Impact of N-Acetylcysteine on Modulating Inflammation in Patients Hospitalized with Moderate COVID-19 Infections: A Prospective Randomized Trial
Sara Mohamed Sherkawy, Lamia Elwakeel, Mona F Schaalan, Ayman N Moharram, Mohamed Ahmed Abouelwafa
Archives of Pharmaceutical Sciences Ain Shams University, doi:10.21608/aps.2023.212265.1122
N-acetylcysteine (NAC) is a widely used safe mucolytic, that demonstrated positive impacts on various respiratory diseases via its anti-inflammatory and antioxidant effects. The study aimed to evaluate the potential benefit of adding high-dose oral N-acetylcysteine in hospitalized moderate-severity COVID-19 patients. A prospective, single-center, randomized clinical trial on 60 hospitalized moderate COVID-19 patients who were randomly assigned to the NAC group (30); received NAC daily at 1800 mg added to the institutional protocol, or non-NAC group (30); received only the institutional protocol. Outcomes. The primary outcome was the change in plasma TNF-α, IL-6, and glutathione peroxidase levels. Secondary outcomes were the length of hospital stay, need for oxygen support, duration of oxygenation, and mortality rate between the two study groups. At the study end, a significant decline in TNF-α levels (p< 0.001) and a significant increase in glutathione peroxidase in the NACtreated group (p= 0.001) were evident. Groups were comparable in IL-6 levels (p= 0.810). The duration of oxygen support significantly decreased in the NAC group (p= 0.005). On the contrary, hospital stay length and oxygen support need was not affected by the addition of 0.45, 0.42, respectively). The mortality rate was comparable in both groups. In conclusion, the Addition of 1800 mg of NAC to the institutional treatment protocol for moderate COVID-19 patients has led to a decline in the levels of plasma TNF-α and increased glutathione peroxidase levels. Moreover, the duration required for oxygen support decreased in patients needing supplemental oxygenation.
Declarations
Ethics approval and consent to participate The study protocol was approved by the Scientific Research Ethics Committee, Faculty of Pharmacy, Ain Shams University (No. 128). Written informed consents were signed and collected from all the study participants.
Consent to publish All authors have read and agreed to the published version of the manuscript.
Competing interests The authors have no competing interests.
References
Andreou, Trantza, Filippou, Sipsas, Tsiodras, COVID-19: The Potential Role of Copper and N-acetylcysteine (NAC) in a Combination of Candidate Antiviral Treatments Against SARS-CoV-2, In Vivo,
doi:10.21873/invivo.11946Baj, Karakuła-Juchnowicz, Teresiński, Buszewicz, Ciesielka et al., COVID-19: Specific and Non-Specific Clinical Manifestations and Symptoms: The Current State of Knowledge, J Clin Med,
doi:10.3390/jcm9061753Bhattacharya, Mondal, Naiya, Lyngdoh, Mukherjee et al., The beneficial role of N-acetylcysteine as an adjunctive drug in treatment of COVID-19 patients in a tertiary care hospital in India: an observational study, Int J Res Med Sci,
doi:10.18203/2320-6012.ijrmsCalverley, Rogliani, Papi, Safety of N-Acetylcysteine at High Doses in Chronic Respiratory Diseases: A Review, Drug Saf,
doi:10.1007/s40264-020-01026-yCheng, He, Clinical and Biochemical Potential of Antioxidants in Treating Polycystic Ovary Syndrome, Int J Womens Health,
doi:10.2147/IJWH.S345853Dekhuijzen, Van Beurden, The role for N-acetylcysteine in the management of COPD, Int J Chron Obstruct Pulmon Dis,
doi:10.2147/copd.2006.1.2.99Devrim-Lanpir, Hill, Knechtle, How N-Acetylcysteine Supplementation Affects Redox Regulation, Especially at Mitohormesis and Sarcohormesis Level: Current Perspective. Antioxidants (Basel),
doi:10.3390/antiox10020153Dikalov, Nazarewicz, Angiotensin IIinduced production of mitochondrial reactive oxygen species: potential mechanisms and relevance for cardiovascular disease, Antioxid Redox Signal,
