Available from: https://clinicaltrials.gov/ct2/show/, Lai-Becker M. Cambridge Health Alliance. 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. The patient was mechanically ventilated for only 3 days, was then transferred from the ICU to the general ward on Day 7, and was finally discharged from the hospital on Day 12 with stable vital signs and normalized laboratory results.73, In another case report, a 64-year-old man presented with acute respiratory distress syndrome due to COVID-19 severe pneumonia and secondary bacterial lung infection was admitted to Taihe Hospital in Shiyan, China and was given repeated bedside bronchoscopy at intervals of 1 day or 2 days with a large dose of 10,00015,000 mg/time of N-acetylcysteine nebulized inhalation solution lavage combined with routine nebulization and sputum suction airway management. Xu XQ, Xu T, Ji W, Wang C, Ren Y, Xiong X, Zhou X, Lin SH, Xu Y, Qiu Y. mBio. The efficacy of N-Acetylcysteine in severe COVID-19 patients: A In 1997 an Italian study was published on the effects of n-acetylcysteine on influenza at a dosage of 600mg twice daily. Natural small molecules as inhibitors of coronavirus lipid-dependent attachment to host cells: a possible strategy for reducing SARS-COV-2 infectivity? The site is secure. Substituting Angiotensin-(1-7) to Prevent Lung Damage in SARS-CoV-2 Infection? N-acetylcysteine has recently been suggested as an adjunctive therapy to the standard care for SARS-CoV-2 infection considering the favorable risk and benefit ratio and its effects on synthesizing glutathione, improving immune function, and modulating inflammatory response.3234 It achieves the therapeutic effects through two main activities: 1) mucolytic action conferred by the free sulfhydryl group which reduces disulfide bonds in the cross-linked mucus glycoproteins matrix, thus decreasing the viscosity of mucus; 2) antioxidative action attributable to a direct interaction with free radicals, an indirect effect as a precursor to cysteine which is required for glutathione biosynthesis, and a replenishment of thiol pools that is central to redox regulation and control.35 In light of these properties, we hypothesize that N-acetylcysteine plays a role in the treatment of COVID-19 infection by the following postulated mechanisms of action (Figure 1): Schematic representation of the possible effects of N-acetylcysteine on SARS-CoV-2 infection. 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. 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. Garigliany MM, Habyarimana A, Lambrecht B, et al. The novel coronavirus disease (COVID-19) is caused by a virus (SARS-Cov-2) and is known for inducing multisystem organ dysfunction associated with significant morbidity and mortality. 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). Vitamins & Supplements N-Acetyl Cysteine (Nac) Reviews User Reviews for n-acetyl cysteine (nac) Comments & ratings on the side effects, benefits, and effectiveness of n-acetyl cysteine (nac).. Lane CJ, Redding DR, Gonzalez KA, Cardenas VJ, Boldogh I, Sur S. Topical N-acetyl cysteine (NAC) Reduces Late Phase Nasal Symptoms Following Ragweed Challenge. Patients will receive N-acetylcysteine IV 6 g/day in addition to supportive and/or COVID-19 directed treatments at the discretion of the treating physician. It also diminished induction of TNF- and IL-6, decreased NF-B nuclear translocation and p38 mitogen activated protein kinase phosphorylation, abolished intracellular hydrogen peroxide production, restored intracellular thiol levels, and reduced virus titre.56, Likewise, RSV infection of A549 epithelial cell lines showed the inhibitory effects of N-acetylcysteine on virus-induced chemokine expression and DNA-binding activity of NF-B subunits of p50 and p65.60. Antioxidants | Free Full-Text | GlyNAC (Glycine and N-Acetylcysteine 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. Grobler JA, Anderson AS, Fernandes P, et al. Clinical application of methylene blue for treatment of COVID-19 patients (COVID-19). 