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The Rationale for Methylene Blue Utility Against SARS-Cov-2 Infection

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The Rationale for Methylene Blue Utility Against SARS-Cov-2 Infection © 2021 Journal of Pharmacy & Pharmacognosy Research, 9 (3), 379-396, 2021 ISSN 0719-4250 http://jppres.com/jppres Original Article The rationale for methylene blue utility against SARS-CoV-2 infection complications [Fundamentación de la utilidad del azul de metileno contra las complicaciones de la infección por SARS-CoV-2] Gilberto L. Pardo Andreu Center for Research and Biological Evaluations, Institute of Pharmaceutical and Food Sciences, University of Havana (UH), Av. 23 # 2317 b/ 214 and 222, La Coronela, La Lisa, PO 13600 Havana, Cuba. *E-mail: [email protected] Abstract Resumen Context: Almost one year after the onset of COVID-19 pandemic in Contexto: Casi un año después del inicio de la pandemia de COVID-19 Wuhan, China and still no specific therapy has emerged, counting en Wuhan, China, y aún no ha surgido una terapia específica, contando millions of dead worldwide. The association of an uncontrolled SARS- millones de muertos en todo el mundo. La asociación de una replicación CoV-2 replication and host-dependent mechanisms in COVID-19 no controlada del SARS-CoV-2 y los mecanismos dependientes del pathogenesis suggest that any therapeutic strategy must combine hospedero en la patogénesis del COVID-19 sugieren que cualquier antiviral drugs and adjuvant therapy to modulate the host’s responses. estrategia terapéutica debe combinar fármacos antivirales y terapia Owing to the multiplicity of mechanisms involved in COVID-19 adyuvante para modular las respuestas del hospedero. Debido a la pathogenic expressions, such as severe hypoxia, excessive inflammatory multiplicidad de mecanismos involucrados en las expresiones reaction and impaired immune response, an emerging therapeutic patogénicas de la COVID-19, como la hipoxia severa, la reacción paradigm is the searching for agents acting as multifunctional drugs. inflamatoria excesiva y la respuesta inmune deteriorada, un paradigma Methylene blue (MB), the antique medication, seems to meet the above terapéutico emergente es la búsqueda de agentes que actúen como criterion. fármacos multifuncionales. El azul de metileno (AM), un antiguo Aims: To summarize the probable beneficial effects of MB against medicamento, parece cumplir con el criterio anterior. COVID-19 supported by a discussion of the drug mechanisms of action Objetivos: Resumir los probables efectos beneficiosos del AM contra la counteracting the pathogenic mechanisms of the disease. COVID-19 apoyados por una discusión de los mecanismos de acción del Methods: PubMed, Google Scholar, and Scopus databases were used to fármaco que pudieran contrarrestar los mecanismos patogénicos de la collect the biomedical research on MB, and the discussed dataset finally enfermedad. included 150 published articles. Those COVID-19 pathogenic pathways Métodos: Se utilizaron las bases de datos PubMed, Google Scholar y possibly targeted by MB were critically appraised. Scopus para recopilar las investigaciones biomédicas sobre el AM, y el Results: It was found that MB may act as multimodal agent by targeting conjunto de datos que se discutió finalmente incluyó 150 artículos simultaneously several pathogenic mechanisms of COVID-19 as hypoxic publicados. Se evaluaron críticamente aquellos mecanismos patogénicos damage, hyper-inflammatory reaction and death signaling activation. It de la COVID-19 posibles blancos farmacológicos del AM. also may act as a virucidal agent by preventing virus-induced metabolic Resultados: Se encontró que el AM puede actuar como un agente re-orientation. Its high safety profile, low cost, along with the multimodal al actuar simultáneamente sobre varios mecanismos mechanisms discussed herein might be essential criteria to test MB as an patogénicos de la COVID-19 como el daño hipóxico, la reacción adjuvant therapy against COVID-19. hiperinflamatoria y la activación de señalizaciones de muerte. También Conclusions: Overall, this critical review provides theoretical grounds for puede actuar como agente virucida al prevenir la reorientación MB clinical evaluation in the therapeutic management of SARS-CoV-2 metabólica del hospedero inducida por el virus. Su elevado perfil de infection. seguridad, bajo costo, junto con los mecanismos discutidos en este documento, podrían ser criterios esenciales para probar el AM como terapia adyuvante contra la COVID-19. Conclusiones En general, esta revisión crítica proporciona las bases teóricas para la evaluación clínica del AM en el manejo terapéutico de la infección por SARS-CoV-2. Keywords: COVID-19; methylene blue; SARS-CoV-2. Palabras Clave: azul de metileno; COVID-19; SARS-CoV-2. ARTICLE INFO AUTHOR INFO Received: January 14, 2021. ORCID: 0000-0001-7040-7031 Received