Repurposed Drugs for COVID-19 Treatment

Main Article Content

Kesara Na-Bangchang
Juntra Karbwang

Abstract

The outbreak of Covid-19 has increasingly affected an alarming number of patients and deaths around the world. The case-fatality rate is about 1.4% and up to 14.8% in people age80  and older. In this situation, the search for new drugs is urgently needed to combat new outbreaks but it will take years to develop a new drug from scratch. The repurposing of approved drugs has become a strategy for prompt response to emerging infectious diseases. A number of drugs have been selected for further development as COVID-19 treatment, including malaria drugs (chloroquine and hydroxychloroquine), anthelmintics (ivermectin), and influenza (favipiravir) and the herb Andrographis paniculata, etc. There is sufficient evidence that the World Health Organization has recommended against the use of malaria drugs. For other drugs, most of the available evidence has been rated as low-certainty because of imprecision in most outcomes with wide confidence intervals and there were serious concerns related to the risk of bias on study design. The quality of research for repurposed drug development should be the same as those of new drug development. The data should clearly demonstrate evidence of efficacy and safety of the drug. Scientific and ethical validity of clinical research is therefore essential. Future studies should focus on quality and appropriate study design, such a a double-blinded randomized-controlled trial (RCT) with sufficient power and appropriate outcome measures for patients with varying degrees of severity. In addition, a dose finding study may be needed to determine the appropriate dose for COVID-19. This paper presents four important clinical studies of repurposed antivirals that are being used in Thailand officially or unofficially. The information may assist in the decision to use, discontinue or further develop these drugs for COVID-19.

Downloads

Download data is not yet available.

Article Details

Section
Special Article

References

Plipat T. 80% of COVID-19 patients present with mild symptoms and 30% of these patients are asymptomatic

only 20% need hospitalization. [Internet]. 2020 [cited 2021 Jul 20]; Available from: https://www.hfocus.org/

content/2020/04/18886 (in Thai)

WHO. COVID-19 clinical management: living guidance. [Internet]. 2021 [cited: 2021 Jun 26]; Available

from: https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1.

Siddiqi H, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical -therapeutic staging

proposal. J Heart Lung Transplant. 2020;39(5):405-7.

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu

S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult in patients with COVID-19

in Wuhan, China: a retrospective cohort study. Lancet. 2020;395 (10229):1054-62.

Liu B, Li M, Zhou Z, Guan X, Xiang Y. Can we use interleukin-6 (IL-6) blockage for coronavirus disease 2019

(COVID-19)-induced cytokine release syndrome (CRS)?. J Autoimmun. 2020;111:102452

The U.S. Food and Drug Administration. FDA approves first treatment for COVID-19. [Internet]. FDA News

release October 22, 2020. [cited 2021 Jul 20]; Available from: https://www.fda.gov/news-events/pressannouncements/fda-approves-first-treatment-covid-19

NIH. COVID-19 treatment guidelines. [Internet]. 24May 2021. [cited: 2021 May 30]; Available from: https://

www.covid19treatmentguidelines.nih.gov/therapeuticmanagement/.

White NJ. Guidelines should not pool evidence from uncomplicated and severe COVID-19. Lancet.

;397:1262-3.

Lu H. Drug treatment option for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020;14(1):69-71.

Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019

(COVID-19): a review. JAMA. 2020;323(18):1824-36.

Dos Santos WG. Natural history of COVID-19 and current knowledge on treatment therapeutic options. Biomed & Pharmacother. 2020;129(8):110493.

Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication

of SARS-CoV-2 in vitro. Antiviral Res. 2020;178:104787.

Kanjanasirirat P, Suksatu A, Manopwisedjaroen S, Munyoo B, Tuchinda P, Jearawuttanakul K, Seemakhan

S, Charoensutthivarakul S, Wongtrakoongate P, Rangkasenee N, Pitiporn S, Waranuch N, Chabang N,

Khemawoot P, Sa-Ngiamsuntorn K, Pewkliang Y, Thongsri P, Chutipongtanate S, Hongeng S, Borwornpinyo

S, Thitithanyanont A. High-content screening of Thai medicinal plants reveals Boesenbergia rotunda extract

and its component panduratin A as anti-SARS-CoV-2 agents. Sci Rep. 2020;10(1):19963.

