Role of Supplements in the Management of COVID-19 - A Comprehensive
Review

Rajkapoor      Balasubramanian; Naina   Mohamed Pakkir   Maideen; Sudha      Muthusamy; Sambathkumar      Ramanathan; Mohamed   Harsath   Jahir Hussain
Abstract

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) and patients with COVID-19 may be treated primarily with SARS CoV- 2-targeting drugs and the therapeutic agents assisting in the management of COVID-19 complications. This review focuses on the supplements like vitamins, minerals, herbal constituents, and others that help prevent or manage negative outcomes among COVID-19 patients. The literature was searched in databases such as Medline/PubMed Central/PubMed, Google Scholar, Science Direct, EBSCO, Scopus, EMBASE, the Directory of Open Access Journals (DOAJ), and reference lists to identify relevant articles. The vitamins, including vitamin C, and vitamin D, minerals such as zinc, selenium, and copper, herbal constituents like thymoquinone, curcumin, naringenin, quercetin, and glycyrrhizin, and other supplements, including N-acetylcysteine and melatonin. Melatonin have been identified as having the potential to manage patients with COVID-19 along with standard care. Some of the ongoing clinical trials are investigating the effectiveness of different supplements among COVID-19 patients.
Graphical Abstract

[1]
Ludwig S, Zarbock A. Coronaviruses and SARS-CoV-2: A Brief Overview. Anesth Analg  2020; 131(1): 93-6.
 [http://dx.doi.org/10.1213/ANE.0000000000004845] [PMID:  32243297]

[2]
W.H.O. Coronavirus.  (COVID-19) Dashboard.  Available from:  https://covid19.who.int/
          (Accessed 07 June 2022).
      

[3]
Maideen NMP. Prophetic Medicine-Nigella Sativa (Black cumin seeds) - Potential herb for COVID-19? J Pharmacopuncture  2020; 23(2): 62-70.
 [http://dx.doi.org/10.3831/KPI.2020.23.010] [PMID:  32685234]

[4]
Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area. JAMA  2020; 323(20): 2052-9.
 [http://dx.doi.org/10.1001/jama.2020.6775] [PMID:  32320003]

[5]
Ponti G, Maccaferri M, Ruini C, Tomasi A, Ozben T. Biomarkers associated with COVID-19 disease progression. Crit Rev Clin Lab Sci  2020; 57(6): 389-99.
 [http://dx.doi.org/10.1080/10408363.2020.1770685] [PMID:  32503382]

[6]
Kermali M, Khalsa RK, Pillai K, Ismail Z, Harky A. The role of biomarkers in diagnosis of COVID-19 - A systematic review. Life Sci  2020; 254: 117788.
 [http://dx.doi.org/10.1016/j.lfs.2020.117788] [PMID:  32475810]

[7]
Velavan TP, Meyer CG. Mild versus severe COVID-19: Laboratory markers. Int J Infect Dis  2020; 95: 304-7.
 [http://dx.doi.org/10.1016/j.ijid.2020.04.061] [PMID:  32344011]

[8]
Lippi G, Plebani M. Laboratory abnormalities in patients with COVID-2019 infection. Clin Chem Lab Med  2020; 58(7): 1131-4.
 [http://dx.doi.org/10.1515/cclm-2020-0198] [PMID:  32119647]

[9]
.World Health Organization Clinical management of COVID-19: Interim guidance.  2020. Available from :  [https://apps.who.int/iris/bitstream/handle/10665/332196/WHO-2019-nCoV-clinical-2020.5-eng.pdf

[10]
Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant  2020; 39(5): 405-7.
 [http://dx.doi.org/10.1016/j.healun.2020.03.012] [PMID:  32362390]

[11]
de Simone G, Mancusi C. COVID-19: Timing is important. Eur J Intern Med  2020; 77: 134-5.
 [http://dx.doi.org/10.1016/j.ejim.2020.04.019] [PMID:  32362362]

[12]
Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends  2020; 14(1): 64-8.
 [http://dx.doi.org/10.5582/bst.2020.01030] [PMID:  32037389]

[13]
Patel RS, Patel N, Baksh M, Zaidi A, Patel J. Clinical perspective on 2019 novel coronavirus pneumonia: A systematic review of published case reports. Cureus  2020; 12(6): e8488.
 [http://dx.doi.org/10.7759/cureus.8488] [PMID:  32656006]

