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Therapeutic potential of N-acetyl cysteine (NAC) in preventing cytokine storm in COVID-19: review of current evidence.
Mohanty, RR, Padhy, BM, Das, S, Meher, BR
European review for medical and pharmacological sciences. 2021;(6):2802-2807
Abstract
Since November 2019, SARS Coronavirus 2 disease (COVID-19) pandemic has spread through more than 195 nations worldwide. Though the coronavirus infection affects all age and sex groups, the mortality is skewed towards the elderly population and the cause of death is mostly acute respiratory distress syndrome (ARDS). There are data suggesting the role of excessive immune activation and cytokine storm as the cause of lung injury in COVID-19. The excessive immune activation and cytokine storm usually occurs due to an imbalance in redox homeostasis of the individuals. Considering the antioxidant and free radical scavenging action of N acetyl cysteine (NAC), its use might be useful in COVID-19 patients by decreasing the cytokine storm consequently decreasing the disease severity. Therefore, we reviewed all the available resources pertaining to the role of reactive oxygen species (ROS) in cytokine storm and the mechanism of action of NAC in preventing ROS. We also reviewed the use of NAC in COVID-19.
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Rationale for the use of N-acetylcysteine in both prevention and adjuvant therapy of COVID-19.
De Flora, S, Balansky, R, La Maestra, S
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020;(10):13185-13193
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Abstract
COVID-19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID-19 patients. N- Acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH). Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. At very high doses, NAC is also used as an antidote against paracetamol intoxication. Thiols block the angiotensin-converting enzyme 2 thereby hampering penetration of SARS-CoV-2 into cells. Based on a broad range of antioxidant and anti-inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID-19, as it was previously demonstrated for influenza and influenza-like illnesses. Moreover, high-dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID-19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.
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Mercapturate Pathway in the Tubulocentric Perspective of Diabetic Kidney Disease.
Gonçalves-Dias, C, Morello, J, Correia, MJ, Coelho, NR, Antunes, AMM, Macedo, MP, Monteiro, EC, Soto, K, Pereira, SA
Nephron. 2019;(1):17-23
Abstract
BACKGROUND The recent growing evidence that the proximal tubule underlies the early pathogenesis of diabetic kidney disease (DKD) is unveiling novel and promising perspectives. This pathophysiological concept links tubulointerstitial oxidative stress, inflammation, hypoxia, and fibrosis with the progression of DKD. In this new angle for DKD, the prevailing molecular mechanisms on proximal tubular cells emerge as an innovative opportunity for prevention and management of DKD as well as to improve diabetic dysmetabolism. SUMMARY The mercapturate pathway (MAP) is a classical metabolic detoxification route for xenobiotics that is emerging as an integrative circuitry detrimental to resolve tubular inflammation caused by endogenous electrophilic species. Herein we review why and how it might underlie DKD. Key Messages: MAP is a hallmark of proximal tubular cell function, and cysteine-S-conjugates might represent targets for early intervention in DKD. Moreover, the biomonitoring of urinary mercapturates from metabolic inflammation products might be relevant for the implementation of preventive/management strategies in DKD.
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Mechanisms of acetaminophen-induced liver injury and its implications for therapeutic interventions.
Yan, M, Huo, Y, Yin, S, Hu, H
Redox biology. 2018;:274-283
Abstract
Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure in many developed countries. Mitochondrial oxidative stress is considered to be the predominant cellular event in APAP-induced liver injury. Accordingly, N-acetyl cysteine, a known scavenger of reactive oxygen species (ROS), is recommended as an effective clinical antidote against APAP-induced acute liver injury (AILI) when it is given at an early phase; however, the narrow therapeutic window limits its use. Hence, the development of novel therapeutic approaches that can offer broadly protective effects against AILI is clearly needed. To this end, it is necessary to better understand the mechanisms of APAP hepatotoxicity. Up to now, in addition to mitochondrial oxidative stress, many other cellular processes, including phase I/phase II metabolism, endoplasmic reticulum stress, autophagy, sterile inflammation, microcirculatory dysfunction, and liver regeneration, have been identified to be involved in the pathogenesis of AILI, providing new targets for developing more effective therapeutic interventions against APAP-induced liver injury. In this review, we summarize intracellular and extracellular events involved in APAP hepatotoxicity, along with emphatic discussions on the possible therapeutic approaches targeting these different cellular events.
