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Review

Exploring the room for repurposed hydroxychloroquine to impede COVID-19: toxicities and multipronged combination approaches with pharmaceutical insights

ORCID Icon, ORCID Icon, , ORCID Icon & ORCID Icon
Pages 715-734 | Received 01 Oct 2020, Accepted 24 Mar 2021, Published online: 09 Jun 2021

References

  • WHO. Novel coronavirus (2019-nCoV) situation reports 2020. [cited 2021 Feb 12]. Available from: http://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/
  • Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497–506.
  • Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020 Mar;579(7798):270–273.
  • Wan Y, Shang J, Graham R, et al. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020 Mar 17;94(7). DOI:10.1128/JVI.00127-20
  • Tufan A, Avanoglu Guler A, Matucci-Cerinic M. COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs. Turk J Med Sci. 2020 Apr 21;50(SI–1):620–632.
  • Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: a Randomized Trial. Ann Intern Med. 2020 Jul 16;173(8):623-631.
  • [cited 2020 May 27]. Available form: www.cdc.gov
  • Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: the reality and challenges. J Microbiol Immunol Infect. 2020 Jun;53(3):436–443.
  • Tu YF, Chien CS, Yarmishyn AA, et al. A Review of SARS-CoV-2 and the Ongoing Clinical Trials. Int J Mol Sci. 2020 Apr 10;21(7):2657.
  • Chandwani A, Shuter J. Lopinavir/ritonavir in the treatment of HIV-1 infection: a review. Ther Clin Risk Manag. 2008 Oct;4(5):1023–1033.
  • Harrison C. Coronavirus puts drug repurposing on the fast track. Nat Biotechnol. 2020 Apr;38(4):379–381.
  • Gao Q, Bao L, Mao H, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020. DOI:10.1126/science.abc1932
  • Kumar N, Sood D, Chandra R. Design and optimization of a subunit vaccine targeting COVID-19 molecular shreds using an immunoinformatics framework. RSC Adv. 2020;10(59):35856–35872.
  • Riad A. Oral side effects of COVID-19 vaccine. Br Dent J. 2021;230(2):59.
  • Cirillo N. Reported orofacial adverse effects of COVID‐19 vaccines: the knowns and the unknowns. J Oral Pathol Med. 2021. DOI:10.1111/jop.13165
  • NHI PM. Covaxin and ZyCoV-D: Recent Update of Covid-19 Vaccine Candidates in India.
  • Thiagarajan K Covid-19: india is at centre of global vaccine manufacturing, but opacity threatens public trust. British Medical Journal Publishing Group; 2021.
  • Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383(27):2603–2615.
  • Al Noman A, Ekra JE, Meem RI, et al. The COVID-19 pandemic: A Comprehensive Review of the Genomic variations, Epidemiological features, Diagnosis, Treatment and Intervention schemes in South Asia. Authorea Preprints. 2021.
  • Krishna S, Augustin Y, Wang J, et al. Repurposing antimalarials to tackle the COVID-19 pandemic. Trends Parasitol. 2020.
  • Quang Bui P, Hong Huynh Q, Thanh Tran D, et al. Pyronaridine-artesunate efficacy and safety in uncomplicated Plasmodium falciparum malaria in areas of artemisinin-resistant falciparum in Viet Nam (2017–2018). Clin Infect Dis. 2020;70(10):2187–2195.
  • Gendrot M, Duflot I, Boxberger M, et al. Antimalarial artemisinin-based combination therapies (ACT) and COVID-19 in Africa: in vitro inhibition of SARS-CoV-2 replication by mefloquine-artesunate. Int J Infect Dis. 2020;99:437–440.
  • Saha BK, Bonnier A, Chong W. Antimalarials as Antivirals for COVID-19: believe it or Not! Am J Med Sci. 2020. DOI:10.1016/j.amjms.2020.08.019
  • Swaminathan S. Dexamethasone: Game-changer in the COVID-19 battle?: ETHealthWorld; 2020 cited 2020 10-02-2021 02 10. Available from: https://health.economictimes.indiatimes.com/news/pharma/dexamethasone-game-changer-in-the-covid-19-battle/76817741
  • Jorge A, Ung C, Young LH, et al. Hydroxychloroquine retinopathy—implications of research advances for rheumatology care. Nat Rev Rheumatol. 2018;14(12):693–703.
  • Mohammadpour F, Kargar M, Hadjibabaie M. The role of hydroxychloroquine as a steroid-sparing agent in the treatment of immune thrombocytopenia: a review of the literature. J Res Pharm Pract. 2018;7(1):4.
  • Pareek A, Purkait I, Mehta RT, et al. Metabolic and cardiovascular benefits of hydroxychloroquine: exploration in a wider population at high CV risk. Ann Rheum Dis. 2018;77(9):e59–e59.
  • Rempenault C, Combe B, Barnetche T, et al. Clinical and structural efficacy of hydroxychloroquine in rheumatoid arthritis: a systematic review. Arthritis Care Res. 2019; 72(1):36–40.
  • Sahraei Z, Shabani M, Shokouhi S, et al. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020 Apr;55(4):105945.
  • Singh AK, Singh A, Shaikh A, et al. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: a systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr. 2020;4(3):241–2461.
