Chemistry:Acetylcysteine

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Short description: Medication used to treat overdose of paracetamol
Acetylcysteine
Acetylcysteine2DACS.svg
Acetylcysteine-from-xtal-3D-bs-17.png
Clinical data
Pronunciation/əˌsiːtəlˈsɪstiːn/ and similar (/əˌsɛtəl-, ˌæsɪtəl-, -tiːn/)
Trade namesACC 200, Acetadote, Fluimucil, Mucomyst, others
Other namesN-acetylcysteine; N-acetyl-L-cysteine; NALC; NAC
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth, intravenous, inhalation
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability10% (Oral)[6]
Protein binding50 to 83%[7]
MetabolismLiver[7]
Elimination half-life5.6 hours[5]
ExcretionKidney (30%),[7] faecal (3%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC5H9NO3S
Molar mass163.19 g·mol−1
3D model (JSmol)
Specific rotation+5° (c = 3% in water)[9]
Melting point109 to 110 °C (228 to 230 °F) [9]
  (verify)

Acetylcysteine, also known as N-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis.[7] It has been used to treat lactobezoar in infants. It can be taken intravenously, by mouth, or inhaled as a mist.[7] Some people use it as a dietary supplement.[10][11]

Common side effects include nausea and vomiting when taken by mouth.[7] The skin may occasionally become red and itchy with any route of administration.[7] A non-immune type of anaphylaxis may also occur.[7] It appears to be safe in pregnancy.[7] For paracetamol overdose, it works by increasing the level of glutathione, an antioxidant that can neutralise the toxic breakdown products of paracetamol.[7] When inhaled, it acts as a mucolytic by decreasing the thickness of mucus.[12]

Acetylcysteine was initially patented in 1960 and came into medical use in 1968.[13][14][15] It is on the World Health Organization's List of Essential Medicines.[16][17] It is available as a generic medication.[18]

The sulfur-containing amino acids cysteine and methionine are more easily oxidized than the other amino acids.[19][20]

Uses

Medical uses

Paracetamol overdose

Main page: Medicine:Paracetamol poisoning

Intravenous and oral formulations of acetylcysteine are available for the treatment of paracetamol (acetaminophen) overdose.[21] When paracetamol is taken in large quantities, a minor metabolite called N-acetyl-p-benzoquinone imine (NAPQI) accumulates within the body. It is normally conjugated by glutathione, but when taken in excess, the body's glutathione reserves are not sufficient to deactivate the toxic NAPQI. This metabolite is then free to react with key hepatic enzymes, thereby damaging liver cells. This may lead to severe liver damage and even death by acute liver failure.

In the treatment of paracetamol (acetaminophen) overdose, acetylcysteine acts to maintain or replenish depleted glutathione reserves in the liver and enhance non-toxic metabolism of acetaminophen.[22] These actions serve to protect liver cells from NAPQI toxicity. It is most effective in preventing or lessening hepatic injury when administered within 8–10 hours after overdose.[22] Research suggests that the rate of liver toxicity is approximately 3% when acetylcysteine is administered within 10 hours of overdose.[21]

Although IV and oral acetylcysteine are equally effective for this indication, oral administration is generally poorly tolerated due to the higher dosing required to overcome its low oral bioavailability,[23] its foul taste and odour, and a higher incidence of adverse effects when taken by mouth, particularly nausea and vomiting. Prior pharmacokinetic studies of acetylcysteine did not consider acetylation as a reason for the low bioavailability of acetylcysteine.[24] Oral acetylcysteine is identical in bioavailability to cysteine precursors.[24] However, 3% to 6% of people given intravenous acetylcysteine show a severe, anaphylaxis-like allergic reaction, which may include extreme breathing difficulty (due to bronchospasm), a decrease in blood pressure, rash, angioedema, and sometimes also nausea and vomiting.[25] Repeated doses of intravenous acetylcysteine will cause these allergic reactions to progressively worsen in these people.

