USESPrescription NAC is used as a mucolytic to relieve mucosal obstructions in bronchial diseases and tracheotomy procedures. IV NAC administration is the treatment of choice for acetaminophen overdose because it replenishes the glutathione in the liver which the drug depletes. Glutathione clears the toxic metabolite of acetaminophen, which would otherwise damage liver cells and trigger an immune response.2

NAC is prescribed as a renal protectant for contrast (dye)-induced nephropathy. It is also prescribed for psychiatric and neurological conditions.As a dietary supplement, NAC is used to support sinus and respiratory health as well as liver, detoxifi cation and glutathione support.

N-ACETYLCYSTEINE (NAC)N-acetylcysteine (NAC), the N-acetyl derivative of the natural amino acid l-cysteine, is a naturally occurring substance that’s used both as an FDA approved prescription medication and as a dietary supplement. As a drug, it has been prescribed as a mucolytic agent since the 1960s and used for the treatment of acetaminophen poisoning since the 1970s.

Recent studies on NAC illuminate its potential role as both a preventive and recovery support agent for infectious illness through synergistic pathways.

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N-ACETYLCYSTEINE (NAC)

USUAL DOSAGE 500-600 mg po daily for detoxifi cation support and maintenance of normal glutathione levels500-600 mg po bid or tid for acute support during active illness.

ACTIVE CONSTITUENTSNAC is a derivative of the amino acid cysteine. The only difference between the two compounds is that NAC has an acetyl group (-CH3O) bound to the nitrogen on cysteine. Both compounds also contain a free thiol group (-SH).

MECHANISMS OF ACTIONAntioxidant activity: NAC has direct antioxidant action. Its free thiol group can interact with electrons to directly neutralize some reactive oxygen species. Although NAC has a negligible effect on some of the most powerful oxidants, such as hydrogen peroxide and superoxide anion, there are two categories of oxidative species that NAC can neutralize: hypochlorous acid and related compounds (HOX) and nitrogen oxide (NO2). HOX compounds are produced by activated neutrophils and monocytes through the activity of myeloperoxidase (MPO), and play a role in the immune response to pathogens. HOX oxidants are also involved in lung diseases and other infl ammatory chronic diseases. NO2 is a major component of indoor and outdoor air pollution (from motor vehicles, cigarette smoke, burning fuel, and other sources) and is involved in epithelial injury to the lungs.5 Replenishes Glutathione: NAC gives up its acetyl group leaving cysteine, which is then available to replenish glutathione. Although glutathione synthesis depends on cysteine, glutamine, and glycine, cysteine is the rate-limiting substance for the reaction and arguably the most infl uential on glutathione status. Animal studies suggest that NAC administration increases GSH levels in numerous body tissues. Human studies show that oral intake of NAC increases GSH in both red and white blood cells. Intravenous administration of NAC has also been shown to increase GSH in lung fl uids and other tissues.

Liver Detoxifi cation: Glutathione is one of several substances in the liver that acts in phase II to conjugate toxic metabolites. It’s especially important for conjugating xenobiotics, such as chemicals in plastics and personal care products. Because of its role in regenerating glutathione, NAC is commonly used to support everyday detoxifi cation pathways.1Mucolytic: NAC is a disulfi de-breaking agent, and mucus gels in the respiratory tract are highly cross-linked by disulfi de bonds (S-S). NAC breaks the bonds and adds hydrogens, thus splitting the molecule in two. This reaction is called a thiol-disulfi de interchange. This serves to break up the mucus gels into smaller sections, reducing viscosity and facilitating clearance.5Thrombolytic: In vitro and in vivo animal studies have demonstrated NAC’s thrombolytic activity, through the same disulfi de bond breaking action in thrombi, while preserving hemostasis.4,5Neurotropic: The rationale for the administration of NAC in psychiatric conditions is based on its role as a precursor to the antioxidant glutathione, and its action as a modulating agent of glutamatergic, dopaminergic, neurotropic and infl ammatory pathways.6

RESEARCHIn a clinical study in 1997, a total of 262 subjects were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. NAC treatment resulted in a signifi cant decrease in the frequency of infl uenza-like episodes, severity, and length of time confi ned to bed. Both local and systemic symptoms demonstrated sharp and signifi cant reductions in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 infl uenza virus was similar in the two groups, but only 25% of virus-infected subjects in the NAC group developed a symptomatic form, versus 79% in the placebo group. Administration of N-acetylcysteine appeared to help provide a signifi cant attenuation of infl uenza and infl uenza-like episodes, especially in the elderly participants. N-acetylcysteine did not prevent A/H1N1 virus infl uenza infection but demonstrated signifi cantly reduced incidence of clinically apparent disease.1

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N-ACETYLCYSTEINE (NAC)