[14]
Phua J, Weng L, Ling L, et al. Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. Lancet Respir Med  2020; 8(5): 506-17.
 [http://dx.doi.org/10.1016/S2213-2600(20)30161-2] [PMID:  32272080]

[15]
Maideen NMP. Adjuvant therapies of COVID-19 - A literature review. Coronaviruses  2021; 2(10): e170821190562.
 [http://dx.doi.org/10.2174/2666796702666210121144902]

[16]
Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ  2020; 368: m1091.
 [http://dx.doi.org/10.1136/bmj.m1091] [PMID:  32217556]

[17]
Yang F, Shi S, Zhu J, Shi J, Dai K, Chen X. Analysis of 92 deceased patients with COVID‐19. J Med Virol  2020; 92(11): 2511-5.
 [http://dx.doi.org/10.1002/jmv.25891] [PMID:  32293741]

[18]
Maideen NM. Recent updates in the pharmacological management of COVID-19. Lett Appl NanoBioScience  2020; 10(1): 1969-80.
 [http://dx.doi.org/10.33263/LIANBS101.19691980]

[19]
Lai CC, Chao CM, Hsueh PR. Clinical efficacy of antiviral agents against coronavirus disease 2019: A systematic review of randomized controlled trials. J Microbiol Immunol Infect  2021; 54(5): 767-75.
 [http://dx.doi.org/10.1016/j.jmii.2021.05.011] [PMID:  34253490]

[20]
Vegivinti CTR, Evanson KW, Lyons H, et al. Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials. BMC Infect Dis  2022; 22(1): 107.
 [http://dx.doi.org/10.1186/s12879-022-07068-0] [PMID:  35100985]

[21]
Abd-Elsalam S, Ahmed OA, Mansour NO, et al. Remdesivir efficacy in COVID-19 treatment: a randomized controlled trial. Am J Trop Med Hyg  2021; 106(3): 886-90.
 [http://dx.doi.org/10.4269/ajtmh.21-0606] [PMID:  34649223]

[22]
Singh S, Khera D, Chugh A, Khera PS, Chugh VK. Efficacy and safety of remdesivir in COVID-19 caused by SARS-CoV-2: a systematic review and meta-analysis. BMJ Open  2021; 11(6): e048416.
 [http://dx.doi.org/10.1136/bmjopen-2020-048416] [PMID:  34168031]

[23]
Lai CC, Chen CH, Wang CY, Chen KH, Wang YH, Hsueh PR. Clinical efficacy and safety of remdesivir in patients with COVID-19: a systematic review and network meta-analysis of randomized controlled trials. J Antimicrob Chemother  2021; 76(8): 1962-8.
 [http://dx.doi.org/10.1093/jac/dkab093] [PMID:  33758946]

[24]
Hung DT, Ghula S, Aziz JMA, et al. The efficacy and adverse effects of favipiravir on patients with COVID-19: A systematic review and meta-analysis of published clinical trials and observational studies. Int J Infect Dis  2022; 120: 217-27.
 [http://dx.doi.org/10.1016/j.ijid.2022.04.035] [PMID:  35470021]

[25]
Abd-Elsalam S, Noor RA, Badawi R, et al. Clinical study evaluating the efficacy of ivermectin in COVID‐19 treatment: A randomized controlled study. J Med Virol  2021; 93(10): 5833-8.
 [http://dx.doi.org/10.1002/jmv.27122] [PMID:  34076901]

[26]
Abd-Elsalam S, Soliman S, Esmail ES, et al. Do zinc supplements enhance the clinical efficacy of hydroxychloroquine?: a randomized, multicenter trial. Biol Trace Elem Res  2021; 199(10): 3642-6.
 [http://dx.doi.org/10.1007/s12011-020-02512-1] [PMID:  33247380]

[27]
Wichmann D, Sperhake JP, Lütgehetmann M, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Ann Intern Med  2020; 173(4): 268-77.
 [http://dx.doi.org/10.7326/M20-2003] [PMID:  32374815]

[28]
Mousavi S, Bereswill S, Heimesaat MM. Immunomodulatory and antimicrobial effects of vitamin C. Eur J Microbiol Immunol (Bp)  2019; 9(3): 73-9.
 [http://dx.doi.org/10.1556/1886.2019.00016] [PMID:  31662885]

