Application of methylene blue for the prevention and treatment of COVID-19, a narrative review

Document Type : Review Article

Authors

1 Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Lung Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

The newest virus from the SARS family of viruses called acute syndrome-coronavirus-2 (SARS-CoV-2), which causes COVID-19 disease, was identified in China at the end of 2019. In March 2020, after it spread to 29 additional countries, it was declared a pandemic by the World Health Organization (WHO). SARS-CoV-2 infection mainly starts through the respiratory tract and causes a wide spectrum of symptoms from asymptomatic infections to acute respiratory distress syndrome with multi-organ failure and vasoplegic shock. Among the many immunomodulatory and antiviral drugs that have been studied for the treatment of COVID-19, methylene blue (MB) may play an influential role. This article reviews the history of MB applications, the antiviral effects of MB against SARS-CoV-2, and the results of in vivo and in vitro studies of the use of MB in COVID-19. Based on studies, MB can simultaneously affect most of the host’s harmful responses caused by SARS-CoV-2 infection due to its multiple properties, including anti-hypoxemia, anti-oxidant, immune system modulator, and antiviral. The use of MB is associated with a reduction in the possibility of getting infection, and mortality, and can be used as a safe, effective, cheap, and available treatment option with minimal side effects for the clinical management of COVID-19.

Keywords

Main Subjects

References

1. 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.
2. Henry M, Summa M, Patrick L, Schwartz L. A cohort of cancer patients with no reported cases of SARS-CoV-2 infection: the possible preventive role of Methylene Blue. Substantia 2020:888.
3. 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. bioRxiv 2020;1-20.
4. Saikrupa B, Muthukumar M, Kavya S, Suma PK. Rational Use of Methylene Blue in COVID-19 Treatment. JDDT 2022; 12:181-186.
5. Joshi S, Parkar J, Ansari A, Vora A, Talwar D, Tiwaskar M, et al. Role of favipiravir in the treatment of COVID-19. Int J Infect Dis 2021; 102:501-508.
6. Gendrot M, Jardot P, Delandre O, Boxberger M, Andreani J, Duflot I, et al. In vitro evaluation of the antiviral activity of methylene blue alone or in combination against SARS-CoV-2. J Clin Med 2021; 10:3007.
7. Scigliano G, Scigliano GA. Methylene blue in COVID-19. Med Hypotheses 2021; 146:110455.
8. Hamidi-Alamdari D, Moghaddam AB, Amini S, Hamidi-Alamdari A, Damsaz M, Yarahmadi A. The application of a reduced dye used in orthopedics as a novel treatment against coronavirus (COVID-19): a suggested therapeutic protocol. Arch Bone Jt Surg 2020; 8:291.
9. Gendrot M, Andreani J, Duflot I, Boxberger M, Le Bideau M, Mosnier J, et al. Methylene blue inhibits replication of SARS-CoV-2 in vitro. Int J Antimicrob Agents 2020; 56:106202.
10. Hamidi-Alamdari D, Lotfabadi SH, Darban BM, Agheli-Rad M, Saadatian S, Hashemi SH, et al. Methylene blue for treatment of hospitalized COVID-19 patients, randomized, controlled, open-label clinical trial, Phase 3. Aristotle Biomedical J 2021; 3:12-18.
11. Dabholkar N, Gorantla S, Dubey SK, Alexander A, Taliyan R, Singhvi G. Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations. Biomed Pharmacother 2021; 142:112023.
12. Hamidi-Alamdari D, Bhushan B. Methylene Blue for the Treatment of COVID-19 in Pediatrics. Int J Pediatr 2022; 10:15281-15284.
13. Indika N-LR, Fonseka NG. Methylene blue inhibits the interaction between heparan sulfate and SARS-COV-2 spike protein; a review of evidence for a hypothesis. MJMR 2021; 5:4-11.
14. Hutter S, La Scola B, Pradines B. In vitro evaluation of the antiviral activity of repurposable drugs against SARS-CoV-2: Methylene blue.
