and tetracyclines are the most commonly used antiviral and antibiotics to control mild to severe COVID-19 illnesses in the clinic. Despite the efficacy of drugs solely and in combination, medicinal herbs and natural products were considered in some clinical trials due to the high cost and unwanted side effects. However, no substantial evidence has been reported to confirm the significant anti-COVID-19 impact of synthetic and herbal medicines. This scenario opens an exciting new perspective for the elucidation of convenient therapeutic pipelines.

Keywords

Main Subjects


Abd-Elsalam, S., Esmail, E. S., Khalaf, M., Abdo, E. F., Medhat, M. A., Abd El Ghafar, M. S., ... & Alboraie, M. (2020). Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. American Journal of Tropical Medicine and Hygiene, 103(4), 1635-1639. https://doi.org/10.4269%2Fajtmh.20-0873.
Abd‐Elsalam, S., Noor, R. A., Badawi, R., Khalaf, M., Esmail, E. S., Soliman, S., ... & Esmat, G. (2021). Clinical study evaluating the efficacy of ivermectin in COVID‐19 treatment: a randomized controlled study. Journal of Medical Virology, 93(10), 5833-38. https://doi.org/10.1002/jmv.27122.
Ader, F., Bouscambert-Duchamp, M., Hites, M., Peiffer-Smadja, N., Poissy, J., Belhadi, D., ... & Ribeiro, J. M. F. (2022). Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. The Lancet Infectious Diseases, 22(2), 209-221. https://doi.org/10.1016/S1473-3099(21)004-85-0.
Al-Kuraishy, H. M., Al-Fakhrany, O. M., Elekhnawy, E., Al-Gareeb, A. I., Alorabi, M., De Waard, M., ... & Batiha, G. E. S. (2022). Traditional herbs against COVID-19: back to old weapons to combat the new pandemic. European Journal of Medical Research, 27(1), 186. https://doi.org/10.1186/s40001-022-00818-5.
Angriman, F., Ferreyro, B. L., Burry, L., Fan, E., Ferguson, N. D., Husain, S., ... & Del Sorbo, L. (2021). Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context. The Lancet Respiratory Medicine, 9(6), 655-664. https://doi.org/10.1016/S2213-2600(21)001-39-9.
Arevalo, A. P., Pagotto, R., Pórfido, J., Daghero, H., Segovia, M., Yamasaki, K., … & Crispo, M. (2020). Ivermectin reduces coronavirus infection in vivo: a mouse experimental model. BioRxiv, 11(1), 7132. https://doi.org/10.1101/2020.11.02.363242.
Barrows, N. J., Campos, R. K., Powell, S. T., Prasanth, K. R., Schott-Lerner, G., Soto-Acosta, R., ... & Garcia-Blanco, M. A. (2016). A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host and Microbe, 20(2), 259-270. https://doi.org/10.1016/j.chom.2016.07.004.
Borujerdi, R., Adeli, S. H., Mohammadbeigi, A., Aliasl, F., Asghari, A., Hormati, A., ... & Asghari, M. (2022). Effects of Iranian Polyherbal Syrup (Zufa syrup) on oxygen saturation and clinical symptoms in suspected patients with COVID-19: a triple-blinded, randomized, placebo-controlled trial. Medical Gas Research, 12(2), 44-50. https://doi.org/10.4103/2045-9912.325991.
Brown, M. J., Alazawi, W., & Kanoni, S. (2021). Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. New England Journal of Medicine, 385(12), 1147-1149. https://doi.org/10.1056/nejmc2108482.
Bryant, A., Lawrie, T. A., Dowswell, T., Fordham, E. J., Mitchell, S., Hill, S. R., & Tham, T. C. (2021). Ivermectin for prevention and treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform clinical guidelines. American Journal of Therapeutics, 28(4), e434. https://doi.org/10.1097%2FMJT.0000000000001402.
Buonfrate, D., Chesini, F., Martini, D., Roncaglioni, M. C., Fernandez, M. L. O., Alvisi, M. F., ... & Bisoffi, Z. (2022). High-dose ivermectin for early treatment of COVID-19 (COVER study): a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. International Journal of Antimicrobial Agents, 59(2), 106516. https://doi.org/https://doi.org/10.1016/j.ijantimicag.2021.106516.
Calusic, M., Marcec, R., Luksa, L., Jurkovic, I., Kovac, N., Mihaljevic, S., & Likic, R. (2022). Safety and efficacy of fluvoxamine in COVID‐19 ICU patients: an open label, prospective cohort trial with matched controls. British Journal of Clinical Pharmacology, 88(5), 2065-2073. https://doi.org/10.1111/bcp.15126.
Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., ... & Wang, C. (2020). A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New England Journal of Medicine, 382(19), 1787-1799. http://doi.org/10.1056/NEJMoa2001282.
Capuano, A., Rossi, F., & Paolisso, G. (2020). Covid-19 kills more men than women: an overview of possible reasons. Frontiers in Cardiovascular Medicine, 7, 131. https://doi.org/10.3389/fcvm.2020.00131.