[29]
Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol  2020; 11: 1451.
 [http://dx.doi.org/10.3389/fimmu.2020.01451] [PMID:  32636851]

[30]
Colunga Biancatelli RML, Berrill M, Marik PE. The antiviral properties of vitamin C. Expert Rev Anti Infect Ther  2020; 18(2): 99-101.
 [http://dx.doi.org/10.1080/14787210.2020.1706483] [PMID:  31852327]

[31]
Soto ME, Guarner-Lans V, Soria-Castro E, Manzano Pech L, Pérez-Torres I. Is antioxidant therapy a useful complementary measure for COVID-19 treatment? An algorithm for its application. Medicina (Kaunas)  2020; 56(8): 386.
 [http://dx.doi.org/10.3390/medicina56080386] [PMID:  32752010]

[32]
Farjana M, Moni A, Sohag AAM, et al. Repositioning vitamin C as a promising option to alleviate complications associated with COVID-19. Infect Chemother  2020; 52(4): 461-77.
 [http://dx.doi.org/10.3947/ic.2020.52.4.461] [PMID:  33263242]

[33]
Hartman ME, Hernandez RA, Patel K, et al. COVID-19 respiratory failure: Targeting inflammation on VV-ECMO support. ASAIO J  2020; 66(6): 603-6.
 [http://dx.doi.org/10.1097/MAT.0000000000001177] [PMID:  32304395]

[34]
Waqas Khan HM, Parikh N, Megala SM, Predeteanu GS. Unusual early recovery of a critical COVID-19 patient after administration of intravenous vitamin C. Am J Case Rep  2020; 21: e925521.
 [http://dx.doi.org/10.12659/AJCR.925521] [PMID:  32709838]

[35]
Hiedra R, Lo KB, Elbashabsheh M, et al. The use of IV vitamin C for patients with COVID-19: a case series. Expert Rev Anti Infect Ther  2020; 18(12): 1259-61.
 [http://dx.doi.org/10.1080/14787210.2020.1794819] [PMID:  32662690]

[36]
Feyaerts AF, Luyten W. Vitamin C as prophylaxis and adjunctive medical treatment for COVID-19? Nutrition  2020; 79-80: 110948.
 [http://dx.doi.org/10.1016/j.nut.2020.110948] [PMID:  32911430]

[37]
Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Medicine in Drug Discovery  2020; 5: 100028.
 [http://dx.doi.org/10.1016/j.medidd.2020.100028] [PMID:  32328576]

[38]
Anderson PS. Intravenous ascorbic acid for supportive treatment in hospitalized COVID-19 patients. J Orthomol Med  2020; 35(1): 1-3.

[39]
Carr AC. A new clinical trial to test high-dose vitamin C in patients with COVID-19. Crit Care  2020; 24(1): 133.
 [http://dx.doi.org/10.1186/s13054-020-02851-4] [PMID:  32264963]

[40]
Teymoori-Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol  2019; 29(2): e2032.
 [http://dx.doi.org/10.1002/rmv.2032] [PMID:  30614127]

[41]
Martineau AR, Forouhi NG. Vitamin D for COVID-19: a case to answer? Lancet Diabetes Endocrinol  2020; 8(9): 735-6.
 [http://dx.doi.org/10.1016/S2213-8587(20)30268-0] [PMID:  32758429]

[42]
Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency and community-acquired pneumonia. Medicine (Baltimore)  2019; 98(38): e17252.
 [http://dx.doi.org/10.1097/MD.0000000000017252] [PMID:  31567995]

[43]
Grant W, Lahore H, McDonnell S, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients  2020; 12(4): 988.
 [http://dx.doi.org/10.3390/nu12040988] [PMID:  32252338]

[44]
Panfili FM, Roversi M, D’Argenio P, Rossi P, Cappa M, Fintini D. Possible role of vitamin D in COVID-19 infection in pediatric population. J Endocrinol Invest  2021; 44(1): 27-35.
 [http://dx.doi.org/10.1007/s40618-020-01327-0] [PMID:  32557271]

[45]
Liu W, Zhang L, Xu HJ, et al. The anti-inflammatory effects of vitamin D in tumorigenesis. Int J Mol Sci  2018; 19(9): 2736.
 [http://dx.doi.org/10.3390/ijms19092736] [PMID:  30216977]