in revised form: January 20, 2021. Accepted: January 21, 2021. Available Online: January 23, 2021. _____________________________________ Pardo Andreu Methylene blue therapy against COVID-19 INTRODUCTION antioxidants (Lythgoe and Middleton, 2020; Otta- viani and Stebbing, 2020). Yet, nonstand- Coronavirus infectious disease (COVID-19), the ard/specific treatment has emerged against ongoing pandemic infection caused by severe COVID-19, which keeps active the quest for other acute respiratory syndrome coronavirus 2 (SARS- anti-COVID-19 compounds (Huang et al., 2020). CoV-2), has generated significant socio-economic disruption, overwhelming national’s health sys- Methylene Blue (MB) was first synthesized as a tems worldwide. At the time this review was be- dye in 1876, and soon after Paul Erlich demon- ing written, more than 90 million reported cases strated its antimalarial effects (Guttmann and Ehr- and over 2 million deaths have been already re- lich, 1891). As early as in the 1930s, MB began to ported globally (WHO, 2021). Approximately 10- be used for the treatment of methemoglobinemia 20% of confirmed cases progress to critical illness, (Mansouri and Lurie, 1993), while it proved to be with a higher mortality rate than less severe pa- an effective antidote for carbon monoxide and tients (Huang et al., 2020; Zhou et al., 2020). In- cyanide (CN) poisoning as well (Brooks, 1933; deed, mortality of critically ill patients is around Draize, 1933). MB is also a recommended treat- 50%, by contrast with 2.3% for overall COVID-19 ment for vasoplegic syndrome in critically ill car- patients (Guan et al., 2020; Huang et al., 2020; Wu diac surgical patients (Evora et al., 1997; Evora, and McGoogan, 2020). This phenomenon unravels 2000; McCartney et al., 2018), and in septic shock, particularities of pathogenesis mechanisms and if administered early (Puntillo et al., 2020). It is risk factors interactions leading to a critical illness currently being utilized as antimalarial agent state, characterized by severe pneumonia, acute (Dicko et al., 2018; Mendes et al., 2019) and for the respiratory distress syndrome (ARDS), septic decontamination of plasma by various European shock and/or multiple organ failure (Huang et al., blood collection/treatment agencies (Wainwright 2020; Xu et al., 2020). Currently, there are no clini- 2000; 2002). Recently, a phase I clinical trials cally approved vaccines or specific therapeutic (NCT04370288; April 19, 2020) reported the benefi- drugs available for COVID-19, being the sympto- cial effects of MB administration to five critical matic management and oxygen supply the main COVID-19 patients: four patients surmounted the clinical treatment options. disease by this intervention (Alamdari et al., 2020). Although vaccines seem to be the ultimate solu- This review is intended to provide mechanistic tion against COVID-19, therapeutics targeting the evidence supporting the findings cited above. At abovementioned pathogenic mechanisms, and the same time, we suggest that MB acting multi- related to the host responses, are needed. Howev- functionally against key pathogenic components of er, drug development is a costly and timely pro- COVID-19 might have supportive adjuvant use- cess with a high attrition rate (Lythgoe and Mid- fulness in treating the infection, particularly its dleton, 2020). Drugs repurposing seems to be the complications, including severe hypoxemia, hy- expedite way to deliver a medication to the bed- per-inflammatory reactions, and apoptotic- side with the minimum bench time. Along these mediated lymphopenia. The long period of safe lines, several proposals have emerged since use of MB in humans makes it much easier thera- COVID-19 has spread (Jean et al., 2020; Kandeel peutically to develop and it is one of the reasons and Al-Nazawi, 2020; Li and De Clercq, 2020; Ser- why there is so much interest in it. Bearing in afin et al., 2020), and more than 600 clinical trials mind that the pathogenesis of COVID-19 has been have launched, including repurposed antivirals, recently extensively reviewed (Chu et al., 2020; antibiotics, and host-targeted agents like im- Domingo et al., 2020; Li et al., 2020), only those munomodulators, anti-inflammatory drugs, and pathogenic pathways possibly targeted by MB will be discussed here. http://jppres.com/jppres J Pharm Pharmacogn Res (2021) 9(3): 380 Pardo Andreu Methylene blue therapy against COVID-19 MATERIAL AND METHODS Studies with model viruses indicate that MB- photomediated viral RNA-protein cross linkage is This study was conducted as a systematic re- a crucial lethal lesion, most likely promoted by view in which was explored the biomedical litera- singlet oxygen as a key intermediate (Foote, 1976; ture on methylene blue (1891-2020) using PubMed, Floyd et al., 2004). The positive charge of MB in- Google Scholar, and Scopus databases,
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