FDA News Release. Coronavirus (COVID-19) Update:FDA revokes emergency use authorizaition for chloroquine and hydroxychloroquine. [Internet]. June 2020 [cited 2021 Jun 26]; Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorizationchloroquine-and.

Matichon online. Dr. Surachoke Tangwiwat, FDA warns not to use ivermectin to treat COVID-19. [Internet].

Jun 30, 2021 [cited 2021 Jun 30]; Available from: https://www.matichon.co.th/covid19/covid19-alert/

news_2803628 (in Thai)

Department of medical service. Guidelines for medical practice, diagnosis, care and prevention of

hospital infections in the case of Coronavirus Disease 2019 (COVID-19). [Internet]. Jul 21, 2021 [cited

Jul 30]; Available from: https://covid19.dms.go.th/backend/Content/Content_File/Covid_Health/

Attach/25640625085440AM_CPG_COVID_v.15_n%2020210625.pdf (in Thai)

Sa-Ngiamsuntorn K, Suksatu A, Pewkliang Y, Thongsri P, Kanjanasirirat P, Manopwisedjaroen S, Charoensutthivarakul S, Wongtrakoongate P, Pitiporn S, Chaopreecha J, Kongsomros S, Jearawuttanakul K, Wannalo W, Khemawoot P, Chutipongtanate S, Borwornpinyo S, Thitithanyanont A, Hongeng S. Anti-SARS-CoV-2

Activity of Andrographis paniculata extract and its major component andrographolide in human lung epithelial

cells and cytotoxicity evaluation in major organ cell representatives. J Nat Prod. 2021;84(4):1261-70.

The Government Gazette, Volume 138, Special Section 120 Ngor, dated June 4, 2021. (in Thai)

Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269–71

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline

S, de Castilla DL, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes R, Sweeney DA, Short

WR, Touloumi G, Lye DC, Ohmagari N, Oh MD, Ruiz-Palacios GM, Benfield T, Fätkenheuer G, Kortepeter MG,

Atmar RL, Creech CB, Lundgren J, Babiker AG, Pett S, Neaton JD, Burgess TH, Bonnett T, Green M, Makowski

M, Osinusi A, Nayak S, Lane HC, ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 -

final report. N Engl J Med. 2020;383(19):1813-26.

Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Viladomiu AS, Ogbuagu O, Malhotra

P, Mullane KM, Castagna A, Chai LYA, Roestenberg M, Tsang OTY, Bernasconi E, Turnier PL, Chang SC,

SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wang H, Gaggar A, Brainard DM, McPhail MJ,

Bhagani S, Ahn MY, Sanyal AJ, Huhn G, Marty FM, GS-US-540-5774 Investigators. Effect of remdesivir vs

standard care on clinical status at 11 days in patients with moderate COVID-19: A randomized clinical trial.

JAMA 2020;324(11):1048-57.

Goldman J, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, Galli M, Ahn MY, Nahass

RG, Chen YS, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wei X, Gaggar A, Brainard DM, Towner WJ,

Muñoz J, Mullane KM, Marty FM, Tashima KT, Diaz G, Subramanian A, GS-US-540-5773 Investigators. Remdesivir

for 5 or 10 days in patients with Severe Covid-19. N Engl J Med. 2020;383(19):1827-37

WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Karim QA, Alejandria MM, García CH, Kieny MP, Malekzadeh R,Murthy S, Reddy KS, Periago MR, Hanna PA, Ader F,

Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due

A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S,

Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan

J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina

MT, Rubio MLM, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H,

Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen

KAO, Trelle S, Zaid H, Røttingen JA, Swaminathan S. Repurposed antiviral drugs for COVID-19 –interim WHO

solidarity trial results. N Engl J Med. 2021;384(6):497-511.

Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S,

Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou

F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW,

Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled,multicentre trial. Lancet 2020;395(10236):1569-78.