  • Ferner RE, Aronson JK. Chloroquine and hydroxychloroquine in covid-19. BMJ. 2020. DOI:10.1136/bmj.m1432
  • Ruamviboonsuk P, Lai TYY, Chang A, et al. Chloroquine and Hydroxychloroquine Retinal Toxicity Consideration in the Treatment of COVID-19. Asia-Pacific J Ophthalmology. 2020 Mar-Apr;9(2):85–87.
  • Boeckmans J, Rodrigues RM, Demuyser T, et al. COVID-19 and drug-induced liver injury: a problem of plenty or a petty point? Arch Toxicol. 2020 Apr;94(4):1367–1369.
  • Ponticelli C, Moroni G. Hydroxychloroquine in systemic lupus erythematosus (SLE). Expert Opin Drug Saf. 2017 Mar;16(3):411–419.
  • Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 Mar;38(1):1–9.
  • Li H, Liu L, Zhang D, et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020 May 9;395(10235):1517–1520.
  • Kaur H, Sehgal R, Goyal K, et al. Genetic diversity of Plasmodium falciparum merozoite surface protein‐1 (block 2), glutamate‐rich protein and sexual stage antigen Pfs25 from Chandigarh, North India. Trop Med Int Health. 2017;22(12):1590–1598.
  • Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2(1):69.
  • Shukla AM, Archibald LK, Wagle Shukla A, et al. Chloroquine and hydroxychloroquine in the context of COVID-19. Drugs Context. 2020;9. DOI:10.7573/dic.2020-4-5
  • Olofsson S, Kumlin U, Dimock K, et al. Avian influenza and sialic acid receptors: more than meets the eye? Lancet Infect Dis. 2005;5(3):184–188.
  • Schaper C A Mechanism of Action for Hydroxychloroquine and Azithromycin to Inhibit Coronavirus Disease COVID-19. 2020.
  • Savarino A, Di Trani L, Donatelli I, et al. New insights into the antiviral effects of chloroquine. Lancet Infect Dis. 2006;6(2):67–69.
  • Dijkmans B, Verweij C. Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells. J Rheumatol. 1997;24(1):55–60.
  • Infante M, Ricordi C, Alejandro R, et al. Hydroxychloroquine in the COVID-19 pandemic era: in pursuit of a rational use for prophylaxis of SARS-CoV-2 infection. Expert Rev Anti Infect Ther. 2021;19(1):5–16.
  • Wang H, Li X, Li T, et al. The genetic sequence, origin, and diagnosis of SARS-CoV-2. Eur J Clin Microbiol Infect Dis. 2020;39:1629–1635.
  • [cited 2020 May 27]. Available from: www.fda.gov.
  • D’Cruz M. The ICMR bulletin on targeted hydroxychloroquine prophylaxis for Covid-19: need to interpret with caution. Indian J Med Ethics. 2020 Apr-Jun;V(2):100–102.
  • Dousa KM, Malavade SS, Furin J, et al. SARS-CoV-2 infection in a patient on chronic hydroxychloroquine therapy: implications for prophylaxis. IDCases. 2020 Apr 27:e00778. DOI:10.1016/j.idcr.2020.e00778
  • https://clinicaltrials.gov/ct2/show/NCT04318444. Hydroxychloroquine Post Exposure Prophylaxis for Coronavirus Disease (Covid-19) 2020 05 27.
  • Schwartz J, King -C-C, Yen M-Y. Protecting health care workers during the COVID-19 coronavirus outbreak-Lessons from Taiwan’s SARS response. Clin Infect Dis. 2020; ciaa255. DOI:10.1093/cid/ciaa255
  • Pagliano P, Piazza O, De Caro F, et al. Is Hydroxychloroquine a Possible Postexposure Prophylaxis Drug to Limit the Transmission to Healthcare Workers Exposed to Coronavirus Disease 2019? Clin Infect Dis. 2020. DOI:10.1093/cid/ciaa320
  • Shah S, Das S, Jain A, et al. A systematic review of the prophylactic role of chloroquine and hydroxychloroquine in coronavirus disease‐19 (COVID‐19). Int J Rheum Dis. 2020;23(5):613–619.
  • Baildya N, Ghosh NN, Chattopadhyay AP. Inhibitory activity of hydroxychloroquine on COVID-19 main protease: an insight from MD-simulation studies. J Mol Struct. 2020 2020 11 05;1219:128595.
  • Group RC. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383(21):2030-2040.
  • Abd-Elsalam S, Esmail ES, Khalaf M, et al. Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. The American Journal of Tropical Medicine and Hygiene. 2020;103(4):1635–1639.
  • Emani VR, Goswami S, Nandanoor D, et al. Randomized controlled trials for COVID-19: evaluation of optimal randomization methodologies-need for the data validation of the completed trials, and to improve the ongoing and future randomized trial designs. Int J Antimicrob Agents. 2020:106222.
  • Mobeen S. All about SARS-CoV-2 and COVID-19: drbeen; 2021. [cited 2021 Mar 03]. Available from: https://members.drbeen.com/view/all-about-sars-cov-2-and-covid-19-march-31st-update/S1sKnB-vI
  • Pormohammad A, Monych NK, Turner RJ. Zinc and SARS‑CoV‑2: A molecular modeling study of Zn interactions with RNA‑dependent RNA‑polymerase and 3C‑like proteinase enzymes. Int J Mol Med. 2021;47(1):326–334.-558.
