Available from: https://clinicaltrials.gov/ct2/show/, O'Connell JJ, Martin J. Prisma Health-Upstate. The product code (s) for this leaflet is: 44490/0006. No differences were noted in the duration of mechanical ventilation, death rate, rate of ICU admission, duration of stay in the ICU, and hospital stay.71, Results from Human Trials of N-Acetylcysteine in COVID-19 Infection, A single-center, randomized, double-blind, placebo-controlled trial evaluating a combined metabolic cofactors supplementation encompassing L-serine, N-acetylcysteine, nicotinamide riboside, and L-carnitine tartrate in 309 adult patients with laboratory-confirmed COVID-19 infection reported that mean recovery time in the intervention group was significantly shorter compared to the placebo group (5.7 vs 9.2 days, P<0.0001). Curr Pharm Biotechnol. On top of understanding the microbial pathogenesis and the molecular and cellular mechanisms of disease biology, activity of a therapeutic agent in a translational research, be it either in vitro or in vivo, is critical to proffer advancement to first-in-human clinical trials based on laboratory findings of pharmacology, toxicology, and immunology.13 For COVID-19 repurposing of an existing clinically approved drug, it is pivotal to demonstrate its antiviral, anti-inflammatory, and related effects against SARS-CoV-2 in cell-based systems in vitro. N-acetylcysteine (NAC) has been used in clinical practice to treat critically ill septic patients, and more recently for COVID-19 patients. The site is secure. N-acetylcysteine is a mucolytic drug which exhibits antioxidant and anti-inflammatory effects.26 The compound has been available in clinical practice for several decades to treat various medical conditions, including bronchitis, acute respiratory distress syndrome, paracetamol intoxication, chemotherapy-related toxicity, doxorubicin cardiotoxicity, heavy metal intoxication, ischemia-reperfusion cardiac injury, human immunodeficiency virus infection or acquired immunodeficiency syndrome, and neuropsychiatric disorders. Karimi Zarchi AA, Faramarzi MA, Gilani K, Ghazi-Khansari M, Ghamami G, Amani A. N-acetylcysteine-loaded PLGA nanoparticles outperform conventional N-acetylcysteine in acute lung injuries in vivo, Nanoparticle formulations in pulmonary drug delivery, Nanoparticle-mediated pulmonary drug delivery: a review. Patients received standard care only (n=146). The https:// ensures that you are connecting to the In vitro studies show that N-acetylcysteine holds therapeutic promise in numerous viral respiratory tract infections. No patient experienced any adverse drug reactions. Both patients experienced a mild rash on the upper body and they completed. The authors report no conflicts of interest for this work. Life Sci. N-acetylcysteine is also used to loosen the thick mucus in the lungs of people with cystic fibrosis or chronic obstructive pulmonary disease (COPD). The patients refractory hypercapnia was gradually improved and was cured and discharged after 46 days of hospitalization.74, Similar clinical benefit was noted in a case study of a 44-year-old man presented to the emergency department of NYU Langone, New York, with a previously diagnosed G6PD deficiency and a current COVID-19 infection with a redisposed risk of hemolysis. Case Report: use of hydroxychloroquine and N-acetylcysteine for treatment of a COVID-19 patient [version 2; peer review: 2 not approved], Experience of N-acetylcysteine airway management in the successful treatment of one case of critical condition with COVID-19: a case report, Therapeutic blockade of inflammation in severe COVID-19 infection with intravenous N-acetylcysteine. N-Acetylcysteine to Combat COVID-19: An Evidence Review An official website of the United States government. The antioxidant effect of N-acetylcysteine ameliorates oxidative stress and inflammatory response in COVID-19. Detailed Description: After being informed of the study and potential risks and benefits, patients meeting eligibility requirements will be randomized to receive oral N-acetylcysteine (NAC) as follows: Inpatients: N-acetylcystine (NAC) 25 mg/kg PO (rounded up to the nearest 600 mg) q4hrs until discharge In a single-center, randomized, double-blind, placebo-controlled trial conducted at the Emergency Department of a hospital in Brazil, 140 patients with severe COVID-19 infection and oxyhemoglobin saturation of less than 94% or respiratory rate higher than 24 breaths/minute were randomized to receive N-acetylcysteine 21,000 mg (approximately 300 mg/kg) for 20 hours or dextrose 5% (placebo). 