National Institute of Health. Remdesivir: COVID-19 treatment guideline. [Internet]. April 21, 2021 [cited

July 5, 2021]; Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therpay/

remdesivir/

Rochwerg B, Agarwal A, Zeng L, Leo Y-S, Appiah JA, Agoritsas T, Bartoszko J, Brignardello-Petersen R, Ergan

B, Ge L, Geduld H, Gershengorn HB, Manai H, Huang M, Lamontagne F, Kanda S, Kawano-Dourado L, Kurian L,

Kwizera A, Murthy S, Qadir N, Siemieniuk R, Silvestre MA, Vandvik PO, Ye Z, Zeraatkar D, Guyatt G. Remdesivir

for severe covid-19: a clinical practice guideline. BMJ. 2020;370:m2924.

World Health Organization. Therapeutics and COVID-19: living guideline. [Internet]. 2021 [cited July 10, 2021];

Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2021.2

Siemieniuk RAC, Bartoszko JJ, Ge L, Zeraatkar D, Izcovich A, Kum E, Pardo-Hernandez H, Qasim A, Martinez

JPD, Rochwerg B, Lamontagne F, Han MA, Liu Q, Agarwal A, Agoritsas T, Chu DK, Couban R, Cusano E,

Darzi A, Devji T, Fang B, Fang C, Flottorp SA, Foroutan F, Ghadimi M, Heels-Ansdell D, Honarmand K, Hou L, Hou

X, Ibrahim Q, Khamis A, Lam B, Loeb M, Marcucci M, McLeod SL, Motaghi S, Murthy S, Mustafa RA, Neary JD,

Rada G, Riaz IB, Sadeghirad B, Sekercioglu N, Sheng L, Sreekanta A, Switzer C, Tendal B, Thabane L, Tomlinson

G, Turner T, Vandvik PO, Vernooij RW, Viteri-García A, Wang Y, Yao L, Ye Z, Guyatt GH, Brignardello-Petersen

R. Drug treatments for COVID-19: living systematic review and network meta-analysis. BMJ. 2020;370:m2980

ClinicalTrial.gov. [Internet]. April 21, 2021 [cited July 5, 2021]; Available from: https://clinicaltrials.gov/ct2/results?recrs=&cond=Covid19&term=Remdesivir&cntry=&state=&city=&dist=

Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC. Ivermectin for prevention and

treatment of COVID-19 infection: a systematic review, meta-analysis, and trial sequential analysis to inform

clinical guidelines. Am J Ther. 2021;28(4):e434-60.

Schmith VD, Zhou J, Lobmer LRL. The approved dose of ivermectin alone is not ideal dose for the treatment

of COVID-19. Clin Pharmacol Ther. 2020;108(4):762-5.

Bangkok Business News. Quality of life team, Get to know Ivermectin, a parasitic drug repurposing to

anti-COVID drug Can it really help? [Internet]. 1 Jul 2021 [cited July 5, 2021]; Available from: https://www.

bangkokbiznews.com/news/detail/946317 (in Thai)

BBC News Thai. Ivermectin, a parasitic drug. [Internet]. March 28, 2021 [cited July 10, 2021]; Available from:

https://www.bbc.com/thai/international-56549526

Ivashchenko AA, Dmitriev KA, Vostokova NV, Azarova VN, Blinow AA, Egorova AN, Gordeev IG, Ilin AP, Karapetian RN, Kravchenko DV, Lomakin NV, Merkulova EA, Papazova NA, Pavlikova EP, Savchuk NP, Simakina

EN, Sitdekov TA, Smolyarchuk EA, Tikhomolova EG, Yakubova EV, Ivachtchenko AV. AVIFAVIR for treatment

of patients with moderate COVID-19: interim results of a phase II/III multicenter randomized clinical

trial. Clin.Infect. Dis. 2021;73(3):531-4.

Chen PJ, Chao CM, Lai CC. Clinical efficacy and safety of favipiravir in the treatment ofCOVID-19patients. J.Infect. 2021;82(5):186-230

Dabbous HM, El-Sayed MH, El Assal G, Elghazaly H, Ebeid FF, Sherief AF, Elgaafary M, Fawzy E, Hassany

SM, Riad AR, TagelDin MA. Safety and efficacy of favipiravir versus hydroxychloroquine in management

of COVID-19: A randomised controlled trial. Sci. Rep. 2021;11:1–7

Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, Mutoh Y, Homma Y, Terada M, Ogawa T,

Kashizaki F, Yokoyama T, Koba H, Kasahara H, Yokota K, Kato H, Yoshida J, Kita T, Kato Y, Kamio T, Kodama

N, Yujiro Uchida Y, Ikeda N, Shinoda M, Nakagawa A, Nakatsumi H, Horiguchi T, Iwata M, Matsuyama A,

Banno S, Koseki T, Teramachi M, Miyata M, Tajima S, Maeki T, Nakayama E, Taniguchi S, Lim CK, Saijo M,

Imai T, Yoshida H, Kabata D, Shintani A, Yuzawa Y, KondoM. A prospective, randomized, open-label trial

of early versus late favipiravir therapy in hospitalized patients with COVID-19. Antimicrob Agents Chemother.