Several studies have found this anaphylaxis-like reaction to occur more often in people given intravenous acetylcysteine despite serum levels of paracetamol not high enough to be considered toxic.[26][27][28][29]

Lungs

Inhaled acetylcysteine has been used for mucolytic ("mucus-dissolving") therapy in addition to other therapies in respiratory conditions with excessive and/or thick mucus production. It is also used post-operatively, as a diagnostic aid, and in tracheotomy care. It may be considered ineffective in cystic fibrosis.[30] A 2013 Cochrane review in cystic fibrosis found no evidence of benefit.[31]

Acetylcysteine is used in the treatment of obstructive lung disease as an adjuvant treatment.[32][33][34]

Other uses

Acetylcysteine has been used to complex palladium, to help it dissolve in water. This helps to remove palladium from drugs or precursors synthesized by palladium-catalyzed coupling reactions.[35] N-acetylcysteine can be used to protect the liver.[36]

Microbiological use

Acetylcysteine can be used in Petroff's method of liquefaction and decontamination of sputum, in preparation for recovery of mycobacterium.[37] It also displays significant antiviral activity against the influenza A viruses.[38]

Acetylcysteine has bactericidal properties and breaks down bacterial biofilms of clinically relevant pathogens including Pseudomonas aeruginosa, Staphylococcus aureus, Enterococcus faecalis, Enterobacter cloacae, Staphylococcus epidermidis, and Klebsiella pneumoniae.[39]

Side effects

The most commonly reported adverse effects for IV formulations of acetylcysteine are rash, urticaria, and itchiness.[22]

Adverse effects for inhalational formulations of acetylcysteine include nausea, vomiting, stomatitis, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. Although infrequent, bronchospasm has been reported to occur unpredictably in some patients.[40]

Adverse effects for oral formulations of acetylcysteine have been reported to include nausea, vomiting, rash, and fever.[40]

Large doses in a mouse model showed that acetylcysteine could potentially cause damage to the heart and lungs.[41] They found that acetylcysteine was metabolized to S-nitroso-N-acetylcysteine (SNOAC), which increased blood pressure in the lungs and right ventricle of the heart (pulmonary artery hypertension) in mice treated with acetylcysteine. The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronic hypoxia). The authors also found that SNOAC induced a hypoxia-like response in the expression of several important genes both in vitro and in vivo.

The implications of these findings for long-term treatment with acetylcysteine have not yet been investigated. The dose used by Palmer and colleagues was dramatically higher than that used in humans, the equivalent of about 20 grams per day.[41] In humans, a much lower dosages (600 mg per day) have been observed to counteract some age-related decline in the hypoxic ventilatory response as tested by inducing prolonged hypoxia.[42]

Although N-acetylcysteine prevented liver damage in mice when taken before alcohol, when taken four hours after alcohol it made liver damage worse in a dose-dependent fashion.[43]

Pharmacology

Pharmacodynamics

Acetylcysteine serves as a prodrug to L-cysteine, a precursor to the biologic antioxidant glutathione. Hence administration of acetylcysteine replenishes glutathione stores.[44]

  • Glutathione, along with oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO), have been found to bind to the glutamate recognition site of the NMDA and AMPA receptors (via their γ-glutamyl moieties), and may be endogenous neuromodulators.[45][46] At millimolar concentrations, they may also modulate the redox state of the NMDA receptor complex.[46] In addition, glutathione has been found to bind to and activate ionotropic receptors that are different from any other excitatory amino acid receptor, and which may constitute glutathione receptors, potentially making it a neurotransmitter.[47] As such, since N-acetylcysteine is a prodrug of glutathione, it may modulate all of the aforementioned receptors as well.
  • Glutathione also modulates the NMDA receptor by acting at the redox site.[48][49]

L-cysteine also serves as a precursor to cystine, which in turn serves as a substrate for the cystine-glutamate antiporter on astrocytes; hence there is increasing glutamate release into the extracellular space. This glutamate in turn acts on mGluR2/3 receptors, and at higher doses of acetylcysteine, mGluR5.[50][51]

Acetylcysteine also possesses some anti-inflammatory effects possibly via inhibiting NF-κB and modulating cytokine synthesis.[48]

Pharmacokinetics

Acetylcysteine is extensively liver metabolized, CYP450 minimal, urine excretion is 22–30% with a half-life of 5.6 hours in adults and 11 hours in newborns.

