Rational Use of Methylene Blue in COVID-19 Treatment
Abstract
Methylene blue entered the medical field when Robert Koch and Paul Ehrlich introduced the staining of tuberculosis microorganisms using methylene blue. It is used as an anesthetic agent for its sensory nerve ending blocking property, and its antimicrobial activity was useful as an antimalarial therapy in the 1890s. In the modern medical field, methylene blue was majorly used for investigational purposes as contrast in many radiological diagnostic techniques. Further applications of methylene blue in various clinical indications like Alzheimer's disease, depression, and psychosis are under investigation. Human Coronavirus invasion through the ACE 2 receptor causes the immune system's activation and induces apoptosis in human cells like monocytes, macrophages, T lymphocytes, and dendritic cells, which results in the activation of the innate and acquired immune system. This process results in the massive elimination of the infected cells. Methylene blue can play a significant role in treating SARS-CoV-2 infection by inhibiting viral replication and preventing sepsis due to covid illness. Theoretically, anti-inflammatory activity, oxidative stress, and tissue damage caused by covid infection can be minimized, and thereby it can also be beneficial for the patients suffering from cytokine storm. From this review article, we conclude that methylene blue should be evaluated for its role in covid treatment at a clinical level.
Keywords: SARS-CoV-2, Antiviral activity, Cytokine storm, Nitric oxide, Antidote activity.
Keywords:
SARS-CoV-2, Antiviral activity, Cytokine storm, Nitric oxide, Antidote activityDOI
https://doi.org/10.22270/jddt.v12i3.5438References
Clinical trial.gov[internet].USA: u.s. national library of medicine[uptated may 4, 2020] Available Form:https://clinicaltrials.gov/ct2/show/NCT04635605
Pub med[internet]. Maryland: u.s. national library of medicine Available Form:https://pubmed.ncbi.nlm.nih.gov/?term=methylene+blue
Alhenc-Gelas F, Girolam's JP, Molecular and genetic aapects of the Kallikerin-Kinin System. In:Michael Bader,editors. Kinins. German: De gruyter, 2011, page no7-37. https://doi.org/10.1515/9783110252354.7
Michael Titford, HTL (ASCP)HT. Paul Ehrlich: Histological Staining, Immunology, Chemotherapy. Laboratory Medicine, Volume 41, Issue 8, August 2010, Pages 497-498 https://doi.org/10.1309/LMHJS86N5ICBIBWM
Tan KY, Seow-Choen F. Methylene blue injection reduces pain after lateral anal sphincterotomy. Tech Coloproctol. 2007; 11:68-69 doi.org/10.1111/j.1445-2197.2007.04116_16.x
Guttmann P, Ehrlich P. Über die Wirkung des Methylenblau bei Malaria. In: The Collected Papers of Paul Ehrlich. Elsevier; 1960. p. 9-14. https://doi.org/10.1016/B978-0-08-009056-6.50006-3
Wainwright M, Crossley KB. Methylene Blue--a therapeutic dye for all seasons? J Chemother. 2002 Oct; 14(5):431 https://doi.org/10.1179/joc.2002.14.5.431
Wischik CM, Edwards PC, Lai RY, Roth M, Harrington CR. Selective inhibition of Alzheimer disease-like tau aggregation by phenothiazines. Proc Natl AcadSci U S A. 1996; 93:11213-11218 https://doi.org/10.1073/pnas.93.20.11213