2022 Aug 2;6(3):100-114. doi: 10.26502/fjppr.055. No significant differences were observed in rates of mortality (13.4% vs 13.2%), ICU admission (43.3% vs 47.1%), ICU stay (9 vs 8 days), hospital stay (11 vs 10 days), and invasive mechanical ventilation use (23.9% vs 20.6%) between the intervention and control groups. All patients tolerated the drug and the volume well. Efficacy outcome measures include rate of hospitalization and time to symptom resolution. N-acetylcysteine: A rapid review of the evidence for - COVID-19 This also implies the possibility that N-acetylcysteine has a role in inhibiting arthropodcoronavirus interaction and producing antimicrobial effect on endosymbionts of Demodex folliculorum.108 Ivermectin is a broad-spectrum anti-parasitic drug which elicits anti-inflammatory and acaricidal actions against Demodex mites,109,110 in addition to antiviral activity against a range of viruses.111 Possible mechanisms include downregulation of the expression of pro-inflammatory genes, including those of IL-8, TNF-, and cathelicidin LL-37 and downregulation of the ACE-2 receptor and viral entry into the cells of the respiratory epithelium and olfactory bulb.112 As a free radical scavenger, N-acetylcysteine can prevent ivermectin-induced cell death due to reactive oxygen species generation,113 suggestive of potential benefits with their combined use. The duration of symptoms was also significantly shorter in the ImmunoFormulation cohort compared to the control group, notably for fever (2.25 vs 21.78 days), dry cough (4.38 vs 24.00 days), dyspnea (3.67 vs 20.00 days), headache (2.00 vs 26.50 days), diarrhea (5.25 vs 25.25 days), and weakness (1.92 vs 23.30 days) (all P<0.05). However, the inhibitory effect of N-acetylcysteine was significantly less than that observed with H5N1, suggesting the susceptibility is strain-dependent.58, In in vitro modeling of RSV infection carried out in cultures of primary normal human bronchial epithelial cells, N-acetylcysteine significantly inhibited viral infection, re-established the number of beating cells, restored the virus-induced decrease in expression of -tubulin and genes involved in ciliagenesis such as DNAI2 and FOXJ1, inhibited IL-13, MUC5AC, and GOB5 upregulation, inhibited ICAM1 expression, increased heme-oxygenase 1 expression which correlated with the restoration of cellular antioxidant capacity, and enhanced intracellular hydrogen peroxide and glutathione concentrations.59, In another experiment, N-acetylcysteine significantly reduced MUC5AC expression in RSV-infected A549 cells. Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment. 2023 Feb 28;14(1):e0237022. Oka S, Kamata H, Kamata K, Yagisawa H, Hirata H. N-Acetylcysteine suppresses TNF-induced NF-B activation through inhibition of IB kinases. Patients will receive standard care only. The surfaces can be easily modified for additional targeting. The COVID-19 pandemic has highlighted the critical need for new drugs to complement existing therapies. *, The effect of 30 min incubation of neutrophils with different NAC concentrations on the fMLP (10. 90.0% of patients receiving ImmunoFormulation recovered compared to 47.4% in the control group (, Single center, non-randomized, open-label, parallel-group trial, Phase 2. Currently, there are some clinical trials assessing the potential use of NAC against COVID-19; for example, the 'Efficacy and Safety of Nebulized Heparin-N-acetylcysteine in COVID-19 Patients by Evaluation of Pulmonary Function Improvement (HOPE)' clinical trial is aimed at determining the efficacy of nebulized NAC and heparin in ventilated . Williams TC, Burgers WA. 0011). N-Acetylcysteine to Combat COVID-19: An Evidence Review. Abstract. Rodrguez-Beltrn J, Cabot G, Valencia EY, et al. Patients aged 18 years or older diagnosed with severe COVID-19 (suspected or confirmed) with oxyhemoglobin saturation of less than 94% while breathing ambient air and respiratory rate higher than 24 breaths/min. The 10 or 20% solution may be used for inhalation as a heavy mist in a tent or croupette. Hadzic T, Li L, Cheng N, Walsh SA, Spitz DR, Knudson CM. Whillier S, Raftos JE, Chapman B, Kuchel PW. SARS-CoV-2 and Coronavirus Disease 2019: what We Know So Far, Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study, Coronavirus Disease 2019 (COVID-19): a Short Review on Hematological Manifestations. Lpez-Medina E, Lpez P, Hurtado IC, et al. N-acetylcysteine is also marketed as a dietary supplement that is suggested to possess antioxidant and hepatic-protecting effects. Interleukin-6: designing specific therapeutics for a complex cytokine, Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer, Interleukin-6 receptor blockade in patients with COVID-19: placing clinical trials into context. Landini G, Di Maggio T, Sergio F, Docquier J-D, Rossolini GM, Pallecchi L. Effect of High N-Acetylcysteine Concentrations on Antibiotic Activity against a Large Collection of Respiratory Pathogens, The chemistry and biological activities of N-acetylcysteine. Yilmaz B, Trk G, engl E, Gl A, zkurt FE, Akda M. Efficacy of N-Acetylcysteine on Wound Healing of Nasal Mucosa. N-acetylcysteine (NAC) was introduced in the 1960s as a mucolytic drug for chronic respiratory diseases. Epub 2022 Dec 12. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why, Coronavirus envelope protein: current knowledge, Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: a Review, Cell entry by enveloped viruses: redox considerations for HIV and SARS-coronavirus. J Inflamm Res. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: a Randomized Clinical Trial, COVID-19 and its implications for thrombosis and anticoagulation, Coagulation abnormalities and thrombosis in patients with COVID-19, The Impact of COVID-19 Disease on Platelets and Coagulation, D-dimer level in COVID-19 infection: a systematic review, D-dimer tests detect both plasmin and neutrophil elastase derived split products, Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy, Disseminated intravascular coagulation: a devastating systemic disorder of special concern with COVID-19. National Library of Medicine Apart from the fact that acetylcysteine is able to normalise a state of glutathione depletion, it is able to conjugate with various toxic compounds. Lai KY, Ng WY, Osburga Chan PK, Wong KF, Cheng F. High-dose N-acetylcysteine therapy for novel H1N1 influenza pneumonia. government site. N-acetylcysteine for prevention and treatment of COVID-19: Current Since the drug candidate has already been translated into the clinic for several decades, its established pharmacological properties and safety and side-effect profiles expedite preclinical and clinical assessment for the treatment of COVID-19. -, Schulte-Schrepping J, Reusch N, Paclik D, et al. Improvement of N-Acetylcysteine Loaded in PLGA Nanoparticles by Nanoprecipitation Method. NAC might also increase immune function, help fight viruses, and reduce . In mice following intranasal infection with a lethal dose of influenza A virus A/PR/8, the use of N-acetylcysteine increased survival rate from 58% (ribavirin monotherapy) to 92% (N-acetylcysteine and ribavirin), suggesting the antioxidants role in improving host defense mechanism and preventing pathogenesis of lung inflammation.61,62 Further experiment depicted that survival rates of mice were 20% in the N-acetylcysteine group, 60% in the oseltamivir group, and 100% in combination treatment of N-acetylcysteine and oseltamivir.63 In these three models, the mice were infected with 23 LD50 of influenza virus and N-acetylcysteine was administered as a single daily dose of 1,000 mg/kg.6163 N-acetylcysteine increased survival by contributing to host defense mechanisms or by direct antioxidant effect against oxidative stress associated with viral infection.63 On the contrary, mice infected intranasally with a deadly dose of porcine A/swine/Iowa/4 (H1N1) influenza strain showed no significant difference in percent survival and mean survival time between N-acetylcysteine and control groups, showing that different virus strains resulted in different susceptibilities to N-acetylcysteine.58 The porcine A/swine/Iowa/4 (H1N1) strain was found to be more resistant to N-acetylcysteine than the human strain A/PR/8 (H1N1) deployed in other animal models.6163 The lack of treatment effect was possibly due to the virus phenotypic susceptibility to N-acetylcysteine and the viral pathotype.64, Findings from H9N2 swine influenza virus-infected murine model indicated that N-acetylcysteine ameliorated pulmonary edema and inflammatory response, reduced myeloperoxidase activity in the lungs, decreased total and differential cell counts, neutrophils, macrophages, IL-6, IL-1, TNF-, and CXCL-10 in the bronchoalveolar lavage fluid, and inhibited protein expression of TLR4 and its mRNA in the lungs.65, In an experiment of H3N2-infected mice, N-acetylcysteine decreased pulmonary responsiveness and increased immune cytokine expression of IFN- in comparison to saline controls, with no effect on virus titers and expression of IL-4, IL-13, and IL-12p40.66, Currently, there have been several clinical studies to measure the effects of N-acetylcysteine on viral respiratory tract infections. A search on 3rd April 2020 did not reveal any COVID-specific evidence for NAC, so we have fallen back on evidence in other acute respiratory disorders. N-acetylcysteine (NAC) has been used in clinical practice to treat critically ill septic patients, and more recently for COVID-19 patients. 