Cascella, M., Rajnik, M., Aleem, A., Dulebohn, S. C., & Di Napoli, R. (2023). Features, evaluation, and treatment of coronavirus (COVID-19). StatPearls, Treasure Island.
Chen, C., Huang, J., Yin, P., Zhang, Y., Cheng, Z., Wu, J., ... & Wang, X. (2020a). Favipiravir versus arbidol for COVID-19: a randomized clinical trial. MedRxiv, 2020-03. https://doi.org/10.1101/2020.03.17.20037432.
Chen, J., Xia, L., Liu, L., Xu, Q., Ling, Y., Huang, D., ... & Lu, H. (2020b). Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infectious Diseases, 7(7), ofaa241. https://doi.org/10.1093/ofid/ofaa241.
Ci, X., Li, H., Yu, Q., Zhang, X., Yu, L., Chen, N., ... & Deng, X. (2009). Avermectin exerts anti‐inflammatory effect by downregulating the nuclear transcription factor kappa‐B and mitogen‐activated protein kinase activation pathway. Fundamental and Clinical Charmacology, 23(4), 449-455. https://doi.org/10.1111/j.1472-8206.2009.0-0684.x.
Consortium, W. S. T. (2020). Repurposed antiviral drugs for COVID-19-interim WHO SOLIDARITY trial results. New England Journal of Medicine, 384(6), 497-511. http://doi.org/10.1056/NEJMoa2023184.
Cox, M. J., Loman, N., Bogaert, D., & O'Grady, J. (2020). Co-infections: potentially lethal and unexplored in COVID-19. The Lancet Microbe, 1(1), e11. https://doi.org/10.1016/S2666-5247(20)300-09-4.
Dhawan, M., Parmar, M., Sharun, K., Tiwari, R., Bilal, M., & Dhama, K. (2021). Medicinal and therapeutic potential of withanolides from Withania somnifera against COVID-19. Journal of Applied Pharmaceutical Science, 11(4), 6-13. http://doi.org/10.7324/JAPS.2021.110402.
Di Castelnuovo, A., Costanzo, S., Antinori, A., Berselli, N., Blandi, L., Bonaccio, M., ... & COVID-19 RISK and Treatments (CORIST) Collaboration. (2021). Lopinavir/ritonavir and darunavir/cobicistat in hospitalized COVID-19 patients: findings from the multicenter Italian CORIST study. Frontiers in Medicine, 8, 639970. https://doi.org/10.3389/fmed.2021.639970.
Ding, X. J., Zhang, Y., He, D. C., Zhang, M. Y., Tan, Y. J., Yu, A., ... & Liu, L. (2020). Clinical effect and mechanism of Qingfei Touxie Fuzheng recipe in the treatment of novel coronavirus pneumonia. Herald Med, 39(05), 640-644. 10.3870/j.issn.1004-0781.2020.05.012.
DiNicolantonio, J. J., Barroso-Arranda, J., & McCarty, M. (2020). Ivermectin may be a clinically useful anti-inflammatory agent for late-stage COVID-19. Open Heart, 7(2), e001350. http://doi.org/10.1136/openhrt-2020-001350.
Ebina-Shibuya, R., Namkoong, H., Horita, N., Kato, H., Hara, Y., Kobayashi, N., & Kaneko, T. (2021). Hydroxychloroquine and chloroquine for treatment of coronavirus disease 19 (COVID-19): a systematic review and meta-analysis of randomized and non-randomized controlled trials. Journal of Thoracic Disease, 13(1), 202-212. https://doi.org/10.21037%2Fjtd-20-2022.
Echeverría-Esnal, D., Martin-Ontiyuelo, C., Navarrete-Rouco, M. E., De-Antonio Cuscó, M., Ferrández, O., Horcajada, J. P., & Grau, S. (2021). Azithromycin in the treatment of COVID-19: a review. Expert Review of Anti-infective Therapy, 19(2), 147-163. https://doi.org/10.1080/14787210.2020.1813024.
Fallah, A., Razavi Nikoo, H., Abbasi, H., Mohammad-Hasani, A., Hosseinzadeh Colagar, A., & Khosravi, A. (2022). Features of pathobiology and clinical translation of approved treatments for coronavirus disease 2019. Intervirology, 65(3), 119-133. https://doi.org/10.1159/000520234
Fang, J., Li, H., Du, W., Yu, P., Guan, Y. Y., Ma, S. Y., ... & Bian, X. L. (2020). Efficacy of early combination therapy with lianhuaqingwen and arbidol in moderate and severe COVID-19 patients: a retrospective cohort study. Frontiers in Pharmacology, 11, 1465. https://doi.org/10.3389/fphar.2020.560209.