15. Lobo CS, Rodrigues-Santos P, Pereira D, Núñez J, Trêpa JC, Sousa DL, et al. Photodynamic disinfection of SARS-CoV-2 clinical samples using a methylene blue formulation. Photochem Photobiol Sci 2022:1-9.
16. Hamidi-Alamdari D, Moghaddam AB, Amini S, Keramati MR, Zarmehri AM, Hamidi-Alamdari A, et al. Application of methylene blue-vitamin C–N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial. Eur J Pharmacol 2020; 885:173494.
17. Yang L, Youngblood H, Wu C, Zhang Q. Mitochondria as a target for neuroprotection: role of methylene blue and photobiomodulation. Transl Neurodegener 2020; 9:1-22.
18. Patidar V, Sharma A, Bhoraskar S, Tripathi AP, Dhaneriya S. The role of nebulized methylene blue [NMB] in the management of COVID-19 cases: an observational study. International Journal of Medical Arts 2022; 4:2129-2132.
19. Cagno V, Medaglia C, Cerny A, Cerny T, Zwygart ACA, 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; 11:1-8.
20. Giles SMG. Recent german researches on malaria: its treatment by methylene blue. With introductory remarks. Ind Med Gaz 1892; 27:326.
21. Moore J. The use of methylene blue in Gonorrhoea. BMJ 1897; 1:140.
22. Frost G. Methylene-blue in fevers. Ind Med Gaz 1908; 43:395.
23. Mahale N, Godavarthy P, Marreddy S, Gokhale SD, Funde P, Rajhans PA, 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; 25:934.
24. Carvalho PR, Sirois P, Fernandes PD. The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection. Peptides 2021; 135:170428.
25. Hanzlik P. Methylene blue as antidote for cyanide poisoning. JAMA 1933; 100:357.
26. Bodansky O. Mechanism of action of methylene blue in treatment of methemoglobinemia. JAMA 1950; 142:923.
27. Andreu GLP. The rationale for methylene blue utility against SARS-CoV-2 infection complications. J Pharm Pharmacogn Res 2021; 9:379-396.
28. Kwok ES, Howes D. Use of methylene blue in sepsis: a systematic review. J Intensive Care Med 2006; 21:359-363.
29. Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Müller TH, et al. Inactivation of Ebola virus and Middle East respiratory syndrome coronavirus in platelet concentrates and plasma by ultraviolet C light and methylene blue plus visible light, respectively. Transfusion 2018; 58:2202-2207.
30. Eickmann M, Gravemann U, Handke W, Tolksdorf F, Reichenberg S, Müller TH, et al. Inactivation of three emerging viruses–severe acute respiratory syndrome coronavirus, Crimean–Congo haemorrhagic fever virus and Nipah virus–in platelet concentrates by ultraviolet C light and in plasma by methylene blue plus visible light. Vox sanguinis 2020; 115:146-151.
31. 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 2021:2255.
32. Chuang S-T, Papp H, Kuczmog A, Eells R, Condor Capcha JM, Shehadeh LA, et al. Methylene blue is a nonspecific protein–protein interaction inhibitor with potential for repurposing as an antiviral for COVID-19. Pharmaceuticals 2022; 15:621.
33. Barron EG. The catalytic effect of methylene blue on the oxygen consumption of tumors and normal tissues. J Exp Med 1930; 52:447.
34. Schirmer RH, Adler H, Pickhardt M, Mandelkow E. Lest we forget you—methylene blue. Neurobiol Aging 2011;32:2325.e7-16.
35. Shaw JD, Miller S, Plourde A, Shaw DL, Wustrack R, Hansen EN. Methylene blue–guided debridement as an intraoperative adjunct for the surgical treatment of periprosthetic joint infection. J Arthroplasty 2017; 32:3718-3723.
36. Arakeri G, Us VR. Methylene blue as an anti-COVID-19 mouthwash in dental practice. Br J Oral Maxillofac Surg 2021; 59:135.
37. Choo SY. Rapidly rising methemoglobinemia in a patient with severe COVID‐19 treated successfully with red cell exchange transfusion. Ther Apher Dial 2021; 25:710.
38. Jack Clifton I, Leikin JB. Methylene blue. Am J Ther 2003; 10:289-291.
39. Ghahestani SM, Shahab E, Karimi S, Madani MH. Methylene blue may have a role in the treatment of COVID-19. Med Hypotheses 2020; 144:110163.
40. Gillman P. Methylene blue implicated in potentially fatal serotonin toxicity. Anaesthesia 2006; 61:1013-1014.
