Why #NACinCOVID

NAC (N-acetyl-cysteine)

C5H9NO3S


Why NAC?

NAC is a powerful antioxidant

  • 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)

NAC is an Anti-inflammatory/immunomodulatory agent

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 has antiviral activity

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

NAC has anticoagulant/antithrombotic activity

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)

NAC has already been shown to work favorably in other pulmonary disease processes

  • NAC has worked as adjunctive therapy in other respiratory disease with oxidative stress injury.(Santus et al):

  • Already shown to work favorably in COPD. (Santus et al, Nanda et al) Reduces exacerbations at doses of at least 1200 mg/day (Matera et al, Tse et al)

  • Abrogates Acute Lung Injury (Kao et al)

  • With dexmedetomidine may attenuate ALI by rebalancing Th1/Th2/Th17 cytokines. (Song et al)

  • Decrease in RR in pts with silicosis (Sun et al)

  • Nebulized NAC + bronchoscopy decreased time on ventilator and use of abx in elderly pts with VAP (L Wu et al)

  • Relieved dyspnea in small case series of pts with COVID-19 (Horowitz et al - April 2020)


Minimal/negligible side effects of NAC

NAC has a longstanding track record of having an excellent safety profile

In general, it has a very low side-effect profile, especially in oral administration

  • Primary side effect with PO = GI: nausea/vomiting (?related to sulfur “rotten egg” scent from thiol groups. (If COVID-related anosmia and dysgeusia (loss of taste) is real, pts should tolerate the PO solution formulation.)

IV dosing: rare anaphylactoid (not anaphylactic) response (hypersensitivity rash, flushing; CV mild hypotension; Resp: rare bronchospasm) addressed with administration of diphenhydramine and restart of medication at lower rate.




NAC, Glutathione (GSH), and COVID-19: Reviews and concepts from www.medcram.com May 2020

Coronavirus Pandemic Update 69: "NAC" Supplementation and COVID-19 (N-Acetylcysteine) from www.medcram.com (26:45) - May 11, 2020

Coronavirus Pandemic Update 70: Glutathione Deficiency, Oxidative Stress, and COVID 19 from www.medcram.com (13:32) - May 14, 2020