A pilot study on intravenous N-Acetylcysteine treatment in patients with mild-to-moderate COVID19-associated acute respiratory distress syndrome.
Acetylcysteine
/ administration & dosage
Administration, Intravenous
Adult
Aged
Aged, 80 and over
COVID-19
/ complications
Double-Blind Method
Female
Humans
Male
Middle Aged
Mortality
Pilot Projects
Prospective Studies
Respiratory Distress Syndrome
/ drug therapy
SARS-CoV-2
Severity of Illness Index
Treatment Outcome
COVID-19 Drug Treatment
Acute respiratory distress syndrome
COVID-19
Inflammation
N-Acetylcysteine
Oxidative stress
Journal
Pharmacological reports : PR
ISSN: 2299-5684
Titre abrégé: Pharmacol Rep
Pays: Switzerland
ID NLM: 101234999
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
14
04
2021
accepted:
03
06
2021
revised:
31
05
2021
pubmed:
12
6
2021
medline:
1
12
2021
entrez:
11
6
2021
Statut:
ppublish
Résumé
We designed this single-centre clinical trial to assess the potential benefits of N-Acetylcysteine (NAC) in patients with COVID19-associated acute respiratory distress syndrome (ARDS). Ninety-two patients with mild-to-moderate COVID19-associated ARDS were allocated to the placebo (45-cases) or NAC groups (47-cases). Besides standard-of-care treatment, the patients received either intravenous NAC at a dose of 40 mg/kg/day or the placebo for three consecutive days. The efficacy outcomes were overall mortality over 28-day, clinical status on day 28, based on the WHO Master Protocol, the proportion of patients requiring mechanical ventilation, changes in ARDS-severity (based on the PaO Our pilot study did not support the potential benefits of intravenous NAC in treating patients with COVID-19-associated ARDS. More studies are needed to determine which COVID-19 patients benefit from the NAC administration. The trial was registered at Clinicaltrials.gov (identifier code: IRCT20120215009014N355). Registration date: 2020-05-18.
Sections du résumé
BACKGROUND
BACKGROUND
We designed this single-centre clinical trial to assess the potential benefits of N-Acetylcysteine (NAC) in patients with COVID19-associated acute respiratory distress syndrome (ARDS).
METHODS
METHODS
Ninety-two patients with mild-to-moderate COVID19-associated ARDS were allocated to the placebo (45-cases) or NAC groups (47-cases). Besides standard-of-care treatment, the patients received either intravenous NAC at a dose of 40 mg/kg/day or the placebo for three consecutive days. The efficacy outcomes were overall mortality over 28-day, clinical status on day 28, based on the WHO Master Protocol, the proportion of patients requiring mechanical ventilation, changes in ARDS-severity (based on the PaO
CONCLUSIONS
CONCLUSIONS
Our pilot study did not support the potential benefits of intravenous NAC in treating patients with COVID-19-associated ARDS. More studies are needed to determine which COVID-19 patients benefit from the NAC administration.
TRIAL REGISTRATION
BACKGROUND
The trial was registered at Clinicaltrials.gov (identifier code: IRCT20120215009014N355). Registration date: 2020-05-18.
Identifiants
pubmed: 34114174
doi: 10.1007/s43440-021-00296-2
pii: 10.1007/s43440-021-00296-2
pmc: PMC8191712
doi:
Substances chimiques
Acetylcysteine
WYQ7N0BPYC
Banques de données
IRCT
['IRCT20120215009014N355']
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
1650-1659Informations de copyright
© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.
Références
WHO. WHO director-general’s remarks at the media briefing on 2019-nCoV on 11 February 2020. WHO; 2020.
CPERE Novel. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41:145.
Yang X, Yu Y, Xu J, Shu H, Liu H, Wu Y, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8:475–81.
pubmed: 32105632
pmcid: 7102538
Force ADT, Ranieri V, Rubenfeld G, Thompson B, Ferguson N, Caldwell E. Acute respiratory distress syndrome. JAMA. 2012;307:2526–33.
Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana JP, et al. Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.
pubmed: 32179124
pmcid: 32179124
Lugrin J, Rosenblatt-Velin N, Parapanov R, Liaudet L. The role of oxidative stress during inflammatory processes. Biol Chem. 2014;395:203–30.
pubmed: 24127541
Wu J. Tackle the free radicals damage in COVID-19. Nitric Oxide. 2020;102:39–41. https://doi.org/10.1016/j.niox.2020.06.002 . Accessed 17 June 2020.
doi: 10.1016/j.niox.2020.06.002
pubmed: 32562746
pmcid: 7837363
Zhang C, Wu Z, Li J-W, Zhao H, Wang G-Q. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents. 2020;55:105954.
pubmed: 32234467
pmcid: 7118634
Fu Y, Cheng Y, Wu Y. Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools. Virol Sin. 2020;35:266–71.
pubmed: 32125642
pmcid: 7090474
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020;80:607–13.
pubmed: 32283152
pmcid: 7194613
Lapenna D Antioxidant therapy in COVID-19: the crucial role of early treatment and antioxidant typology. Clin Infect Dis. 2021. https://doi.org/10.1093/cid/ciab055 .
WHO. Corticosteroids for COVID-19: living guidance, 2 September 2020. World Health Organization; 2020.
Zafarullah M, Li W, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Mol Life Sci. 2003;60:6–20.
pubmed: 12613655
Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician. 2009;80:265–9.
pubmed: 19621836
Dass E. Brief review of N-acetylcysteine as antiviral agent: potential application in COVID-19. J Biomed Pharm Res. 2020;9(3):69–73.
De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997;10:1535–41.
pubmed: 9230243
Mata M, Morcillo E, Gimeno C, Cortijo J. N-acetyl-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. 2011;82:548–55.
pubmed: 21635874
Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS. Chest. 1997;112:164–72.
pubmed: 9228372
Soltan-Sharifi MS, Mojtahedzadeh M, Najafi A, Khajavi MR, Rouini MR, Moradi M, 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. 2007;26:697–703.
pubmed: 17984140
Mohanty R, Padhy B, Das S, Meher B. Therapeutic potential of N-acetyl cysteine (NAC) in preventing cytokine storm in COVID-19: review of current evidence. Eur Rev Med Pharmacol Sci. 2021;25:2802–7.
pubmed: 33829465
Puyo C, Kreig D, Saddi V, Ansari E, Prince O. Case report: Use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 positive patient. F1000Research. 2020;9:491.
Liu Y, Wang M, Luo G, Qian X, Wu C, Zhang Y, et al. Experience of N-acetylcysteine airway management in the successful treatment of one case of critical condition with COVID-19: a case report. Medicine. 2020;99(42):e22577. https://doi.org/10.1097/MD.0000000000022577 .
doi: 10.1097/MD.0000000000022577
pubmed: 33080692
pmcid: 7571913
Nasi A, McArdle S, Gaudernack G, Westman G, Melief C, Rockberg J, et al. 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. Toxicol Rep. 2020;7:768–71.
pubmed: 32632359
pmcid: 7301821
Ibrahim H, Perl A, Smith D, Lewis T, Kon Z, Goldenberg R, et al. Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. Clin Immunol. 2020;219:108544.
pubmed: 32707089
pmcid: 7374140
Suter PM, Domenighetti G, Schaller M-D, Laverrière M-C, Ritz R, Perret C. N-acetylcysteine enhances recovery from acute lung injury in man: a randomized, double-blind, placebo-controlled clinical study. Chest. 1994;105:190–4.
pubmed: 8275731
Radomska-Leśniewska DM, Skopiński P. Review paper N-acetylcysteine as an anti-oxidant and anti-inflammatory drug and its some clinical applications. Cent Eur J Immunol. 2012;37:57–66.
Chertoff J. N-acetylcysteine’s role in sepsis and potential benefit in patients with microcirculatory derangements. J Intensive Care Med. 2018;33:87–96.
pubmed: 28299952
Poppe M, Wittig S, Jurida L, Bartkuhn M, Wilhelm J, Müller H, et al. The NF-κB-dependent and-independent transcriptome and chromatin landscapes of human coronavirus 229E-infected cells. PLoS Pathog. 2017;13:e1006286.
pubmed: 28355270
pmcid: 5386326
Ghezzi P, Ungheri D. Synergistic combination of N-acetylcysteine and ribavirin to protect from lethal influenza viral infection in a mouse model. Int J Immunopathol Pharmacol. 2004;17:99–102.
pubmed: 15000873
Mata M, Sarrion I, Armengot M, Carda C, Martinez I, Melero JA, et al. Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine. PLoS ONE. 2012;7:e48037.
pubmed: 23118923
pmcid: 3485262
Geiler J, Michaelis M, Naczk P, Leutz A, Langer K, Doerr H-W, et al. 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. Biochem Pharmacol. 2010;79:413–20.
pubmed: 19732754
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71:762–8.