41. Andrei C, Laurentiu C, Fazel N, Mohammad N, Ioana B. Multiple potential targets of methylene blue against enveloped viruses: lessons from three nobel laureates. J Clin Cell Immunol 2021; 12:611.
42. Mengist HM, Mekonnen D, Mohammed A, Shi R, Jin T. Potency, safety, and pharmacokinetic profiles of potential inhibitors targeting SARS-CoV-2 main protease. Front Pharmacol 2021; 11:630500.
43. Milani D, Caruso L, Zauli E, Al Owaifeer AM, Secchiero P, Zauli G, et al. p53/NF-kB balance in SARS-CoV-2 infection: from OMICs, genomics and pharmacogenomics insights to tailored therapeutic perspectives (COVIDomics). Front Pharmacol 2022; 13.
44. Attiq A, Yao LJ, Afzal S, Khan MA. The triumvirate of NF-κB, inflammation and cytokine storm in COVID-19. Int Immunopharmacol 2021; 101:108255.
45. Vora SM, Lieberman J, Wu H. Inflammasome activation at the crux of severe COVID-19. Nat Rev Immunol 2021; 21:694-703.
46. Schoeman D, Fielding BC. Is there a link between the pathogenic human coronavirus envelope protein and immunopathology? a review of the literature. Front Microbiol 2020; 11:2086.
47. Davies DA, Adlimoghaddam A, Albensi BC. The effect of COVID-19 on NF-κB and neurological manifestations of disease. Mol Neurobiol 2021; 58:4178-4187.
48. Liu K, Fang Y-Y, Deng Y, Liu W, Wang M-F, Ma J-P, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chinese medical journal 2020; 133:1025-1031.
49.Channappanavar R, Perlman S, editors. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunopathol; 2017: Springer.
50. Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, et al. Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID‐19) infected patients. Br J Haematol 2020; 189:428-437.
51. Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med 2020; 217.
52. Oronsky BT, Knox SJ, Scicinski JJ. Is nitric oxide (NO) the last word in radiosensitization? a review. Transl Oncol 2012; 5:66-71.
53. Becker RC. COVID-19 update: COVID-19-associated coagulopathy. J Thromb Thrombolysis 2020; 50:54-67.
54. Huang C, Tong L, Lu X, Wang J, Yao W, Jiang B, et al. Methylene blue attenuates iNOS induction through suppression of transcriptional factor binding amid iNOS mRNA transcription. J Cell Biochem 2015; 116:1730-1740.
55. Sahu KK, Mishra AK, Mishra K. Methemoglobinemia in COVID-19. Am J Med Sci 2021; 362:222-224.
56. Taylor CT, Moncada S. Nitric oxide, cytochrome C oxidase, and the cellular response to hypoxia. Arterioscler Thromb Vasc Biol 2010; 30:643-647.
57.Farhana A, Lappin SL. Biochemistry, lactate dehydrogenase.  StatPearls 2022.
58. Zhao RZ, Jiang S, Zhang L, Yu ZB. Mitochondrial electron transport chain, ROS generation and uncoupling. Int J Mol Med 2019; 44:3-15.
59. Poteet E, Winters A, Yan L-J, Shufelt K, Green KN, Simpkins JW, et al. Neuroprotective actions of methylene blue and its derivatives. PloS one 2012; 7:e48279.
60. Chesney JA, Eaton JW, Mahoney Jr JR. Bacterial glutathione: a sacrificial defense against chlorine compounds. J Bacteriol 1996; 178:2131-2135.
61. Ramalingam S, Cai B, Wong J, Twomey M, Chen R, Fu RM, et al. Antiviral innate immune response in non-myeloid cells is augmented by chloride ions via an increase in intracellular hypochlorous acid levels. Sci Rep 2018; 8:1-11.
62. Salaris SC, Babbs CF, Voorhees III WD. Methylene blue as an inhibitor of superoxide generation by xanthine oxidase: a potential new drug for the attenuation of ischemia/reperfusion injury. Biochem Pharmacol 1991; 42:499-506.
63. Imai S-I, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000; 403:795-800.
64. Meng T, Qin W, Liu B. SIRT1 antagonizes oxidative stress in diabetic vascular complication. Front Endocrinol 2020; 11:568861.
65. Golestaneh N, Chu Y, Cheng SK, Cao H, Poliakov E, Berinstein DM. Repressed SIRT1/PGC-1α pathway and mitochondrial disintegration in iPSC-derived RPE disease model of age-related macular degeneration. J Transl Med 2016; 14:1-17.
