Application of methylene blue -vitamin C –N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial

Abstract

COVID-19 is a global catastrophic event that causes severe acute respiratory syndrome. The mechanism of the disease remains unclear, and hypoxia is one of the main complications. There is no currently approved protocol for treatment. The microbial threat as induced by COVID-19 causes the activation of macrophages to produce a huge amount of inflammatory molecules and nitric oxide (NO). Activation of macrophages population into a pro-inflammatory phenotype induces a self-reinforcing cycle. Oxidative stress and NO contribute to this cycle, establishing a cascade inflammatory state that can kill the patient. Interrupting this vicious cycle by a simple remedy may save critical patients’ lives. Nitrite, nitrate (the metabolites of NO), methemoglobin, and prooxidant-antioxidant-balance levels were measured in 25 ICU COVID-19 patients and 25 healthy individuals. As the last therapeutic option, five patients were administered methylene blue-vitamin C–N-acetyl Cysteine (MCN). Nitrite, nitrate, methemoglobin, and oxidative stress were significantly increased in patients in comparison to healthy individuals. Four of the five patients responded well to treatment. In conclusion, NO, methemoglobin and oxidative stress may play a central role in the pathogenesis of critical COVID-19 disease. MCN treatment seems to increase the survival rate of these patients. Considering the vicious cycle of macrophage activation leading to deadly NO, oxidative stress, and cytokine cascade syndrome; the therapeutic effect of MCN seems to be reasonable. Accordingly, a wider clinical trial has been designed. It should be noted that the protocol is using the low-cost drugs which the FDA approved for other diseases. Trial registration number NCT04370288.

The Role of Methemoglobin and Carboxyhemoglobin in COVID-19: A Review

“…COVID-19 patients (n = 25) were shown to have a higher MetHb compared to healthy individuals (n = 25) as demonstrated in a cross-sectional study by Alamdari et al [21], supporting the findings reported. However, the cross-sectional study of Soltan et al [19] with a large cohort (534 COVID-19 patients and 114,957 pre-pandemic controls) showed no statistically significant differences in the MetHb values despite the fact that MetHb was an important parameter for the prediction of COVID-19 based on the algorithm the group developed.…”

“…Based on the inclusion and exclusion criteria, seven duplicates were removed and 187 articles were excluded after abstract review. After the full set of remaining articles was screened, seven reports were finally included in the present study [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The study selection process is shown in Figure 1 a.…”

The Role of Vitamin C, Vitamin D, and Selenium in Immune System against COVID-19

“…Increasing antiviral cytokines, such as interferon (IFN)-α/β [24] Increasing free radical formation to decrease viral yield [25] Attenuating excessive inflammatory response [27] Ameliorating hyperactivation of immune cells by altering energy metabolism [30] Decreased flu or cold symptoms due to treatment with high dose of vitamin C [22,23] Decreased inflammatory mediators/ markers due to the administration of vitamin C in COVID-19 patients [28,29] Table 1. Cont.…”

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

“…MeBlu has also been explored in one Phase 1 clinical trial (NCT04370288) for treatment of critically ill COVID-19 patients in Iran as part of a three-drug last therapeutic option add-on cocktail (MeBlu 1 mg/kg, vitamin C 1500 mg/kg, and N-acetyl cysteine 2000 mg/kg) based on the hypothesis that this combination could rebalance NO, methemoglobin, and oxidative stress. Four of the five patients responded well to treatment (Alamdari et al, 2020).…”