Farooq, S. and Ngaini, Z., (2021). Natural and synthetic drugs as potential treatment for coronavirus disease 2019 (COVID-2019). Chemistry Africa, 4(1), 1-13. https://doi.org/10.1007/s42250-020-00203-x
Fischer, W., Eron Jr, J. J., Holman, W., Cohen, M. S., Fang, L., Szewczyk, L. J., ... & Painter, W. P. (2021). Molnupiravir, an oral antiviral treatment for COVID-19. MedRxiv, 2021.06.17.21258639. https://doi.org/10.1126/scitranslmed.abl7430.
Gautret, P., Lagier, J. C., Honoré, S., Colson, P., & Raoult, D. (2021). Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial revisited. International Journal of Antimicrobial Agents, 57(1), 106243. https://doi.org/10.1016%2Fj.ijantimicag.2020.106243.
Giollo, A., Adami, G., Gatti, D., Idolazzi, L., & Rossini, M. (2020). Coronavirus disease 19 (Covid-19) and non-steroidal anti-inflammatory drugs (NSAID). Annals of the Rheumatic Diseases, 80(2), e12.  https://doi.org/10.1136/annrheumdis-2020-217598.
Group, R. C. (2021). Dexamethasone in hospitalized patients with Covid-19. New England Journal of Medicine, 384(8), 693-704. http://doi.org/10.1056/NEJMoa2021436.
Guimarães, P. O., Quirk, D., Furtado, R. H., Maia, L. N., Saraiva, J. F., Antunes, M. O., ... & Berwanger, O. (2021). Tofacitinib in patients hospitalized with COVID-19 pneumonia. New England Journal of Medicine, 385(5), 406-415. http://doi.org/10.1056/NEJMoa2101643.
Gupta, A., Gonzalez-Rojas, Y., Juarez, E., Crespo Casal, M., Moya, J., Falci, D. R., ... & Shapiro, A. E. (2021). Early treatment for Covid-19 with SARS-CoV-2 neutralizing antibody sotrovimab. New England Journal of Medicine, 385(21), 1941-1950. http://doi.org/10.1056/NEJMoa2107934.
Gyselinck, I., Janssens, W., Verhamme, P., & Vos, R. (2021). Rationale for azithromycin in COVID-19: an overview of existing evidence. BMJ Open Respiratory Research, 8(1), e000806. http://doi.org/10.1136/bmjresp-2020-000806.
Hamilton, F. W., Lee, T., Arnold, D. T., Lilford, R., & Hemming, K. (2021). Is convalescent plasma futile in COVID-19? a Bayesian re-analysis of the RECOVERY randomized controlled trial. International Journal of Infectious Diseases, 109, 114-117. https://doi.org/10.1016/j.ijid.2021.06.034.
Hermine, O., Mariette, X., Porcher, R., Resche-Rigon, M., Tharaux, P. L., & Ravaud, P. (2022). Effect of interleukin-6 receptor antagonists in critically ill adult patients with COVID-19 pneumonia: two randomised controlled trials of the CORIMUNO-19 Collaborative Group. European Respiratory Journal, 60(2). http://doi.org/10.1183/13993003.02523-2021.
Ho, T. Y., Wu, S. L., Chen, J. C., Li, C. C., & Hsiang, C. Y. (2007). Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Research, 74(2), 92-101. https://doi.org/10.1016/j.antiviral.2006.04.014.
Horby, P. W., Mafham, M., Bell, J. L., Linsell, L., Staplin, N., Emberson, J., ... & Landray, M. J. (2020). Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. The Lancet, 396(10259), 1345-52. https://doi.org/10.1016/S0140-6736(20)320-13-4.
Horby, P. W., Mafham, M., Peto, L., Campbell, M., Pessoa-Amorim, G., Spata, E., . . . Hine, P. (2021). Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv, 2021-06. https://doi.org/10.1101/2021.06.15.21258542.
Hu, B., Guo, H., Zhou, P. and Shi, Z.L., (2021). Characteristics of SARS-CoV-2 and COVID-19. Nature Reviews Microbiology, 19(3), 141-154. https://doi.org/10.1038/s41579-020-00459-7 
Humar, A., McGilvray, I., Phillips, M. J., & Levy, G. A. (2004). Severe acute respiratory syndrome and the liver. Hepatology (Baltimore, Md.), 39(2), 291. https://doi.org/10.1002/hep.20069.
Iastrebner, M., Castro, J., Espina, E. G., Lettieri, C., Payaslian, S., Cuesta, M. C., ... & Caruso, V. (2021). Ruxolitinib in severe covid-19 results of a multicenter, prospective, single arm, open-label clinical study to investigate the efficacy and safety of ruxolitinib in patients with covid-19 and severe acute respiratory syndrome. Revista de la Facultad de Ciencias Médicas, 78(3), 294-302. https://doi.org/10.3105310.31053%2F1853.0605.v78.n3.32800
Javorac, D., Grahovac, L., Manić, L., Stojilković, N., Anđelković, M., Bulat, Z., ... & Djordjevic, A. B. (2020). An overview of the safety assessment of medicines currently used in the COVID-19 disease treatment. Food and Chemical Toxicology, 144, 111639. https://doi.org/10.1016/j.fct.2020.111639.
