In particular, NAC has the ability to improve the efficacy and structural conformational integrity of α1‐antitrypsin via a GSH‐mediated mechanism, and it enhances α1‐antitrypsin transcytosis thus improving its cellular uptake and functions.32 In experimental studies, the oral administration of NAC to pregnant mice enhanced the expression of the gene encoding for an α1‐antitrypsin precursor in the fetal liver.33 Together with redox imbalance, α1‐antitrypsin deficiency is involved in the pathogenesis of COPD. Could it have something to do with CBD, which is also potentially covered by the Drug Exclusion Provision? Using a Chevron analysis, the Court of Appeals deferred to FDA’s position “that the phrase ‘an article that is approved as a new drug’ is properly understood to contemplate [Active Pharmaceutical Ingredients] as well as finished drug products.”  221 F.3d 1151, 1154 (2000). NAC inhibited the replication of these viruses and restored the normal functions of alveolar type II A549 cells by modulating MUC5AC overexpression and release and by inhibiting IL‐8, IL‐6, and TNF‐ α as well as NF‐κB translocation to the nucleus and phosphorylation of MAPK p38.53, Furthermore, it has been known for almost 30 years that GSH plays an important defense role against HIV and that NAC may exert protective effects toward this viral infection. Treatment with the N‐butanoyl GSH derivative (GSH‐C4) of old mice infected with influenza A PR8/H1N1 virus increased GSH content in organs, reduced viral replication, and induced an immune response, in particular the Th1 (T helper‐1) cytokine profile.52, Influenza A and B viruses and respiratory syncytial virus (RSV) are responsible for COPD by increasing inflammatory and apoptosis events through mechanisms involving ROS generation and release of mucins from epithelial cells. N-acetylcysteine (NAC) is inexpensive, has very low toxicity, has been FDA approved for many years, and has the potential to improve therapeutic strategies for COVID-19. Exposure of cells either to the hydroxyl radical (•OH) or the superoxide radical anion (O2•−) induces a dose‐dependent release of pro‐inflammatory cytokines. For instance, in agreement with data obtained in cells exposed to herpesvirus type 1 (DNA virus) or to Sendai (an RNA virus belonging to the family of Paramyxoviridae), it was shown that GSH inhibits HIV envelope glycoproteins (gp120) and interferes with late stages of virus replication in chronically infected macrophages, a known reservoir of the virus in the body.54 Both GSH and NAC inhibited the induction of HIV‐1 expression in a chronically HIV‐1‐infected promonocytic cell line (U1/HIV) and in human primary monocyte/macrophages cultured in vitro, where both thiols decreased HIV‐1 p24 antigen levels as well as reverse transcriptase activity.55, Interestingly, NAC appears to synergize with antivirals in the protection toward influenza in mouse models, as shown with ribavirin56 and oseltamivir.57, Smokers are more vulnerable to infectious diseases, as shown in the case of influenza and of the MERS‐CoV outbreak. But on July 23, 2020, FDA sent a warning letter to Purple Biosciences LLC about its NAC product. The receptor binding domain of the viral spike proteins and ACE2 has several cysteine residues. FDA Approved: Yes (First approved January 23, 2004) Brand name: Acetadote. Accordingly, all its intracellular effects are mediated by GSH replenishment. Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. § 355] on September 14, 1963. For most people, oral NAC is safe and without side effects and is an is an FDA-approved supplement. Oral NAC is irritating to the gastrointestinal track and should be diluted to a final concentration of no more than 5% to reduce the risk for vomiting. COVID‐19 is particularly severe in individuals who are at risk either because of old age or of pre‐existing pathological conditions. § 321(ff)(3)(B)(i)]. The ingredient was first approved as a mucolytic drug sometime around 1963 (the precise date is somewhat unclear). An example of reactive intermediate is the paracetamol metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI) formed via cytochrome P450 enzymes. N-acetyl cysteine (NAC) is used by the body to build antioxidants.Antioxidants are vitamins, minerals, and other nutrients that protect and repair cells from damage. Through warning letters sent in late July to companies selling products that purportedly claimed to cure, treat, mitigate or prevent hangovers, FDA stated NAC was approved as a drug in 1963. The Drug Exclusion Provision is found at 21 U.S.C. A library composed of 958 FDA-approved drugs was screened and five drugs, N-acetylcysteine (NAC), tiopronin (TPR), verteporfin (VP), calcitriol and racecadotril, were identified to inhibit RBD/ACE2 interaction at both low and high concentrations selected (Fig. Moreover, administration