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Review Ther Clin Risk Manag
. 2020 Nov 2;16:1047-1055. doi: 10.2147/TCRM.S273700. eCollection 2020.
N-Acetylcysteine to Combat COVID-19: An Evidence Review
Zhongcheng Shi 1 2, Carlos A Puyo 3
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PMID: 33177829 PMCID: PMC7649937 DOI: 10.2147/TCRM.S273700
Free PMC article
Abstract
The novel coronavirus disease (COVID-19) is caused by a virus (SARS-Cov-2) and is known for inducing multisystem organ dysfunction associated with significant morbidity and mortality. Current therapeutic strategies for COVID-19 have failed to effectively reduce mortality rate, especially for elderly patients. A newly developed vaccine against SARS-Cov-2 has been reported to induce the production of neutralizing antibodies in young volunteers. However, the vaccine has shown limited benefit in the elderly, suggesting an age-dependent immune response. As a result, exploring new applications of existing medications could potentially provide valuable treatments for COVID-19. N-acetylcysteine (NAC) has been used in clinical practice to treat critically ill septic patients, and more recently for COVID-19 patients. NAC has antioxidant, anti-inflammatory and immune-modulating characteristics that may prove beneficial in the treatment and prevention of SARS-Cov-2. This review offers a thorough analysis of NAC and discusses its potential use for treatment of COVID-19.

Keywords: COVID-19; N-acetylcysteine; SARS-Cov-2.

© 2020 Shi and Puyo.
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Case Reports Eur J Pharmacol
. 2020 Oct 15;885:173494. doi: 10.1016/j.ejphar.2020.173494. Epub 2020 Aug 20.
Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial
Daryoush Hamidi Alamdari 1, Ahmad Bagheri Moghaddam 2, Shahram Amini 3, Mohammad Reza Keramati 4, Azam Moradi Zarmehri 5, Aida Hamidi Alamdari 6, Mohammadamin Damsaz 6, Hamed Banpour 4, Amir Yarahmadi 7, George Koliakos 8
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PMID: 32828741 PMCID: PMC7440159 DOI: 10.1016/j.ejphar.2020.173494
Free PMC article
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.

Keywords: COVID-19; Coronavirus; Methylene blue; N-acetyl cysteine; Treatment; Vitamin C.

Copyright © 2020 Elsevier B.V. All rights reserved.

Conflict of interest statement
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Med Hypotheses
. 2020 Apr 22;140:109778. doi: 10.1016/j.mehy.2020.109778. Online ahead of print.
N-acetyl-cysteine may prevent COVID-19-associated cytokine storm and acute respiratory distress syndrome
Stelios F Assimakopoulos 1, Markos Marangos 2
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PMID: 32344315 PMCID: PMC7195028 DOI: 10.1016/j.mehy.2020.109778
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Editorial Future Microbiol
. 2020 Jul;15:959-962. doi: 10.2217/fmb-2020-0074. Epub 2020 Jul 14.
N-acetylcysteine as a potential treatment for COVID-19
Rangel-Méndez Jorge-Aarón 1, Moo-Puc Rosa-Ester 1
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PMID: 32662664 PMCID: PMC7359418 DOI: 10.2217/fmb-2020-0074
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Cleve Clin J Med
. 2020 Jun 8. doi: 10.3949/ccjm.87a.ccc046. Online ahead of print.
What is the role of supplementation with ascorbic acid, zinc, vitamin D, or N-acetylcysteine for prevention or treatment of COVID-19?
Seth R Bauer 1, Aanchal Kapoor 2, Mary Rath 3, Suma A Thomas 4
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PMID: 32513807 DOI: 10.3949/ccjm.87a.ccc046
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Abstract
Several agents intended to supplement dietary intake or endogenous molecules may have a theoretical role in preventing or treating COVID-19. Because of their potential to influence immune response, ascorbic acid (vitamin C), zinc, vitamin D, and N-acetylcysteine have been hypothesized to be useful for prevention or treatment of COVID-19. The authors outline the biologic plausibility, applicable clinical data, and potential role of each of these agents.

Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.
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Case Reports Clin Immunol
. 2020 Oct;219:108544. doi: 10.1016/j.clim.2020.108544. Epub 2020 Jul 22.
Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine
Homam Ibrahim 1, Andras Perl 2, Deane Smith 3, Tyler Lewis 3, Zachary Kon 3, Ronald Goldenberg 3, Kinan Yarta 3, Cezar Staniloae 3, Mathew Williams 3
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PMID: 32707089 PMCID: PMC7374140 DOI: 10.1016/j.clim.2020.108544
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Abstract
Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.

Keywords: C-reactive protein; COVID-19; Coronavirus 19; Extracorporeal membrane oxygenation; Ferritin; Glucose 6-phosphate dehydrogenase; Glutathione; Mechanistic target of rapamycin; N-acetylcysteine; Respirator.

Copyright © 2020 Elsevier Inc. All rights reserved.
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Curr Pharm Biotechnol
. 2021;22(12):1584-1590. doi: 10.2174/1389201021999201228212043.
The Potential Mechanism of N-acetylcysteine in Treating COVID-19
Nan Zhou 1, Xiaofan Yang 1, Aie Huang 2, Zhenbing Chen 1
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PMID: 33371832 DOI: 10.2174/1389201021999201228212043
Abstract
N-Acetylcysteine (NAC) has been proposed to be used to treat Coronavirus Disease 2019 (COVID-19). By reviewing the existing pathological studies of COVID-19, it was found that abundant mucus secretion, formation of a hyaline membrane (supportive of acute respiratory distress syndrome), and interstitial fibrous exudation may be important characteristics of COVID-19 and pathological targets of drug therapy. In addition, multiple extrapulmonary organ injuries in COVID- 19 may be associated with cytokine storm. NAC is an important antioxidant and anti-inflammatory drug. NAC has been demonstrated to have mucolytic effects in bronchitis, relieve respiratory failure in acute respiratory distress syndrome, and inhibit fibrous exudation in interstitial lung disease in clinical studies. These findings suggest that NAC may have a therapeutic effect on the pathological targets of COVID-19. Furthermore, NAC decreases TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-17 serum levels in patients with sepsis, severe burns, acute liver failure, or peritoneal dialysis and may also reduce cytokine storm in COVID-19. The antiviral effect of NAC on other respiratory viruses may also benefit COVID-19 patients. Summarizing the potential mechanisms of NAC in treating COVID-19 suggests that the role of NAC in COVID-19 treatment is worthy of further research.

Keywords: COVID-19; N-acetylcysteine; SARS-CoV-2; drug; mechanism; treatment..

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