Jeronimo, C. M. P., Farias, M. E. L., Val, F. F. A., Sampaio, V. S., Alexandre, M. A. A., Melo, G. C., ... & Lacerda, M. V. G. (2021). Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): a randomized, double-blind, phase IIb, placebo-controlled trial. Clinical Infectious Diseases, 72(9), e373-e381. https://doi.org/10.1093/cid/ciaa1177.
Jiang, Y., Yin, W., & Xu, H. E. (2021). RNA-dependent RNA polymerase: Structure, mechanism, and drug discovery for COVID-19. Biochemical and Biophysical Research Communications, 538, 47-53. https://doi.org/10.1016/j.bbrc.2020.08.116.
Jin, L., Xu, Y., & Yuan, H. (2020). Effects of four types of integrated Chinese and Western medicines for the treatment of COVID-19 in China: a network meta-analysis. Revista da Associação Médica Brasileira, 66, 771-777. https://doi.org/10.1590/1806-9282.66.6.771.
Kageyama, Y., Aida, K., Kawauchi, K., Morimoto, M., Ebisui, T., Akiyama, T., & Nakamura, T. (2022). Jinhua Qinggan granule, a Chinese herbal medicine against COVID‑19, induces rapid changes in the neutrophil/lymphocyte ratio and plasma levels of IL‑6 and IFN‑γ: An open‑label, single‑arm pilot study. World Academy of Sciences Journal, 4(1), 1-8. htts://doi.org/10.3892/wasj.2021.137.
Kalil, A. C., Mehta, A. K., Patterson, T. F., Erdmann, N., Gomez, C. A., Jain, M. K., ... & Colombo, R. E. (2021a). Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-blind, randomised, placebo-controlled, phase 3 trial. The lancet Respiratory Medicine, 9(12), 1365-1376. https://doi.org/10.1016/S2213-2600(21)00384-2.
Kalil, A. C., Patterson, T. F., Mehta, A. K., Tomashek, K. M., Wolfe, C. R., Ghazaryan, V., ... & Beigel, J. H. (2021b). Baricitinib plus remdesivir for hospitalized adults with Covid-19. New England Journal of Medicine, 384(9), 795-807. http://doi.org/10.1056/NEJMoa2031994.
Khan, S., Ali, A., Shi, H., Siddique, R., Nabi, G., Hu, J., ... & Han, G. (2020). COVID-19: Clinical aspects and therapeutics responses. Saudi Pharmaceutical Journal, 28(8), 1004-1008. https://doi.org/10.1016/j.jsps.2020.06.022.
Ko, W. C., Rolain, J. M., Lee, N. Y., Chen, P. L., Huang, C. T., Lee, P. I., & Hsueh, P. R. (2020). Arguments in favour of remdesivir for treating SARS-CoV-2 infections. International Journal of Antimicrobial Agents, 55(4), 105933. https://doi.org/10.1016/j.ijantimicag.2020.105933.
Koshak, A. E., Koshak, E. A., Mobeireek, A. F., Badawi, M. A., Wali, S. O., Malibary, H. M., ... & Madani, T. A. (2021). Nigella sativa for the treatment of COVID-19: An open-label randomized controlled clinical trial. Complementary Therapies in Medicine, 61, 102769. https://doi.org/https://doi.org/10.1016/j.ctim.2021.102769.
Laborda, P., Wang, S.-Y., & Voglmeir, J. (2016). Influenza neuraminidase inhibitors: synthetic approaches, derivatives and biological activity. Molecules, 21(11), 1513.https://doi.org/10.3390/molecules21111513.
Lee, T. C., McDonald, E. G., Butler-Laporte, G., Harrison, L. B., Cheng, M. P., & Brophy, J. M. (2021). Remdesivir and systemic corticosteroids for the treatment of COVID-19: a Bayesian re-analysis. International Journal of Infectious Diseases, 104, 671-676. https://doi.org/10.1016/j.ijid.2021.01.065.
Lehrer, S., & Rheinstein, P. H. (2020). Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain attached to ACE2. In vivo, 34(5), 3023-3026. https://doi.org/10.21873/invivo.12134.
Lenze, E. J., Mattar, C., Zorumski, C. F., Stevens, A., Schweiger, J., Nicol, G. E., ... & Reiersen, A. M. (2020). Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. The Journal of the American Medical Association, 324(22), 2292-2300. https://doi.org/10.1001/jama.2020.22760.
Li, Z., Chen, H., Zhang, H., Li, Y., Wang, C., Bai, L., ... & Jiang, Z. (2020). Similarity and specificity of traditional Chinese medicine formulas for management of coronavirus disease 2019 and rheumatoid arthritis. ACS Omega, 5(47), 30519-30530. https://doi.org/10.1021/acsomega.0c04377.