of GSH with the drinking water to BALB/c mice decreased the viral titer in both lung and trachea 4 days after intranasal inoculation of the mouse‐adapted influenza strain A/X‐31.49, It has also been demonstrated that NAC inhibits virus replication and expression of pro‐inflammatory molecules in adenocarcinoma human alveolar basal epithelial (A549) cells infected by the highly pathogenic H5N1 influenza virus.50 NAC inhibited the pulmonary inflammation and edema as well as myeloperoxidase (MPO) activity, total cells, neutrophils, macrophages, TNF‐α, IL‐6, IL‐1β, and chemokine (C‐X‐C motif) ligand‐10 (CXCL‐10) in the bronchoalveolar lavage fluid and reduced the levels of toll‐like receptor 4 (TLR4) protein and mRNA in the lungs of BALB/c mice inoculated intranasally with A/swine/HeBei/012/2008/ H9N2 influenza virus.51 A study in the same strain of mice showed that old animals had lower GSH concentrations than young animals in spleen, lymph nodes, lungs, and pancreas. Various carnosine-related compounds, including N-acetylcarnosine (NAC), occur naturally in the body. Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. § 355] on September 14, 1963. It is well established that ROS play a key role in the pathogenesis of the acute lung injury and that the alveolar epithelial lining fluid of patients with ARDS is deficient in GSH, which may predispose these patients to that disease.36 A randomized, double‐blind, placebo‐controlled, prospective clinical trial in 5 ICUs in the USA and Canada showed that the intravenous administration of NAC (70 mg/kg body weight), every 8 hours for 10 days, effectively repleted GSH in red blood cells, decreased the number of days of acute lung injury, and significantly increased the cardiac index.37 NAC (50 mg/kg body weight in 250 mL of 5% dextrose for 6 days) protected the lungs of ARDS patients, as evaluated by measuring the expired ethane and malondialdehyde (MDA) as well as GSSG and GSH in the epithelial lining fluid.38 In another study, patients hospitalized in ICU who received NAC (150 mg/kg body weight on the first day, followed by 50 mg/kg for 3 days) had a better clinical outcome as compared with patients in the placebo group. NAC is approved by FDA under various formulations and is popular as a health supplement, this molecule having been proposed as a nutraceutical that might aid the control of RNA viruses including influenza and coronavirus.64-66 Almost 60 years of experience in the prophylaxis and therapy of a variety of clinical conditions have established the safety of this drug, even at very high doses and for long‐term treatments. FDA Cracks Down on NAC. Biostratum had filed an IND with FDA in 1999 for use of the vitamin to slow or prevent the progression of kidney disease in diabetics, and argued there was no evidence that it was marketed as a dietary supplement or food prior to its IND and Phase II investigations. Learn more. FDA’s letter asserts that the product itself is illegal because NAC was approved as a drug on September 14, 1963. § 355], then products containing that article are outside the definition of a dietary supplement, unless before such approval that article was marketed as a dietary supplement or as a food. But what is unusual about this one is that FDA has sent warning letters to many companies about NAC in the past and never before asserted the ingredient itself is not legal. Different pathogenic disturbances are involved, such as acute changes in myocardial demand and supply due to tachycardia, hypotension, and hypoxemia resulting in type 2 myocardial infarction; acute coronary syndrome due to acute atherothrombosis in a virally induced thrombotic and inflammatory milieu; microvascular dysfunction due to diffuse microthrombi or vascular injury; stress‐related cardiomyopathy (Takotsubo syndrome); direct viral cardiomyocyte toxicity and myocarditis.3 All of these complications reflect inflammatory reactions stimulated by the viral infection. On July 23, 2020, FDA sent a warning letter to Purple Biosciences LLC about its NAC (N-Acetyl-Cysteine) product. Moreover, only 25% of A/H1N1 influenza virus‐infected subjects under NAC treatment developed a symptomatic form vs 79% in the placebo group.47, 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 and that the GSH content contributes to downregulate influenza virus replication.48 An experimental study showed that GSH decreased the production of influenza virus particles in canine kidney cells or human small airway epithelial cells, where it inhibited the expression of viral matrix protein, caspase activation, and Fas upregulation. National Centre of Oncology, Sofia, Bulgaria. The Drug Exclusion Provision has only been invoked by FDA a few times. Treatment for: Acetaminophen Overdose. (Red yeast rice is a fermented product that is used in traditional Chinese cooking as a spice or colorant). Moreover, high‐dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID‐19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events. Note: FDA has exempted almost all class I devices (with the exception of reserved devices) from the premarket notification requirement, including those devices that were exempted by final regulation published in the Federal Registers of December 7, 1994, and January 16, 1996. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. FDA said industry submissions did not include documentation of marketing, such as catalogs, from the relevant time period. At doses as high as 150 mg/kg intravenously, NAC is extensively used and is in standard practice as a clinically approved antidote against paracetamol (acetaminophen) intoxication, and it is almost 100% effective if given within 8 hours postingestion.15 Paracetamol overdosage may cause mitochondrial oxidative imbalance and nitrosative stress leading to liver injury, which is the most common cause of acute liver failure in many countries.16 The intravenous administration of NAC is also used to prevent contrast‐induced nephropathy that, again, is an inflammatory condition.15, In addition, this pleiotropic drug has been proposed to attenuate the toxicity of various agents that cause the generation of free radicals as well as for the therapy and/or prevention of a variety of diseases involving GSH depletion and redox status alterations, such as heart diseases, diabetes, AIDS, neurodegenerative diseases, neuropsychiatric disorders, and several other conditions.14, 17, Oxidative stress and inflammation are strictly inter‐related. NAC is FDA approved for the treatment of hepatotoxicity due to acetaminophen. S1B and S1C). The agency also warned that NAC, a popular supplement ingredient, cannot legally be used in dietary supplements. Based on a broad range of antioxidant and anti‐inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID‐19, as it was previously demonstrated for influenza and influenza‐like illnesses. 2 As such, NAC cannot be marketed as a supplement. Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, Major mechanisms involved in the antioxidant and anti‐inflammatory action of NAC via GSH (modified and updated from Sadowska, 2012, © 2021 Federation of American Societies for Experimental Biology (FASEB), By continuing to browse this site, you agree to its use of cookies as described in our, I have read and accept the Wiley Online Library Terms and Conditions of Use, COVID‐19: immunopathology and its implications for therapy, Molecular immune pathogenesis and diagnosis of COVID‐19, A current review of COVID‐19 for the cardiovascular specialist [published online ahead of print, 2020 May 3], Sexual dimorphism in glutathione metabolism and glutathione‐dependent responses, Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS‐CoV‐2 in an ageing population, consider N‐acetylcysteine as early therapeutic intervention, Clinical features of patients infected with the 2019 novel coronavirus (COVID‐19) in Shanghai, China, Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death from novel coronavirus infection(COVID‐19): a hypothesis based on literature data and own observations, SARS‐CoV‐2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor, Impact of thiol‐disulfide balance on the binding of Covid‐19 spike protein with angiotensin converting enzyme 2 receptor, N‐acetylcysteine inhibits angiotensin converting enzyme in vivo, N‐acetylcysteine as a potential treatment for novel coronavirus disease 2019, N‐Acetylcysteine mucolysis in the management of chronic obstructive pulmonary disease, Medical and dietary uses of N‐acetylcysteine, Mechanisms of N‐acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking‐related end‐points, Glutathione depletion is associated with augmenting a proinflammatory signal: evidence for an antioxidant/pro‐oxidant mechanism regulating cytokines in the alveolar epithelium, Role of glutathione in immunity and inflammation in the lung, New insights into the role of glutathione in the mechanism of fever. However, being a tripeptide (γ‐glutamylcysteinylglycine), it poorly penetrates cells. Why now? It’s also used to prevent serious liver damage from acetaminophen poisoning. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID‐19 patients. The daily administration of NAC (600 mg) to postmenopausal women strengthened the immune defenses thereby decreasing the probability of immune system‐related diseases in aging, such as infections, as shown by monitoring several lymphocyte functions (adherence, chemotaxis, proliferation, and natural killer activity) and neutrophil functions (adherence, chemotaxis, phagocytosis, and superoxide) as well as cytokine levels (IL‐2, IL‐8, and TNF‐α).24, NAC works via a broad variety of mechanisms, which inside cells are mediated by GSH replenishment. 