Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness?
Piero Sestili, Carmela Fimognari
Frontiers in Pharmacology, doi:10.3389/fphar.2020.579944
COVID-19 pandemic is posing an unprecedented sanitary threat: antiviral and hostdirected medications to treat the disease are urgently needed. A great effort has been paid to find drugs and treatments for hospitalized, severely ill patients. However, medications used for the domiciliary management of early symptoms, notwithstanding their importance, have not been and are not presently regarded with the same attention and seriousness. In analogy with other airways viral infections, COVID-19 patients in the early phase require specific antivirals (still lacking) and non-etiotropic drugs to lower pain, fever, and control inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (PAC) are widely used as non-etiotropic agents in common airways viral infections and hence are both theoretically repurposable for COVID-19. However, a warning from some research reports and National Authorities raised NSAIDs safety concerns because of the supposed induction of angiotensin-converting enzyme 2 (ACE2) levels (the receptor used by SARS-CoV2 to enter host airways cells), the increased risk of bacterial superinfections and masking of disease symptoms. As a consequence, the use of NSAIDs was, and is still, discouraged while the alternative adoption of paracetamol is still preferred. On the basis of novel data and hypothesis on the possible role of scarce glutathione (GSH) levels in the exacerbation of COVID-19 and of the GSH depleting activity of PAC, this commentary raises the question of whether PAC may be the better choice.
AUTHOR CONTRIBUTIONS PS: conceptualization and writing. CF: bibliographic search, revision of the text. All authors contributed to the article and approved the submitted version. 
 Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Aydemir, Ulusu, Is glucose-6-phosphate dehydrogenase enzyme deficiency a factor in Coronavirus-19 (COVID-19) infections and deaths?, Pathog. Glob. Health, 
doi:10.1080/20477724.2020.1751388Bolt, Thier, Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology, Curr. Drug Metab, 
doi:10.2174/138920006778017786Bruce, Barlow-Pay, Short, Vilches-Moraga, Price et al., Prior Routine Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Important Outcomes in Hospitalised Patients with COVID-19, J. Clin. Med, 
doi:10.3390/jcm9082586Brune, Renner, Tiegs, Acetaminophen/paracetamol: A history of errors, failures and false decisions, Eur. J. Pain, 
doi:10.1002/ejp.621Burgunder, Varriale, Lauterburg, Effect of Nacetylcysteine on plasma cysteine and glutathione following paracetamol administration, Eur. J. Clin. Pharmacol, 
doi:10.1007/BF00609183Cantoni, Sestili, Palomba, Guidarelli, Cattabeni et al., Isolation and preliminary characterization of a Chinese hamster ovary cell line with high-degree resistance to hydrogen peroxide, Biochem. Pharmacol, 
doi:10.1016/0006-2952(95)02436-0Capuano, Scavone, Racagni, Scaglione, NSAIDs in patients with viral infections, including Covid-19: Victims or perpetrators?, Pharmacol. Res, 
doi:10.1016/j.phrs.2020.104849Cumhur Cure, Kucuk, Cure, NSAIDs may increase the risk of thrombosis and acute renal failure in patients with COVID-19 infection, Therapie, 
doi:10.1016/j.therap.2020.06.012Danser, Epstein, Batlle, Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers, Hypertension, 
doi:10.1161/hypertensionaha.120.15082Day, Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists, BMJ, 
doi:10.1136/bmj.m1086De Flora, Balansky, Maestra, Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19, FASEB J, 
doi:10.1096/fj.202001807De Flora, Grassi, Carati, Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with longterm N-acetylcysteine treatment, Eur. Respir. J, 
doi:10.1183/09031936.97.10071535De Tours, De Marseille, Rapport d'expertise -Infections bacteŕiennes graves (de la peau et des tissus mous, pleuro-pulmonaires, neurologiques et ORL) rapporteés avec l'ibuprofène ou le ketoprofène dans le traitement symptomatique de la fièvre ou de douleur non rhumatologique
Dimova, Hoet, Dinsdale, Nemery, Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro, Int. J. Biochem. Cell Biol, 
doi:10.1016/j.biocel.2005.03.005Driver, Marks, Van Der Wal, Not all (N)SAID and done: Effects of nonsteroidal anti-inflammatory drugs and paracetamol intake on platelets, Res. Pract. Thromb. Haemost, 
doi:10.1002/rth2.12283Estevez, De Angelo, Vesell, Basal and paracetamol-depleted glutathione from human lymphocytes: ethnic variability, Acta Physiol. Pharmacol. Ther. Latinoam
Farouk, Fiaccadori, Cravedi, Campbell, COVID-19 and the kidney: what we think we know so far and what we don't, J. Nephrol, 