Limen, R. Y., Sedono, R., Sugiarto, A., & Hariyanto, T. I. (2022). Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis. Expert Review of Anti-Infective Therapy, 20(3), 425-434. https://doi.org/10.1080/14787210.2021.1982695.
Little, P. (2020). Non-steroidal anti-inflammatory drugs and covid-19. British Medical Journal, 368, m1185. https://doi.org/10.1136/bmj.m1185.
Liu, M., Gao, Y., Yuan, Y., Yang, K., Shi, S., Tian, J., & Zhang, J. (2021). Efficacy and safety of herbal medicine (Lianhuaqingwen) for treating COVID-19: a systematic review and meta-analysis. Integrative Medicine Research, 10(1), 100644. https://doi.org/10.1016/j.imr.2020.100644.
Liu, Y., & Breukink, E. (2016). The membrane steps of bacterial cell wall synthesis as antibiotic targets. Antibiotics, 5(3), 28. https://doi.org/10.3390/antibiotics5030028
Liu, Z., Li, X., Gou, C., Li, L., Luo, X., Zhang, C., . . . Li, H. (2020). Effect of Jinhua qinggan granules on novel coronavirus pneumonia in patients. Journal of Traditional Chinese Medicine, 40(3), 467-472. https://doi.org/10.19852/j.cnki.jtcm.2020.03.016.
Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., ... & Tan, W. (2020). Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet, 395(10224), 565-574. https://doi.org/10.1016/S0140-6736(20)30251-8.
Mahase, E. (2021a). Covid-19: Molnupiravir reduces risk of hospital admission or death by 50% in patients at risk, MSD reports. British Medical Journal, 375, n2422. https://doi.org/10.1136/bmj.n2422.
Mahase, E. (2021b). Covid-19: Pfizer’s paxlovid is 89% effective in patients at risk of serious illness, company reports. British Medical Journal, 375, n2713. https://doi.org/10.1136/bmj.n2713.
Mahase, E. (2021c). Covid-19: UK becomes first country to authorise antiviral molnupiravir. In: British Medical Journal, 375: n2697. https://doi.org/10.1136/bmj.n2697.
Mahmoud, D. B., Shitu, Z., & Mostafa, A. (2020). Drug repurposing of nitazoxanide: can it be an effective therapy for COVID-19? Journal of Genetic Engineering and Biotechnology, 18, 1-10. https://doi.org/10.1186%2Fs43141-020-00055-5.
Marconi, V. C., Ramanan, A. V., de Bono, S., Kartman, C. E., Krishnan, V., Liao, R., . . . de Cassia Pellegrini, R. (2021a). Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. The Lancet Respiratory Medicine, 9(12), 1407-1418. https://doi.org/10.1016/S2213-2600(21)00-331-3.
Marconi, V. C., Ramanan, A. V., de Bono, S., Kartman, C. E., Krishnan, V., Liao, R., ... & Zirpe, K. (2021b). Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. The Lancet Respiratory Medicine, 9(12), 1407-1418. https://doi.org/10.1016/s2213-2600(21)003-31-3
Martinez, M. A. (2020). Clinical trials of repurposed antivirals for SARS-CoV-2. Antimicrobial agents and chemotherapy, 64(9), 10-1128. https://doi.org/10.1128/aac.01101-20
Matthay, M. A., & Luetkemeyer, A. F. (2021). IL-6 receptor antagonist therapy for patients hospitalized for COVID-19: who, when, and how? The Journal of the American Medical Association, 326(6), 483-485. https://doi.org/doi:10.1001/jama.2021.11121
Mendieta Zerón, H., Meneses Calderón, J., Paniagua Coria, L., Meneses Figueroa, J., Vargas Contreras, M. J., Vives Aceves, H. L., ... & Anaya Herrera, J. (2021). Nitazoxanide as an early treatment to reduce the intensity of COVID‑19 outbreaks among health personnel. World Academy of Sciences Journal, 3(3), 1-6. https://doi.org/10.3892/wasj.2021.94
Mohan, A., Tiwari, P., Suri, T. M., Mittal, S., Patel, A., Jain, A., . . . Pandey, R. M. (2021). Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): a single-centre randomized, placebo-controlled trial. Journal of Infection and Chemotherapy, 27(12), 1743-1749. https://doi.org/10.1016/j.jiac.2021.08.021.