1 The only products on the market here in the United States are the oral and topical skin formulations or glutathione and NAC. In other words, FDA’s position is that the Drug Exclusion Provision makes pyridoxamine illegal as a dietary ingredient because pyridoxamine (the article) would have had to have been marketed and sold as pyridoxamine (rather than merely be present as a naturally occurring constiuent of another article, such as beef) prior to the filing of the IND — but is this a valid position? The FDA recently warned seven companies not to claim that their dietary supplements can prevent, treat, or cure a hangover, because only FDA-approved drugs can make such claims. Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID‐19: Potential of pentoxifylline and dipyridamole, Treatments administered to the first 9152 reported cases of COVID‐19: A systematic review, Use of N‐acetylcysteine in the management of coronary artery diseases, Early use of N‐acetylcysteine with nitrate therapy in patients undergoing primary percutaneous coronary intervention for ST‐segment‐elevation myocardial infarction reduces myocardial infarct size (the NACIAM Trial [N‐acetylcysteine in Acute Myocardial Infarction]), “War to the knife” against thromboinflammation to protect endothelial function of COVID‐19 patients, COVID‐19: the potential role of copper and N‐acetylcysteine (NAC) in a combination of candidate antiviral treatments against SARS‐CoV‐2, N‐Acetylcysteine: a potential therapeutic agent for SARS‐CoV‐2, https://doi.org/10.1038/s41577‐020‐0308‐3, https://doi.org/10.1016/j.jpha.2020.03.001, https://doi.org/10.1016/j.ahj.2020.04.025, https://www.epicentro.iss.it/en/coronavirus/sars‐cov‐2‐analysis‐of‐death, https://doi.org/10.1016/j.redox.2019.101410, https://doi.org/10.1016/j.toxrep.2020.06.003, https://doi.org/10.1101/2020.03.04.20030395, https://doi.org/10.1021/acsinfecdis.0c00288, https://doi.org/10.1016/j.cell.2020.02.052, https://doi.org/10.1101/2020.05.07.083147, https://doi.org/10.1016/j.mam.2008.05.005, https://doi.org/10.1007/s41030‐020‐00118‐5, https://doi.org/10.1016/j.jaci.2020.05.006, https://doi.org/10.1016/j.freeradbiomed.2008.07.014, https://doi.org/10.1080/10715762.2018.1468564, https://doi.org/10.1016/0891‐5849(89)90066‐x, https://doi.org/10.3390/molecules23123305, https://doi.org/10.1016/j.oraloncology.2012.08.003, https://doi.org/10.1186/s12931‐019‐1042‐x, https://doi.org/10.1007/s00018‐018‐2852‐6, https://doi.org/10.4172/2161‐105X.1000245, https://doi.org/10.1080/17476348.2018.1495562, https://doi.org/10.1016/j.cct.2019.105894, https://doi.org/10.1016/j.intimp.2014.06.013, https://doi.org/10.1016/j.bcp.2011.05.014, https://doi.org/10.1016/j.pcad.2020.02.007, https://doi.org/10.1007/s40121‐020‐00303‐8, https://doi.org/10.1161/CIRCULATIONAHA.117.027575, https://doi.org/10.1186/s13054‐020‐03060‐9, https://doi.org/10.21873/invivo.11946.1007/s40121‐020‐00303‐8, https://doi.org/10.1016/j.mehy.2020.109862, reduced glutathione (γ‐glutamylcysteinylglycine), nuclear factor kappa‐light‐chain‐enhancer of activated B cells, nuclear factor erythroid 2–related factor 2, severe acute respiratory syndrome coronaviruses, inflammasome activator thioredoxin interacting protein. Vitamin B6 is naturally present in yeast, milk and beef. Complement activation in patients with COVID‐19: A novel therapeutic target, Effect of oral N‐acetylcysteine treatment on immune system in continuous ambulatory peritoneal dialysis patients, The glutathione precursor N‐acetylcysteine improves immune function in postmenopausal women, Antioxidant action via p53‐mediated apoptosis, N‐Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why, The antioxidant action of N‐acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid, NAD(P)H oxidase: role in cardiovascular biology and disease, Overview on the effects of N‐acetylcysteine in neurodegenerative diseases, Nitric oxide insufficiency, platelet activation, and arterial thrombosis, N‐acetylcysteine (NAC) inhibits cell growth by mediating the EGFR/Akt/HMG box‐containing protein 1 (HBP1) signaling pathway in invasive oral cancer, N‐acetylcysteine potentiates the protective effects of α‐1‐antitrypsin in a mouse model of orthotopic lung transplantation, Genomic and transcriptional alterations in mouse fetus liver after transplacental exposure to cigarette smoke, High‐dose N‐acetylcysteine in patients with exacerbations of chronic obstructive pulmonary disease, Effect of N‐acetylcysteine on exacerbations of bronchiectasis (BENE): a randomized controlled trial, Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome, A trial of antioxidants N‐acetylcysteine and procysteine in ARDS. FDA has warned numerous parties that CBD is not a legal dietary supplement ingredient due to the Drug Exclusion Provision. Although it’s not FDA approved for its use, metformin