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N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review.
Chughlay, MF, Kramer, N, Spearman, CW, Werfalli, M, Cohen, K
British journal of clinical pharmacology. 2016;(6):1021-9
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AIMS: N-acetylcysteine (NAC) may be useful in the management of non-paracetamol drug-induced liver injury (DILI). Our objective was to review systematically evidence for the use of NAC as a therapeutic option for non-paracetamol DILI. METHODS We searched for randomized controlled trials (RCTs) and prospective cohort studies. We searched several bibliographic databases, grey literature sources, conference proceedings and ongoing trials. Our pre-specified primary outcomes were all cause and DILI related mortality, time to normalization of liver biochemistry and adverse events. Secondary outcomes were proportion receiving liver transplant, time to transplantation, transplant-free survival and hospitalization duration. RESULTS We identified one RCT of NAC vs. placebo in patients with non-paracetamol acute liver failure. There was no difference in the primary outcomes of overall survival at 3 weeks between NAC [70%, 95% confidence interval (CI) = 60%, 81%, n = 81] and placebo (66%, 95% CI = 56%, 77%, n = 92). NAC significantly improved the secondary outcomes of transplant-free survival compared with placebo: 40% NAC (95% CI = 28%, 51%) vs. 27% placebo (95% CI = 18%, 37%). A subgroup analysis according to aetiology found improved transplant-free survival in patients with non-paracetamol DILI, NAC (58%, n = 19) vs. placebo (27%, n = 26), odds ratio (OR) 0.27 (95% CI = 0.076, 0.942). Overall survival was similar, NAC (79%) vs. placebo (65%);, OR 0.50 (95% CI = 0.13, 1.98). CONCLUSION Current available evidence is limited and does not allow for any firm conclusions to be made regarding the role of NAC in non-paracetamol DILI. We therefore highlight the need for further research in this area.
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Treatment of Severe Alcoholic Hepatitis.
Thursz, M, Morgan, TR
Gastroenterology. 2016;(8):1823-34
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Abstract
Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.
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Efficacy of N-Acetylcysteine in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.
Sun, T, Liu, J, Zhao, W
Medicine. 2016;(19):e3629
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Abstract
There are a number of conflicting reports describing the clinical outcomes of using N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis. We have, therefore, performed a meta-analysis to evaluate the efficacy of N-acetylcysteine, compared with control, for the treatment of idiopathic pulmonary fibrosis.Original controlled clinical trials evaluating the efficacy of N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis were included in the analysis. Searches for relevant articles were carried out in July 2014 by 2 independent researchers using PubMed, Embase, Cochrane Central, and Google Scholar. Change in forced vital capacity, change in percentage of predicted vital capacity, change in percentage of predicted carbon monoxide diffusing capacity, changes in 6 minutes walking test distance, rate of adverse events, and rate of death were expressed as outcomes using RevMan 5.0.1.Five trials, with a total of 564 patients, were included in this meta-analysis. The meta-analysis showed that the control group had significant decreases in percentage of predicted vital capacity (standardized mean difference [SMD] = 0.37; 95% confidence interval [CI]: 0.13 to -0.62; P = 0.003) and 6 minutes walking test distance (SMD = 0.25; 95% CI: 0.02-0.48; P = 0.04). There were no statistically significant differences in forced vital capacity (SMD = 0.07; 95% CI: -0.13-0.27; P = 0.52), percentage of predicted carbon monoxide diffusing capacity (SMD = 0.12; 95% CI: -0.06-0.30; P = 0.18), rates of adverse events (odd ratio = 4.50; 95% CI: 0.19-106.41; P = 0.35), or death rates (odd ratio = 1.79; 95% CI: 0.3-5.12; P = 0.28) between the N-acetylcysteine group and the control group.N-Acetylcysteine was found to have a significant effect only on decreases in percentage of predicted vital capacity and 6 minutes walking test distance. N-acetylcysteine showed no beneficial effect on changes in forced vital capacity, changes in predicted carbon monoxide diffusing capacity, rates of adverse events, or death rates.
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Treatment of Cannabis Use Disorder: Current Science and Future Outlook.