doi:10.1007/s40620-020-00789-yGiardini, Carrer, Casati, Contro, Vergani et al., Increased sFLT1/PlGF ratio in COVID-19: a novel link to Angiotensin II-mediated endothelial dysfunction, Am. J. Hematol, 
doi:10.1002/ajh.25882Grant, Lahore, Mcdonnell, Baggerly, Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths, Nutrients, 
doi:10.3390/nu12040988Hati, Bhattacharyya, Impact of Thiol-Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor, ACS Omega, 
doi:10.1021/acsomega.0c02125Horowitz, Freeman, Bruzzese, Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases, Respir. Med. Case Rep, 
doi:10.1016/j.rmcr.2020.101063Ibrahim, El-Meligi, Abdel-Hamid, Elhendy, Relations between von Willebrand factor, markers of oxidative stress and microalbuminuria in patients with type 2 diabetes mellitus, Med. Sci. Monit
Ibrahim, Perl, Smith, Lewis, Kon et al., Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine, Clin. Immunol, 
doi:10.1016/j.clim.2020.108544Jain, Micinski, Huning, Kahlon, Bass et al., Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients, Eur. J. Clin. Nutr, 
doi:10.1038/ejcn.2014.114Jain, Parsanathan, Can Vitamin D and L-Cysteine Co-Supplementation Reduce 25(OH)-Vitamin D Deficiency and the Mortality Associated with COVID-19 in African Americans?, J. Am. Coll. Nutr, 
doi:10.1080/07315724.2020.1789518Kaufmann, Dorhoi, Hotchkiss, Bartenschlager, Host-directed therapies for bacterial and viral infections, Nat. Rev. Drug Discov, 
doi:10.1038/nrd.2017.162Khomich, Kochetkov, Bartosch, Redox biology of respiratory viral infections, Viruses, 
doi:10.3390/v10080392Klopcǐc, Poberzňik, Mavri, Dolenc, A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione, Chem. Biol. Interact, 
doi:10.1016/j.cbi.2015.11.002Kowalewski, Fina, Słomka, Raffa, Martucci et al., COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review, Crit. Care, 
doi:10.1186/s13054-020-02925-3Kutti Sridharan, Kotagiri, Chandiramani, Mohan, Vegunta et al., COVID-19 and Avoiding Ibuprofen. How Good Is the Evidence?, Am. J. Ther, 
doi:10.1097/mjt.0000000000001196Lee, Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway, Oxid. Med. Cell Longev, 
doi:10.1155/2018/6208067Martins-Filho, Do Nascimento-Juńior, Santos, No current evidence supporting risk of using Ibuprofen in patients with COVID-19, Int. J. Clin. Pract, 
doi:10.1111/ijcp.13576Mast, Dardevet, Papet, Impact of medication on protein and amino acid metabolism in the elderly: the sulfur amino acid and paracetamol case, Nutr. Res. Rev, 
doi:10.1017/S0954422418000021Meltzer, Best, Zhang, Vokes, Arora et al., Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results, JAMA Netw. Open, 
doi:10.1001/jamanetworkopen.2020.19722Messika, Sztrymf, Bertrand, Billard-Pomares, Barnaud et al., Risks of nonsteroidal antiinflammatory drugs in undiagnosed intensive care unit pneumococcal pneumonia: younger and more severely affected patients, J. Crit. Care, 
doi:10.1016/j.jcrc.2014.05.021Mukhtar, Anwar, Hussain, Rasul, Naqvi et al., Detection of Paracetamol as substrate of the gut microbiome, Pak. J. Pharm. Sci
Nencioni, Iuvara, Aquilano, Ciriolo, Cozzolino et al., Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2, FASEB J, 
doi:10.1096/fj.02-0508fjeNuttall, Khan, Thorpe, Langford, Kendall, The impact of therapeutic doses of paracetamol on serum total antioxidant capacity, J. Clin. Pharm. Ther, 
doi:10.1046/j.1365-2710.2003.00493.xNydlova, Vrbova, Cesla, Jankovicǒva, Ventura et al., Comparison of inhibitory effects between acetaminophen-glutathione conjugate and reduced glutathione in human glutathione reductase, J. Appl. Toxicol, 
doi:10.1002/jat.2914Pacht, Timerman, Lykens, Merola, Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome, Chest, 
doi:10.1378/chest.100.5.1397Palamara, Perno, Aquaro, Buè, Dini et al., Glutathione inhibits HIV replication by acting at late stages of the virus life cycle, AIDS Res. Hum. Retroviruses, 
doi:10.1089/aid.1996.12.1537Poggiali, Bastoni, Ioannilli, Vercelli, Magnacavallo, Deep Vein Thrombosis and Pulmonary Embolism: Two Complications of COVID-19 Pneumonia?, Eur. J. Case Rep. Internal Med, 
doi:10.12890/2020_001646Polonikov, Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients, ACS Infect. Dis, 
doi:10.1021/acsinfecdis.0c00288Pujos-Guillot, Pickering, Lyan, Ducheix, Brandolini-Bunlon et al., Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids, Age (Dordr, 
doi:10.1007/s11357-011-9218-4Roberts, Delgado Nunes, Buckner, Latchem, Constanti et al., Paracetamol: not as safe as we thought? A systematic literature review of observational studies, Ann. Rheum. Dis, 
doi:10.1136/annrheumdis-2014-206914Rothuizen, Livio, Buclin, Drugs that aggravate the course of COVID-19: really?