;64e01897-20.

Khamis F, Naabi HA, Lawati AA, Ambusaidi Z, Sharji MA, Barwani UA, Pandak N, Balushi ZA, Bahrani MA,

Salmi IA, Al-Zakwani I. Randomized controlled open label trial on the use of favipiravir combined with inhaled

interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia. Int. J. Infect. Dis

;102:538-43

Lou Y, Liu L, Yao H, Hu X, Su J, Xu K, Luo R, Yang X, He L, Lu X, Zhao Q, Liang T, Qiu Y. Clinical outcomes and plasma concentrations of Baloxavir Marboxil and favipiravir in COVID-19 patients: An exploratory randomized,

controlled trial. Eur. J. Pharmaceut.Sci. 2020;157:105631

Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, Kadam J, Wu W, Caracta CF, Tandon M. Efficacy

and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate

COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial. Int. J. Infect. Dis.

;103:62-71

Zhao H, Zhu Q, Zhang C, Li J, Wei M, Qin Y, Chen G, Wang K, Yu J, Wu Z, Chen X, Wang G. Tocilizumab

combined with favipiravir in the treatment of COVID-19: A multi center trial in a small sample size. Biomed.

Pharmacother. 2021;133

Manabe T, Kambaysshi D, Akatsu H, Kudo K. favipiravir for the treatment of patients with COVID-19: a

systematic review and meta-analysis. BMC infect Dis 2021;21:489

Hassanipour S, Arab-Zozani M, Amani B, Heidarzad F, Fathalipour M, Martinez-de-Hoyo R. The efficacy

and safety of favipiravir in treatment of COVID-19: a systematic review and meta-analysis of clinical trials.

Sci Rep. 2021;11:11022.

Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J, Liao X, Gu Y, Cai Q, Yang Y, Shen C, Li X, Peng L, Huang D, Zhang

J, Zhang S, Wang F, Liu J, Chen L, Chen S, Wang Z, Zhang Z, Cao R, Zhong W, Liu Y, Liu L. Experimental

treatment with favipiravir for COVID-19: an open-label control study. Engineering. 2020;6(10):1192-8

Doi K, Ikeda M, Hayase N, Moriya K, Morimura N, COVID-UTH Study Group. Nafamostat mesylate treatment

in combination with favipiravir for patients critically ill with Covid-19: a case series. Crit Care. 2020;24(1):392.

Yamamura H, Matsuura H, Nakagawa J, Fukuoka H, Domi H, Chujoh S. Effect of favipiravir and an

anti-inflammatory strategy for COVID-19. Crit Care. 2020;413(1):413.

Rattanaumpawan P, Jirajariyavej S, Lerdlamyong K, Palavutitotai N, Saiyarin J. Real-world experience with

favipiravir for treatment of COVID-19 in Thailand: Results from a multi-center observational study. medRxiv.

doi: 10.1101/2020.06.24.20133249.

Murohashi K, Hagiwara E, Kitayama T, Yamaya T, Higa K, Sato Y, Otoshi R, Shintani R, Okabayashi H, Ikeda

S, Niwa T, Nakazawa A, Oda T, Okuda R, Sekine A, Kitamura H, Baba T, Komatsu S, Iwasawa T, Kaneko, T,

Ogura T. Outcome of early-stage combination treatment with favipiravir and methylprednisolone for severe COVID-19 pneumonia: A report of 11 cases. Respir Investig. 2020;S2212–5345(20):30117–9.