66. Shin SY, Kim TH, Wu H, Choi YH, Kim SG. SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis. Eur J Pharmacol 2014; 727:115-124.
67. Petri S, Körner S, Kiaei M. Nrf2/ARE signaling pathway: key mediator in oxidative stress and potential therapeutic target in ALS. Neurol Res Int 2012; 2012.
68. Mendonca P, Soliman KF. Flavonoids activation of the transcription factor Nrf2 as a hypothesis approach for the prevention and modulation of SARS-CoV-2 infection severity. Antioxidants 2020; 9:659.
69. Olagnier D, Farahani E, Thyrsted J, Blay-Cadanet J, Herengt A, Idorn M, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat Commun 2020; 11:1-12.
70. Sadovnikova IS, Gureev AP, Ignatyeva DA, Gryaznova MV, Chernyshova EV, Krutskikh EP, et al. Nrf2/ARE activators improve memory in aged mice via maintaining of mitochondrial quality control of brain and the modulation of gut microbiome. Pharmaceuticals 2021; 14:607-633.
71. Meini S, Zanichelli A, Sbrojavacca R, Iuri F, Roberts AT, Suffritti C, et al. Understanding the pathophysiology of COVID-19: could the contact system be the key? Front Immunol 2020; 11:2014-2022.
72. Silva GM, da Silva MC, Nascimento DVG, Lima Silva EM, Gouvêa FFF, de França Lopes LG, et al. Nitric oxide as a central molecule in hypertension: Focus on the vasorelaxant activity of new nitric oxide donors. Biology 2021; 10:1041-1066.
73. Gorog DA, Storey RF, Gurbel PA, Tantry US, Berger JS, Chan MY, et al. Current and novel biomarkers of thrombotic risk in COVID-19: a consensus statement from the international COVID-19 thrombosis biomarkers colloquium. Nat Rev Cardiol 2022:1-21.
74. Al-Kuraishy HM, Hussien NR, Al-Naimi MS, Al-Buhadily AK, Al-Gareeb AI, Lungnier C. Renin–Angiotensin system and fibrinolytic pathway in COVID-19: One-way skepticism. Biomed Biotechnol Res J 2020; 4:33.
75. Tolouian R, Vahed SZ, Ghiyasvand S, Tolouian A, Ardalan M. COVID-19 interactions with angiotensin-converting enzyme 2 (ACE2) and the kinin system; looking at a potential treatment. J Renal Inj Prev 2020; 9:e19.
76.Alorend EJ. The effect of dietary arachidonic acid concentration on Atlantic halibut (Hippoglossus hippoglossus) broodstock performance. Assessment of egg, milt and larval quality: University of Stirling (United Kingdom); 2004.
77. Evora PRB. Methylene blue is a guanylate cyclase inhibitor that does not interfere with nitric oxide synthesis. Tex Heart Inst J 2016; 43:103.
78. Yap JK, Moriyama M, Iwasaki A. Inflammasomes and pyroptosis as therapeutic targets for COVID-19. J Immunol 2020; 205:307-312.
79. Naymagon L, Berwick S, Kessler A, Lancman G, Gidwani U, Troy K. The emergence of methemoglobinemia amidst the COVID‐19 pandemic. Am J Hematol 2020.
80. Faisal H, Bloom A, Gaber AO. Unexplained methemoglobinemia in coronavirus disease 2019: a case report. A&a Practice 2020; 14:e01287.
81. Strakhovskaya M, Meerovich G, Kuskov A, Gonchukov S, Loschenov V. Photoinactivation of coronaviruses: going along the optical spectrum. Laser Phys Lett 2020; 17:093001.
82. Ramires MCCH, Mattia MB, Tateno RY, Palma LF, Campos L. A combination of phototherapy modalities for extensive lip lesions in a patient with SARS‐CoV‐2 infection. Photodiagnosis Photodyn Ther 2021; 33:102196.
83. Hamidi-Alamdari D, Hafizi-Lotfabadi S, Bagheri-Moghaddam A, Safari H, Mozdourian M, Javidarabshahi Z, et al. Methylene blue for treatment of hospitalized covid-19 patients: a randomized, controlled, open-label clinical trial, phase 2. Rev Invest Clin 2021; 73:190-198.
84. Lotfabadi S, Moghaddam A, Shamsi M, Hoseini H, Khaleghimanesh B, Saadatian S. Methylene blue as rescue therapy for COVID-19 patients who failed to respond to other thera-pies (Final Report). Am J Clin Case Rep 2021; 2:1040.
85. Moghaddam AB, Lotfabadi SH, Agheli-Rad M, Safar MHE, Toghraei M, Arastoo m, et al. Methylene blue as rescue therapy for COVID-19 patients who failed to respond to other therapies (first report). J Case Rep Med Sci 2021:4-10.