Saadat, An evidence for correlation between the glutathione Stransferase T1 (GSTT1) polymorphism and outcome of COVID-19, Clin. Chim. Acta, 
doi:10.1016/j.cca.2020.05.041Sansgiry, Bhansali, Bapat, Xu, Abuse of over-thecounter medicines: a pharmacist's perspective, Integr. Pharm. Res. Pract, 
doi:10.2147/iprp.s103494Schönrich, Raftery, Samstag, Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression, Adv. Biol. Regul, 
doi:10.1016/j.jbior.2020.100741Siddiqi, Mehra, COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal, J. Heart Lung Transplant, 
doi:10.1016/j.healun.2020.03.012Smart, Fawkes, A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality, Inflammopharmacology, 
doi:10.1007/s10787-020-00745-zSoeiro, Bourneau-Martin, Micallef, Jonville-Beŕa, Selected Abstracts from Pharmacology 2019 -Multisource comprehensive review on whether ibuprofen exacerbates bacterial infections, Br. J. Clin. Pharmacol, 
doi:10.1111/bcp.14266Soltan-Sharifi, Mojtahedzadeh, Najafi, Reza Khajavi, Reza Rouini et al., Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms, Hum. Exp. Toxicol, 
doi:10.1177/0960327107083452Stahl, Yates, Nicholls, Kenna, Coen et al., Systems toxicology: modelling biomarkers of glutathione homeostasis and paracetamol metabolism, Drug Discovery Today Technol, 
doi:10.1016/j.ddtec.2015.06.003Sun, Song, Shi, Liu, Li et al., Combination of four clinical indicators predicts the severe/critical symptom of patients infected COVID-19, J. Clin. Virol, 
doi:10.1016/j.jcv.2020.104431Tomera, Malone, Kittah, Hospitalized COVID-19 Patients Treated With Celecoxib and High Dose Famotidine Adjuvant Therapy Show Significant Clinical Responses, 
doi:10.2139/ssrn.3646583Vaja, Chan, Ferreira, Harky, Rogers et al., The COVID-19 ibuprofen controversy: A systematic review of NSAIDs in adult acute lower respiratory tract infections, Br. J. Clin. Pharmacol, 
doi:10.1111/bcp.14514Verdecchia, Cavallini, Spanevello, Angeli, The pivotal link between ACE2 deficiency and SARS-CoV-2 infection, Eur. J. Intern. Med, 
doi:10.1016/j.ejim.2020.04.037Veronese, Demurtas, Yang, Tonelli, Barbagallo et al., Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature, Front. Med, 
doi:10.3389/fmed.2020.00170Violi, Loffredo, Carnevale, Pignatelli, Pastori, Atherothrombosis and Oxidative Stress: Mechanisms and Management in Elderly, Antioxid. Redox Signal, 
doi:10.1089/ars.2016.6963Zolk, Hafner, Schmidt, COVID-19 pandemic and therapy with ibuprofen or renin-angiotensin system blockers: no need for interruptions or changes in ongoing chronic treatments, Naunyn Schmiedebergs Arch. Pharmacol, 
doi:10.1007/s00210-020-01890-6DOI record:
{
  "DOI": "10.3389/fphar.2020.579944",
  "ISSN": [
    "1663-9812"
  ],
  "URL": "http://dx.doi.org/10.3389/fphar.2020.579944",
  "alternative-id": [
    "10.3389/fphar.2020.579944"
  ],
  "author": [
    {
      "affiliation": [],
      "family": "Sestili",
      "given": "Piero",
      "sequence": "first"
    },
    {
      "affiliation": [],
      "family": "Fimognari",
      "given": "Carmela",
      "sequence": "additional"
    }
  ],
  "container-title": "Frontiers in Pharmacology",
  "container-title-short": "Front. Pharmacol.",
  "content-domain": {
    "crossmark-restriction": true,
    "domain": [
      "frontiersin.org"
    ]
  },
  "created": {
    "date-parts": [
      [
        2020,
        10,
        7
      ]
    ],
    "date-time": "2020-10-07T14:30:37Z",
    "timestamp": 1602081037000
  },
  "deposited": {
    "date-parts": [
      [
        2020,
        10,
        7
      ]
    ],
    "date-time": "2020-10-07T14:30:48Z",
    "timestamp": 1602081048000
  },
  "funder": [
    {
      "DOI": "10.13039/501100010608",
      "doi-asserted-by": "publisher",
      "name": "Università degli Studi di Urbino Carlo Bo"
    }
  ],
  "indexed": {
    "date-parts": [
      [
        2022,
        8,
        26
      ]
    ],
    "date-time": "2022-08-26T15:53:17Z",
    "timestamp": 1661529197692
  },
  "is-referenced-by-count": 20,
  "issued": {
    "date-parts": [
      [
        2020,
        10,
        7
      ]
    ]
  },
  "license": [
    {
      "URL": "https://creativecommons.org/licenses/by/4.0/",
      "content-version": "vor",
      "delay-in-days": 0,
      "start": {
        "date-parts": [
          [
            2020,
            10,
            7
          ]
        ],
        "date-time": "2020-10-07T00:00:00Z",
        "timestamp": 1602028800000
      }
    }
  ],
  "link": [
    {
      "URL": "https://www.frontiersin.org/article/10.3389/fphar.2020.579944/full",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "member": "1965",
  "original-title": [],
  "prefix": "10.3389",
  "published": {
    "date-parts": [
      [
        2020,
        10,
        7
      ]
    ]
  },
  "published-online": {
    "date-parts": [
      [
        2020,
        10,
        7
      ]
    ]
  },
  "publisher": "Frontiers Media SA",
  "reference": [
    {
      "DOI": "10.3906/biy-2005-102",
      "article-title": "Gut-lung axis and dysbiosis in COVID-19",
      "author": "Aktas",
      "doi-asserted-by": "publisher",
      "first-page": "265",
      "journal-title": "Turk. J. Biol.",
      "key": "B1",
      "volume": "44",