Chemistry

Acetylcysteine is the N-acetyl derivative of the amino acid L-cysteine, and is a precursor in the formation of the antioxidant glutathione in the body. The thiol (sulfhydryl) group confers antioxidant effects and is able to reduce free radicals.

N-acetyl-L-cysteine is soluble in water and alcohol, and practically insoluble in chloroform and ether.[52]

It is a white to white with light yellow cast powder, and has a pKa of 9.5 at 30 °C.[9]

Society and culture

Acetylcysteine was first studied as a drug in 1963. Amazon removed acetylcysteine for sale in the US in 2021, due to claims by the FDA of it being classified as a drug rather than a supplement.[53][54][55][56] In April 2022, the FDA released draft guidance on FDA's policy regarding products labeled as dietary supplements that contain N-acetyl-L-cysteine.[57] Amazon subsequently re-listed NAC products as of August 2022.[58]

Research

While many antioxidants have been researched to treat a large number of diseases by reducing the negative effect of oxidative stress, acetylcysteine is one of the few that has yielded promising results, and is currently already approved for the treatment of paracetamol overdose.[59]

  • In mouse mdx models of Duchenne's muscular dystrophy, treatment with 1–2% acetylcysteine in drinking water significantly reduces muscle damage and improves strength.[59]
  • It is being studied in conditions such as autism, where cysteine and related sulfur amino acids may be depleted due to multifactorial dysfunction of methylation pathways involved in methionine catabolism.[60]
  • Animal studies have also demonstrated its efficacy in reducing the damage associated with moderate traumatic brain or spinal injury, and also ischaemia-induced brain injury. In particular, it has been demonstrated to reduce neuronal losses and to improve cognitive and neurological outcomes associated with these traumatic events.[61]
  • It has been suggested that acetylcysteine may help people with aspirin-exacerbated respiratory disease by increasing levels of glutathione allowing faster breakdown of salicylates, although there is no evidence that it is of benefit.[62]
  • Small studies have shown acetylcysteine to be of benefit to people with blepharitis.[63] It has been shown to reduce ocular soreness caused by Sjögren's syndrome.[64]
  • It has been shown that N-acetylcysteine may protect the human cochlea from subclinical hearing loss caused by loud noises such as impulse noise.[65] In animal models, it reduced age-related hearing loss.
  • It has been shown effective in the treatment of Unverricht-Lundborg disease in an open trial in four patients. A marked decrease in myoclonus and some normalization of somatosensory evoked potentials with acetylcysteine treatment has been documented.[66][67]
  • Addiction to certain addictive drugs (including cocaine, heroin, alcohol, and nicotine) is correlated with a persistent reduction in the expression of excitatory amino acid transporter 2 (EAAT2) in the nucleus accumbens (NAcc);[68] the reduced expression of EAAT2 in this region is implicated in addictive drug-seeking behavior.[68] In particular, the long-term dysregulation of glutamate neurotransmission in the NAcc of long-term, drug-dependent users is associated with an increase in vulnerability to relapse after re-exposure to the addictive drug or its associated drug cues.[68] Drugs that help to normalize the expression of EAAT2 in this region, such as N-acetylcysteine, have been proposed as an adjunct therapy for the treatment of addiction to cocaine, nicotine, alcohol, and other drugs.[68]
  • It has been tested for the reduction of hangover symptoms, though the overall results indicate very limited efficacy.[69][70]
  • A double-blind placebo controlled trial of 262 patients has shown NAC treatment was well-tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed.[71]

Kidney and bladder

Evidence for the benefit of acetylcysteine to prevent radiocontrast induced kidney disease is mixed.[72]

Acetylcysteine has been used for cyclophosphamide-induced haemorrhagic cystitis, although mesna is generally preferred due to the ability of acetylcysteine to diminish the effectiveness of cyclophosphamide.[73]

Psychiatry

Acetylcysteine has been studied for major psychiatric disorders,[74][75][48][61] including bipolar disorder,[74] major depressive disorder, and schizophrenia.[75][48]