3 common drugs being tested to treat early-stage COVID-19 Maffezzoni E, Notargiacomo M, Agostini S, Gelardi M. Efficacy of a nasal spray containing N-acetylcysteine in hypertonic solution in the treatment of nonallergic chronic rhinitis with goblet cell metaplasia, Recurrent acute rhinosinusitis: a single blind clinical study of N-acetylcysteine vs ambroxol associated to corticosteroid therapy. The study is scheduled to complete in February 2021. Bateman DN, Dear JW, Thanacoody HKR, et al. Expand All. Improvement of N-Acetylcysteine Loaded in PLGA Nanoparticles by Nanoprecipitation Method. N-Acetylcysteine as Adjuvant Therapy for COVID-19 - A Perspective on the Current State of the Evidence. In the intervention group, serum alanine aminotransferase (P=0.032), lactate dehydrogenase (P<0.0001), and creatinine levels (P<0.0001) were significantly lower on Day 14 compared to Day 0. sharing sensitive information, make sure youre on a federal SARS-CoV-2 virus has engendered 10-fold higher in the number of cases than the 2003 SARS epidemic in a quarter of the time.6 The rapid transmission of this highly pathogenic virus has warranted a pressing global need for the instantaneous development and deployment of therapeutic approaches and preventive measures against the disease.7, Common hematological manifestations of COVID-19 infection include lymphocytopenia associated with intensification of the inflammatory process and direct infection of lymphocytes and destruction of lymphoid organs, increased ferritin levels owing to inflammation, and a higher rate of erythrocyte sedimentation in severe disease. Antioxidant therapy for COVID-19 study (GSHSOD-COVID). N-acetylcysteine: A rapid review of the evidence for - COVID-19 2020;395(10223):497506. These clinical applications stem from its . 2020 May 21;8(5):129. doi: 10.3390/biomedicines8050129. A549 cells were, The effect of 30 min incubation of neutrophils with different NAC concentrations on. doi:10.1002/jmv.20255 Severity and mortality have been related to a cytokine storm, an imbalance of oxidative stress, and a pro-thrombot 2021;22(12):1584-1590. doi: 10.2174/1389201021999201228212043. Sharafkhah M, Abdolrazaghnejad A, Zarinfar N, Mohammadbeigi A, Massoudifar A, Abaszadeh S. Safety and efficacy of N-acetyl-cysteine for prophylaxis of ventilator-associated pneumonia: a randomized, double blind, placebo-controlled clinical trial. Further studies with cautious approach are needed to establish the benefits and risks before considering NAC as an adjuvant treatment for COVID-19. We reported earlier that ACD in older humans is . In a G6PD deficient patient, N-acetylcysteine elicited improvements in hemolysis indices (direct bilirubin), liver enzymes (ALT and AST), and inflammatory markers (C-reactive protein and ferritin), decreased dependence on respirator and veno-venous extracorporeal membrane oxygenator, and reduced neutrophil to lymphocyte ratio. Currently, there is some evidence supporting the use of N-acetylcysteine as an adjunctive therapy for COVID-19. Treatment interruptions for up to 48 hours are permissible if there is a clinical indication to hold the study drug. There has been no in vitro or in vivo research that specifically examines the effect of N-acetylcysteine on COVID-19 infection. N-acetyl cysteine is an antioxidant that might play a role in preventing cancer. Kalra RS, Tomar D, Meena AS, Kandimalla R. SARS-CoV-2, ACE2, and Hydroxychloroquine: cardiovascular Complications, Therapeutics, and Clinical Readouts in the Current Settings, ACTIVating Resources for the COVID-19 Pandemic: in Vivo Models for Vaccines and Therapeutics. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic 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. Chaccour C, Casellas A, Blanco-Di Matteo A, et al. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery, Nano based drug delivery systems: recent developments and future prospects. Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19), Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19. N-Acetylcysteine as Adjuvant Therapy for COVID-19 - A Perspective on Aljihani SA, Alehaideb Z, Alarfaj RE, et al. -. Oka S, Kamata H, Kamata K, Yagisawa H, Hirata H. N-Acetylcysteine suppresses TNF-induced NF-B activation through inhibition of IB kinases. Bethesda, MD 20894, Web Policies N-acetylcysteine for chronic kidney disease: a systematic review and The use of intravenous N-acetylcysteine at 30,000 mg in three divided doses over 24 hours was associated with an immediate improvement in hemolysis indices (direct bilirubin levels), liver enzyme levels (alanine aminotransferase and aspartate aminotransferase), resolution of hemolysis as quantified by a sustained reduction in total and direct bilirubin and an elevated haptoglobin, and a sustained decrease in neutrophil to lymphocyte ratio which was an inflammatory predictor. 