Mosquera-Sulbaran, J. A., & Hernández-Fonseca, H. (2021). Tetracycline and viruses: a possible treatment for COVID-19? Archives of Virology, 166, 1-7. https://doi.org/10.1007%2Fs00705-020-04860-8
Mostafa, A., Kandeil, A., AMM Elshaier, Y., Kutkat, O., Moatasim, Y., Rashad, A. A., ... & Ali, M. A. (2020). FDA-approved drugs with potent in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2. Pharmaceuticals, 13(12), 443. https://doi.org/10.3390/ph13120443
Muthuri, S. G., Venkatesan, S., Myles, P. R., Leonardi-Bee, J., Al Khuwaitir, T. S., Al Mamun, A., ... & Nguyen-Van-Tam, J. S. (2014). Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. The Lancet Respiratory Medicine, 2(5), 395-404. https://doi.org/10.1016/S2213-2600(14)700-41-4
Nagy-Agren, S. E., & Vasudeva, S. S. (2021). Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial. Lancet Infectious Diseases, 22(5), 622-635. https://doi.org/10.1016/S1473-3099(21)007-51-9
Natarajan, S., Anbarasi, C., Sathiyarajeswaran, P., Manickam, P., Geetha, S., Kathiravan, R., ... & Balaji, P. (2020). The efficacy of Siddha Medicine, Kabasura Kudineer (KSK) compared to Vitamin C & Zinc (CZ) supplementation in the management of asymptomatic COVID-19 cases: a structured summary of a study protocol for a randomised controlled trial. Trials, 21(1), 892. https://doi.org/10.1186/s13063-020-04823-z.
National Health Commission & National Administration of Traditional Chinese Medicine. (2020). Diagnosis and treatment protocol for novel coronavirus pneumonia (Trial Version 7). Chinese Medical Journal, 133(09), 1087-1095. https://doi.org/10.1097/CM9.0000000000000819
O’Brien, M. P., Forleo-Neto, E., Musser, B. J., Isa, F., Chan, K. C., Sarkar, N., ... & Weinreich, D. M. (2021). Subcutaneous REGEN-COV antibody combination to prevent Covid-19. New England Journal of Medicine, 385(13), 1184-1195. https://doi.org/10.1056/NEJMoa2109682
Ōmura, S., & Crump, A. (2014). Ivermectin: panacea for resource-poor communities? Trends in Parasitology, 30(9), 445-455. https://doi.org/10.1016/j.pt.2014.07.005
Parums, D. V. (2021). Tocilizumab, a humanized therapeutic IL-6 Receptor (IL-6R) monoclonal antibody, and future combination therapies for severe COVID-19. Medical Science Monitor, 27, e933973-1. https://doi.org/10.12659%2FMSM.933973.
Pindiprolu, S. K. S., & Pindiprolu, S. H. (2020). Plausible mechanisms of Niclosamide as an antiviral agent against COVID-19. Medical Hypotheses, 140, 109765. https://doi.org/10.1016/j.mehy.2020.109765.
Pushpakom, S., Iorio, F., Eyers, P. A., Escott, K. J., Hopper, S., Wells, A., ... & Pirmohamed, M. (2019). Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), 41-58. https://doi.org/10.1038/nrd.2018.168.
Ranjbar, K., Moghadami, M., Mirahmadizadeh, A., Fallahi, M. J., Khaloo, V., Shahriarirad, R., . . . Gholampoor Saadi, M. H. (2021). Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infectious Diseases, 21(1), 1-8. https://doi.org/10.1186/s12879-021-06045-3.
Reis, G., dos Santos Moreira-Silva, E. A., Silva, D. C. M., Thabane, L., Milagres, A. C., Ferreira, T. S., ... & Mills, E. J. (2022). Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the together randomised, platform clinical trial. The Lancet Global Health, 10(1), e42-e51. https://doi.org/10.1016/S2214-109X(21)004-48-4.
Rejinold N, S., Choi, G., Piao, H., & Choy, J. H. (2021). Bovine serum albumin-coated niclosamide-zein nanoparticles as potential injectable medicine against COVID-19. Materials, 14(14), 3792. https://doi.org/10.3390/ma14143792
Rocco, P. R., Silva, P. L., Cruz, F. F., Melo-Junior, M. A. C., Tierno, P. F., Moura, M. A., ... & e Silva, J. R. L. (2021). Early use of nitazoxanide in mild Covid-19 disease: randomised, placebo-controlled trial. European Respiratory Journal, 58(1): 2003725. https://doi.org/10.1183/13993003.03725-2020
Romani, D., Noureddine, O., Issaoui, N., & Brandán, S. A. (2020). Properties and reactivities of niclosamide in different media, a potential antiviral to treatment of COVID-19 by using DFT calculations and molecular docking. Biointerface Research in Applied Chemistry, 10(6), 7295-7328. https://doi.org/10.33263/BRIAC106.72957328.
Rosenberg, E. S., Dufort, E. M., Udo, T., Wilberschied, L. A., Kumar, J., Tesoriero, J., ... & Zucker, H. A. (2020). Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. Journal of the American Medical Association, 323(24), 2493-2502. https://doi.org/10.1001/jama.2020.8630.