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In a 2010 study, the effects of NAC on virus replication, virus-induced pro-infl ammatory responses and virus-induced apoptosis were investigated in vitro with H5N1-infected lung epithelial (A549) cells. NAC demonstrated reduced H5N1-induced cytopathogenic effects (CPEs), virus-induced apoptosis and infectious viral yields 24 h post-infection. NAC also showed decrease in the production of pro-infl ammatory molecules (CXCL8, CXCL10, CCL5 and interleukin-6 (IL-6)) in H5N1-infected A549 cells and reduced monocyte migration towards supernatants of H5N1-infected A549 cells. The mechanisms of NAC included inhibition of activation of oxidant sensitive pathways including transcription factor NF-kappaB and mitogen activated protein kinase p38. The combination of NF-kappaB and MAPK p38 inhibition resulted in increased inhibitory effects on virus replication and production of pro-infl ammatory molecules. The authors concluded that NAC inhibits H5N1 replication and H5N1-induced production of pro-infl ammatory molecules.3A 2018 study investigating the thrombolytic effect of NAC, discovered that the molecular target underlying the thrombolytic effects of NAC is principally the von Willebrand Factor (VWF) that cross-links platelets in arterial thrombi. In vitro and in vivo experiments demonstrated that intravenous NAC:1. has thrombolytic effects in the arterial circulation

by reducing the size of von Willebrand Factor (VWF) multimers, a key constituent of platelet-rich thrombi.

2. exerts its thrombolytic effect essentially by reducing the disulfi de bonds in large VWF multimers, leading to their fragmentation and subsequent platelet disaggregation.

3. induces arterial recanalization and restores vessel patency.4. exerts thrombolytic effects without signifi cantly

impairing normal hemostasis. The authors concluded that NAC may be an effective and safe alternative to currently available antithrombotic agents to restore vessel patency after arterial occlusion.4

The hypothesis in favor of NAC supplementation is that when a virus attaches to ACE2 receptors which decrease ACE 2, this increases AT II and decreases AT 1,7, in turn increasing superoxide. The increased oxidative stress causes endothelial dysfunction and increases von Willebrand Factor which causes thrombosis and, as it occurs in the lungs, results in hypoxemia. It is hypothesized that NAC may affect this process in two ways by decreasing oxidative stress and decreasing VWF.5

SIDE EFFECTS / CONTRAINDICATIONS Oral doses above 1200 mg per day can result in headache, nausea, abdominal pain, vomiting, constipation, and diarrhea.People who take nitroglycerine should not take NAC unless supervised by a physician since it can cause the nitroglycerine to work more intensely and cause an unsafe drop in blood pressure. Caution with dosing is recommended as excessive antioxidant use can result in pro-oxidant activity due to the “antioxidant paradox” effect. Studies have shown that excessive antioxidant therapy can act as a potential immunosuppressant and increase the chance of tumorigenesis. Therefore, lower doses are recommended if using preventively to maintain adequate levels of glutathione, while higher dosing is appropriate during periods of active illness when glutathione is being used and depleted.7,8

RESOURCES1. De Flora S, Grassi C, Carati L. Attenuation of infl uenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997;10(7):1535-1541. doi:10.1183/09031936.97.100715352. Kelly GS. Clinical applications of N-acetylcysteine. Altern Med Rev. 1998;3(2):114-127.3. Geiler J, Michaelis M, Naczk P, et al. N-acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-infl ammatory molecules in A549 cells infected with highly pathogenic H5N1 infl uenza A virus. Biochem Pharmacol. 2010;79(3):413-420. doi:10.1016/j.bcp.2009.08.025

N-ACETYLCYSTEINE (NAC)

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Disclaimer: Emerson Ecologics does not distribute any products to treat or prevent diseases related to the various forms of infl uenza or coronavirus. The scientifi c articles provided are for informational and research purposes only and are not a substitute for your professional judgment. We expressly deny that the information being provided is intended to assist in the cure, diagnosis, prevention, or treatment of infl uenza or coronavirus-related diseases, including but not limited to COVID-19, MERS, or SARS. You should always exercise your professional judgment when reviewing scientifi c literature.

by Emerson Ecologics

4. Martinez de Lizarrondo S, Gakuba C, Herbig BA, et al. Potent Thrombolytic Effect of N-Acetylcysteine on Arterial Thrombi. Circulation. 2017;136(7):646-660. doi:10.1161/CIRCULATIONAHA.117.0272905. Aldini G, Altomare A, Baron G, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;52(7):751-762. doi:10.1080/10715762.2018.14685646. Deepmala, Slattery J, Kumar N, et al. Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neurosci Biobehav Rev. 2015;55:294-321. doi:10.1016/j.neubiorev.2015.04.015

7. Tiwari AK. The antioxidant paradox. Phcog Mag 2019;15, Suppl S2:173-58. Anu Rahal, Amit Kumar, Vivek Singh, Brijesh Yadav, Ruchi Tiwari, Sandip Chakraborty, Kuldeep Dhama, “Oxidative Stress, Prooxidants, and Antioxidants: The Interplay”, BioMed Research International, vol. 2014, Article ID 761264, 19 pages, 2014. https://doi.org/10.1155/2014/761264