Methylene Blue for Treatment of Hospitalized COVID-19 Patients: A Randomized, Controlled, Open-Label Clinical Trial, Phase 2
Daryoush Hamidi-Alamdari, Saied Hafizi-Lotfabadi, Ahmad Bagheri-Moghaddam, Hossin Safari, Mahnaz Mozdourian, Zahra Javidarabshahi, Arash Peivandi-Yazdi, Abass Ali-Zeraati, Alireza Sedaghat, Farid Poursadegh, Fatemeh Barazandeh-Ahmadabadi, Marzieh Agheli-Rad, Seyed M Tavousi, Shohreh Vojouhi, Shahram Amini, Mahnaz Amini, Seyed Majid-Hosseini, Ashraf Tavanaee-Sani, Amin Ghiabi, Shima Nabavi-Mahalli, Negar Morovatdar, Omid Rajabi, George Koliakos
Revista de investigaci�n Cl�nica, doi:10.24875/ric.21000028
Background: There is no pharmacological intervention on the treatment of hypoxemia and respiratory distress in COVID-19 patients. Objective: The objective of the study was to study the effect of the reduced form of methylene blue (MB) on the improvement of oxygen saturation (SpO 2 ) and respiratory rate (RR). Methods: In an academic medical center, 80 hospitalized patients with severe COVID-19 were randomly assigned to receive either oral MB along with standard of care (SOC) (MB group, n = 40) or SOC only (SOC group, n=40). The primary outcomes were SpO 2 and RR on the 3 rd and 5 th days. The secondary outcomes were hospital stay and mortality within 28 days. Results: In the MB group, a significant improvement in SpO 2 and RR was observed on the 3 rd day (for both, p < 0.0001) and also the 5 th day (for both, p < 0.0001). In the SOC group, there was no significant improvement in SpO 2 (p = 0.24) and RR (p = 0.20) on the 3 rd day, although there was a significant improvement of SpO 2 (p = 0.002) and RR (p = 0.01) on the 5 th day. In the MB group in comparison to the SOC group, the rate ratio of increased SpO 2 was 13.5 and 2.1 times on the 3 rd and 5 th days, respectively. In the MB group compared with the SOC group, the rate ratio of RR improvement was 10.1 and 3.7 times on the 3 rd and 5 th days, respectively. The hospital stay was significantly shortened in the MB group (p = 0.004), and the mortality was 12.5% and 22.5% in the MB and SOC groups, respectively. Conclusions: The addition of MB to the treatment protocols significantly improved SpO 2 and respiratory distress in COVID-19 patients, which resulted in decreased hospital stay and mortality. ClinicalTrials.gov: NCT04370288 (REV INVEST CLIN. 2021;73(3):XX-XX)
References
Alamdari, Moghaddam, Amini, Keramati, Zarmehri et al., Application of methylene blue -vitamin C -N-acetyl for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial, Eur J Pharmacol
Bojadzic, Alcazar, Buchwald, Methylene blue inhibits the SARS-CoV-2 spike-ACE2 protein-protein interaction-a mechanism that can contribute to its antiviral activity against COV-ID-19, Front Pharmacol
Chan, Yang, Kwan, Cheng, Lee et al., Structure-based optimization of FDA-approved drug methylene blue as a c-myc G-quadruplex DNA stabilizer, Biochimie
Haynes, Chan, Wong, Li, Wu et al., Facile oxidation of leucomethylene blue and dihydroflavins by artemisinins: relationship with flavoenzyme function and antimalarial mechanism of action, ChemMed Chem
Janssen, Ekström, Currow, Johnson, Maddocks et al., COVID-19: guidance on palliative care from a European Respiratory Society international task force, Eur Respir J
Kovacs, Prevention of cytopathic effect and propagation of poliovirus by methylene blue, Z Naturforsch B
Lin, Wang, Chen, Zhuang, Ke et al., Methylene blue mitigates acute neuroinflammation after spinal cord injury through inhibiting NLRP3 inflammasome activation in microglia, Front Cell Neurosci
May, Qu, Cobb, Reduction and uptake of methylene blue by human erythrocytes, Am J Physiol Cell Physiol
May, Qu, Whitesell, Generation of oxidant stress in cultured endothelial cells by methylene blue: protective effects of glucose and ascorbic acid, Biochem Pharmacol
Mayer, Brunner, Schmidt, Inhibition of nitric oxide synthesis by methylene blue, Biochem Pharmacol
Mcpherson, Henry's Clinical Diagnosis and Management by Laboratory Methods: First South Asia Edition
Miclescu, Wiklund, Methylene blue, an old drug with new indications, J Rom Anest Terap Int
Oz, Lorke, Hasan, Petroianu, Cellular and molecular actions of methylene blue in the nervous system, Med Res Rev
Perkins, Couper, Connolly, Baillie, Bradley et al., RECOVERY-respiratory support: respiratory strategies for patients with suspected or proven COVID-19 respiratory failure; continuous positive airway pressure, high-flow nasal oxygen, and standard care: a structured summary of a study protocol for a randomised controlled trial, Trials
Prakash, Saini, Mullick, Pawar, Green urine: a cause for concern?, J Anaesthesiol Clin Pharmacol
Riedel, Lang, Oetjen, Schlapp, Shibata, Inhibition of oxygen radical formation by methylene blue, aspirin, or alphalipoic acid, prevents bacterial-lipopolysaccharide-induced fever, Mol Cel Biochem
Salaris, Babbs, Voorhees, Methylene blue as an inhibitor of superoxide generation by xanthine oxidase. A potential new drug for the attenuation of ischemia/reperfusion injury, Biochem Pharmacol
Shenoy, Luchtel, Gulani, Considerations for target oxygen saturation in COVID-19 patients: are we under-shooting?, BMC Med
Smith, Bushek, Leclaire, Prosser, COVID-19 Drug Therapy, Clinical Drug Information
Woo, Heil, A prospective evaluation of methylene blue and gentian violet dressing for management of chronic wounds with local infection, Int Wound J