Tentative evidence exists for N-acetylcysteine also in the treatment of Alzheimer's disease, autism, obsessive-compulsive disorder, specific drug addictions (cocaine), drug-induced neuropathy, trichotillomania, excoriation disorder, and a certain form of epilepsy (progressive myoclonic).[75][48][76] Preliminary evidence showed efficacy in anxiety disorder, attention deficit hyperactivity disorder and mild traumatic brain injury although confirmatory studies are required.[76][77][78][79] Tentative evidence also supports use in cannabis use disorder.[80]

It is also being studied for use as a treatment of body-focused repetitive behavior.[81][82]

Addiction

Evidence to date does not support the efficacy for N-acetylcysteine in treating addictions to gambling, methamphetamine, or nicotine.[76] Based upon limited evidence, NAC appears to normalize glutamate neurotransmission in the nucleus accumbens and other brain structures, in part by upregulating the expression of excitatory amino acid transporter 2 (EAAT2), a.k.a. glutamate transporter 1 (GLT1), in individuals with addiction.[68] While NAC has been demonstrated to modulate glutamate neurotransmission in adult humans who are addicted to cocaine, NAC does not appear to modulate glutamate neurotransmission in healthy adult humans.[68] NAC has been hypothesized to exert beneficial effects through its modulation of glutamate and dopamine neurotransmission as well as its antioxidant properties.[48]

Bipolar disorder

In bipolar disorder, N-acetylcysteine has been repurposed as an augmentation strategy for depressive episodes in light of the possible role of inflammation in the pathogenesis of mood disorders. Nonetheless, meta-analytic evidence shows that add-on N-acetylcysteine was more effective than placebo only in reducing depression scales scores (low quality evidence), without positive effects on response and remission outcomes, limiting its possible role in clinical practice to date.[74][83]

COVID-19

Acetylcysteine is being considered as a possible treatment for COVID-19.[84][85][86]

A combination of guanfacine and N-acetylcysteine has been found to lift the "brain fog" of eight patients with long COVID, according to researchers.[87]

A combination of glycine and N-acetylcysteine is suspected to have potential to safely replenish depleted glutathione levels in COVID-19 patients.[88]