Runfeng, L., Yunlong, H., Jicheng, H., Weiqi, P., Qinhai, M., Yongxia, S., ... & Zifeng, Y. (2020). Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacological Research, 156, 104761. https://doi.org/10.1016/j.phrs.2020.104761
Russell, B., Moss, C., Rigg, A., & Van Hemelrijck, M. (2020). COVID-19 and treatment with NSAIDs and corticosteroids: should we be limiting their use in the clinical setting? Ecancermedicalscience, 14, 1023. https://doi.org/10.3332%2Fecancer.2020.1023 
Samimi Nemati, A., Tafrihi, M., Sheikhi, F., Rostamian Tabari, A., & Haditabar, A. H. (2020). Designing a new multiepitope-based vaccine against COVID-19. Research in Molecular Medicine, 9(2), 103-118. https://doi.org/10.1155/2020/2683286
Sargiacomo, C., Sotgia, F., & Lisanti, M. P. (2020). COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? Aging (Albany NY), 12(8), 6511. https://doi.org/10.18632%2Faging.103001
Scheffers, D. J., & Pinho, M. G. (2005). Bacterial cell wall synthesis: new insights from localization studies. Microbiology and Molecular Biology Reviews, 69(4), 585-607. https://doi.org/10.1128/mmbr.69.4.585-607.2005
Seftel, D., & Boulware, D. R. (2021). Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infectious Diseases, 8(2): ofab050. https://doi.org/10.1093/ofid/ofab050.
Sen, I. K., Chakraborty, I., Mandal, A. K., Bhanja, S. K., Patra, S., & Maity, P. (2021). A review on antiviral and immunomodulatory polysaccharides from Indian medicinal plants, which may be beneficial to COVID-19 infected patients. International Journal of Biological Macromolecules, 181, 462-470. https://doi.org/10.1016/j.ijbiomac.2021.03.162
Shen, P., Li, J., Tu, S., Wu, Y., Peng, Y., Chen, G., & Chen, C. (2021). Positive effects of Lianhuaqingwen granules in COVID-19 patients: a retrospective study of 248 cases. Journal of Ethnopharmacology, 278, 114220. https://doi.org/10.1016/j.jep.2021.114220
Shi, N., Liu, B., Liang, N., Ma, Y., Ge, Y., Yi, H., ... & Wang, Y. (2020). Association between early treatment with Qingfei Paidu decoction and favorable clinical outcomes in patients with COVID-19: a retrospective multicenter cohort study. Pharmacological Research, 161, 105290. https://doi.org/10.1016/j.phrs.2020.105290
Silveira, D., Prieto-Garcia, J. M., Boylan, F., Estrada, O., Fonseca-Bazzo, Y. M., Jamal, C. M., ... & Heinrich, M. (2020). COVID-19: is there evidence for the use of herbal medicines as adjuvant symptomatic therapy? Frontiers in Pharmacology, 11, 1479. https://doi.org/10.3389/fphar.2020.581840.
Sodhi, M., & Etminan, M. (2020). Therapeutic potential for tetracyclines in the treatment of COVID‐19. Pharmacotherapy, 40(5), 487-488. https://doi.org/10.1002%2Fphar.2395.
Kang, S., & Kishimoto, T. (2021). Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Experimental and Molecular Medicine, 53(7), 1116-1123. https://doi.org/10.1038/s12276-021-00649-0.
Tarighi, P., Eftekhari, S., Chizari, M., Sabernavaei, M., Jafari, D., & Mirzabeigi, P. (2021). A review of potential suggested drugs for coronavirus disease (COVID-19) treatment. European Journal of Pharmacology, 895, 173890. https://doi.org/10.1016/j.ejphar.2021.173890
Tay, M. Y. F., Fraser, J. E., Chan, W. K. K., Moreland, N. J., Rathore, A. P., Wang, C., ... & Jans, D. A. (2013). Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Research, 99(3), 301-306. https://doi.org/10.1016/j.antiviral.2013.06.002
Tian, J., Yan, S., Wang, H., Zhang, Y., Zheng, Y., Wu, H., ... & Tong, X. (2020). Hanshiyi Formula, a medicine for Sars-CoV2 infection in China, reduced the proportion of mild and moderate COVID-19 patients turning to severe status: A cohort study. Pharmacological Research, 161, 105127. https://doi.org/10.1016/j.phrs.2020.105127
Vecchié, A., Batticciotto, A., Tangianu, F., Bonaventura, A., Pennella, B., Abenante, A., ... & Dentali, F. (2021). High-dose dexamethasone treatment for COVID-19 severe acute respiratory distress syndrome: a retrospective study. Internal and Emergency Medicine, 16(7), 1913-1919. https://doi.org/10.1007/s11739-021-02800-1
Venditto, V. J., Haydar, D., Abdel-Latif, A., Gensel, J. C., Anstead, M. I., Pitts, M. G., ... & Feola, D. J. (2021). Immunomodulatory effects of azithromycin revisited: potential applications to COVID-19. Frontiers in Immunology, 12, 574425. https://doi.org/10.3389/fimmu.2021.574425
Wagstaff, K. M., Sivakumaran, H., Heaton, S. M., Harrich, D., & Jans, D. A. (2012). Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochemical Journal, 443(3), 851-856. https://doi.org/10.1042/BJ20120150