[46]
Mokhtari Z, Hekmatdoost A, Nourian M. Antioxidant efficacy of vitamin D. J Parathyroid Dis 2016; 5(1): 11-6.
 [http://dx.doi.org/ 10.3390/ijms1909273]

[47]
Arboleda JF, Urcuqui-Inchima S, Vitamin D. Vitamin D supplementation: A potential approach for coronavirus/COVID-19 therapeutics? Front Immunol  2020; 11: 1523.
 [http://dx.doi.org/10.3389/fimmu.2020.01523] [PMID:  32655583]

[48]
Carpagnano GE, Di Lecce V, Quaranta VN, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest  2021; 44(4): 765-71.
 [http://dx.doi.org/10.1007/s40618-020-01370-x] [PMID:  32772324]

[49]
Pinzon RT. Angela, Pradana AW. Vitamin D deficiency among patients with COVID-19: case series and recent literature review. Trop Med Health  2020; 48(1): 102.
 [http://dx.doi.org/10.1186/s41182-020-00277-w] [PMID:  33342439]

[50]
Shakoor H, Feehan J, Al Dhaheri AS, et al. Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: Could they help against COVID-19? Maturitas  2021; 143: 1-9.
 [http://dx.doi.org/10.1016/j.maturitas.2020.08.003] [PMID:  33308613]

[51]
Prasad AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care  2009; 12(6): 646-52.
 [http://dx.doi.org/10.1097/MCO.0b013e3283312956] [PMID:  19710611]

[52]
Hojyo S, Fukada T. Roles of zinc signaling in the immune system. J Immunol Res  2016; 2016: 1-21.
 [http://dx.doi.org/10.1155/2016/6762343] [PMID:  27872866]

[53]
Skrajnowska D, Bobrowska-Korczak B. Role of zinc in immune system and anti-cancer defense mechanisms. Nutrients  2019; 11(10): 2273.
 [http://dx.doi.org/10.3390/nu11102273] [PMID:  31546724]

[54]
Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The role of zinc in antiviral immunity. Adv Nutr  2019; 10(4): 696-710.
 [http://dx.doi.org/10.1093/advances/nmz013] [PMID:  31305906]

[55]
Finzi E. Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients. Int J Infect Dis  2020; 99: 307-9.
 [http://dx.doi.org/10.1016/j.ijid.2020.06.006] [PMID:  32522597]

[56]
de Almeida Brasiel PG. The key role of zinc in elderly immunity: A possible approach in the COVID-19 crisis. Clin Nutr ESPEN  2020; 38: 65-6.
 [http://dx.doi.org/10.1016/j.clnesp.2020.06.003] [PMID:  32690179]

[57]
Kieliszek M, Lipinski B. Selenium supplementation in the prevention of coronavirus infections (COVID-19). Med Hypotheses  2020; 143: 109878.
 [http://dx.doi.org/10.1016/j.mehy.2020.109878] [PMID:  32464491]

[58]
Duntas LH. Selenium and inflammation: underlying anti-inflammatory mechanisms. Horm Metab Res  2009; 41(6): 443-7.
 [http://dx.doi.org/10.1055/s-0029-1220724] [PMID:  19418416]

[59]
Raha S, Mallick R, Basak S, Duttaroy AK. Is copper beneficial for COVID-19 patients? Med Hypotheses  2020; 142: 109814.
 [http://dx.doi.org/10.1016/j.mehy.2020.109814] [PMID:  32388476]

[60]
Mittra I, de Souza R, Bhadade R, et al. Resveratrol and Copper for treatment of severe COVID-19: an observational study (RESCU 002). medRxiv 2020.
 [http://dx.doi.org/10.1101/2020.07.21.20151423]

[61]
Maideen NMP. Potential of black seeds (Nigella sativa) in the management of COVID-19 among children. Int J Med Dev Adjuvant Treat  2021; 4: e366.