De Flora S, Balansky R, La Maestra S. Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19. FASEB J. 2020;34:13185–93.
pubmed: 32780893
Jaiswal N, Bhatnagar M, Shah H. N-acetylcysteine: a potential therapeutic agent in COVID-19 infection. Med Hypotheses. 2020;144:110133.
pubmed: 32758904
pmcid: 7380211
Van Hecke O, Lee J. N-acetylcysteine: a rapid review of the evidence for effectiveness in treating COVID-19. 2020. https://hdl.handle.net/20.500.12663/1089 .
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506.
pubmed: 31986264
pmcid: 31986264
Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet. 2003;361:1773–8.
pubmed: 12781536
pmcid: 7112492
Shi Z, Puyo CA. N-acetylcysteine to combat COVID-19: an evidence review. Ther Clin Risk Manag. 2020;16:1047.
pubmed: 33177829
pmcid: 7649937
Moradi M, Mojtahedzadeh M, Mandegari A, Soltan-Sharifi MS, Najafi A, Khajavi MR, et al. The role of glutathione-S-transferase polymorphisms on clinical outcome of ALI/ARDS patient treated with N-acetylcysteine. Respir Med. 2009;103:434–41.
pubmed: 18993042
Ortolani O, Conti A, De Gaudio AR, Masoni M, Novelli G. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock. 2000;13:14–8.
pubmed: 10638663
Domenighetti G, Suter PM, Schaller M-D, Ritz R, Perret C. Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study. J Crit Care. 1997;12:177–82.
pubmed: 9459113
Jepsen S, Herlevsen P, Knudsen P, Bud MI, Klausen N. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study. Crit Care Med. 1992;20:918–23.
pubmed: 1617983
Zhang Y, Ding S, Li C, Wang Y, Chen Z, Wang Z. Effects of N-acetylcysteine treatment in acute respiratory distress syndrome: a meta-analysis. Exp Ther Med. 2017;14:2863–8.
pubmed: 28928799
pmcid: 5590037
Alamdari DH, Moghaddam AB, Amini S, Keramati MR, Zarmehri AM, Alamdari AH, et al. Application of methylene blue-vitamin C–N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial. Eur J Pharmacol. 2020;885:173494.
pubmed: 32828741
pmcid: 7440159
García LF. Immune response, inflammation, and the clinical spectrum of COVID-19. Front Immunol. 2020;11:1441.
pubmed: 32612615
pmcid: 7308593
Lariccia V, Magi S, Serfilippi T, Toujani M, Gratteri S, Amoroso S. Challenges and opportunities from targeting inflammatory responses to SARS-CoV-2 infection: a narrative review. J Clin Med. 2020;9:4021.
pmcid: 7763517
Sochman J. N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know?! J Am Coll Cardiol. 2002;39:1422–8.
pubmed: 11985902
Sabetghadam M, Mazdeh M, Abolfathi P, Mohammadi Y, Mehrpooya M. Evidence for a beneficial effect of oral N-acetylcysteine on functional outcomes and inflammatory biomarkers in patients with acute ischemic stroke. Neuropsychiatr Dis Treat. 2020;16:1265.
pubmed: 32547030
pmcid: 7244239
Samidurai A, Das A. Cardiovascular complications associated with COVID-19 and potential therapeutic ~ strategies. Int J Mol Sci. 2020;21:6790.
pmcid: 7554795
Ahmad I, Rathore FA. Neurological manifestations and complications of COVID-19: a literature review. J Clin Neurosci. 2020;77:8–12. https://doi.org/10.1016/j.jocn.2020.05.017 . Accessed 6 May 2020.
doi: 10.1016/j.jocn.2020.05.017
pubmed: 32409215
pmcid: 7200361
Meri W, Koutsogiannis Z, Kerr D, Kelly. How safe is intravenous N-Acetylcysteine for the treatment of paracetamol poisoning?. Hong Kong J Emerg Med 2007, 14(4):198–203.
Sadowska AM, Manuel-y-Keenoy B, Vertongen T, Schippers G, Radomska-Lesniewska D, Heytens E, et al. Effect of N-acetylcysteine on neutrophil activation markers in healthy volunteers: in vivo and in vitro study. Pharmacol Res. 2006;53:216–25.
pubmed: 16384711
Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet. 1991;20:123–34.
pubmed: 2029805
Kearns SR, O’Briain DE, Sheehan KM, Kelly C, Bouchier-Hayes D. N-acetylcysteine protects striated muscle in a model of compartment syndrome. Clin Orthop Relat Res. 2010;468:2251–9.
pubmed: 20309660
pmcid: 2895823