Naylor GJ, Martin B, Hopwood SE, Watson Y. A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry. 1986; 21:915-920 https://doi.org/10.1016/0006-3223(86)90265-9
Narsapur SL, Naylor GJ. Methylene blue. A possible treatment for manic depressive psychosis. J Affect Disord. 1983; 5:155-1561 https://doi.org/10.1016/0165-0327(83)90008-3
World Health Organisation. CoronaVirus Disease 2019 Situation report 94, 23 april2020[internet]. Geneva Available Form: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200423-sitrep-94-covid-19.pdf
Masters PS. The molecular biology of coronaviruses. Adv. Virus Res. 2006; 66:193-292 https://doi.org/10.1016/S0065-3527(06)66005-3
Luo H, Chen Q, Chen J, Chen K, Shen X, Jiang H.Thenucleocapsid protein of SARS coronavirus has a high binding affinity to the human cellular heterogeneous nuclear ribonucleoprotein A1. FEBS Lett. 2005 May 9; 579(12):2623-8 https://doi.org/10.1016/j.febslet.2005.03.080
Neuman BW, Kiss G, Kunding AH, Bhella D, Baksh MF, Connelly S, Droese B, Klaus JP, Makino S, Sawicki SG, Siddell SG, Stamou DG, Wilson IA, Kuhn P, Buchmeier MJ. A structural analysis of M protein in coronavirus assembly and morphology.JStruct Biol. 2011 Apr; 174(1):11-22 https://doi.org/10.1016/j.jsb.2010.11.021
Luo H, Wu D, Shen C, Chen K, Shen X, Jiang H.Severe acute respiratory syndrome coronavirus membrane protein interacts with nucleocapsid protein mostly through their carboxyl termini by electrostatic attraction.Int J Biochem Cell Biol. 2006; 38(4):589-99 https://doi.org/10.1016/j.biocel.2005.10.022
Gu J, KortewegC.Pathology and pathogenesis of severe acute respiratory syndrome.Am J Pathol. 2007 Apr; 170(4):1136-47 https://doi.org/10.2353/ajpath.2007.061088
Spiegel M, Schneider K, Weber F, Weidmann M, Hufert FT,. Interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells.J Gen Virol. 2006 Jul; 87(Pt 7):1953-1960 https://doi.org/10.1099/vir.0.81624-0
Michael Bader. Kinins. Walter de Gruyter GmbH & Co. KG, Berlin/Boston
Sodhi, C. P, et al,. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. American Journal of Physiology-Lung Cellular and Molecular Physiology, 314(1), L17-L31. https://doi.org/10.1152/ajplung.00498.2016
Shahad A. AbasaeedElhag, MMBS, Halah Ibrahim, MD, MEHP, and ShadenAbdelhadi, MD. Angioedema and urticaria in a COVID-19 patient: A case report and review of the literature. JAAD Case Rep. 2020 Oct; 6(10):1091-1094. https://doi.org/10.1016/j.jdcr.2020.07.042
Jun wu, Nitric Oxide: Trackle the free radicals damage in covid-19, Elsevier, 2020; 102(1):39-41. https://doi.org/10.1016/j.niox.2020.06.002
Li Y, Hu Y, Yu J, Ma T. Retrospective analysis of laboratory testing in 54 patients with severe- or critical-type 2019 novel coronavirus pneumonia. Lab Invest. 2020; 100(6):794-800. https://doi.org/10.1038/s41374-020-0431-6
Hibbs, J.B., Jr., et al., Evidence for cytokine-inducible nitric oxide synthesis from Larginine in and vascular leak syndrome. J Immunother patients receiving interleukin-2 therapy. J Clin Invest, 1992; 89(3):867-77. https://doi.org/10.1172/JCI115666