[62]
Balasubramanian R, Pakkir Maideen NM, Gobinath M, Rafiullah M, Muthusamy S. Therapeutic potentials of black seeds (Nigella sativa) in the management of COVID-19 -A review of clinical and in silico studies. Antiinfect Agents  2023; 21(1): e020822207222.
 [http://dx.doi.org/10.2174/2211352520666220802150156]

[63]
Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S. Thymoquinone and its therapeutic potentials. Pharmacol Res  2015; 95-96: 138-58.
 [http://dx.doi.org/10.1016/j.phrs.2015.03.011] [PMID:  25829334]

[64]
Sommer AP, Försterling HD, Naber KG. Thymoquinone: shield and sword against SARS-CoV-2. Precis Nanomed  2020; 20: 541-8.
 [http://dx.doi.org/10.33218/001c.12984]

[65]
Forouzanfar F, Bazzaz BS, Hosseinzadeh H. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Iran J Basic Med Sci  2014; 17(12): 929-38.
 [PMID:  25859296]

[66]
Majdalawieh AF, Fayyad MW. Immunomodulatory and anti-inflammatory action of Nigella sativa and thymoquinone: A comprehensive review. Int Immunopharmacol  2015; 28(1): 295-304.
 [http://dx.doi.org/10.1016/j.intimp.2015.06.023] [PMID:  26117430]

[67]
Taka E, Mazzio EA, Goodman CB, et al. Anti-inflammatory effects of thymoquinone in activated BV-2 microglial cells. J Neuroimmunol  2015; 286: 5-12.
 [http://dx.doi.org/10.1016/j.jneuroim.2015.06.011] [PMID:  26298318]

[68]
Ahmad A, Rehman MU, Ahmad P, Alkharfy KM. COVID‐19 and thymoquinone: Connecting the dots. Phytother Res  2020; 34(11): 2786-9.
 [http://dx.doi.org/10.1002/ptr.6793] [PMID:  32588453]

[69]
Shaghaghi N. Molecular docking study of novel COVID-19 protease with low risk terpenoides compounds of plants. Cambridge 2020.
 [http://dx.doi.org/10.26434/chemrxiv.11935722.v1]

[70]
Ahmad S, Abbasi HW, Shahid S, Gul S, Abbasi SW. Molecular docking, simulation and MM-PBSA studies of Nigella sativa compounds: A computational quest to identify potential natural antiviral for COVID-19 treatment. J Biomol Struct Dyn  2020; 39(12): 4225-33.
 [http://dx.doi.org/10.1080/07391102.2020.1775129]

[71]
Hewlings S, Kalman D. Curcumin: A review of its effects on human health. Foods  2017; 6(10): 92.
 [http://dx.doi.org/10.3390/foods6100092] [PMID:  29065496]

[72]
Ciavarella C, Motta I, Valente S, Pasquinelli G. Pharmacological (or synthetic) and nutritional agonists of PPAR-γ as candidates for cytokine storm modulation in COVID-19 disease. Molecules  2020; 25(9): 2076.
 [http://dx.doi.org/10.3390/molecules25092076] [PMID:  32365556]

[73]
Liczbiński P, Michałowicz J, Bukowska B. Molecular mechanism of curcumin action in signaling pathways: Review of the latest research. Phytother Res  2020; 34(8): 1992-2005.
 [http://dx.doi.org/10.1002/ptr.6663] [PMID:  32141677]

[74]
Boroumand N, Samarghandian S, Hashemy SI. Immunomodulatory, anti-inflammatory, and antioxidant effects of curcumin. J Herbmed Pharmacol  2018; 7(4): 211-9.
 [http://dx.doi.org/10.15171/jhp.2018.33]

[75]
Suresh PS. Curcumin and Coagulopathy in the COVID-19 Era. Indian J Clin Biochem  2020; 35(4): 504-5.
 [http://dx.doi.org/10.1007/s12291-020-00914-5] [PMID:  32837032]

[76]
Zahedipour F, Hosseini SA, Sathyapalan T, et al. Potential effects of curcumin in the treatment of COVID‐19 infection. Phytother Res  2020; 34(11): 2911-20.
 [http://dx.doi.org/10.1002/ptr.6738] [PMID:  32430996]

[77]
Utomo RY, Ikawati M, Meiyanto E. Revealing the potency of citrus and galangal constituents to halt SARS-CoV-2 infection. Preprints  2020; 2020030214.

[78]
Suravajhala R, Parashar A, Malik B, Nagaraj VA, Padmanaban G. Comparative docking studies on curcumin with COVID-19 proteins. Preprints  2020; 2020050439.

[79]
Khaerunnisa S, Kurniawan H, Awaluddin R, Suhartati S, Soetjipto S. Potential inhibitor of COVID-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints  2020; 2020030226.