References

  1. ↑ DBL ACETYLCYSTEINE injection concentrate acetylcysteine 2 g/ 10 mL injection ampoule
  2. ↑ "TGA eBS - Product and Consumer Medicine Information Licence". http://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent=&id=CP-2018-PI-01811-1. 
  3. ↑ Australia, Healthdirect (30 November 2022). "Acetylcysteine (Omegapharm)". https://www.healthdirect.gov.au/medicines/brand/amt,26341000036106/acetylcysteine-omegapharm. 
  4. ↑ "Acepiro 600 mg effervescent tablets - Summary of Product Characteristics (SmPC)". 30 August 2022. https://www.medicines.org.uk/emc/product/13849/smpc. 
  5. ↑ 5.0 5.1 "Acetadote- acetylcysteine injection, solution". 1 October 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=472f158a-5ab9-4308-8e49-1116e6ea3d39. 
  6. ↑ Chronic Obstructive Pulmonary Disease a Practical Guide to Management.. Chichester: John Wiley & Sons. 2008. p. 750. ISBN 9780470755280. https://books.google.com/books?id=y9li1geShyYC&pg=PA750. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 "Acetylcysteine". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/acetylcysteine.html. 
  8. ↑ "L-Cysteine, N-acetyl- — Compound Summary". PubChem. National Center for Biotechnology Information. 25 March 2005. Identification. https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=581. 
  9. ↑ 9.0 9.1 9.2 "N-Acetyl-L-cysteine Product Information". Sigma-Aldrich. https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma-Aldrich/Product_Information_Sheet/a7250pis.pdf. 
  10. ↑ A Guide to Understanding Dietary Supplements. Routledge. 2012. p. 469. ISBN 9781136805707. https://books.google.com/books?id=9ZZrW_j9XrcC&pg=PA469. 
  11. ↑ "Cysteine". http://www.umm.edu/health/medical/altmed/supplement/cysteine. 
  12. ↑ "Role of N-acetylcysteine in the management of COPD". International Journal of Chronic Obstructive Pulmonary Disease 1 (4): 425–434. December 2006. doi:10.2147/copd.2006.1.4.425. ISSN 1176-9106. PMID 18044098. 
  13. ↑ Analogue-Based Drug Discovery. Weinheim: Wiley-VCH. 2006. p. 544. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA544. 
  14. ↑ , Sheffner Aaron"Mucolytic-nu-acylated sulfhydryl compositions and process for treating animal mucus" patent US3091569A, issued 28 May 1963
  15. ↑ "Mucolytic-N-acylated sulfhydryl compositions and process for treating animal mucus" US patent 3091569, published 28 May 1963, issued 28 May 1963, assigned to Mead Johnson & Co
  16. ↑ Organization, World Health (2019). World Health Organization Model List of Essential Medicines: 21st list 2019. Geneva: World Health Organization. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  17. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  18. ↑ Top 100 Drugs: Clinical pharmacology and practical prescribing. Elsevier Health Sciences. 2014. ISBN 9780702055157. https://books.google.com/books?id=oeYjAwAAQBAJ&pg=PT44. 
  19. ↑ "Oxidation Resistance of the Sulfur Amino Acids: Methionine and Cysteine.". BioMed Research International 2017: 9584932. 2017. doi:10.1155/2017/9584932. PMID 29445748. 
  20. ↑ "Functions and evolution of selenoprotein methionine sulfoxide reductases". Biochimica et Biophysica Acta (BBA) - General Subjects 1790 (11): 1471–1477. 2009. doi:10.1016/j.bbagen.2009.04.014. PMID 19406207. 
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  22. ↑ 22.0 22.1 22.2 "Acetadote Package Insert". FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021539s004lbl.pdf. 
  23. ↑ "Pharmacokinetics of N-acetylcysteine in man". European Journal of Clinical Pharmacology 31 (2): 217–222. 1986. doi:10.1007/bf00606662. PMID 3803419. 
  24. ↑ 24.0 24.1 "Oral N-acetyl-L-cysteine is a safe and effective precursor of cysteine". Journal of Animal Science 85 (7): 1712–1718. July 2007. doi:10.2527/jas.2006-835. PMID 17371789. 
  25. ↑ "Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning". American Journal of Health-System Pharmacy 63 (19): 1821–1827. October 2006. doi:10.2146/ajhp060050. PMID 16990628. 