  • Rahman MT, Idid SZ. Can Zn Be a Critical Element in COVID-19 Treatment? Biol Trace Elem Res. 2021 2021/02/01;199(2):550The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale. Ann Intern Med. 2020 Jul 16;173(8): 662–663.
  • Schluger NW. The Saga of Hydroxychloroquine and COVID-19: a Cautionary Tale. Ann Intern Med. 2020 Jul 16;173(8):662–663.
  • Khuroo MS, Sofi AA, Khuroo M. Chloroquine and Hydroxychloroquine in Coronavirus Disease 2019 (COVID-19). Facts, Fiction & the Hype. A Critical Appraisal. Int J Antimicrob Agents. 2020;106101. DOI:10.1016/j.ijantimicag.2020.106101
  • Lauriola M, Pani A, Ippoliti G, et al. Effect of combination therapy of hydroxychloroquine and azithromycin on mortality in COVID-19 patients. Clin Transl Sci. 2020;13:1071–1076.
  • Gupta A, Malviya A. Chloroquine and hydroxychloroquine for COVID-19: time to close the chapter. Postgrad Med J. 2020: postgradmedj-2020-138585. DOI:10.1136/postgradmedj-2020-138585
  • Sinha N, Balayla G. Hydroxychloroquine and covid-19. Postgrad Med J. 2020 Apr 15. DOI:10.1136/postgradmedj-2020-137785
  • Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf. 2004;27(1):25–61.
  • Sargin G, Yavaşoğlu Sİ, Yavasoglu I. Is Coronavirus Disease 2019 (COVID-19) Seen Less in Countries More Exposed to Malaria? Med Hypotheses. 2020. DOI:10.1016/j.mehy.2020.109756
  • Perricone C, Triggianese P, Bartoloni E, et al. The anti-viral facet of anti-rheumatic drugs: lessons from COVID-19. J Autoimmun. 2020;111:102468.
  • Bonow RO, Hernandez AF, Turakhia M. Hydroxychloroquine, Coronavirus Disease 2019, and QT Prolongation. JAMA Cardiol. 2020 May 1. DOI:10.1001/jamacardio.2020.1782
  • Chorin E, Dai M, Shulman E, et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat Med. 2020;26(6):808–809.
  • Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020. DOI:10.1001/jamacardio.2020.1834
  • Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2010 Jun;62(6):775–784.
  • Munster T, Gibbs JP, Shen D, et al. Hydroxychloroquine concentration–response relationships in patients with rheumatoid arthritis. Arthritis Rheum. 2002;46(6):1460–1469.
  • Marmor MF. COVID-19 and Chloroquine/Hydroxychloroquine: is there Ophthalmological Concern? Am J Ophthalmol. 2020. DOI:10.1016/j.ajo.2020.03.029
  • Chu KH, Tsang WK, Tang CS, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int. 2005 Feb;67(2):698–705.
  • Diao B, Feng Z, Wang C, et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. MedRxiv. 2020. DOI: https://doi.org/10.1101/2020.03.04.20031120.
  • Pan XW, Xu D, Zhang H, et al. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis. Intensive Care Med. 2020 Jun;46(6):1114–1116.
  • Frie K, Gbinigie K Chloroquine and hydroxychlThe Centre for Evidence-Based Medicineoroquine: Current evidence for their effectiveness in treating COVID-19. . 2020.
  • Furst DE, Lindsley H, Baethge B, et al. Dose‐loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double‐blind six‐week trial with eighteen‐week extension. Arthritis Rheum. 1999;42(2):357–365.
  • Temprano KK, Florea SC, Florea SC Rheumatoid Arthritis and Pregnancy: Effects of Pregnancy on Rheumatoid Arthritis, Preconception Counseling, Peripartum Concerns. 2020.
  • Peng S, Yuan X, Lin W, et al. pH-responsive controlled release of mesoporous silica nanoparticles capped with Schiff base copolymer gatekeepers: experiment and molecular dynamics simulation. Colloids Surf B Biointerfaces. 2019 Apr 1;176:394–403.
  • Nevin RL, Croft AM. Psychiatric effects of malaria and anti-malarial drugs: historical and modern perspectives. Malar J. 2016 Jun 22;15(1):332.
  • Uvais N. The Risks of Prescribing Hyodroxychloroquine in COVID-19-Infected Patients With Schizophrenia. Prim Care Companion CNS Disord. 2020;22(3). DOI:10.4088/PCC.20com02635
  • Leckie M, Rees R. Stevens–Johnson syndrome in association with hydroxychloroquine treatment for rheumatoid arthritis. Rheumatology. 2002;41(4):473–474.
  • Cameron MC, Word AP, Dominguez A. Hydroxychloroquine-induced fatal toxic epidermal necrolysis complicated by angioinvasive rhizopus. Dermatol Online J. 2014 Nov 15;20(11):13030/qt1q90q0h5.
  • Sheikhbahaie F, Amini M, Gharipour M, et al. The effect of hydroxychloroquine on glucose control and insulin resistance in the prediabetes condition. Adv Biomed Res. 2016;5:145.