doi:10.1089/ars.2012.4604Dodd, Dean, Copolov, Malhi, Berk, N-acetylcysteine for antioxidant therapy: pharmacology and clinical utility, Expert Opin Biol Ther,
doi:10.1517/14728220802517901Dogra, Goyal, Sharma, Corona virus: A novel outbreak, Biomedical and Pharmacology Journal,
doi:10.13005/bpj/1853Doughan, Harrison, Dikalov, Molecular mechanisms of angiotensin IImediated mitochondrial dysfunction: Linking mitochondrial oxidative damage and vascular endothelial dysfunction, Circulation Research,
doi:10.1161/CIRCRESAHA.107.162800Esakandari, Nabi-Afjadi, Fakkari-Afjadi, Farahmandian, Miresmaeili et al., A comprehensive review of COVID-19 characteristics, Biol Proced Online,
doi:10.1186/s12575-020-00128-2Faghfouri, Zarezadeh, Tavakoli-Rouzbehani, Radkhah, Faghfuri et al., The effects of Nacetylcysteine on inflammatory and oxidative stress biomarkers: A systematic review and meta-analysis of controlled clinical trials, Eur J Pharmacol,
doi:10.1016/j.ejphar.2020.173368Flora, Balansky, Maestra, Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19, FASEB J,
doi:10.1096/fj.202001807Flora, Grassi, Carati, Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment, Eur Respir J,
doi:10.1183/09031936.97.10071535Gennaro, Pizzol, Marotta, Antunes, Racalbuto et al., Coronavirus Diseases (COVID-19) Current Status and Future Perspectives: A Narrative Review, Int J Environ Res Public Health,
doi:10.3390/ijerph17082690Ghafouri-Fard, Noroozi, Omrani, Branicki, Pośpiech et al., Angiotensin converting enzyme: A review on expression profile and its association with human disorders with special focus on SARS-CoV-2 infection, Vascul Pharmacol,
doi:10.1016/j.vph.2020.106680Göbölös, Rácz, Hogan, Remsey-Semmelweis, Atallah et al., The role of renin-angiotensin system activated phagocytes in the SARS-CoV-2 coronavirus infection, J Vasc Surg,
doi:10.1016/j.jvs.2020.12.056Hoffmann, Kleine-Weber, Schroeder, Krüger, Herrler et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor, Cell,
doi:10.1016/j.cell.2020.02.052Izquierdo, Soriano, González, Lumbreras, Ancochea et al., Use of N-Acetylcysteine at high doses as an oral treatment for patients hospitalized with COVID-19, Sci Prog,
doi:10.1177/00368504221074574Kasal, Lorenzo, Tibiriçá, COVID-19 and Microvascular Disease: Pathophysiology of SARS-CoV-2 Infection With Focus on the Renin-Angiotensin System. Heart Lung Circ,
doi:10.1016/j.hlc.2020.08.010Khomich, Kochetkov, Bartosch, Ivanov, Redox Biology of Respiratory Viral Infections, Viruses,
doi:10.3390/v10080392Marco, Foti, Corsico, Where are we with the use of N-acetylcysteine as a preventive and adjuvant treatment for COVID-19?, Eur Rev Med Pharmacol Sci,
doi:10.26355/eurrev_202201_27898Mata, Morcillo, Gimeno, Cortijo, Nacetyl-L-cysteine (NAC) inhibit mucin synthesis and pro-inflammatory mediators in alveolar type II epithelial cells infected with influenza virus A and B and with respiratory syncytial virus (RSV), Biochem Pharmacol,
doi:10.1016/j.bcp.2011.05.014Medina-Enríquez, Lopez-León, Escalante, Aponte-Torres, Cuapio et al., ACE2: the molecular doorway to SARS-CoV-2. Cell Biosci,
doi:10.1186/s13578-020-00519-8Muhammad, Kani, Iliya, Muhammad, Binji et al., Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria, SAGE Open Med. Feb,
doi:10.1177/2050312121991246Oliver, Dean, Camfield, Blair-West, Ng et al., N-acetyl cysteine in the treatment of obsessive compulsive and related disorders: a systematic review, Clin Psychopharmacol Neurosci,
doi:10.9758/cpn.2015.13.1.12Paschalis, Theodorou, Margaritelis, Kyparos, Nikolaidis, N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione, Free Radic Biol Med,
doi:10.1016/j.freeradbiomedPoppe, Wittig, Jurida, Bartkuhn, Wilhelm et al., The NF-κBdependent and -independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells, PLoS Pathog,
doi:10.1371/journal.ppat.1006286Pueyo, Gonzalez, Nicoletti, Savoie, Arnal et al., Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress, Arterioscler Thromb Vasc Biol,