Sherman, BJ, McRae-Clark, AL
Pharmacotherapy. 2016;(5):511-35
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Cannabis is the most commonly used illicit substance in the United States. Rates of cannabis use and cannabis use disorder (CUD) have increased in the past decade, paralleling changes in the legal and political climate favoring legalization. Almost 20 million people 12 years or older report past-month cannabis use, and 8 million report daily or near-daily use. Concurrently, the perception that cannabis use poses a significant risk of negative consequences has decreased. Contrary to this perception, heavy cannabis use is associated with cognitive impairment, increased risk for psychotic disorders and other mental health problems, lower education attainment, and unemployment. Clinical trials of various treatments for CUD have likewise increased, focusing primarily on psychotherapy treatments, specifically motivational enhancement therapy, cognitive behavioral therapy, and contingency management. Their findings suggest that a combination of these three modalities produces the best abstinence outcomes, although abstinence rates remain modest and decline after treatment. More recently, pharmacotherapy trials have been conducted as adjunctive interventions to psychosocial treatment. N-acetylcysteine and gabapentin are two of the most promising medications, although no pharmacologic treatment has emerged as clearly efficacious. In this review, we provide a detailed summary of clinical trials that evaluated psychotherapy and pharmacotherapy for treating CUD and discuss emerging areas of clinical research and cannabis-specific barriers to treatment.
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Efficacy of N-acetylcysteine in preventing atrial fibrillation after cardiac surgery: a meta-analysis of published randomized controlled trials.
Liu, XH, Xu, CY, Fan, GH
BMC cardiovascular disorders. 2014;:52
Abstract
BACKGROUND Atrial fibrillation is a common complication after cardiac surgery. The aim of this study is to evaluate whether N-acetylcysteine (NAC) could prevent postoperative atrial fibrillation (POAF). METHODS PubMed, Embase and Cochrane Center Register of Controlled Trials were searched from the date of their inception to 1 July 2013 for relevant randomized controlled trials (RCTs), in which NAC was compared with controls for adult patients undergoing cardiac surgery. Outcome measures comprised the incidence of POAF, all-cause mortality, length of intensive care unit (ICU) stay, hospital length of stay, and the incidence of cerebrovascular events. The meta-analysis was performed with the fixed-effect model or random-effect model according to the heterogeneity. RESULTS We retrieved ten studies enrolling a total of 1026 patients. Prophylactic NAC reduced the incidence of POAF (OR 0.56; 95% CI 0.40 to 0.77; P < 0.001) and all-cause mortality (OR 0.40; 95% CI 0.17 to 0.93; P = 0.03) compared with controls, but failed to reduce the stay in ICU and overall stay in hospital. No difference in the incidence of cerebrovascular events was observed. CONCLUSIONS Prophylactic use of NAC could reduce the incidence of POAF and all-cause mortality in adult patients undergoing cardiac surgery. However, larger RCTs evaluating these and other postoperative complication endpoints are needed.
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Systematic review of N-acetylcysteine in the treatment of addictions.
Asevedo, E, Mendes, AC, Berk, M, Brietzke, E
Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999). 2014;(2):168-75
Abstract
OBJECTIVE To conduct the first systematic literature review of clinical trials of N-acetylcysteine (NAC) for the treatment of substance abuse disorders and addictive behaviors. METHODS A search of the MEDLINE, Embase and PsycINFO databases was conducted. The inclusion criteria for the review were clinical trials that used NAC in the treatment of a disorder related to substance use and/or addictive behaviors, limited to texts in English, Spanish, or French. The selected studies were evaluated with respect to type of trial, sample size, diagnostic input, intervention, length of follow-up, outcome variables, and results. RESULTS Nine studies analyzing a total of 165 patients met the eligibility criteria and were included in qualitative analysis. These studies evaluated the role of NAC in cocaine dependence (three studies), cannabis dependence (two studies), nicotine dependence (two studies), methamphetamine addiction (one study), and pathological gambling (one study). Five of these trials were double-blind, randomized, and placebo-controlled. CONCLUSIONS The studies analyzed suggest a potential role for NAC in the treatment of addiction, especially of cocaine and cannabis dependence. These results are concordant with the hypothesis of the involvement of glutamatergic pathways in the pathophysiology of addiction.