  • Türsen Ü, Türsen B, Lotti T. Cutaneous Sıde‐Effects of the Potentıal Covıd‐19 Drugs. Dermatol Ther. 2020;e13476. DOI:10.1111/dth.13476. Available from: https://escholarship.org/uc/item/1q90q0h5
  • Salido M, Joven B, D’cruz D, et al. Increased cutaneous reactions to hydroxychloroquine (Plaquenil) possibly associated with formulation change: comment on the letter by Alarcón. Arthritis Rheum. 2002;46(12):3392–3396.
  • Recalcati S. Cutaneous manifestations in COVID‐19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34(5):e212-e213. DOI: 10.1111/jdv.16387.
  • Choreño Parra J. Cutaneous susceptibility to SARS-CoV-2 infection according to the expression of viral entry factors in the skin. Gac Med Mex. 2020;156:354–357. DOI: 10.24875/GMM.20000308.
  • Kim KA, Park JY, Lee JS, et al. Cytochrome P450 2C8 and CYP3A4/5 are involved in chloroquine metabolism in human liver microsomes. Arch Pharm Res. 2003 Aug;26(8):631–637.
  • Somer M, Kallio J, Pesonen U, et al. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmacol. 2000 Jun;49(6):549–554.
  • Marcucci C, Sandson N, DeCaro M Summary of Chloroquine and Hydroxychloroquine Drug-Drug Interactions. APSF Website. 2020.
  • Van Roon EN, Van Den Bemt PM, Tim LTA, et al. An evidence-based assessment of the clinical significance of drug-drug interactions between disease-modifying antirheumatic drugs and non-antirheumatic drugs according to rheumatologists and pharmacists. Clin Ther. 2009;31(8):1737–1746.
  • Simpson T, Kovacs R, Stecker E. Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19. Cardiology. 2020. Available from: https://www.acc.org/latest-in-cardiology/articles/2020/03/27/14/00/ventricular-arrhythmia-risk-due-to-hydroxychloroquine-azithromycin-treatment-for-covid-19
  • Saleh M, Gabriels J, Chang D, et al. Effect of Chloroquine, Hydroxychloroquine, and Azithromycin on the Corrected QT Interval in Patients With SARS-CoV-2 Infection. Circ Arrhythm Electrophysiol. 2020 Jun;13(6):e008662.
  • Marmor MF, Kellner U, Lai TY, et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016 Jun;123(6):1386–1394.
  • Chanda-Kapata P, Kapata N, Zumla A. COVID-19 and malaria: a symptom screening challenge for malaria endemic countries. Int J Infect Dis. 2020 May;94:151–153.
  • Gonzalez D, Rao GG, Bailey SC, et al. Precision Dosing: public Health Need, Proposed Framework, and Anticipated Impact. Clin Transl Sci. 2017 Nov;10(6):443–454.
  • Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020 Mar 3;323(15):1488–1494.
  • Jones HM, Mayawala K, Poulin P. Dose selection based on physiologically based pharmacokinetic (PBPK) approaches. Aaps J. 2013 Apr;15(2):377–387.
  • Collins KP, Jackson KM, Gustafson DL. Hydroxychloroquine: a Physiologically-Based Pharmacokinetic Model in the Context of Cancer-Related Autophagy Modulation. J Pharmacol Exp Ther. 2018 Jun;365(3):447–459.
  • Savarino A, Tarek M. Pharmacokinetic bases of the hydroxychloroquine response in COVID-19: implications for therapy and prevention. medRxiv. 2020. DOI: https://doi.org/10.1101/2020.04.23.20076471.
  • Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Mar 9. DOI:10.1093/cid/ciaa237
  • Chowdhury MS, Rathod J, Gernsheimer J, et al. Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19. Acad Emerg Med. 2020 Jun;27(6):493–504.
  • Mak KK, Pichika MR. Artificial intelligence in drug development: present status and future prospects. Drug Discov Today. 2019 Mar;24(3):773–780.
  • Yella JK, Yaddanapudi S, Wang Y, et al. Changing Trends in Computational Drug Repositioning. Pharmaceuticals (Basel). 2018 Jun 5;11(2):57.
  • Kumar N, Sood D, Singh S, et al. High bio-recognizing aptamer designing and optimization against human herpes virus-5. Eur J Pharm Sci. 2020;156:105572.
  • Kumar N, Sood D, Sharma N, et al. Multiepitope Subunit Vaccine to Evoke Immune Response against Acute Encephalitis. J Chem Inf Model. 2019;60(1):421–433.
  • Kumar N, Sood D, Tomar R, et al. Antimicrobial Peptide Designing and Optimization Employing Large-Scale Flexibility Analysis of Protein-Peptide Fragments. ACS Omega. 2019;4(25):21370–21380.
  • Xiao X, Chang H, Li M. Molecular mechanisms underlying noncoding risk variations in psychiatric genetic studies. Mol Psychiatry. 2017 Apr;22(4):497–511.
  • Taherian E, Rao A, Malemud CJ, et al. The biological and clinical activity of anti-malarial drugs in autoimmune disorders. Curr Rheumatol Rev. 2013;9(1):45–62.