Wang, H., Xu, B., Zhang, Y., Duan, Y., Gao, R., He, H., ... & Li, J. (2021). Efficacy and safety of traditional Chinese medicine in coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Frontiers in Pharmacology, 12, 609213. https://doi.org/10.3389/fphar.2021.609213
Wang, J. (2020). Fast identification of possible drug treatment of coronavirus disease-19 (COVID-19) through computational drug repurposing study. Journal of Chemical Information and Modeling, 60(6), 3277-3286. https://doi.org/10.1021/acs.jcim.0c00179
Weinreich, D. M., Sivapalasingam, S., Norton, T., Ali, S., Gao, H., Bhore, R., ... & Yancopoulos, G. D. (2021). REGEN-COV antibody combination and outcomes in outpatients with Covid-19. New England Journal of Medicine, 385(23), e81. https://doi.org/10.1056/nejmoa2108163
Wen, W., Chen, C., Tang, J., Wang, C., Zhou, M., Cheng, Y., ... & Mao, Q. (2022). Efficacy and safety of three new oral antiviral treatment (molnupiravir, fluvoxamine and Paxlovid) for COVID-19: a meta-analysis. Annals of Medicine, 54(1), 516-523. https://doi.org/10.1080/07853890.2022.2034936
World Health Organization. (2022). Weekly epidemiological update on COVID-19. (Ed 144). [25 May 2022]. Retrieved from https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---25-may-2022
Wu, R., Wang, L., Kuo, H. C. D., Shannar, A., Peter, R., Chou, P. J., ... & Kong, A. N. (2020). An update on current therapeutic drugs treating COVID-19. Current Pharmacology Reports, 6(3), 56-70. https://doi.org/10.1007/s40495-020-00216-7
Xiong, W. Z., Wang, G., Du, J., & Ai, W. (2020). Efficacy of herbal medicine (Xuanfei Baidu decoction) combined with conventional drug in treating COVID-19: a pilot randomized clinical trial. Integrative Medicine Research, 9(3), 100489. https://doi.org/10.1016/j.imr.2020.100489.
Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., ... & Wei, H. (2020). Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences, 117(20), 10970-10975. https://doi.org/10.1073/pnas.2005615117.
Yadav, R., Hasan, S., Mahato, S., Celik, I., Mary, Y. S., Kumar, A., ... & Chaudhary, J. K. (2021). Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2. Journal of Molecular Liquids, 342, 116942. https://doi.org/10.1016/j.molliq.2021.116942
Yang, S. N., Atkinson, S. C., Wang, C., Lee, A., Bogoyevitch, M. A., Borg, N. A., & Jans, D. A. (2020). The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Research, 177, 104760. https://doi.org/10.1016/j.antiviral.2020.104760.
Yin, W., Mao, C., Luan, X., Shen, D. D., Shen, Q., Su, H., ... & Xu, H. E. (2020). Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science, 368(6498), 1499-1504. https://doi.org/10.1126/science.abc1560.
Yu, S., Piao, H., Rejinold, N. S., Jin, G., Choi, G., & Choy, J. H. (2021). Niclosamide-clay intercalate coated with nonionic polymer for enhanced bioavailability toward covid-19 treatment. Polymers, 13(7), 1044. https://doi.org/10.3390/polym13071044.
Zakeri, B., & Wright, G. D. (2008). Chemical biology of tetracycline antibiotics. Biochemistry and Cell Biology, 86(2), 124-136. https://doi.org/10.1139/o08-002.
Zhang, X., Song, Y., Ci, X., An, N., Ju, Y., Li, H., ... & Deng, X. (2008). Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflammation Research, 57(11), 524-529. https://doi.org/10.1007/s00011-008-8007-8.
Zhang, X., Xue, Y., Chen, X., Wu, J. M., Su, Z. J., Sun, M., ... & Chen, Q. (2021). Effects of Tanreqing Capsule on the negative conversion time of nucleic acid in patients with COVID-19: a retrospective cohort study. Journal of Integrative Medicine, 19(1), 36-41. https://doi.org/10.1016/j.joim.2020.10.002.
Zhang, Y., Yao, Y., Yang, Y., & Wu, H. (2021). Investigation of anti-SARS, MERS, and COVID-19 effect of Jinhua Qinggan granules based on a network pharmacology and molecular docking approach. Natural Product Communications, 16(5), 1934578X211020619. https://doi.org/10.1177/1934578X211020619.
Zou, L., Dai, L., Zhang, X., Zhang, Z., & Zhang, Z. (2020). Hydroxychloroquine and chloroquine: a potential and controversial treatment for COVID-19. Archives of Pharmacal Research, 43, 765-772. https://doi.org/10.1007/s12272-020-01258-7.
Zumla, A., Chan, J. F., Azhar, E. I., Hui, D. S., & Yuen, K. Y. (2016). Coronaviruses-drug discovery and therapeutic options. Nature Reviews Drug Discovery, 15(5), 327-347. https://doi.org/10.1038/nrd.2015.37