remains a commonly-prescribed medication to help women with PCOS who have insulin resistance. In other words, there are many years of use and sales with no objection from FDA. These findings are consistent with the view that the reduction of disulfides into sulfhydryl groups completely impairs the binding of SARS‐CoV/CoV‐2 spike protein to ACE2 (see Figure 1) and provide a molecular basis for the severity of COVID‐19 infection due to oxidative stress.10 Furthermore, both animal studies and clinical studies suggested that supplementation of NAC, which is known to attenuate the tolerance to nitrates, modifies the function of the renin/angiotensin system in vivo. In spite of this, FDA has only removed CBD products from the market that make aggressive drug-type claims or that have significant safety issues. Dosage form: Injection. In 2005, Biostratum (a drug manufacturer) submitted a petition to FDA, asking the agency to prohibit the sale of dietary supplements containing pyridoxamine. NAC was approved as a new drug under section 505 of the Act [21 U.S.C. Therefore, NAC works per se in the extracellular environment and as a precursor of GSH inside cells. FDA has had ample opportunity to raise this issue in the past and yet has never done so. Drug repurposing is the fastest strategy toward an effective and accessible treatment against COVID‐19 before a vaccine is available,67 and molecules working via multiple mechanisms of action, such as NAC, are more likely to be effective as compared with drugs having a single target. If you want to see the whole conference, you can purchase access here. Learn about our remote access options, Department of Health Sciences, University of Genoa, Genoa, Italy. Biologics Products and Establishments, where information about vaccines, allergenics, and blood products is available. These notices may include a list of possible medication recalls, market withdrawals, alerts and warnings. The Food and Drug Administration (FDA) has not approved any form of carnosine for the treatment of cataracts. CBD can be derived from hemp as well as other plants. R. Balansky and S. La Maestra critically reviewed the manuscript and contributed to the hypothesis exploration. Red yeast rice as a supplement remains widely available in spite of the Pharmanex decision. * Drugs@FDA includes information about drugs, including biological products, approved for human use in the United States (see FAQ), but does not include information about FDA-approved products regulated by the Center for Biologics Evaluation and Research (for example, vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products). N‐ Acetyl‐L‐cysteine (NAC) is a precursor of reduced glutathione (GSH). I’m sure you will shortly hear objections from the major trade associations, who are likely to work with industry to try to find evidence that NAC was part of the supplement or food supply prior to 1963 or find some other basis to challenge FDA’s position. In addition, NAC can exert antioxidant activity via p53‐mediated apoptosis.25 L‐Cys, derived by NAC catabolism, is readily bioconverted to the vasodilator, anti‐inflammatory and readily diffusible hydrogen sulfide. In fact, Nrf‐2 is essential for the antioxidant responsive element (ARE)‐mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO‐1), NAD(P)H dehydrogenase [quinone] 1 (NQO‐1), and GCL.41 Interestingly, it has been proposed that targeting the heme‐heme oxygenase system may prevent severe complications following COVID‐19 infection.42 In parallel, NAC inhibits the oxidative stress‐mediated activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) and biochemical pathways upregulating pro‐inflammatory genes.14 NAC also reduced the intracellular hydrogen peroxide concentration and restored the intracellular total thiol contents by inhibiting NFκB translocation to the cellular nucleus and phosphorylation of p38 mitogen‐activated protein kinase (MAPK p38).43 In influenza infection, NAC inhibits the induction of pro‐inflammatory cytokine response through endosomal toll‐like receptor 3/hemagglutinin (TLR3/HA)‐induced, ROS‐dependent NFκB activation.44, Furthermore, NAC has anti‐inflammatory activity independently of its antioxidant activity, as shown by the finding that it inhibited the LPS‐mediated neurogenic inflammation by counteracting the release of Na,K‐ATPase (NKA), a marker for cell necrosis, which could explain the fall in IL‐6 with NAC.45 A multicenter, randomized, placebo‐controlled trial, sequentially testing early use of intravenous NAC, followed by oral ramipril for 12 weeks, is based on the rationale that these agents have the ability to limit nitrosative stress and expression of the inflammasome activator thioredoxin interacting protein (TXNIP).46, NAC has been demonstrated to attenuate the incidence and severity of influenza and influenza‐like illnesses.