Methylene Blue for Treatment of Hospitalized COVID-19 Patients: A Randomized, Controlled, Open-Label Clinical Trial, Phase 2

Hamidi-Alamdari, Daryoush; Hafizi-Lotfabadi, Saied; Bagheri-Moghaddam, Ahmad; Safari, Hossin; Mozdourian, Mahnaz; Javidarabshahi, Zahra; Peivandi-Yazdi, Arash; Ali-Zeraati, Abass; Sedaghat, Alireza; Poursadegh, Farid; Barazandeh-Ahmadabadi, Fatemeh; Agheli-Rad, Marzieh; Tavousi, Seyed M.; Vojouhi, Shohreh; Amini, Shahram; Amini, Mahnaz; Majid-Hosseini, Seyed; Tavanaee-Sani, Ashraf; Ghiabi, Amin; Nabavi-Mahalli, Shima; Morovatdar, Negar; Rajabi, Omid; Koliakos, George

doi:10.24875/ric.21000028

Cited by 21 publications

(24 citation statements)

References 9 publications

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“…For instance, 2 mg/kg dosage (recommended for treatment of methemoglobinemia) yields plasma levels of about 0.1 μM with a half life of 5–6h. Remarkably, a COVID-19 phase II clinical trial at 1 mg/kg per oral (every 8 h for two days, and then twice daily for the following 12 days) reported a 50% mortality reduction of severe COVID-19 cases, as well as increased blood oxygenation and respiratory rate ( Hamidi-Alamdari et al, 2021 ). Clinical trials comparing regular as well as reduced dosages of MB and Remdesivir may be warranted ( Beigel et al, 2020a ; Hamidi-Alamdari et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Remarkably, a COVID-19 phase II clinical trial at 1 mg/kg per oral (every 8 h for two days, and then twice daily for the following 12 days) reported a 50% mortality reduction of severe COVID-19 cases, as well as increased blood oxygenation and respiratory rate ( Hamidi-Alamdari et al, 2021 ). Clinical trials comparing regular as well as reduced dosages of MB and Remdesivir may be warranted ( Beigel et al, 2020a ; Hamidi-Alamdari et al, 2021 ). Endpoints may include survival and blood oxygenation levels, both of which are expected to be enhanced by the combination treatment due to the anti-viral effects of both agents and the potency of MB to treat methemoglobinemia in patients resistant to oxygen therapy.…”

Section: Discussionmentioning

confidence: 99%

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Identification of broad anti-coronavirus chemical agents for repurposing against SARS-CoV-2 and variants of concern

Murer¹,

Volle²,

Andriasyan³

et al. 2022

Current Research in Virological Science

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Endemic human coronaviruses (hCoVs) 229E and OC43 cause respiratory disease with recurrent infections, while severe acute respiratory syndrome (SARS)-CoV-2 spreads across the world with impact on health and societies. Here, we report an image-based multicycle infection procedure with α-coronavirus hCoV-229E-eGFP in an arrayed chemical library screen of 5440 clinical and preclinical compounds. Toxicity counter selection and challenge with the β-coronaviruses OC43 and SARS-CoV-2 in tissue culture and human airway epithelial explant cultures (HAEEC) identified four FDA-approved compounds with oral availability. Methylene blue (MB, used for the treatment of methemoglobinemia), Mycophenolic acid (MPA, used in organ transplantation) and the anti-fungal agent Posaconazole (POS) had the broadest anti-CoV spectrum. They inhibited the shedding of SARS-CoV-2 and variants-of-concern (alpha, beta, gamma, delta) from HAEEC in either pre- or post exposure regimens at clinically relevant concentrations. Co-treatment of cultured cells with MB and the FDA-approved SARS-CoV-2 RNA-polymerase inhibitor Remdesivir reduced the effective anti-viral concentrations of MB by 2-fold, and Remdesivir by 4 to 10-fold, indicated by BLISS independence synergy modelling. Neither MB, nor MPA, nor POS affected the cell delivery of SARS-CoV-2 or OC43 (+)sense RNA, but blocked subsequent viral RNA accumulation in cells. Unlike Remdesivir, MB, MPA or POS did not reduce the release of viral RNA in post exposure regimen, thus indicating infection inhibition at a post-replicating step as well. In summary, the data emphasize the power of unbiased, full cycle compound screens to identify and repurpose broadly acting drugs against coronaviruses.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of broad anti-coronavirus chemical agents for repurposing against SARS-CoV-2 and variants of concern