      "year": "2020"
    },
    {
      "DOI": "10.3389/fmed.2020.00458",
      "article-title": "Relationship Between COVID-19 Infection and Liver Injury: A Review of Recent Data",
      "author": "Ali",
      "doi-asserted-by": "publisher",
      "journal-title": "Front. Med.",
      "key": "B2",
      "volume": "7",
      "year": "2020"
    },
    {
      "DOI": "10.1080/20477724.2020.1751388",
      "article-title": "Is glucose-6-phosphate dehydrogenase enzyme deficiency a factor in Coronavirus-19 (COVID-19) infections and deaths",
      "author": "Aydemir",
      "doi-asserted-by": "publisher",
      "first-page": "109",
      "journal-title": "Pathog. Glob. Health",
      "key": "B3",
      "volume": "114",
      "year": "2020"
    },
    {
      "DOI": "10.2174/138920006778017786",
      "article-title": "Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology",
      "author": "Bolt",
      "doi-asserted-by": "publisher",
      "first-page": "613",
      "journal-title": "Curr. Drug Metab.",
      "key": "B4",
      "volume": "7",
      "year": "2006"
    },
    {
      "DOI": "10.3390/jcm9082586",
      "article-title": "Prior Routine Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Important Outcomes in Hospitalised Patients with COVID-19",
      "author": "Bruce",
      "doi-asserted-by": "publisher",
      "journal-title": "J. Clin. Med.",
      "key": "B5",
      "volume": "9",
      "year": "2020"
    },
    {
      "DOI": "10.1002/ejp.621",
      "article-title": "Acetaminophen/paracetamol: A history of errors, failures and false decisions",
      "author": "Brune",
      "doi-asserted-by": "publisher",
      "first-page": "953",
      "journal-title": "Eur. J. Pain",
      "key": "B6",
      "volume": "19",
      "year": "2015"
    },
    {
      "DOI": "10.1007/BF00609183",
      "article-title": "Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration",
      "author": "Burgunder",
      "doi-asserted-by": "publisher",
      "first-page": "127",
      "journal-title": "Eur. J. Clin. Pharmacol.",
      "key": "B7",
      "volume": "36",
      "year": "1989"
    },
    {
      "DOI": "10.1007/BF02714149",
      "article-title": "Glutathione and inflammatory disorders of the lung",
      "author": "Cantin",
      "doi-asserted-by": "publisher",
      "first-page": "123",
      "journal-title": "Lung",
      "key": "B8",
      "volume": "169",
      "year": "1991"
    },
    {
      "DOI": "10.1016/0006-2952(95)02436-0",
      "article-title": "Isolation and preliminary characterization of a Chinese hamster ovary cell line with high-degree resistance to hydrogen peroxide",
      "author": "Cantoni",
      "doi-asserted-by": "publisher",
      "first-page": "1021",
      "journal-title": "Biochem. Pharmacol.",
      "key": "B9",
      "volume": "51",
      "year": "1996"
    },
    {
      "DOI": "10.1016/j.phrs.2020.104849",
      "article-title": "NSAIDs in patients with viral infections, including Covid-19: Victims or perpetrators",
      "author": "Capuano",
      "doi-asserted-by": "publisher",
      "first-page": "104849",
      "journal-title": "Pharmacol. Res.",
      "key": "B10",
      "volume": "157",
      "year": "2020"
    },
    {
      "key": "B11",
      "unstructured": "Comité technique de pharmacovigilance FrancaiseRapport d’expertise – Infections bactériennes graves (de la peau et des tissus mous, pleuro-pulmonaires, neurologiques et ORL) rapportées avec l’ibuprofène ou le kétoprofène dans le traitement symptomatique de la fièvre ou de douleur non rhumatologique2019"
    },
    {
      "DOI": "10.1016/j.therap.2020.06.012",
      "article-title": "NSAIDs may increase the risk of thrombosis and acute renal failure in patients with COVID-19 infection",
      "author": "Cumhur Cure",
      "doi-asserted-by": "publisher",
      "first-page": "387",
      "journal-title": "Therapie",
      "key": "B12",
      "volume": "75",
      "year": "2020"
    },
    {
      "DOI": "10.1161/hypertensionaha.120.15082",
      "article-title": "Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers",
      "author": "Danser",
      "doi-asserted-by": "publisher",
      "first-page": "1382",
      "journal-title": "Hypertension",
      "key": "B13",
      "volume": "75",
      "year": "2020"
    },
    {
      "DOI": "10.1136/bmj.m1086",
      "article-title": "Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists",
      "author": "Day",
      "doi-asserted-by": "publisher",
      "first-page": "m1086",
      "journal-title": "BMJ",
      "key": "B14",
      "volume": "368",
      "year": "2020"
    },
    {
      "DOI": "10.1183/09031936.97.10071535",
      "article-title": "Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment",
      "author": "De Flora",
      "doi-asserted-by": "publisher",
      "first-page": "1535",
      "journal-title": "Eur. Respir. J.",
      "key": "B15",
      "volume": "10",
      "year": "1997"
    },
    {
      "DOI": "10.1096/fj.202001807",
      "article-title": "Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19",
      "author": "De Flora",
      "doi-asserted-by": "publisher",
      "first-page": "13185",
      "journal-title": "FASEB J",
      "key": "B16",