doi:10.1161/01.atv.20.3.645References, None
Ruiz-Ortega, Lorenzo, Rupérez, König, Wittig et al., Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells: molecular mechanisms, Circ Res,
doi:10.1161/01.res.86.12.1266Ruiz-Ortega, Ruperez, Lorenzo, Esteban, Blanco et al., Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney, Kidney Int Suppl,
doi:10.1046/j.1523-1755.62.s82.4.xSadeghi-Haddad-Zavareh, Bayani, Shokri, Ebrahimpour, Babazadeh et al., C-Reactive Protein as a Prognostic Indicator in COVID-19 Patients, Interdiscip Perspect Infect Dis,
doi:10.1155/2021/5557582Shang, Pan, Yang, Zhong, Shang et al., Management of critically ill patients with COVID-19 in ICU: statement from frontline intensive care experts in Wuhan, Ann Intensive Care,
doi:10.1186/s13613-020-00689-1Sharafkhah, Abdolrazaghnejad, Zarinfar, Mohammadbeigi, Massoudifar et al., Safety and efficacy of N-acetylcysteine for prophylaxis of ventilatorassociated pneumonia: a randomized, double blind, placebo-controlled clinical trial, Med Gas Res,
doi:10.4103/2045-9912.229599Sungnak, Huang, Bécavin, Berg, Queen et al., SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes, Nat Med,
doi:10.1038/s41591-020-0868-6Taher, Lashgari, Sedighi, Rahimi-Bashar, Poorolajal et al., A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome, Pharmacol Rep
Wiersinga, Rhodes, Cheng, Peacock, Prescott, Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review, JAMA,
doi:10.1001/jama.2020.12839Zhang, Zhu, Wang, Yang, Liu et al., Characterizing COVID-19 transmission: Incubation period, reproduction rate, and multiple-generation spreading, Front Phys,
doi:10.3389/fphy.2020.589963{ 'indexed': {'date-parts': [[2023, 7, 18]], 'date-time': '2023-07-18T04:29:45Z', 'timestamp': 1689654585069},
'reference-count': 0,
'publisher': 'Egypts Presidential Specialized Council for Education and Scientific Research',
'issue': '1',
'content-domain': {'domain': ['aps.journals.ekb.eg'], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2023, 6, 1]]},
'DOI': '10.21608/aps.2023.212265.1122',
'type': 'journal-article',
'created': {'date-parts': [[2023, 7, 17]], 'date-time': '2023-07-17T18:09:29Z', 'timestamp': 1689617369000},
'page': '129-146',
'update-policy': 'http://dx.doi.org/10.21608/crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 0,
'title': 'Impact of N-Acetylcysteine on Modulating Inflammation in Patients Hospitalized with Moderate '
'COVID-19 Infections: A Prospective Randomized Trial',
'prefix': '10.21608',
'volume': '7',
'author': [ {'given': 'Sara', 'family': 'Sherkawy', 'sequence': 'first', 'affiliation': []},
{'given': 'Lamia', 'family': 'Elwakeel', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mona', 'family': 'Schaalan', 'sequence': 'additional', 'affiliation': []},
{'given': 'Ayman', 'family': 'Moharram', 'sequence': 'additional', 'affiliation': []},
{'given': 'Mohamed', 'family': 'Abouelwafa', 'sequence': 'additional', 'affiliation': []}],
'member': '9060',
'published-online': {'date-parts': [[2023, 6, 1]]},
'container-title': 'Archives of Pharmaceutical Sciences Ain Shams University',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://aps.journals.ekb.eg/article_306468_420dd7e7231b0a5b2177d63fb6d2c8c7.pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2023, 7, 17]],
'date-time': '2023-07-17T18:19:19Z',
'timestamp': 1689617959000},
'score': 1,
'resource': {'primary': {'URL': 'https://aps.journals.ekb.eg/article_306468.html'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2023, 6, 1]]},
'references-count': 0,
'journal-issue': { 'issue': '1',
'published-online': {'date-parts': [[2023, 6, 1]]},
'published-print': {'date-parts': [[2023, 6, 1]]}},
'URL': 'http://dx.doi.org/10.21608/aps.2023.212265.1122',
'relation': {},
'ISSN': ['2356-8399'],
'subject': ['General Medicine'],
'container-title-short': 'Archives of Pharmaceutical Sciences Ain Shams University',
'published': {'date-parts': [[2023, 6, 1]]}}