  • Paumgartten FJR, Delgado IF, Da Rocha Pitta L, et al. Chloroquine and hydroxychloroquine repositioning in times of COVID-19 pandemics, all that glitters is not gold. Cad Saude Publica. 2020;36(5):e00088520.
  • Mohamed K, Yazdanpanah N, Saghazadeh A, et al. Computational Drug Discovery and Repurposing for the Treatment of COVID-19: a Systematic Review. Available at SSRN 3583748. 2020.
  • Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modeling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020:105960. DOI:10.1016/j.ijantimicag.2020.105960
  • Narkhede RR, Cheke RS, Ambhore JP, et al. The molecular docking study of potential drug candidates showing anti-COVID-19 activity by exploring of therapeutic targets of SARS-CoV-2. screening. 2020;5:8.
  • Kumar N, Sood D, Van Der Spek PJ, et al. Molecular binding mechanism and pharmacology comparative analysis of noscapine for repurposing against SARS-CoV-2 protease. J Proteome Res. 2020. DOI:10.1021/acs.jproteome.0c00367
  • Watkins J Preventing a covid-19 pandemic. British Medical Journal Publishing Group; 2020.
  • Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors—lessons from available evidence and insights into COVID-19. Hypertens Res. 2020;43:648–654.
  • Richardson P, Griffin I, Tucker C, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30.
  • Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. 2005;11(8):875–879.
  • Rice GI, Thomas DA, Grant PJ, et al. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004 Oct 1;383(Pt 1):45–51.
  • Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA. 2020. DOI:10.1001/jama.2020.4812
  • Zhou QT, Leung SSY, Tang P, et al. Inhaled formulations and pulmonary drug delivery systems for respiratory infections. Adv Drug Del Rev. 2015;85:83–99.
  • Rowlatt J. Coronavirus: protein treatment trial ‘a breakthrough’. BBC News [Health]. 2020. [cited 2020 Jul 20]. Available from: https://www.bbc.com/news/health-53467022
  • Klimke A, Hefner G, Will B, et al. Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection. Med Hypotheses. 2020:109783. DOI:10.1016/j.mehy.2020.109783
  • Mei D, Tan WSD, Tay Y, et al. Therapeutic RNA Strategies for Chronic Obstructive Pulmonary Disease. Trends Pharmacol Sci. 2020 Jul;41(7):475–486.
  • Fassihi SC, Nabar NR, Fassihi R. Novel Approach for Low‐Dose Pulmonary Delivery of Hydroxychloroquine in COVID‐19. Br J Pharmacol. 2020. DOI:10.1111/bph.15167
  • Jain A, Sahu A, Aviral J, et al. Chapter 5: prodrugs and Bioconjugate Hydrogels: a Valuable Strategy for the Prolonged-delivery of Drugs. In: Umile Gianfranco Spizzirri, Giuseppe Cirillo, editors. Functional hydrogels in drug delivery: key features and future perspectives, CRC Press, UK. 2017. p. 89–113.
  • Poorvashree J, Suneela D. Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: design, kinetics and pharmacological study. Drug Deliv Transl Res. 2017;7(5):709–730.
  • Cojocaru FD, Botezat D, Gardikiotis I, et al. Nanomaterials Designed for Antiviral Drug Delivery Transport across Biological Barriers. Pharmaceutics. 2020 Feb 18;12(2):171.
  • Liu Q, Zheng X, Zhang C, et al. Conjugating influenza a (H1N1) antigen to n‐trimethylaminoethylmethacrylate chitosan nanoparticles improves the immunogenicity of the antigen after nasal administration. J Med Virol. 2015;87(11):1807–1815.
  • Francica JR, Lynn GM, Laga R, et al. Thermoresponsive polymer nanoparticles co-deliver RSV F trimers with a TLR-7/8 adjuvant. Bioconj Chem. 2016;27(10):2372–2385.
  • Dhakal S, Hiremath J, Bondra K, et al. Biodegradable nanoparticle delivery of inactivated swine influenza virus vaccine provides heterologous cell-mediated immune response in pigs. J Control Release. 2017 Feb 10;(247):194–205. DOI:10.1016/j.jconrel.2016.12.039
  • Jain A, Jain S. Ligand-mediated drug-targeted liposomes. UK: Future Medicine; 2016.
  • Jain A, Jain SK. Environmentally Responsive Chitosan-based Nanocarriers (CBNs). Handbook Polym Pharmaceut Technol Biodegradable Polym. 2015;3:105.
  • Jain A, Gulbake A, Shilpi S, et al. A new horizon in modifications of chitosan: syntheses and applications. Crit Rev Ther Drug Carrier Syst. 2013;30(2):91–181.
  • Kunda NK, Alfagih IM, Miyaji EN, et al. Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles. Int J Pharm. 2015 Nov 30;495(2):903–912.
  • Itani R, Tobaiqy M, Al Faraj A. Optimizing use of theranostic nanoparticles as a life-saving strategy for treating COVID-19 patients [Review]. Theranostics. 2020;10(13):5932–5942.
