The rationale for methylene blue utility against SARS-CoV-2 infection complications

Abstract

Context: Almost one year after the onset of COVID-19 pandemic in Wuhan, China and still no specific therapy has emerged, counting millions of dead worldwide. The association of an uncontrolled SARS-CoV-2 replication and host-dependent mechanisms in COVID-19 pathogenesis suggest that any therapeutic strategy must combine antiviral drugs and adjuvant therapy to modulate the host’s responses. Owing to the multiplicity of mechanisms involved in COVID-19 pathogenic expressions, such as severe hypoxia, excessive inflammatory reaction and impaired immune response, an emerging therapeutic paradigm is the searching for agents acting as multifunctional drugs. Methylene blue (MB), the antique medication, seems to meet the above criterion. Aims: To summarize the probable beneficial effects of MB against COVID-19 supported by a discussion of the drug mechanisms of action counteracting the pathogenic mechanisms of the disease. Methods: PubMed, Google Scholar, and Scopus databases were used to collect the biomedical research on MB, and the discussed dataset finally included 150 published articles. Those COVID-19 pathogenic pathways possibly targeted by MB were critically appraised. Results: It was found that MB may act as multimodal agent by targeting simultaneously several pathogenic mechanisms of COVID-19 as hypoxic damage, hyper-inflammatory reaction and death signaling activation. It also may act as a virucidal agent by preventing virus-induced metabolic re-orientation. Its high safety profile, low cost, along with the mechanisms discussed herein might be essential criteria to test MB as an adjuvant therapy against COVID-19. Conclusions: Overall, this critical review provides theoretical grounds for MB clinical evaluation in the therapeutic management of SARS-CoV-2 infection.

From Palliation to Cure: Two Case Reports on Methylene Blue Benefits in Elderly, Frail, and Critically Ill COVID-19 Patients

“…In particular, the ability of MB to modulate inflammasome activation and cytokine production in different clinical settings [8,[12][13][14] might support in selected cases an early use of the dye to counteract the virus-induced hyperinflammatory status. Beyond its broad-spectrum anti-inflammasome activity, MB's ability to restore mitochondrial function [12,19] could also have contributed to improving the overall clinical picture in our cases. Moreover, whereas the anticytokine drugs (anakinra, tocilizumab) used for the treatment of COVID-19-related ARDS can restrain the action of a few cytokines, MB exhibits multitargeting/ pleiotropic activities [4,6].…”

“…Moreover, in in vitro models, MB was shown to exert antiviral activity against SARS-CoV-2 by inhibiting the binding of the spike protein to the ACE2 receptor [11,13,[16][17][18]. Other studies have shown that MB was able to restore the mitochondrial respiratory chain damaged by SARS-CoV-2 infection [12,19,20].…”

“…In this context, methylene blue (MB), discovered in the late 1800s, could represent a versatile adjuvant agent in the management of patients with severe COVID-19 disease. The drug is currently registered for methaemoglobinaemia and used as an adjuvant in urinary tract inflammation, drug-resistant malaria, and extreme cases of shock of various aetiologies [11][12][13][14]. The kinetic and dynamic profiles of MB are safe and, with adverse effects recorded for very high doses, cautions are requested only in case of combination with selective serotonin reuptake inhibitors for the risk of serotonergic crisis and in patients with glucose-6-phosphate dehydrogenase deficiency for risk of haemolytic anaemia [13,14].…”

“…In reducing the production of free radicals and cytokines and exerting a direct action on the inflammasome, MB has the potential to modulate the hyper inflammatory response responsible for both the severe discomfort and the unfavorable clinical evolution of COVID-19. Notably, several studies have shown that MB may contribute to reducing the inflammation triggered by the activation of alveolar macrophages by inhibiting ROS production via the blockade of superoxide anion synthesis; counteracting the formation of RNS and reducing cytokine release [12][13][14]. The anti-inflammasome activity of MB can also rely upon its ability to down modulate the expression of gene coding for inflammasome components via inhibition of NF-κB signaling [15].…”

COVID-19 vaccine adverse events: Evaluating the pathophysiology from an undersulfated and degraded glycocalyx perspective

“…Low-dose methylene blue is a multimodal drug that has been used successfully to treat severe COVID-19 [376][377][378] . It has antiviral, anti-inflammatory and antioxidant properties, making it a promising treatment option to address mitochondrial dysfunction, chronic and neuroinflammation, oxidative stress, endotheliitis, and metabolic disturbances in COVID-19 vaccine AEs.…”