• NAC is an outstanding antioxidant on its own (reducing power of thiol -SH group)

• NAC is the N-acetyl derivative of the amino acid L-cysteine, a precursor of the body’s primary intracellular antioxidant glutathione (GSH)

• GSH is used by the body to detoxify the toxic metabolite of acetaminophen (APAP) for any pt using APAP for fever/myalgia symptom control; NAC replaces that GSH

As an antioxidant, NAC provides multiple benefits to a body under severe oxidative stress from SARS-Cov-2:

NAC suppresses cytokine storm-inciting molecules and cells

• NAC scavenges free radicals such as Reactive Oxygen Species

• NAC suppresses macrophages, neutrophils, leukocyte endothelial cell adhesion, and cytokines that lead to and damage lung cells in acute lung injury (ALI) and ARDS

NAC improves oxygenation without ROS generation

• increases O2 delivery to extrahepatic organs

• increases ATP production

May work synergystically with antivirals

• Reduction of oxidative stress through antioxidants has been shown to enhance antiviral agents such as interferon when used vs hepatitis C (Beloqui et al, Neri et al)

Severe respiratory disease progressing to ARDS from COVID-19 illness appears to be from cytokine storm syndrome (Mehta et al)

NAC has potential for attenuating/mitigating/preventing cytokine storm and ensuing ARDS. NAC has already been shown to inhibit pro-inflammatory molecules by suppressing TNF and IL-6 (molecules that regulate inflammatory complications leading to ARDS).

NAC rescued cell swelling, downregulated the inflammatory response, and prevented pyroptotic death in hypoxia-cultured myoblasts (Yu et al)

• NAC inhibits production of pro-inflammatory molecules (IL6, TNF-alpha, CCL5, CXCL8, CXCL10) in lung epithelial cells (Liu et al, Horowitz et al,  Saddadi et al 2014, Sun et al)

• Decreases C-RP in H1N1 treatment. (Lai et al)

• Addition of NAC in pts with CAP reduced TNF-a (Zhang et al).

• Decrease in TNF-a in vitro. (Hamzeh et al)

• Decrease in CRP, myeloperoxidase (MPO), Galectin-3 (Gal-3) following AMI. (Wasyanto et al)

NAC may have antiviral properties (Fraternale et al, Ciriolo et al) and has been tried to treat other viral pneumonias: influenza A (Casanova et al, Geiler et al), H1N1 (De Flora et al). 

NAC has been investigated for use vs HIV and was found to suppress replication in 1991 - pre-antiretroviral cocktail therapy (Kalebic et al including Fauci AS).

Mechanism?

• Viral replication is dependent on intracellular antioxidant glutathione (GSH). Low glutathione accelerates viral replication.

• NAC replaces GSH 

With concerns that SARS-COV-2 produces a hypercoagulable state (Bikdeli et al), NAC anticoagulant/thrombotic properties may also be beneficial

(Jang et al, Martinez de Lizarrondo et al, Niemi et al, Wang et al)