  • Prajapati SK, Malaiya A, Kesharwani P, et al. Biomedical applications and toxicities of carbon nanotubes. Drug Chem Toxicol. 2020 Jan 7:1–16. DOI:10.1080/01480545.2019.1709492
  • Prajapati SK, Jain A, Shrivastava C, et al. Hyaluronic acid conjugated multi-walled carbon nanotubes for colon cancer targeting. Int J Biol Macromol. 2019 Feb 15;123:691–703.
  • Lin CJ, Chang L, Chu HW, et al. High Amplification of the Antiviral Activity of Curcumin through Transformation into Carbon Quantum Dots. Small. 2019;15(41):1902641.
  • Xie Z, Huang J, Luo S, et al. Ultrasensitive electrochemical immunoassay for avian influenza subtype H5 using nanocomposite. PLoS One. 2014;9(4):e94685. DOI: 10.1371/journal.pone.0094685.
  • Huang J, Xie Z, Xie Z, et al. Silver nanoparticles coated graphene electrochemical sensor for the ultrasensitive analysis of avian influenza virus H7. Anal Chim Acta. 2016 Mar 24;913:121–127.
  • Iannazzo D, Pistone A, Ferro S, et al. Graphene quantum dots based systems as HIV inhibitors. Bioconj Chem. 2018;29(9):3084–3093.
  • Du X, Xiao R, Fu H, et al. Hypericin-loaded graphene oxide protects ducks against a novel duck reovirus. Mater Sci Eng C Mater Biol Appl. 2019 Dec;105:110052.
  • Palmieri V, Papi M. Can graphene take part in the fight against COVID-19? Nano Today. 2020;100883. DOI:10.1016/j.nantod.2020.100883
  • Lee YT, Ko EJ, Lee Y, et al. Intranasal vaccination with M2e5x virus-like particles induces humoral and cellular immune responses conferring cross-protection against heterosubtypic influenza viruses. PLoS One. 2018;13(1):e0190868.
  • Coleman CM, Venkataraman T, Liu YV, et al. MERS-CoV spike nanoparticles protect mice from MERS-CoV infection. Vaccine. 2017 Mar 14;35(12):1586–1589.
  • Bishnoi M, Jain A, Singla Y, et al. Sublingual delivery of chondroitin sulfate conjugated tapentadol loaded nanovesicles for the treatment of osteoarthritis. J Liposome Res. 2020 Mar 2;31(1):1–15.
  • Jain A, Tiwari A, Verma A, et al. Ultrasound-based triggered drug delivery to tumors. Drug Deliv Transl Res. 2018 Feb;8(1):150–164.
  • Adhikary RR, More P, Banerjee R. Smart nanoparticles as targeting platforms for HIV infections. Nanoscale. 2015;7(17):7520–7534.
  • Jain A, Jain SK. Stimuli-responsive Smart Liposomes in Cancer Targeting. Curr Drug Targets. 2018 Feb 8;19(3):259–270.
  • Jain A, Kumari R, Tiwari A, et al. Nanocarrier based advances in drug delivery to tumor: an overview. Curr Drug Targets. 2018 Jan 30;19(13):1498–1518.
  • Giri N, Oh B, Lee CH. Stimuli-sensitive nanoparticles for multiple anti-HIV microbicides. J Nanopart Res. 2016;18(5):140.
  • Stocke NA, Arnold SM, Hilt JZ. Responsive Hydrogel Nanoparticles for Pulmonary Delivery. J Drug Deliv Sci Technol. 2015 Oct 1;29:143–151.
  • Jain A, Jain SK. Colon Targeted Liposomal Systems (CTLS): theranostic Potential. Curr Mol Med. 2015;15(7):621–633.
  • Singh L, Kruger HG, Maguire GEM, et al. The role of nanotechnology in the treatment of viral infections. Ther Adv Infect Dis. 2017 Jul;4(4):105–131.
  • Draz MS, Shafiee H. Applications of gold nanoparticles in virus detection. Theranostics. 2018;8(7):1985–2017.
  • Skalny AV, Rink L, Ajsuvakova OP, et al. Zinc and respiratory tract infections: perspectives for COVID‑19. Int J Mol Med. 2020;46(1):17–26.
  • Walker CLF, Rudan I, Liu L, et al. Global burden of childhood pneumonia and diarrhoea. Lancet. 2013 Apr 20;381(9875):1405–1416.
  • Sandstead HH, Prasad AS. Zinc intake and resistance to H1N1 influenza. Am J Public Health. 2010 Jun;100(6):970–971.
  • Te Velthuis AJ, Van Den Worm SH, Sims AC, et al. Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6(11):e1001176.
  • Maret W. Zinc in cellular regulation: the nature and significance of “zinc signals”. Int J Mol Sci. 2017;18(11):2285.
  • Xue J, Moyer A, Peng B, et al. Chloroquine is a zinc ionophore. PLoS One. 2014;9(10):e109180.
  • ClinicalTrials.gov. Hydroxychloroquine and Zinc With Either Azithromycin or Doxycycline for Treatment of COVID-19 in Outpatient Setting 2020 2020 07 09. Available from: https://clinicaltrials.gov/ct2/show/NCT04370782
  • Carlucci P, Ahuja T, Petrilli CM, et al. Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients. medRxiv. 2020.
  • Berlutti F, Pantanella F, Natalizi T, et al. Antiviral properties of lactoferrin—a natural immunity molecule. Molecules. 2011;16(8):6992–7018.