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  27. ↑ "Management of anaphylactoid reactions to intravenous N-acetylcysteine". Annals of Emergency Medicine 31 (6): 710–715. June 1998. doi:10.1016/S0196-0644(98)70229-X. PMID 9624310. 
  28. ↑ "Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning". British Journal of Clinical Pharmacology 51 (1): 87–91. January 2001. doi:10.1046/j.1365-2125.2001.01305.x. PMID 11167669. 
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  30. ↑ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
  31. ↑ "Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis.". The Cochrane Database of Systematic Reviews 2013 (7): CD007168. 12 July 2013. doi:10.1002/14651858.CD007168.pub3. PMID 23852992. PMC 8078644. http://www.repository.heartofengland.nhs.uk/157/1/Nebulized%20and%20oral%20thiol%20derivatives%20for%20pulmonary%20disease%20in%20cystic%20fibrosis..pdf. Retrieved 16 May 2018. 
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  34. ↑ "Oral mucolytic drugs for exacerbations of chronic obstructive pulmonary disease: systematic review". BMJ 322 (7297): 1271–1274. May 2001. doi:10.1136/bmj.322.7297.1271. PMID 11375228. 
  35. ↑ "The Art of Meeting Palladium Specifications in Active Pharmaceutical Ingredients Produced by Pd-Catalyzed Reactions". Advanced Synthesis & Catalysis 346 (8): 889–900. 2004. doi:10.1002/adsc.200404071. 
  36. ↑ Acetylcysteine, https://livertox.nih.gov/Acetylcysteine.htm, retrieved 26 April 2019 
  37. ↑ "Comparison of NaOH–N-acetyl cysteine and sulfuric acid decontamination methods for recovery of mycobacteria from clinical specimens". Journal of Microbiological Methods 62 (1): 83–88. July 2005. doi:10.1016/j.mimet.2005.01.010. PMID 15823396. 
  38. ↑ "N-Acetyl-L-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus". Biochemical Pharmacology 79 (3): 413–420. February 2010. doi:10.1016/j.bcp.2009.08.025. PMID 19732754. https://hal.archives-ouvertes.fr/hal-00538093/file/PEER_stage2_10.1016%252Fj.bcp.2009.08.025.pdf. 
  39. ↑ "Role of antibiofilm-antimicrobial agents in controlling device-related infections". The International Journal of Artificial Organs 34 (9): 752–758. September 2011. doi:10.5301/ijao.5000024. PMID 22094553. 
  40. ↑ 40.0 40.1 "Mucomyst Package Insert". http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d2dc24f3-3ad7-4c6c-8e9f-7202d9a146f7. 
  41. ↑ 41.0 41.1 "S-Nitrosothiols signal hypoxia-mimetic vascular pathology". The Journal of Clinical Investigation 117 (9): 2592–2601. September 2007. doi:10.1172/JCI29444. PMID 17786245. 
  42. ↑ "Effect of N-acetyl-cysteine on the hypoxic ventilatory response and erythropoietin production: linkage between plasma thiol redox state and O2 chemosensitivity". Blood 99 (5): 1552–5. March 2002. doi:10.1182/blood.V99.5.1552. PMID 11861267. 
  43. ↑ "A dual effect of N-acetylcysteine on acute ethanol-induced liver damage in mice". Hepatology Research 34 (3): 199–206. March 2006. doi:10.1016/j.hepres.2005.12.005. PMID 16439183. 
  44. ↑ "Product Information: Aceradote® Concentrated Injection" (PDF). TGA eBusiness Services. Phebra Pty Ltd. 16 January 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03960-3. 
  45. ↑ "Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: Relevance to schizophrenia". Neuroscience 137 (3): 807–819. 2006. doi:10.1016/j.neuroscience.2005.10.014. ISSN 0306-4522. PMID 16330153. 
  46. ↑ 46.0 46.1 "Glutathione Is an Endogenous Ligand of Rat Brain N-Methyl-D-Aspartate (NMDA) and 2-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionate (AMPA) Receptors". Neurochemical Research 22 (9): 1165–1171. 1997. doi:10.1023/A:1027377605054. ISSN 0364-3190. PMID 9251108. 
  47. ↑ "Modulation of glutamate receptor functions by glutathione". Neurochemistry International 37 (2–3): 299–306. 2000. doi:10.1016/S0197-0186(00)00031-0. ISSN 0197-0186. PMID 10812215. 