Murer¹,

Volle²,

Andriasyan³

et al. 2022

Current Research in Virological Science

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“…Methylene blue has been assessed in combination with vitamin C and N-acetyl cysteine in severe COVID-19 [ 51 , 52 ]. The addition of methylene blue to standard of care treatment significantly improved respiratory distress, hospital stay and mortality rate in severe patients with confirmed COVID-19 [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

Gendrot

Jardot

Delandre

et al. 2021

JCM

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A new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19), which emerged in Wuhan, China in December 2019, has spread worldwide. Currently, very few treatments are officially recommended against SARS-CoV-2. Identifying effective, low-cost antiviral drugs with limited side effects that are affordable immediately is urgently needed. Methylene blue, a synthesized thiazine dye, may be a potential antiviral drug. Antiviral activity of methylene blue used alone or in combination with several antimalarial drugs or remdesivir was assessed against infected Vero E6 cells infected with two clinically isolated SARS-CoV-2 strains (IHUMI-3 and IHUMI-6). Effects both on viral entry in the cell and on post-entry were also investigated. After 48 h post-infection, the viral replication was estimated by RT-PCR. The median effective concentration (EC50) and 90% effective concentration (EC90) of methylene blue against IHUMI-3 were 0.41 ± 0.34 µM and 1.85 ± 1.41 µM, respectively; 1.06 ± 0.46 µM and 5.68 ± 1.83 µM against IHUMI-6. Methylene blue interacted at both entry and post-entry stages of SARS-CoV-2 infection in Vero E6 cells as retrieved for hydroxychloroquine. The effects of methylene blue were additive with those of quinine, mefloquine and pyronaridine. The combinations of methylene blue with chloroquine, hydroxychloroquine, desethylamodiaquine, piperaquine, lumefantrine, ferroquine, dihydroartemisinin and remdesivir were antagonist. These results support the potential interest of methylene blue to treat COVID-19.

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“…In the MB group, the hospital stay was shortened significantly (p = 0.004), and the mortality rate was 12.5% compared to 22.5% in the SC group. Thus, the addition of MB in the protocol of COVID-19 treatment enhanced the oxygen saturation levels and improved respiratory distress in severe cases of COVID-19, shortened hospital stay, and reduced mortality [75] .…”

Section: Clinical Studies Of Mb In Covid-19 Managementmentioning

confidence: 97%

Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations

Dabholkar¹,

Gorantla²,

Dubey³

et al. 2021

Biomedicine & Pharmacotherapy

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The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is the most recent coronaviruses, which has infected humans, and caused the disease COVID-19. The World Health Organization has declared COVID-19 as a pandemic in March 2020. The SARS-CoV-2 enters human hosts majorly via the respiratory tract, affecting the lungs first. In few critical cases, the infection progresses to failure of the respiratory system known as acute respiratory distress syndrome acute respiratory distress syndrome may be further associated with multi-organ failure and vasoplegic shock. Currently, the treatment of COVID-19 involves use of antiviral and anti-cytokine drugs. However, both the drugs have low efficacy because they cannot inhibit the production of free radicals and cytokines at the same time. Recently, some researchers have reported the use of methylene blue (MB) in COVID-19 management. MB has been used since a long time as a therapeutic agent, and has been approved by the US FDA for the treatment of other diseases. The additional advantage of MB is its low cost. MB is a safe drug when used in the dose of < 2 mg/kg. In this review, the applicability of MB in COVID-19 and its mechanistic aspects have been explored and compiled. The clinical studies have been explained in great detail. Thus, the potential of MB in the management of COVID-19 has been examined.

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Methylene Blue for Treatment of Hospitalized COVID-19 Patients: A Randomized, Controlled, Open-Label Clinical Trial, Phase 2

Cited by 21 publications

References 9 publications

Identification of broad anti-coronavirus chemical agents for repurposing against SARS-CoV-2 and variants of concern

Identification of broad anti-coronavirus chemical agents for repurposing against SARS-CoV-2 and variants of concern

In Vitro Evaluation of the Antiviral Activity of Methylene Blue Alone or in Combination against SARS-CoV-2

Repurposing methylene blue in the management of COVID-19: Mechanistic aspects and clinical investigations

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