86. Lotfabadi SH, Alamdari DH, Darban BM. Treatment of severe COVID-19 outpatients by methylene blue first report. Biomed J Sci Tech Res 2022; 42:33443-33447.
87. Alemany A, Millat-Martinez P, Corbacho-Monné M, Malchair P, Ouchi D, Ruiz-Comellas A, et al. High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial. Lancet Respir Med 2022; 10:278-288.
88. Ghodke BA, Ghodke A, Mahadik V, Thorat P. Methylene blue treatment for moderate-to-severe cases of acute respiratory syndrome due to COVID-19 infection: clinical outcomes—a prospective study. MGM J Med Sci 2022; 9:25-32.
89. Hepburn J, Williams-Lockhart S, Bensadoun RJ, Hanna R. A novel approach of combining methylene blue photodynamic inactivation, photobiomodulation and oral ingested methylene blue in COVID-19 management: A pilot clinical study with 12-month follow-up. Antioxidants 2022; 11:2211.
90. Dos Santos JA, Da Silva RLC, De Jesus TFDA, De Paula RM, El Haje GLC, Germoglio AHB, et al. Herpes-like lesions in patients with covid-19: report of four cases and treatment approach. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 134:e154.
91. Anand D, Lalitha D, Surya Sudhakar G, FHNSO M. Management of COVID-19 positive pregnant women and general population with methylene blue and cefditoren-pivoxil. J MAR Oncol 2022;4:1-14.
92. Franzen D, Klüppelberg J, Hagemeister J, Arentz J. Photodynamic inactivation of symptomatic COVID-19 disease in a married couple. J Immunol Res Infect Dis 2022; 2:1-2.
93. Pires L, Wilson BC, Bremner R, Lang A, Larouche J, McDonald R, et al. Translational feasibility and efficacy of nasal photodynamic disinfection of SARS-CoV-2. Sci Rep 2022; 12:14438.
94. Campos L, Ramires MCCH, Oliveira MTS, Zerbinati R, Braz-Silva P, Martins F, et al. Photodynamic viral inactivation in COVID-19-related orofacial lesions: myth or fact? Photodiagnosis Photodyn Ther 2023.
95. Thimmappa T, Siddesh K, Kumar N, Ramesh S. Role of methylene blue in COVID-19 associated Mucormycosis. J Cardiovasc Dis Res 2023; 14: 1021-1025.
96. Arentz J, von der Heide H-J. Evaluation of methylene blue based photodynamic inactivation (PDI) against intracellular B-CoV and SARS-CoV2 viruses under different light sources in vitro as a basis for new local treatment strategies in the early phase of a COVID-19 infection. Photodiagnosis Photodyn Ther 2022; 37:102642.
97. Scholte FE, Kabra KB, Tritsch SR, Montgomery JM, Spiropoulou CF, Mores CN, et al. Exploring inactivation of SARS-CoV-2, MERS-CoV, Ebola, Lassa, and Nipah viruses on N95 and KN95 respirator material using photoactivated methylene blue to enable reuse. Am J Infect Control 2022; 50:863-870.
98. Lendvay TS, Xu J, Chen J, Clark T, Cui Y. Methylene blue applied to N95 respirators and medical masks for SARS-CoV-2 decontamination: What is the likelihood of inhaling methylene blue? Am J Infect Control 2022; 50:857-862.
99. Lendvay TS, Chen J, Harcourt BH, Scholte FE, Lin YL, Kilinc-Balci FS, et al. Addressing personal protective equipment (PPE) decontamination: Methylene blue and light inactivates severe acute respiratory coronavirus virus 2 (SARS-CoV-2) on N95 respirators and medical masks with maintenance of integrity and fit. Infect Control Hosp Epidemiol 2022; 43:876-885.
100. Volle R, Murer L, Petkidis A, Andriasyan V, Savi A, Bircher C, et al. Methylene blue, Mycophenolic acid, Posaconazole, and Niclosamide inhibit SARS-CoV-2 Omicron variant BA. 1 infection of human airway epithelial organoids. Curr Res Microb Sci 2022; 3:100158.
101. Hobson‐Peters J, Amarilla AA, Rustanti L, Marks DC, Roulis E, Khromykh AA, et al. Inactivation of SARS‐CoV‐2 infectivity in platelet concentrates or plasma following treatment with ultraviolet C light or with methylene blue combined with visible light. Transfusion 2023; 63:288-293.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 7
July 2024
Pages 780-792

Files

Share

How to cite

Statistics