  48. ↑ 48.0 48.1 48.2 48.3 48.4 48.5 "The promise of N-acetylcysteine in neuropsychiatry". Trends in Pharmacological Sciences 34 (3): 167–177. March 2013. doi:10.1016/j.tips.2013.01.001. PMID 23369637. 
  49. ↑ "Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenia patients". Neuropsychopharmacology 33 (9): 2187–2199. August 2008. doi:10.1038/sj.npp.1301624. PMID 18004285. 
  50. ↑ "N-Acetylcysteine for antioxidant therapy: pharmacology and clinical utility". Expert Opinion on Biological Therapy 8 (12): 1955–1962. December 2008. doi:10.1517/14728220802517901. PMID 18990082. 
  51. ↑ "The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine". Biological Psychiatry 71 (11): 978–986. June 2012. doi:10.1016/j.biopsych.2011.10.024. PMID 22137594. 
  52. ↑ "N-Acetyl-L-cysteine | C5H9NO3S". https://pubchem.ncbi.nlm.nih.gov/compound/N-Acetyl-L-cysteine#section=Chemical-and-Physical-Properties. 
  53. ↑ "Amazon confirms plans on removing NAC supplements". 2021-05-06. https://www.naturalproductsinsider.com/regulatory/amazon-confirms-plans-removing-nac-supplements. 
  54. ↑ "Amazon reportedly removes NAC-containing dietary supplements". https://www.naturalproductsinsider.com/regulatory/amazon-reportedly-removes-nac-containing-dietary-supplements. 
  55. ↑ "WARNING LETTER benjaminmcevoy.com". https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/benjaminmcevoycom-607149-05142020. 
  56. ↑ "FDA Sends Warning Letters to Seven Companies Illegally Selling Hangover Products". https://www.fda.gov/food/cfsan-constituent-updates/fda-sends-warning-letters-seven-companies-illegally-selling-hangover-products. 
  57. ↑ "FDA Releases Draft Guidance on Enforcement Discretion for Certain NAC Products". https://www.fda.gov/food/cfsan-constituent-updates/fda-releases-draft-guidance-enforcement-discretion-certain-nac-products. 
  58. ↑ "Amazon resumes sales of NAC supplements". 25 August 2022. https://www.naturalproductsinsider.com/regulatory/amazon-resumes-sales-nac-supplements. 
  59. ↑ 59.0 59.1 "Antioxidant therapy in a mouse model of Duchenne muscular dystrophy: some promising results but with a weighty caveat". The Journal of Physiology 595 (23): 7015. 29 October 2017. doi:10.1113/jp275232. ISSN 0022-3751. PMID 29034480. 
  60. ↑ "Glutathione redox imbalance in brain disorders". Current Opinion in Clinical Nutrition and Metabolic Care 18 (1): 89–95. January 2015. doi:10.1097/MCO.0000000000000134. PMID 25405315. 
  61. ↑ 61.0 61.1 "N-Acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities". Brain and Behavior 4 (2): 108–122. March 2014. doi:10.1002/brb3.208. PMID 24683506. 
  62. ↑ "An update on the diagnosis and treatment of sinusitis and nasal polyposis". Allergy 58 (3): 176–191. March 2003. doi:10.1034/j.1398-9995.2003.02172.x. PMID 12653791. 
  63. ↑ "N-Acetylcysteine – passe-partout or much ado about nothing?". British Journal of Clinical Pharmacology 61 (1): 5–15. January 2006. doi:10.1111/j.1365-2125.2005.02523.x. PMID 16390346. 
  64. ↑ "Management of the dry eye in Sjogren's syndrome". The British Journal of Ophthalmology 58 (9): 798–805. September 1974. doi:10.1136/bjo.58.9.798. PMID 4433493. 
  65. ↑ "The efficacy of N-acetylcysteine to protect the human cochlea from subclinical hearing loss caused by impulse noise: a controlled trial". Noise Health 13 (55): 392–401. November–December 2011. doi:10.4103/1463-1741.90293. PMID 22122955. 
  66. ↑ "N-acetylcysteine and Unverricht-Lundborg disease: variable response and possible side effects". Neurology 59 (9): 1447–1449. November 2002. doi:10.1212/wnl.59.9.1447. PMID 12427904. 
  67. ↑ Ataxia with Identified Genetic and Biochemical Defects at eMedicine
  68. ↑ 68.0 68.1 68.2 68.3 68.4 68.5 "Potential role of N-acetylcysteine in the management of substance use disorders". CNS Drugs 28 (2): 95–106. 2014. doi:10.1007/s40263-014-0142-x. PMID 24442756. 
  69. ↑ Clinical trial number NCT02541422 for "Use of NAC in Alleviation of Hangover Symptoms – Study Results" at ClinicalTrials.gov
