N-Acetylcysteine for COVID-19: A Potential Adjuvant Therapy

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection or known as coronavirus disease 2019 (COVID-19) is a highly infectious disease that has been declared as a world pandemic by WHO. Although the majority of patients only experience mild symptoms, older patients and those with comorbidities are in the risk of falling into critically ill and even death. This is thought to correlate with systemic inflammatory response and oxidative stress imbalance. N-acetylcysteine (NAC) is recognized as a potent mucolytic, yet its lesser-known function as an antioxidant is a precursor of glutathione. Basic aspects and either in vivo or in vitro studies showed various mechanisms of NAC acting as a counterbalance in viral infections and its role in decreasing inflammation and oxidative stress. High-dose NAC is reported to be effective as an antioxidant in pneumonia, influenza, sepsis, and acute respiratory distress syndrome. Early evidence in COVID-19 patients showed that NAC could be beneficial. This review gives the scientific background in considering NAC as an adjuvant treatment for COVID-19.

N-Acetylcysteine and Other Sulfur-Donors as a Preventative and Adjunct Therapy for COVID-19

“…If there is a higher demand for GSH because of oxidative stress, such as during viral infection [ 102 ], extreme or endurance exercise [ 103 ], and hypoxic conditions [ 22 , 94 ], it will have an inhibitory effect on inorganic sulfate synthesis. Lowered redox potential, common in high-risk COVID-19 patients, including older adults and those with uncontrolled DM, causes alterations in the TNF α receptor activity towards a proinflammatory state [ 22 , 31 , 95 ]. It is known that infection by RNA-viruses induces oxidative stress in host cells, and growing evidence indicates that viral replication is regulated by the redox state of the host cell [ 30 , 94 , 104 , 105 ].…”

“…Oxidative processes enhance viral infection by promoting replication in infected cells, inhibition of cell proliferation, and cell apoptosis induction [ 35 , 95 ]. Studies found that NAC treatment significantly reduced the frequency of influenza in the elderly and the severity and duration of most symptoms [ 31 , 95 , 160 , 162 ]. To replicate, RNA-viruses need active NF- κ B pathway support within host cells [ 158 ].…”

“…It was demonstrated that the suppression of hypoxia-inducible NF- κ B [ 92 ] significantly reduced the replication rate of mammalian coronaviruses. NAC has been shown to inhibit NF- κ B [ 30 , 95 , 105 ] and replication of influenza A viruses in human lung EpCs in a dose-dependent manner. NAC also reduced the production of proinflammatory cytokines, such as IL-6, IL-8, CXCL10, and CCL5 [ 106 , 123 , 165 ], hence reducing chemotactic migration of monocytes [ 160 ].…”

“…It was reported that 600 mg NAC in capsule form was able to reach a level of 16 μ M NAC in the peripheral blood within half an hour after administration [ 160 ]. Oral NAC at a dosage of 600 mg bid significantly decreased the frequency and severity of influenza [ 94 , 95 ]. It is, therefore, expected that high dose oral NAC (1200 mg, bid) [ 94 ] can improve innate immunity through sulfation of the GL, and adaptive immunity by elevating GSH levels in lymphocytes, in addition to modulating neutrophil functions during the development of COVID-19 [ 3 , 160 ].…”

Oral high-dose acetylcysteine: Effective against the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?

“…The mechanisms of NAC therapy for COVID-19 include: 1. inhibiting the envelope (E) protein and thorn (s) protein of the virus and reducing its binding to angiotensin II receptors (AT2R); 2. inhibiting angiotensin-converting enzyme (ACE); 3. inducing the synthesis of endogenous GSH so as to enhance antioxidation and reduce intracellular protein glycosylation; and 4. inhibiting the production of proinflammatory mediators and cytokines (12). In addition, high-dose intravenous NAC is reported to play a key role in the treatment of severe cases of COVID-19 (3,13,14).…”