2005;75:185194. An oral placebo was given for the next 14 days (n=22). Mahmoud Abd El Hafiz A, Mohammed El Wakeel L, Mohammed El Hady H, Mourad AER. A 64-year-old Chinese male with an anastomotic fistula after radical treatment of esophageal cancer and right-side encapsulated pyopneumothorax. Left: Placebo group;, Influence of NAC on H5N1 virus replication in A549 cells. Ullian ME, Gelasco AK, Fitzgibbon WR, Beck CN. Indeed, intrinsic Gclc expression in T-cells is necessary for antigen-specific immunity to virus infections. Similar to clinical trials on other infectious respiratory illnesses, study endpoints should appropriately encompass changes in SARS-CoV-2 associated blood cytokine levels, change in peripheral-blood lymphocyte count and activation, improvement in clinical status, hospital length of stay, time to recovery, safety outcomes, and overall mortality. J Med Virol. Package leaflet: Information for the user. Ninety percent of patients in the ImmunoFormulation cohort recovered from the infection as compared to 47% in the control cohort (P=0.006). ClinicalTrials.gov Identifier: Multicenter, randomized, parallel-group, double-blinded, placebo-controlled trial, Phase 3. N-ACETYL CYSTEINE (NAC) Reviews and User Ratings: Effectiveness - WebMD Directly Acting Antivirals for COVID-19: where Do We Stand? SARS-CoV-2 evolution and vaccines: Cause for concern? Viruses. The study is scheduled to complete in August 2021. The overwhelming impact of the COVID-19 crisis has driven the push for reimagining and repositioning of previously approved medical treatments for other indications to speed up the discovery and development of safe and efficacious agents to enlarge the alternatives for adjunctive treatment or prevention of progression into severe COVID-19 illness.14 From the clinical front, it is presently worrisome to have no effective antimicrobial agents to treat the infected individuals and, optimally, eliminate viral shedding and the ensuing transmission cascades. These clinical applications stem from its . 8600 Rockville Pike PMC Pharmaceuticals (Basel). The mean recovery time for the ImmunoFormulation cohort was significantly shorter in comparison to the control cohort for patients with mild symptoms (11.22 vs 28.00 days), moderate symptoms (17.57 vs 28.00 days), and severe symptoms (16.00 vs 25.42 days). Memorial Sloan Kettering Cancer Center. Primary outcome measures include number of patients who are successfully extubated and/or transferred out of critical care due to clinical improvement and number of patients who are discharged from the hospital due to clinical improvement. Federal government websites often end in .gov or .mil. Repeated bedside bronchoscopy with 1015 g/time of N-acetylcysteine nebulized inhalation solution lavage was given in combination with routine nebulization and sputum suction airway management. Where are we with the use of N-acetylcysteine as a preventive and Prophylactic anticoagulation was started with subcutaneous heparin 5,000 units every 8 hours. Myeloid Cells during Viral Infections and Inflammation. However, the vaccine has shown limited benefit in the elderly, suggesting an age-dependent immune response. No adverse drug reaction occurred in any of the study subjects. Accessibility Adults aged 18 to 75 years with COVID-19 infection confirmed 2 days before randomization, currently hospitalized and requiring medical care and had a peripheral capillary oxygen saturation (SpO2) <94% on room air at screening. In addition, acetylcysteine is a precursor of glutathione. The authors received no specific funding for this work. Patients will be treated with mixture of Methylene blue, Vitamin C, N-acetylcysteine. 