  • Gupta I, Sehgal R, Kanwar RK, et al. Nanocapsules loaded with iron-saturated bovine lactoferrin have antimicrobial therapeutic potential and maintain calcium, zinc and iron metabolism. Nanomedicine. 2015;10(8):1289–1314.
  • Kanwar JR, Roy K, Patel Y, et al. Multifunctional iron bound lactoferrin and nanomedicinal approaches to enhance its bioactive functions. Molecules. 2015 May 26;20(6):9703–9731.
  • Sorensen M, Sorensen S. The proteins in whey. Compte rendu des Travaux du Laboratoire de Carlsberg. Ser Chim. 1940;23(7):55–99.
  • Johanson B. Isolation of an iron-containing red protein from human milk. Acta Chem Scand. 1960;14(2):510–512.
  • Kell DB, Heyden EL, Pretorius E. The Biology of Lactoferrin, an Iron-Binding Protein That Can Help Defend Against Viruses and Bacteria. Front Immunol. 2020;11:1221.
  • Anand N, Kanwar RK, Dubey ML, et al. Effect of lactoferrin protein on red blood cells and macrophages: mechanism of parasite-host interaction. Drug Des Devel Ther. 2015;9:3821–3835.
  • Anand N, Kanwar RK, Sehgal R, et al. Antiparasitic and immunomodulatory potential of oral nanocapsules encapsulated lactoferrin protein against Plasmodium berghei. Nanomedicine (Lond). 2016 Jan;11(1):47–62.
  • Gibbons JA, Kanwar JR, Kanwar RK. Iron-free and iron-saturated bovine lactoferrin inhibit survivin expression and differentially modulate apoptosis in breast cancer. BMC Cancer. 2015 May 22;(15):425. DOI:10.1186/s12885-015-1441-4
  • Mahidhara G, Kanwar RK, Roy K, et al. Oral administration of iron-saturated bovine lactoferrin-loaded ceramic nanocapsules for breast cancer therapy and influence on iron and calcium metabolism. Int J Nanomedicine. 2015;10:4081–4098.
  • Gibbons JA, Kanwar RK, Kanwar JR. Lactoferrin and cancer in different cancer models. Front Biosci (Schol Ed). 2011 Jun 1;3:1080–1088.
  • Anand N, Sehgal R, Kanwar RK, et al. Oral administration of encapsulated bovine lactoferrin protein nanocapsules against intracellular parasite Toxoplasma gondii. Int J Nanomedicine. 2015;10:6355–6369.
  • Ebrahim F, Shankaranarayanan JS, Kanwar JR, et al. Identification of unprecedented anticancer properties of high molecular weight biomacromolecular complex containing bovine lactoferrin (HMW-bLf). PLoS One. 2014;9(9):e106568.
  • Sriramoju B, Kanwar RK, Kanwar JR. Lactoferrin induced neuronal differentiation: a boon for brain tumours. Int J Dev Neurosci. 2015 Apr;41:28–36.
  • Kanwar JR, Palmano KP, Sun X, et al. ‘Iron-saturated’ lactoferrin is a potent natural adjuvant for augmenting cancer chemotherapy. Immunol Cell Biol. 2008 Mar-Apr;86(3):277–288.
  • Roy K, Kanwar RK, Kanwar JR. LNA aptamer based multi-modal, Fe3O4-saturated lactoferrin (Fe3O4-bLf) nanocarriers for triple positive (EpCAM, CD133, CD44) colon tumor targeting and NIR, MRI and CT imaging. Biomaterials. 2015 Dec;71:84–99.
  • Shankaranarayanan JS, Kanwar JR, Al-Juhaishi AJA, et al. Doxorubicin conjugated to immunomodulatory anticancer lactoferrin displays improved cytotoxicity overcoming prostate cancer chemo resistance and inhibits tumour development in TRAMP Mice. Sci Rep. 2016;6:32062.
  • Kanwar JR, Kamalapuram SK, Krishnakumar S, et al. Multimodal iron oxide (Fe3O4)-saturated lactoferrin nanocapsules as nanotheranostics for real-time imaging and breast cancer therapy of claudin-low, triple-negative (ER(-)/PR(-)/HER2(-)). Nanomedicine (Lond). 2016 Feb;11(3):249–268.
  • Leng KM, Vijayarathna S, Jothy SL, et al. In vitro and in vivo toxicity assessment of alginate/eudragit S 100-enclosed chitosan-calcium phosphate-loaded iron saturated bovine lactoferrin nanocapsules (Fe-bLf NCs). Biomed Pharmacother. 2018 Jan;97:26–37.
  • Leng KM, Vijayarathna S, Jothy SL, et al. In vitro and in vivo anticandidal activities of alginate-enclosed chitosan-calcium phosphate-loaded Fe-bovine lactoferrin nanocapsules. Future Sci OA. 2018 Feb;4(2):FSO257.
  • K Kanwar R, Kanwar JR. Immunomodulatory lactoferrin in the regulation of apoptosis modulatory proteins in cancer. Protein Pept Lett. 2013;20(4):450–458.