      "volume": "34",
      "year": "2020"
    },
    {
      "DOI": "10.1016/j.biocel.2005.03.005",
      "article-title": "Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro",
      "author": "Dimova",
      "doi-asserted-by": "publisher",
      "first-page": "1727",
      "journal-title": "Int. J. Biochem. Cell Biol.",
      "key": "B17",
      "volume": "37",
      "year": "2005"
    },
    {
      "DOI": "10.1002/rth2.12283",
      "article-title": "Not all (N)SAID and done: Effects of nonsteroidal anti-inflammatory drugs and paracetamol intake on platelets",
      "author": "Driver",
      "doi-asserted-by": "publisher",
      "first-page": "36",
      "journal-title": "Res. Pract. Thromb. Haemost.",
      "key": "B18",
      "volume": "4",
      "year": "2019"
    },
    {
      "article-title": "Basal and paracetamol-depleted glutathione from human lymphocytes: ethnic variability",
      "author": "Estévez",
      "first-page": "48",
      "journal-title": "Acta Physiol. Pharmacol. Ther. Latinoam",
      "key": "B19",
      "volume": "44",
      "year": "1994"
    },
    {
      "DOI": "10.1007/s40620-020-00789-y",
      "article-title": "COVID-19 and the kidney: what we think we know so far and what we don’t",
      "author": "Farouk",
      "doi-asserted-by": "publisher",
      "first-page": "1",
      "journal-title": "J. Nephrol",
      "key": "B20",
      "year": "2020"
    },
    {
      "DOI": "10.1126/science.abb8034",
      "article-title": "Misguided drug advice for COVID-19",
      "author": "FitzGerald",
      "doi-asserted-by": "publisher",
      "first-page": "1434",
      "journal-title": "Science",
      "key": "B21",
      "volume": "367",
      "year": "2020"
    },
    {
      "DOI": "10.1002/ajh.25882",
      "article-title": "Increased sFLT1/PlGF ratio in COVID-19: a novel link to Angiotensin II-mediated endothelial dysfunction",
      "author": "Giardini",
      "doi-asserted-by": "publisher",
      "first-page": "e188",
      "journal-title": "Am. J. Hematol",
      "key": "B22",
      "volume": "95",
      "year": "2020"
    },
    {
      "DOI": "10.3390/nu12040988",
      "article-title": "Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths",
      "author": "Grant",
      "doi-asserted-by": "publisher",
      "first-page": "988",
      "journal-title": "Nutrients",
      "key": "B23",
      "volume": "12",
      "year": "2020"
    },
    {
      "DOI": "10.1021/acsomega.0c02125",
      "article-title": "Impact of Thiol-Disulfide Balance on the Binding of Covid-19 Spike Protein with Angiotensin-Converting Enzyme 2 Receptor",
      "author": "Hati",
      "doi-asserted-by": "publisher",
      "first-page": "16292",
      "journal-title": "ACS Omega",
      "key": "B24",
      "volume": "5",
      "year": "2020"
    },
    {
      "DOI": "10.2174/1389200216666151015114515",
      "article-title": "Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs",
      "author": "Homma",
      "doi-asserted-by": "publisher",
      "first-page": "560",
      "journal-title": "Curr. Drug Metab.",
      "key": "B25",
      "volume": "16",
      "year": "2015"
    },
    {
      "DOI": "10.1016/j.rmcr.2020.101063",
      "article-title": "Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases",
      "author": "Horowitz",
      "doi-asserted-by": "publisher",
      "first-page": "101063",
      "journal-title": "Respir. Med. Case Rep.",
      "key": "B26",
      "volume": "30",
      "year": "2020"
    },
    {
      "article-title": "Relations between von Willebrand factor, markers of oxidative stress and microalbuminuria in patients with type 2 diabetes mellitus",
      "author": "Ibrahim",
      "first-page": "Cr85",
      "journal-title": "Med. Sci. Monit.",
      "key": "B27",
      "volume": "10",
      "year": "2004"
    },
    {
      "DOI": "10.1016/j.clim.2020.108544",
      "article-title": "Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine",
      "author": "Ibrahim",
      "doi-asserted-by": "publisher",
      "first-page": "108544",
      "journal-title": "Clin. Immunol.",
      "key": "B28",
      "volume": "219",
      "year": "2020"
    },
    {
      "DOI": "10.1080/07315724.2020.1789518",
      "article-title": "Can Vitamin D and L-Cysteine Co-Supplementation Reduce 25(OH)-Vitamin D Deficiency and the Mortality Associated with COVID-19 in African Americans",
      "author": "Jain",
      "doi-asserted-by": "publisher",
      "first-page": "1",
      "journal-title": "J. Am. Coll. Nutr.",
      "key": "B29",
      "year": "2020"
    },
    {
      "DOI": "10.1038/ejcn.2014.114",
      "article-title": "Vitamin D and L-cysteine levels correlate positively with GSH and negatively with insulin resistance levels in the blood of type 2 diabetic patients",
      "author": "Jain",
      "doi-asserted-by": "publisher",
      "first-page": "1148",
      "journal-title": "Eur. J. Clin. Nutr.",
      "key": "B30",
      "volume": "68",
      "year": "2014"
    },
    {
      "DOI": "10.1016/j.jhep.2020.06.006",
      "article-title": "COVID-19 and the liver",
      "author": "Jothimani",
      "doi-asserted-by": "publisher",
      "journal-title": "J. Hepatol",
      "key": "B31",