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. Accessibility Responding to Covid-19 a Once-in-a-Century Pandemic? Male sex, older age, and the presence of comorbidities are correlated with increased risk of COVID-19-related mortality.8,9 The development of thrombocytopenia may occur in severe disease due to reduced platelet production and increased destruction or consumption of platelets. The median C-reactive protein level during IV N-acetylcysteine administration was 55 mg/dL which was considerably lower compared to the time before administration (143 mg/dL) or after N-acetylcysteine discontinuation (69 mg/dL). Of the intention-to-treat population comprising 135 patients, 16 patients (24%) receiving placebo required endotracheal intubation and invasive mechanical ventilation compared to 14 patients (21%) in the N-acetylcysteine group (P=0.675). 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. Addition of N-acetylcysteine to Cd4cre-Gclc T-cells increases Myc expression and CD98 production. Further studies are warranted to design a formulation with increased bioavailability or target-oriented delivery, ascertain optimal dosage and route of administration, and conduct well-controlled, adequately powered, randomized clinical trials to determine the safety and efficacy of N-acetylcysteine in patients with COVID-19. An updated insight into the molecular pathogenesis, secondary complications and potential therapeutics of COVID-19 pandemic. No patient experienced any adverse drug reactions. ClinicalTrials.gov Identifier: Single center, randomized, open-label, parallel-group, controlled trial, Phase 1. 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. IV NAC was started again until discharge. Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK, Hua S. Advances and Challenges of Liposome Assisted Drug Delivery. Elevated D-dimer levels concomitant with high levels of fibrin degradation products and low antithrombin activity render COVID-19 patients to be at risk of hypercoagulability and thrombotic complications. 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. Blood group A and males are more likely to become infected. Infection by SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) can be associated with serious and life-threatening conditions, including acute respiratory distress syndrome (ARDS). government site. doi:10.1016/S0140-6736(20)30183-5 Opinion. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19, Dexamethasone in Hospitalized Patients with Covid-19, SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19, Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine, Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Drug treatments for covid-19: living systematic review and network meta-analysis. Intravenous and oral N -acetylcysteine may prevent contrast-medium-induced nephropathy with a dose-dependent effect in patients treated with primary angioplasty and may improve hospital outcome . 2023 Apr;31(2):573-583. doi: 10.1007/s10787-023-01183-3. The study is scheduled to complete in August 2021. MeSH and transmitted securely. 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. Possible uses range from improving athletic performance to managing blood sugar levels and treating chronic lung. Only mild adverse events occurred in two CMCS-treated patients. Patients treated with N-acetylcysteine had significantly shorter length of stay in the ICU, reduced time to hospital discharge, and a higher rate of complete recovery.69 A clinical case study revealed that combination therapy of oseltamivir and N-acetylcysteine improved clinical outcomes in a woman with H1N1 influenza pneumonia, with clearance of pulmonary infiltrates, decreased requirement for oxygen supplementation, and lower plasma level of C-reactive protein.70, Nonetheless, the majority of human studies utilizing N-acetylcysteine in COVID-19 infection have been small in scale, non-randomized, and lack appropriate comparison groups (Table 1).
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