Samlowski, W.E., et al., Endothelial nitric oxide synthase is a key mediator of interleukin-2-induced hypotension, 2011; 34(5):419-27. https://doi.org/10.1097/CJI.0b013e31821dcb50
Tsujimoto, M., et al., Tumor necrosis factor provokes superoxide anion generation from neutrophils. BiochemBiophys Res Commun, 1986; 137(3):1094-100. https://doi.org/10.1016/0006-291X(86)90337-2
Kharazmi, A., et al., Interleukin 6 primes human neutrophil and monocyte oxidative burst response. Immunol Lett, 1989; 21(2):177-84. https://doi.org/10.1016/0165-2478(89)90056-4
Colston, J.T., B. Chandrasekar, and G.L. Freeman, A novel peroxide-induced calcium transient regulates interleukin-6 expression in cardiac-derived fibroblasts. J Biol Chem, 2002; 277(26):23477-83. https://doi.org/10.1074/jbc.M108676200
Rabinovitch, A., et al., Cytotoxic effects of cytokines on rat islets: evidence for involvement of free radicals and lipid peroxidation. Diabetologia, 1992; 35(5):409-13. https://doi.org/10.1007/BF02342435
Casey LC. Role of cytokines in the pathogenesis of cardiopulmonary-induced multisystem organ failure. Ann ThoracSurg 1993 Nov; 56(5 Suppl):S92-6. https://doi.org/10.1016/0003-4975(93)91143-B
Patricia Ribeiro de Carvalho,aPierre Sirois,b and Patricia Dias Fernandesa,* The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection. Peptides. 2021 Jan; 135:170428. https://doi.org/10.1016/j.peptides.2020.170428
Bojadzic D, Alcazar O, Buchwald P. Methylene Blue Inhibits the SARS-CoV-2 Spike-ACE2 Protein-Protein Interaction-a Mechanism that can Contribute to its Antiviral Activity Against COVID-19. Front Pharmacol. 2020; 11:600372. https://doi.org/10.3389/fphar.2020.600372
Crooks J,Haemolytic jaundice in a neonate after intra-amniotic injection of methylene. Archives of disease in childhood. 1982 Nov; https://doi.org/10.1136/adc.57.11.872
Cagno V, Medaglia C, Cerny A, Cerny T, Zwygart AC-A, Cerny E, et al. Methylene Blue has a potent antiviral activity against SARS-CoV-2 and H1N1 influenza virus in the absence of UV-activation in vitro. Sci Rep. 2021; 11(1):14295. https://doi.org/10.1038/s41598-021-92481-9
Huang C, W.Y., Li X, Ren L, Zhao J, Hu Y,, Clinical features of patients infected with 2019 novel coronavirus in Wuhan Lancet, 2020 https://doi.org/10.1016/S0140-6736(20)30183-5
Kim JY, K.J., et al,, Viral Load Kinetics of SARS-CoV-2 Infection in First Two Patients in Korea. J Korean Med Sci, 2020; 35(7):e86. https://doi.org/10.3346/jkms.2020.35.e86
Corman VM, A.A., Omrani AS, Albarrak MM, Farah ME, Almasri M. Viral shedding and antibody response in 37 patients with Middle East respiratory syndrome coronavirus infection. Clin Infect Dis, 2016; 62:477-83 https://doi.org/10.1093/cid/civ951
Grant PR, G.J., et al,, Detection of SARS coronavirus in plasma by real-time RT-PCR. N Engl J Med, 2003; 349:2468-9 https://doi.org/10.1056/NEJM200312183492522
WHO, WHO recommendations on SARS and blood safety. 2003. https://www.who.int/csr/sars/guidelines/bloodsafety/en/.