  70. ↑ "The use of N-acetylcysteine in the prevention of hangover: a randomized trial". Scientific Reports 11 (1): 13397. June 2021. doi:10.1038/s41598-021-92676-0. PMID 34183702. Bibcode: 2021NatSR..1113397C. 
  71. ↑ "Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment". European Respiratory Journal 10 (7): 1535–1541. 1 July 1997. doi:10.1183/09031936.97.10071535. PMID 9230243. 
  72. ↑ "Contrast medium induced acute kidney injury: a narrative review.". Journal of Nephrology 31 (6): 797–812. December 2018. doi:10.1007/s40620-018-0498-y. PMID 29802583. 
  73. ↑ "Hemorrhagic Cystitis Treatment & Management: Approach Considerations, Clot Evacuation, Bladder Irrigation Agents". 5 December 2019. https://emedicine.medscape.com/article/2056130-treatment#d12. 
  74. ↑ 74.0 74.1 74.2 "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials". Journal of Psychiatric Research 143: 230–238. September 2021. doi:10.1016/j.jpsychires.2021.09.018. PMID 34509090. 
  75. ↑ 75.0 75.1 75.2 "N-Acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action". Journal of Psychiatry & Neuroscience 36 (2): 78–86. March 2011. doi:10.1503/jpn.100057. PMID 21118657. 
  76. ↑ 76.0 76.1 76.2 "Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review". Neuroscience and Biobehavioral Reviews 55: 294–321. August 2015. doi:10.1016/j.neubiorev.2015.04.015. PMID 25957927. 
  77. ↑ "The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial". The Journal of Clinical Psychiatry 75 (6): 628–636. June 2014. doi:10.4088/JCP.13m08454. PMID 25004186. 
  78. ↑ "N-Acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review". Clinical Psychopharmacology and Neuroscience 13 (1): 12–24. April 2015. doi:10.9758/cpn.2015.13.1.12. PMID 25912534. 
  79. ↑ "The chemistry and biological activities of N-acetylcysteine". Biochimica et Biophysica Acta (BBA) - General Subjects 1830 (8): 4117–4129. August 2013. doi:10.1016/j.bbagen.2013.04.016. PMID 23618697. 
  80. ↑ "N-Acetylcysteine in the treatment of psychiatric disorders: current status and future prospects.". Expert Opinion on Drug Metabolism & Toxicology 13 (3): 279–292. 2 November 2016. doi:10.1080/17425255.2017.1251580. PMID 27766914. 
  81. ↑ "Evidence of N-acetylcysteine efficacy for skin picking disorder: A retrospective cohort study". Journal of the American Academy of Dermatology 87 (1): 148–150. July 2022. doi:10.1016/j.jaad.2021.06.874. PMID 34224772. 
  82. ↑ "Dramatic Improvement of Trichotillomania with 6 Months of Treatment With N-Acetylcysteine". Global Pediatric Health 9: 2333794X221086576. 2022. doi:10.1177/2333794X221086576. PMID 35647220. 
  83. ↑ "N-acetylcysteine as an adjunctive treatment for bipolar depression: A systematic review and meta-analysis of randomized controlled trials". Bipolar Disorders 23 (7): 707–714. November 2021. doi:10.1111/bdi.13039. PMID 33354859. 
  84. ↑ "N-Acetylcysteine as Adjuvant Therapy for COVID-19 – A Perspective on the Current State of the Evidence". Journal of Inflammation Research 14: 2993–3013. 2021. doi:10.2147/JIR.S306849. PMID 34262324. 
  85. ↑ "N-Acetyl-cysteine reduces the risk for mechanical ventilation and mortality in patients with COVID-19 pneumonia: a two-center retrospective cohort study". Infectious Diseases (London, England) 53 (11): 847–854. 2021. doi:10.1080/23744235.2021.1945675. PMID 34182881. 
  86. ↑ "Therapeutic potential of N-acetyl cysteine during COVID-19 epoch". World Journal of Virology 11 (2): 104–106. 2022. doi:10.5501/wjv.v11.i2.104. PMID 35433335. 
  87. ↑ "Clinical experience with the α2A-adrenoceptor agonist, guanfacine, and N-acetylcysteine for the treatment of cognitive deficits in "Long-COVID19"". Neuroimmunology Reports 3 (3): 100154. 2022. doi:10.1016/j.nerep.2022.100154. 
  88. ↑ "Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID-19: Implications for GlyNAC (Glycine and N-Acetylcysteine) Supplementation". Antioxidants 11 (1): 50. December 2021. doi:10.3390/antiox11010050. PMID 35052554. 



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