Başaran NC, Uyaroğlu OA, Telli Dizman G, Özişik L, şahin TK, Taş Z, İnkaya AC, Sarahan S, Alp S, Apl

A, Metan G, Zarakol P, Guven GS, Oz SG, Topeli A, Uzun O, Akova M, Unal S. Outcome of non-critical

COVID-19 patients with early hospitalization and early antiviral treatment outside the ICU. Turk J Med Sci.

;51(2):411-20

Yaylaci S, Dheir H, Şenocak D, Genc AB, Kocayigit H, Çekiç D, Varim C, Aydin A, Koroglu M, Karabay O. The

effects of favipiravir on hematological parameters of covıd-19 patients. Rev Assoc Med Bras. 2020;66 Suppl

(Suppl 2):65–70.

Cáceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Use of visual analogue scale measurements

(VAS) to assess the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing

the symptoms of common cold. A randomized double blind-placebo study. Phytomed. 1999;6(4):217-23.

Hancke J, Burgos R, Caceres D, Wikman GK. A doubleblind study with a new monodrug Kan Jang: decrease

of symptoms and improvement in the recovery from common colds. Phytothe Res 1995;9:559-62.

Malchior J, Palm S, Wikman GK. Controlled clinical study of standardized Andrographis paniculata extract

in common cold – a pilot trial. Phytomed. 1997;3(4):315-8.

Thamilikitkul V, Dechatiwongse T, Theerapong S, Chantrakul C, Boonroj P, Punkrut W, Espalakorn W,

Boontaeng N, Taechaiya S, Petcharoen S. Efficacy of Andrographis paniculata, Nees for pharyngotonsillitis

in adults. J Med Assoc Thailand. 1991;74(10)437-42.

Malchior J, Spassov AA, Ostrovskij OV, Bulanov AE, Wikman GK. Double-blind, placebo-controlled pilot and

phase III study of activity of standardized Andrographis paniculata herba Nees extract fixed combination (Kan

Jang) in the treatment of uncomplicated upper-respiratory tract infection. Phytomed. 2000;7(5):341-5.

Saxena RC, Singh R, Kumar P, Yadav SC, Negi MPS, Saxena VS, Joshua AJ, Vijayabalaji V, Goudar KS,

Venkateshwarlu K, Amit A. A randomized double blind placebo controlled clinical evaluation of extract

of Andrographis paniculata (KalmCold) in patients with uncomplicated upper respiratory tract infection.

Phytomed. 2009;17(3-4):178-85.

Gupta S, Mishra KP, Ganju L. Broad-spectrum antiviral properties of andrographolide. Arch Virol.

;162(3):611-23.

Puri A, Saxena R, Saxena RP, Saxena KC, Srivastava V, Tandon JS. Immunostimulant agents from Andrographis

paniculata. J Nat Prod. 1993;56(7):995-9.

Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic

review of safety and efficacy. Plant Med. 2004;70:293-8.

Worakunphanich W, Thavorncharoensap M, Youngkong S, Thadanipon K, Thakkinstian A. Safety of Andrographis paniculata: a systematic review and meta-analysis. Pharmacoepidemiol Drug Safety. 2021;30(6):727-39.

Wang C, Sun S, Ding X. The therapeutic effects of traditional Chinese medicine on COVID-19: a narrative

review. Int J Clin Pharm. 2021;43(1):35-45.

Yearsley C. Thailand approves Asian herb andrographis to treat COVID-19. American Botanical Council, HerbalGram. 2021;129:35-7

Benjapolpitak A, Visitanon K, Sawangthum T, Thanirat T, Wanarat K. Short report on the use of Andrographis

panuculata as a treatment of COVID-19 patients. J Thai Trad Alt Med. 2021;19(1):229-33.

Zhang X-Y, Lv L, Zhou Y-L, Xie L-D, Xu Q, Zou XF, Ding Y, Tian J, Fan JL, Fan HW, Yang YX, Ye XQ. Efficacy

and safety of Xiyanping injection in the treatment of COVID-19: a multicenter, prospective, open-label

and randomized controlled trial. Phytother Res. 2021 Aug;35(8):4401-10.

Zhang W-X, Zhang Z-M, Zhang Z-Q, Wang Y, Zhou W. Andrographolide induced acute kidney injury: analysis

of 26 case reported in Chinese literature. Nephrology (Carlton). 2014;19(1):21-6.