  • Kanwar JR, Mahidhara G, Roy K, et al. Fe-bLf nanoformulation targets survivin to kill colon cancer stem cells and maintains absorption of iron, calcium and zinc. Nanomedicine (Lond). 2015 Jan;10(1):35–55.
  • Samarasinghe RM, Kanwar RK, Kanwar JR. The effect of oral administration of iron saturated-bovine lactoferrin encapsulated chitosan-nanocarriers on osteoarthritis. Biomaterials. 2014 Aug;35(26):7522–7534.
  • Burrow H, Kanwar RK, Kanwar JR. Antioxidant enzyme activities of iron-saturated bovine lactoferrin (Fe-bLf) in human gut epithelial cells under oxidative stress. Med Chem. 2011 May;7(3):224–230.
  • Burrow H, Kanwar RK, Mahidhara G, et al. Effect of selenium-saturated bovine lactoferrin (Se-bLF) on antioxidant enzyme activities in human gut epithelial cells under oxidative stress. Anticancer Agents Med Chem. 2011 Oct;11(8):762–771.
  • Kanwar JR, Mahidhara G, Kanwar RK. Novel alginate-enclosed chitosan-calcium phosphate-loaded iron-saturated bovine lactoferrin nanocarriers for oral delivery in colon cancer therapy. Nanomedicine (Lond). 2012 Oct;7(10):1521–1550.
  • Kamalapuram SK, Kanwar RK, Kanwar JR. Nanotheranostic Based Iron Oxide (Fe₃O₄) Saturated Lactoferrin Nanocapsules for Colonic Adenocarcinoma. J Biomed Nanotechnol. 2016 Sep;12(9):1758–1773.
  • Lang J, Yang N, Deng J, et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS One. 2011;6(8):e23710.
  • **Tripathi MK, Singh P, Sharma S, et al. Identification of bioactive molecule from Withania somnifera (Ashwagandha) as SARS-CoV-2 main protease inhibitor. J Biomol Struct Dyn. 2020 Jul 8:1–14. DOI:10.1080/07391102.2020.1790425
  • Kumar V, Dhanjal JK, Kaul SC, et al. Withanone and caffeic acid phenethyl ester are predicted to interact with main protease (Mpro) of SARS-CoV-2 and inhibit its activity. J Biomol Struct Dyn. 2020:1-13. DOI: 10.1080/07391102.2020.1772108. .
  • Grant WB, Lahore H, McDonnell SL, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients. 2020;12(4):988.
  • Cheng RZ. Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? Med Drug Discovery. 2020;5:100028.
  • Andreou A, Trantza S, Filippou D, et al. COVID-19: the Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2. Vivo. 2020;34(3 suppl):1567–1588.
  • Bauer SR, Kapoor A, Rath M, et al. What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19? Cleve Clin J Med. 2020. DOI:10.3949/ccjm.87a.ccc046
  • Poe FL, Corn J. N-Acetylcysteine: a potential therapeutic agent for SARS-CoV-2. Med Hypotheses. 2020;109862. DOI:10.1016/j.mehy.2020.109862
  • Guglielmetti G, Quaglia M, Sainaghi PP, et al. “War to the knife” against thromboinflammation to protect endothelial function of COVID-19 patients. Crit Care. 2020;24(1):1–4.
  • Goodnough R, Canseco K. Truncated IV acetylcysteine treatment duration has potential to safely preserve resources during the COVID-19 pandemic. Clin Toxicol. 2021;59(1):69. DOI: 10.1080/15563650.2020.1758327204.
  • Alam MT, Murshed R, Bhiuyan E, et al. A Case Series of 100 COVID-19 Positive Patients Treated with Combination of Ivermectin and Doxycycline. J Bangladesh Coll Physicians Surgeons. 2020:10–15. DOI:10.3329/jbcps.v38i0.47512.
  • Durojaiye AB, Clarke J-RD, Stamatiades GA, et al. Repurposing cefuroxime for treatment of COVID-19: a scoping review of in silico studies. J Biomol Struct Dyn. 2020:1–8. DOI:10.1080/07391102.2020.1777904.
  • Shang L, Zhao J, Hu Y, et al. On the use of corticosteroids for 2019-nCoV pneumonia. Lancet. 2020;395(10225):683.
  • Lammers T, Sofias AM, Van Der Meel R, et al. Dexamethasone nanomedicines for COVID-19. Nat Nanotechnol. 2020 2020 08 01;15(8):622–624.
  • Health NIo. Corticosteroids: National Institutes of Health; 2020 [updated 2020 Nov 3; cited 2021]. Available from: https://www.covid19treatmentguidelines.nih.gov/immune-based-therapy/immunomodulators/corticosteroids/#:~:text=In%20patients%20with%20severe%20COVID,patients%20who%20were%20mechanically%20ventilated.
  • Fatima SA, Asif M, Khan KA, et al. Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe covid 19 disease. Ann Med Surg. 2020;60:413–416.
  • Cengiz M, Uysal BB, Ikitimur H, et al. Effect of oral L-Glutamine supplementation on Covid-19 treatment. Clin Nutr Exp. 2020. DOI:10.1016/j.yclnex.2020.07.003.
  • Jorge AM, Melles RB, Zhang Y, et al. Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. Arthrit Res Ther. 2018;20(1):133.

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