[80]
Salehi B, Fokou P, Sharifi-Rad M, et al. The therapeutic potential of naringenin: A review of clinical trials. Pharmaceuticals (Basel)  2019; 12(1): 11.
 [http://dx.doi.org/10.3390/ph12010011] [PMID:  30634637]

[81]
Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, Ortega N, Perez-Mateos M, Muñiz P. Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric  2010; 90(7): 1238-44.
 [http://dx.doi.org/10.1002/jsfa.3959] [PMID:  20394007]

[82]
Chin LH, Hon CM, Chellappan DK, et al. Molecular mechanisms of action of naringenin in chronic airway diseases. Eur J Pharmacol  2020; 879: 173139.
 [http://dx.doi.org/10.1016/j.ejphar.2020.173139] [PMID:  32343971]

[83]
Tutunchi H, Naeini F, Ostadrahimi A, Hosseinzadeh-Attar MJ. Naringenin, a flavanone with antiviral and anti‐inflammatory effects: A promising treatment strategy against COVID‐19. Phytother Res  2020; 34(12): 3137-47.
 [http://dx.doi.org/10.1002/ptr.6781] [PMID:  32613637]

[84]
Parasuraman S, Anand David AV, Arulmoli R. Overviews of biological importance of quercetin: A bioactive flavonoid. Pharmacogn Rev  2016; 10(20): 84-9.
 [http://dx.doi.org/10.4103/0973-7847.194044] [PMID:  28082789]

[85]
Xu D, Hu MJ, Wang YQ, Cui YL. Antioxidant activities of quercetin and its complexes for medicinal application. Molecules  2019; 24(6): 1123.
 [http://dx.doi.org/10.3390/molecules24061123] [PMID:  30901869]

[86]
Wu W, Li R, Li X, et al. Quercetin as an antiviral agent inhibits influenza a virus (IAV) entry. Viruses  2015; 8(1): 6.
 [http://dx.doi.org/10.3390/v8010006] [PMID:  26712783]

[87]
Rojas Á, Del Campo JA, Clement S, et al. Effect of quercetin on hepatitis C virus life cycle: from viral to host targets. Sci Rep  2016; 6(1): 31777.
 [http://dx.doi.org/10.1038/srep31777] [PMID:  27546480]

[88]
Wong G, He S, Siragam V, et al. Antiviral activity of quercetin-3-β-O-D-glucoside against Zika virus infection. Virol Sin  2017; 32(6): 545-7.
 [http://dx.doi.org/10.1007/s12250-017-4057-9] [PMID:  28884445]

[89]
Xiaoxia LI, Lian C, Xiaojie LI, Wang G, Naoki I. In vitro antiviral mechanisms of eugeniin and quercetin against varicella-zoster virus. J MicrobiolImmunol  2016; 36(10): 727-33.
 [http://dx.doi.org/10.3760/cma.j.issn.0254-5101.2016.10.002]

[90]
Abd El-Aziz NM, Shehata MG, Awad OM, El-Sohaimy SA. Inhibition of COVID-19 RNA-Dependent RNA Polymerase by Natural Bioactive Compounds: Molecular Docking Analysis. Research square 2020.
 [http://dx.doi.org/10.21203/rs.3.rs-25850/v1]

[91]
Murck H. Symptomatic protective action of glycyrrhizin (licorice) in COVID-19 infection? Front Immunol  2020; 11: 1239.
 [http://dx.doi.org/10.3389/fimmu.2020.01239] [PMID:  32574273]

[92]
Luo P, Liu D, Li J. Pharmacological perspective: glycyrrhizin may be an efficacious therapeutic agent for COVID-19. Int J Antimicrob Agents  2020; 55(6): 105995.
 [http://dx.doi.org/10.1016/j.ijantimicag.2020.105995] [PMID:  32335281]

[93]
Bailly C, Vergoten G. Glycyrrhizin: An alternative drug for the treatment of COVID-19 infection and the associated respiratory syndrome? Pharmacol Ther  2020; 214: 107618.
 [http://dx.doi.org/10.1016/j.pharmthera.2020.107618] [PMID:  32592716]

[94]
Yan Y, Shen X, Cao Y, Zhang J, Wang Y, Cheng Y.  Discovery of
 Anti-2019-nCoV agents from 38 Chinese patent drugs toward respiratory
 diseases via docking screening. Preprint 2020.