      "year": "2020"
    },
    {
      "DOI": "10.1038/nrd.2017.162",
      "article-title": "Host-directed therapies for bacterial and viral infections",
      "author": "Kaufmann",
      "doi-asserted-by": "publisher",
      "first-page": "35",
      "journal-title": "Nat. Rev. Drug Discov.",
      "key": "B32",
      "volume": "17",
      "year": "2018"
    },
    {
      "DOI": "10.3390/v10080392",
      "article-title": "Redox biology of respiratory viral infections",
      "author": "Khomich",
      "doi-asserted-by": "publisher",
      "first-page": "392",
      "journal-title": "Viruses",
      "key": "B33",
      "volume": "10",
      "year": "2018"
    },
    {
      "DOI": "10.1016/j.cbi.2015.11.002",
      "article-title": "A quantum chemical study of the reactivity of acetaminophen (paracetamol) toxic metabolite N-acetyl-p-benzoquinone imine with deoxyguanosine and glutathione",
      "author": "Klopčič",
      "doi-asserted-by": "publisher",
      "first-page": "407",
      "journal-title": "Chem. Biol. Interact.",
      "key": "B34",
      "volume": "242",
      "year": "2015"
    },
    {
      "DOI": "10.1186/s13054-020-02925-3",
      "article-title": "COVID-19 and ECMO: the interplay between coagulation and inflammation-a narrative review",
      "author": "Kowalewski",
      "doi-asserted-by": "publisher",
      "first-page": "205",
      "journal-title": "Crit. Care (London)",
      "key": "B35",
      "volume": "24",
      "year": "2020"
    },
    {
      "DOI": "10.1097/mjt.0000000000001196",
      "article-title": "COVID-19 and Avoiding Ibuprofen. How Good Is the Evidence",
      "author": "Kutti Sridharan",
      "doi-asserted-by": "publisher",
      "first-page": "e400",
      "journal-title": "Am. J. Ther.",
      "key": "B36",
      "volume": "27",
      "year": "2020"
    },
    {
      "DOI": "10.1155/2018/6208067",
      "article-title": "Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway",
      "author": "Lee",
      "doi-asserted-by": "publisher",
      "first-page": "6208067",
      "journal-title": "Oxid. Med. Cell Longev.",
      "key": "B37",
      "volume": "2018",
      "year": "2018"
    },
    {
      "DOI": "10.1111/ijcp.13576",
      "article-title": "No current evidence supporting risk of using Ibuprofen in patients with COVID-19",
      "author": "Martins-Filho",
      "doi-asserted-by": "publisher",
      "first-page": "e13576",
      "journal-title": "Int. J. Clin. Pract.",
      "key": "B38",
      "year": "2020"
    },
    {
      "DOI": "10.1017/S0954422418000021",
      "article-title": "Impact of medication on protein and amino acid metabolism in the elderly: the sulfur amino acid and paracetamol case",
      "author": "Mast",
      "doi-asserted-by": "publisher",
      "first-page": "179",
      "journal-title": "Nutr. Res. Rev.",
      "key": "B39",
      "volume": "31",
      "year": "2018"
    },
    {
      "DOI": "10.1542/peds.2011-1106",
      "article-title": "The association of acetaminophen and asthma prevalence and severity",
      "author": "McBride",
      "doi-asserted-by": "publisher",
      "first-page": "1181",
      "journal-title": "Pediatrics",
      "key": "B40",
      "volume": "128",
      "year": "2011"
    },
    {
      "DOI": "10.1001/jamanetworkopen.2020.19722",
      "article-title": "Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results",
      "author": "Meltzer",
      "doi-asserted-by": "publisher",
      "first-page": "e2019722",
      "journal-title": "JAMA Netw. Open",
      "key": "B41",
      "volume": "3",
      "year": "2020"
    },
    {
      "DOI": "10.1016/j.jcrc.2014.05.021",
      "article-title": "Risks of nonsteroidal antiinflammatory drugs in undiagnosed intensive care unit pneumococcal pneumonia: younger and more severely affected patients",
      "author": "Messika",
      "doi-asserted-by": "publisher",
      "first-page": "733",
      "journal-title": "J. Crit. Care",
      "key": "B42",
      "volume": "29",
      "year": "2014"
    },
    {
      "DOI": "10.1016/j.therap.2020.07.008",
      "article-title": "COVID-19 and NSAIDs: Primum non nocere",
      "author": "Micallef",
      "doi-asserted-by": "publisher",
      "first-page": "30142",
      "journal-title": "Therapie",
      "key": "B43",
      "year": "2020"
    },
    {
      "DOI": "10.1016/j.therap.2020.05.003",
      "article-title": "Non-steroidal anti-inflammatory drugs, pharmacology, and COVID-19 infection",
      "author": "Micallef",
      "doi-asserted-by": "publisher",
      "first-page": "355",
      "journal-title": "Therapie",
      "key": "B44",
      "volume": "75",
      "year": "2020"
    },
    {
      "DOI": "10.1007/s40264-020-00953-0",
      "article-title": "Does Ibuprofen Worsen COVID-19",
      "author": "Moore",
      "doi-asserted-by": "publisher",
      "first-page": "611",
      "journal-title": "Drug Saf",
      "key": "B45",
      "volume": "43",
      "year": "2020"
    },
    {
      "article-title": "Detection of Paracetamol as substrate of the gut microbiome",
      "author": "Mukhtar",
      "first-page": "751",
      "journal-title": "Pak. J. Pharm. Sci.",
      "key": "B46",
      "volume": "32",
      "year": "2019"