1. Interleukin-6: obstacles to targeting a complex cytokine in critical illness. Oral and intravenous N-acetylcysteine regimens are associated with adverse events such as diarrhea, nausea, vomiting, and mild-to-moderate hypersensitivity reactions such as urticaria, rash, angioedema, and wheezing.98,99 Such adverse events are dose-related and antihistamines are effective for treating and preventing recurrence of the anaphylactic reactions. The Problem of Home Therapy during COVID-19 Pandemic in Italy: Government Guidelines versus Freedom of Cure? It is well tolerated without any serious side effects . Currently, there is some evidence supporting the use of N-acetylcysteine as an adjunctive therapy for COVID-19. An additional 200 mg dose of hydroxychloroquine was given on Day 2. The potential use of N-acetylcysteine in COVID-19 is largely inferred from previous research on other viruses such as influenza and respiratory syncytial virus. Of note, one of the important regulators of inflammation in COVID-19 is IL-6.92 Elevations in serum IL-6 concentrations have been identified under critical conditions such as sepsis, acute respiratory distress syndrome, and COVID-19.93,94 IL-6 is crucial for innate and adaptive immunity, efficient pathogen clearance, and physiological functions such as regulation of acute-phase response, hematopoiesis, lipid homeostasis, metabolism, and neural development.95 In essence, anti-inflammatory, pro-resolution, and antimicrobial activities of IL-6 are facilitated by classical signalling, whilst pro-inflammatory activities of IL-6 are facilitated by trans-signalling.96 Targeting the pathological effects of IL-6-mediated inflammation should avoid the unintentional concurrent abolition of its anti-inflammatory and pro-resolution functions.93 Blockade of IL-6 and the consequent reduction of downstream effects on inflammation and the innate immune response may have beneficial effects on clinical outcomes in patients with COVID-19, including those with acute hypoxemic respiratory failure.97 Contemporary in vitro and in vivo evidence indicating a potential effect of N-acetylcysteine in IL-6 inhibition may stimulate further research to understand how the drug affects disease outcomes and maximize its benefits with concomitant pharmacotherapy to selectively inhibit the trans-signalling pathway through which IL-6 signals. At present, there are six registered clinical trials evaluating the potential therapeutic value of N-acetylcysteine against COVID-19.7883 The findings will build on in vitro and early in vivo evidence for the use of N-acetylcysteine as an adjuvant therapy for COVID-19. Puyo C, Kreig D, Saddi V, Ansari E, Prince O. National Library of Medicine Dextrose 5% in water was administered intravenously (n=70). There are many more clinical studies that are currently underway to generate the necessary evidence of its efficacy to inform future patient care and clinical action (Table 2).7883, Protocol Information of Currently Ongoing Human Trials of N-Acetylcysteine in COVID-19 Infection, There has been no in vitro or in vivo research that specifically examines the effect of N-acetylcysteine on COVID-19 infection. Soto ME, Manzano-Pech L, Palacios-Chavarra A, Valdez-Vzquez RR, Guarner-Lans V, Prez-Torres I. Would you like email updates of new search results? 1Department of Microbiology and Immunology, Hospital Canselor Tuanku Muhriz UKM, Cheras, Kuala Lumpur, Malaysia, 2Faculty of Medicine, The National University of Malaysia, Cheras, Kuala Lumpur, Malaysia, 3School of Pharmacy, Monash University, Bandar Sunway, Selangor, Malaysia, 4Asian Centre for Evidence Synthesis in Population, Implementation, and Clinical Outcomes (PICO), Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University, Bandar Sunway, Selangor, Malaysia, 5Gerontechnology Laboratory, Global Asia in the 21st Century (GA21) Platform, Monash University, Bandar Sunway, Selangor, Malaysia, 6Faculty of Health and Medical Sciences, Taylors University, Bandar Sunway, Selangor, Malaysia, 7Puchong Health Clinic, Petaling District Health Office, Ministry of Health Malaysia, Petaling, Selangor, Malaysia. MATERIALS AND METHODS: A search was performed in PubMed/Medline for "NAC", "viral Infection", COVID-19", oxidative stress", "inflammation . 2022 Dec;15(12):1477-1483. doi: 10.1016/j.jiph.2022.11.009. ClinicalTrials.gov Identifier. A brief overview of a NAC therapeutic strategy to combat COVID-19. Albeit some evidence of benefits has been observed in clinical outcomes of patients, precision nanoparticle design of N-acetylcysteine may allow for greater therapeutic efficacy. Matsuyama T, Morita T, Horikiri Y, Yamahara H, Yoshino H. Enhancement of nasal absorption of large molecular weight compounds by combination of mucolytic agent and nonionic surfactant, Enhanced nasal drug delivery efficiency by increasing mechanical loading using hypergravity, http://creativecommons.org/licenses/by-nc/3.0/, https://www.bmj.com/content/371/bmj.m3862/rr-8, https://www.ncbi.nlm.nih.gov/books/NBK548401, Single center, double-blind, randomized, placebo-controlled trial, Phase 4. This review offers a thorough analysis of NAC and discusses its potential use for treatment of COVID-19.

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