[95]
Narkhede RR, Pise AV, Cheke RS, Shinde SD. Recognition of natural products as potential inhibitors of COVID-19 main protease (Mpro): In silico evidences. Nat Prod Bioprospect  2020; 10(5): 297-306.
 [http://dx.doi.org/10.1007/s13659-020-00253-1] [PMID:  32557405]

[96]
Aldini G, Altomare A, Baron G, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res  2018; 52(7): 751-62.
 [http://dx.doi.org/10.1080/10715762.2018.1468564] [PMID:  29742938]

[97]
Puyo C, Kreig D, Saddi V, Ansari E, Prince O. Case Report: Use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 patient. F1000 Res  2020; 9: 491.
 [http://dx.doi.org/10.12688/f1000research.23995.2]

[98]
Ibrahim H, Perl A, Smith D, et al. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clin Immunol  2020; 219: 108544.
 [http://dx.doi.org/10.1016/j.clim.2020.108544] [PMID:  32707089]

[99]
Jorge-Aarón RM, Rosa-Ester MP. N-acetylcysteine as a potential treatment for COVID-19. Future Microbiol  2020; 15(11): 959-62.
 [http://dx.doi.org/10.2217/fmb-2020-0074] [PMID:  32662664]

[100]
Singh M, Jadhav HR. Melatonin: functions and ligands. Drug Discov Today  2014; 19(9): 1410-8.
 [http://dx.doi.org/10.1016/j.drudis.2014.04.014] [PMID:  24792719]

[101]
Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res  2016; 61(3): 253-78.
 [http://dx.doi.org/10.1111/jpi.12360] [PMID:  27500468]

[102]
Zhang R, Wang X, Ni L, et al. COVID-19: Melatonin as a potential adjuvant treatment. Life Sci  2020; 250: 117583.
 [http://dx.doi.org/10.1016/j.lfs.2020.117583] [PMID:  32217117]

[103]
Calvo JR, González-Yanes C, Maldonado MD. The role of melatonin in the cells of the innate immunity: a review. J Pineal Res  2013; 55(2): 103-20.
 [http://dx.doi.org/10.1111/jpi.12075] [PMID:  23889107]

[104]
Castillo RR, Quizon GRA, Juco MJM, et al. Melatonin as adjuvant treatment for coronavirus disease 2019 pneumonia patients requiring hospitalization (MAC-19 PRO): a case series. Melatonin Research  2020; 3(3): 297-310.
 [http://dx.doi.org/10.32794/mr11250063]

[105]
García IG, Rodriguez-Rubio M, Mariblanca AR, et al. A randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial. Trials  2020; 21(1): 466.
 [http://dx.doi.org/10.1186/s13063-020-04436-6] [PMID:  32493475]

[106]
Chavda VP, Patel AB, Vihol D, et al. Herbal remedies, nutraceuticals, and dietary supplements for COVID-19 management: An update. Clin Complementary Med Pharmacol  2022; 2(1): 100021.
 [http://dx.doi.org/10.1016/j.ccmp.2022.100021] [PMID:  36620357]

[107]
Gutiérrez-Castrellón P, Gandara-Martí T, Abreu AT, et al. Efficacy and safety of novel probiotic formulation in adult COVID-19 outpatients: A randomized, placebo-controlled clinical trial. medRxiv 2021.
 [http://dx.doi.org/10.1101/2021.05.20.21256954]

[108]
Wischmeyer PE, Tang H, Ren Y, et al. Daily lactobacillus probiotic versus placebo in COVID-19-exposed household contacts (PROTECT-EHC): A randomized clinical trial. medRxiv 2022.
 [http://dx.doi.org/10.1101/2022.01.04.21268275]

[109]
Louca P, Murray B, Klaser K, et al. Modest effects of dietary supplements during the COVID-19 pandemic: Insights from 445 850 users of the COVID-19 Symptom Study app. BMJ Nutrition. Prevent Health  2021; 4(1): 149-57.
 [http://dx.doi.org/10.1136/bmjnph-2021-000250] [PMID:  34308122]
Cite As
Infectious Disorders - Drug Targets

Role of Supplements in the Management of COVID-19 - A Comprehensive Review

Abstract

Graphical Abstract