    },
    {
      "DOI": "10.1096/fj.02-0508fje",
      "article-title": "Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2",
      "author": "Nencioni",
      "doi-asserted-by": "publisher",
      "first-page": "758",
      "journal-title": "FASEB J.",
      "key": "B47",
      "volume": "17",
      "year": "2003"
    },
    {
      "DOI": "10.1046/j.1365-2710.2003.00493.x",
      "article-title": "The impact of therapeutic doses of paracetamol on serum total antioxidant capacity",
      "author": "Nuttall",
      "doi-asserted-by": "publisher",
      "first-page": "289",
      "journal-title": "J. Clin. Pharm. Ther.",
      "key": "B48",
      "volume": "28",
      "year": "2003"
    },
    {
      "DOI": "10.1002/jat.2914",
      "article-title": "Comparison of inhibitory effects between acetaminophen-glutathione conjugate and reduced glutathione in human glutathione reductase",
      "author": "Nýdlová",
      "doi-asserted-by": "publisher",
      "first-page": "968",
      "journal-title": "J. Appl. Toxicol.",
      "key": "B49",
      "volume": "34",
      "year": "2014"
    },
    {
      "DOI": "10.1378/chest.100.5.1397",
      "article-title": "Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome",
      "author": "Pacht",
      "doi-asserted-by": "publisher",
      "first-page": "1397",
      "journal-title": "Chest",
      "key": "B50",
      "volume": "100",
      "year": "1991"
    },
    {
      "DOI": "10.1089/aid.1996.12.1537",
      "article-title": "Glutathione inhibits HIV replication by acting at late stages of the virus life cycle",
      "author": "Palamara",
      "doi-asserted-by": "publisher",
      "first-page": "1537",
      "journal-title": "AIDS Res. Hum. Retroviruses",
      "key": "B51",
      "volume": "12",
      "year": "1996"
    },
    {
      "DOI": "10.12890/2020_001646",
      "article-title": "Deep Vein Thrombosis and Pulmonary Embolism: Two Complications of COVID-19 Pneumonia",
      "author": "Poggiali",
      "doi-asserted-by": "publisher",
      "first-page": "001646",
      "journal-title": "Eur. J. Case Rep. Internal Med.",
      "key": "B52",
      "volume": "7",
      "year": "2020"
    },
    {
      "DOI": "10.1021/acsinfecdis.0c00288",
      "article-title": "Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients",
      "author": "Polonikov",
      "doi-asserted-by": "publisher",
      "first-page": "1558",
      "journal-title": "ACS Infect. Dis",
      "key": "B53",
      "volume": "6",
      "year": "2020"
    },
    {
      "DOI": "10.1007/s11357-011-9218-4",
      "article-title": "Therapeutic paracetamol treatment in older persons induces dietary and metabolic modifications related to sulfur amino acids",
      "author": "Pujos-Guillot",
      "doi-asserted-by": "publisher",
      "first-page": "181",
      "journal-title": "Age (Dordr.)",
      "key": "B54",
      "volume": "34",
      "year": "2012"
    },
    {
      "DOI": "10.1136/annrheumdis-2014-206914",
      "article-title": "Paracetamol: not as safe as we thought? A systematic literature review of observational studies",
      "author": "Roberts",
      "doi-asserted-by": "publisher",
      "first-page": "552",
      "journal-title": "Ann. Rheum. Dis.",
      "key": "B55",
      "volume": "75",
      "year": "2016"
    },
    {
      "article-title": "[Drugs that aggravate the course of COVID-19: really?]",
      "author": "Rothuizen",
      "first-page": "852",
      "journal-title": "Rev. Med. Suisse",
      "key": "B56",
      "volume": "16",
      "year": "2020"
    },
    {
      "DOI": "10.1016/j.cca.2020.05.041",
      "article-title": "An evidence for correlation between the glutathione S-transferase T1 (GSTT1) polymorphism and outcome of COVID-19",
      "author": "Saadat",
      "doi-asserted-by": "publisher",
      "first-page": "213",
      "journal-title": "Clin. Chim. Acta",
      "key": "B57",
      "volume": "508",
      "year": "2020"
    },
    {
      "DOI": "10.2147/iprp.s103494",
      "article-title": "Abuse of over-the-counter medicines: a pharmacist’s perspective",
      "author": "Sansgiry",
      "doi-asserted-by": "publisher",
      "first-page": "1",
      "journal-title": "Integr. Pharm. Res. Pract.",
      "key": "B58",
      "volume": "6",
      "year": "2017"
    },
    {
      "DOI": "10.1016/j.jbior.2020.100741",
      "article-title": "Devilishly radical NETwork in COVID-19: Oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression",
      "author": "Schönrich",
      "doi-asserted-by": "publisher",
      "first-page": "100741",
      "journal-title": "Adv. Biol. Regul.",
      "key": "B59",
      "volume": "77",
      "year": "2020"
    },
    {
      "DOI": "10.3389/fphar.2020.00854",
      "article-title": "Repositioning Chromones for Early Anti-inflammatory Treatment of COVID-19",
      "author": "Sestili",
      "doi-asserted-by": "publisher",
      "journal-title": "Front. Pharmacol",
      "key": "B60",
      "volume": "11",
      "year": "2020"
    },
    {
      "DOI": "10.1136/thorax.55.4.266",
      "article-title": "Frequent paracetamol use and asthma in adults",
      "author": "Shaheen",
      "doi-asserted-by": "publisher",