Zhiliang Hu, C.S., Chuanjun Xu, et al,. Clinical Characteristics of 24 Asymptomatic Infections with COVID-19 Screened among Close Contacts in Nanjing, China. medRxiv, 2020. doi: https://doi.org/10.1101/2020.02.20.20025619
Bai, Y.Y., Lingsheng & Wei, Tao & Tian,et al,. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA, 2020. https://doi.org/10.1001/jama.2020.2565
Ebrahim SH, Memish ZA. COVID-19: preparing for superspreader potential among Umrah pilgrims to Saudi Arabia. Lancet. 2020; 395(10227):e48. https://doi.org/10.1016/S0140-6736(20)30466-9
Toru Hifumi, A.Y., Manabu Ato, Clinical Serum Therapy: Benefits, Cautions, and Potential Applications. Keio J Med, 2017; 66 (4):57-64. https://doi.org/10.2302/kjm.2016-0017-IR
Patricia Ribeiro de Carvalho,aPierre Sirois,b and Patricia Dias Fernandesa,* The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection. Peptides. 2021 Jan; 135: 170428. https://doi.org/10.1016/j.peptides.2020.170428
Floyd RA, Scheider JE, Dittmer DP, methylene blue photoinactivation of RNA viruses. Antivir Res 2004; 61:141-151 https://doi.org/10.1016/j.antiviral.2003.11.004
Bojadzic D, Alcazar O, Buchwald P. Methylene blue inhibits in vitro the SARS-CoV-2 spike - ACE2 protein-protein interaction - A mechanism that can contribute to its antiviral activity against COVID-19 [Internet]. bioRxiv. 2020. https://doi.org/10.1101/2020.08.29.273441
Cagno V, Medaglia C, Cerny A, Cerny T, Tapparel C, Cerny E. Methylene Blue has a potent antiviral activity against SARS-CoV-2 in the absence of UV-activation in vitro [Internet]. 2020. https://doi.org/10.1101/2020.08.14.251090
Valeria Cagno et al,. Methylene Blue has a potent antiviral activity against SARS-CoV2 in the absence of UV-activation in vitro 2020, Aug 14. https://doi.org/10.1101/2020.08.14.251090
Svyatchenko VA, Nikonov SD, Mayorov AP, Gelfond ML, Loktev VB. Antiviral photodynamic therapy: Inactivation and inhibition of SARS-CoV-2 in vitro using methylene blue and Radachlorin. Photodiagnosis Photodyn Ther. 2021; 33(102112):102112. https://doi.org/10.1016/j.pdpdt.2020.102112
Changzhong Jin et al, Methylene blue photochemical treatmentas a reliable SARS-CoV-2 plasma virus inactivation method for blood safety and convalescent plasma therapy for COVID-19.BMC Infectious Diseases. 2021; 16:21 https://doi.org/10.1186/s12879-021-06344-9 Available: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-021-05993-0
Gliberto L., Pardo A. The rationale for methylene blue utility against SARS-CoV-2 infection Complications.j ppres.2021; 9(3):379-396.
Domingo P, Mur I, Pomar V, Corominas H, Casademont J, deBeenlto N, The four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection(covid-19). EBloMedicine 2020; 58:102887. https://doi.org/10.1016/j.ebiom.2020.102887
Ahn H, et al, Methylene blue inhibits NLRP3, NLRC4, AIM2, and non-cononiccalinflammasome activation. Sci Rep 2017; 7(11):2409 https://doi.org/10.1038/s41598-017-12635-6
Lum H, Roebuck KA. Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 2001; 280:C719-41 https://doi.org/10.1152/ajpcell.2001.280.4.C719
Sciglino G, Sciglino GA. Methyelene blue in covid 19.jmedhy. 2020 Dec 10 ;146 https://doi.org/10.1016/j.mehy.2020.110455
Denny JT, Burr AT, Balzer F, Tse JT, Denny JE, ChyuD.Methylene blue treatment forcytokine release syndrome-associated vasoplegia following a renal transplant with rATG infusion: A Case report and literature review.ExpTher Med 2015; 9(5):1915-2 https://doi.org/10.3892/etm.2015.2349
Zhao RZ et al,. Mitochondrial electron transport chain, ROS generation and uncoupling (Review). Int J Mol Med. 2019 Jul; 44(1):3-15. https://doi.org/10.3892/ijmm.2019.4188
Salaris SC, Babbs CF, Voorhees III WD, methylene blue as an inhibitor of superoxide generation by xanthine oxidase, Biochem pharmacol1991; 42(3): 499-506. . https://doi.org/10.1016/0006-2952(91)90311-R
Salaris SC, Babbs CF, Voorhees WD, 3Rd; methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury; Biochempharmacol. 1991 Jul 15; 42(3):499-506. https://doi.org/10.1016/0006-2952(91)90311-R
Moncad S, Palmer RMJ and Higgs EA, Nitric oxide-physiology , pathophysiology , and pharmacology .pharmacol Rev 1991; 43:19-142,
Mayer B, et al,. Biosynthesis of endothelium-derived relaxing factor: a cytosolic enzyme in porcine aortic endothelial cells Ca2+-dependently converts L-arginine into an activator of soluble guanylyl cyclase. BiochemBiophys Res Commun 1989; 164:678-685.