      "first-page": "266",
      "journal-title": "Thorax",
      "key": "B61",
      "volume": "55",
      "year": "2000"
    },
    {
      "DOI": "10.1016/j.healun.2020.03.012",
      "article-title": "COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal",
      "author": "Siddiqi",
      "doi-asserted-by": "publisher",
      "first-page": "405",
      "journal-title": "J. Heart Lung Transplant",
      "key": "B62",
      "volume": "39",
      "year": "2020"
    },
    {
      "DOI": "10.1007/s10787-020-00745-z",
      "article-title": "A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality",
      "author": "Smart",
      "doi-asserted-by": "publisher",
      "first-page": "1",
      "journal-title": "Inflammopharmacology",
      "key": "B63",
      "year": "2020"
    },
    {
      "DOI": "10.1111/bcp.14266",
      "article-title": "Selected Abstracts from Pharmacology 2019 - Multisource comprehensive review on whether ibuprofen exacerbates bacterial infections",
      "author": "Soeiro",
      "doi-asserted-by": "publisher",
      "first-page": "1180",
      "journal-title": "Br. J. Clin. Pharmacol.",
      "key": "B64",
      "volume": "86",
      "year": "2020"
    },
    {
      "DOI": "10.1177/0960327107083452",
      "article-title": "Improvement by N-acetylcysteine of acute respiratory distress syndrome through increasing intracellular glutathione, and extracellular thiol molecules and anti-oxidant power: evidence for underlying toxicological mechanisms",
      "author": "Soltan-Sharifi",
      "doi-asserted-by": "publisher",
      "first-page": "697",
      "journal-title": "Hum. Exp. Toxicol.",
      "key": "B65",
      "volume": "26",
      "year": "2007"
    },
    {
      "DOI": "10.1016/j.ddtec.2015.06.003",
      "article-title": "Systems toxicology: modelling biomarkers of glutathione homeostasis and paracetamol metabolism",
      "author": "Stahl",
      "doi-asserted-by": "publisher",
      "first-page": "9",
      "journal-title": "Drug Discovery Today Technol.",
      "key": "B66",
      "volume": "15",
      "year": "2015"
    },
    {
      "DOI": "10.1016/j.jcv.2020.104431",
      "article-title": "Combination of four clinical indicators predicts the severe/critical symptom of patients infected COVID-19",
      "author": "Sun",
      "doi-asserted-by": "publisher",
      "first-page": "104431",
      "journal-title": "J. Clin. Virol.",
      "key": "B67",
      "volume": "128",
      "year": "2020"
    },
    {
      "DOI": "10.2139/ssrn.3646583",
      "article-title": "Hospitalized COVID-19 Patients Treated With Celecoxib and High Dose Famotidine Adjuvant Therapy Show Significant Clinical Responses",
      "author": "Tomera",
      "doi-asserted-by": "publisher",
      "journal-title": "SSRN (Preprint)",
      "key": "B68",
      "year": "2020"
    },
    {
      "DOI": "10.1111/bcp.14514",
      "article-title": "The COVID-19 ibuprofen controversy: A systematic review of NSAIDs in adult acute lower respiratory tract infections",
      "author": "Vaja",
      "doi-asserted-by": "publisher",
      "first-page": "1",
      "journal-title": "Br. J. Clin. Pharmacol",
      "key": "B69",
      "year": ""
    },
    {
      "DOI": "10.1016/j.ejim.2020.04.037",
      "article-title": "The pivotal link between ACE2 deficiency and SARS-CoV-2 infection",
      "author": "Verdecchia",
      "doi-asserted-by": "publisher",
      "first-page": "14",
      "journal-title": "Eur. J. Intern. Med.",
      "key": "B70",
      "volume": "76",
      "year": "2020"
    },
    {
      "DOI": "10.3389/fmed.2020.00170",
      "article-title": "Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature",
      "author": "Veronese",
      "doi-asserted-by": "publisher",
      "journal-title": "Front. Med. (Lausanne)",
      "key": "B71",
      "volume": "7",
      "year": "2020"
    },
    {
      "DOI": "10.1089/ars.2016.6963",
      "article-title": "Atherothrombosis and Oxidative Stress: Mechanisms and Management in Elderly",
      "author": "Violi",
      "doi-asserted-by": "publisher",
      "first-page": "1083",
      "journal-title": "Antioxid. Redox Signal",
      "key": "B72",
      "volume": "27",
      "year": "2017"
    },
    {
      "DOI": "10.1007/s00210-020-01890-6",
      "article-title": "COVID-19 pandemic and therapy with ibuprofen or renin-angiotensin system blockers: no need for interruptions or changes in ongoing chronic treatments",
      "author": "Zolk",
      "doi-asserted-by": "publisher",
      "first-page": "1131",
      "journal-title": "Naunyn Schmiedebergs Arch. Pharmacol.",
      "key": "B73",
      "volume": "393",
      "year": "2020"
    }
  ],
  "reference-count": 73,
  "references-count": 73,
  "relation": {},
  "resource": {
    "primary": {
      "URL": "https://www.frontiersin.org/article/10.3389/fphar.2020.579944/full"
    }
  },
  "score": 1,
  "short-title": [],
  "source": "Crossref",
  "subject": [
    "Pharmacology (medical)",
    "Pharmacology"
  ],
  "subtitle": [],
  "title": "Paracetamol-Induced Glutathione Consumption: Is There a Link With Severe COVID-19 Illness?",
  "type": "journal-article",
  "update-policy": "http://dx.doi.org/10.3389/crossmark-policy",
  "volume": "11"
}