Miki N, Kawabe Y and kuriyama K, Activation of cerebral guanylate cyclase by Nitric oxide. Biochem BIOPHYS Res Commun 1977; 75:851-856. https://doi.org/10.1016/0006-291X(77)91460-7
Willis, R.A., et al., Induction of nitric oxide synthase in subsets of murine pulmonary fibroblasts: effect on fibroblast interleukin-6 production. ClinImmunol Immunopathol, 1994; 71(2):231-9. https://doi.org/10.1006/clin.1994.1077
Bernd Mayer, Friedrich Brunner and Kurt Schmidt: Inhibition of nitric oxide synthesis by methylene blue , Biochemical Pharmacology 1993; 45(2):367-374. https://doi.org/10.1016/0006-2952(93)90072-5
Leonard Naymagon , et al,.Troy :the emergence of methemoglobinemia amidst the covid-19 pandemic, American journal hematology: published on 15 may 2020; https://doi.org/10.1002/ajh.25868
Murad F, et al,. Guanylate cyclase: activation by azide , Nitro compunds , and hydroxyl radical and inhibition by hemoglobin. Adv Cyclic Nucleotide Res 1978; 9:145-158,
hinaFaisaL, MD, MRCS, Alexi Bloom, MD, + and A. Osama Gaber, MD, FACS : unexplained Methemoglobinemia in coronavirus disease 2019: A Case Report ; international anesthesia research society; july 2020; 14(9). https://doi.org/10.1213/XAA.0000000000001287
Drugs.com; Methylene blue[internet],USA[updated.February.18.2019;cited February.8.2021]; Available from: https://www.drugs.com/monograph/methylene-blue.html#pharmacokinetics
Choo S.Y, Rapidly rising methemoglobinemia in a patients with severe covid-19 treated successfully with red cell exchange transfusion; TherApher Dial. 2020 oct 11; https://doi.org/10.1111/1744-9987.13598
Dewachter P, Claudiemoutanfaivre, Philippe Trechot, Jean-Claude Lieu, Paul Michel Mertes. Severe anaphylactic shock with methylene blue instillation. AnesthAnalg. 2005; 101:149-50. https://doi.org/10.1213/01.ANE.0000153497.60047.80
Clifton, Jack II, Leikin, Jerrold Methylene blue. America Journal of Therapeutics. 2003; 10:289-91. https://doi.org/10.1097/00045391-200307000-00009
Dalvi P,et al,. Intravenous methylene blue as a rescue therapy in the management of refractory hypoxia in COVID-19 ARDS patients: A case series. Indian J Crit Care Med. 2021; 25(8):934-8. https://doi.org/10.5005/jp-journals-10071-23905
Kidd SA, et al, was DM, Fetal death after exposure to methylene blue dye during mid-trimester amniocentesis in twin pregnancy. Prenatal diagnosis.1996 Jan; https://doi.org/10.1002/(SICI)1097-0223(199601)16:1<39::AID-PD789>3.0.CO;2-P
Martindale SJ Stedeford JC, Neurological sequelae following methylene blue injection for parathyroidectomy. Anaesthesia 2003 OCT; https://doi.org/10.1046/j.1365-2044.2003.03415_23.x
Gillman PK, CNS toxicity involving methylene blue; the exemplar for understanding and predicting drug interactions that precipitate serotonin toxicity .Journal of psychopharmacology 2011; march; https://doi.org/10.1177/0269881109359098
Published
Abstract Display: 988 
PDF Downloads: 466 PDF Downloads: 379 How to Cite
Issue
Section
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
How to Cite
.