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A metabolomic analysis of thiol response for standard and modified N-acetyl cysteine treatment regimens in patients with acetaminophen overdose.
Dear, JW, Ng, ML, Bateman, DN, Leroy Sivappiragasam, P, Choi, H, Khoo, BBJ, Ibrahim, B, Drum, CL
Clinical and translational science. 2021;(4):1476-1489
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Abstract
N-acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol-APAP)-induced acute liver injury (ALI). The 3-bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post-start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post-infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP-metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP-metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP-induced ALI.
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Adjunct N-Acetylcysteine Treatment in Hospitalized Patients With HIV-Associated Tuberculosis Dampens the Oxidative Stress in Peripheral Blood: Results From the RIPENACTB Study Trial.
Safe, IP, Amaral, EP, Araújo-Pereira, M, Lacerda, MVG, Printes, VS, Souza, AB, Beraldi-Magalhães, F, Monteiro, WM, Sampaio, VS, Barreto-Duarte, B, et al
Frontiers in immunology. 2020;:602589
Abstract
Tuberculosis (TB) still causes significant morbidity and mortality worldwide, especially in persons living with human immunodeficiency virus (HIV). This disease is hallmarked by persistent oxidative stress and systemic inflammation. N-acetylcysteine (NAC), a glutathione (GSH) precursor, has been shown in experimental models to limit Mycobacterium tuberculosis infection and disease both by suppression of the host oxidative response and through direct antimicrobial activity. In a recent phase II randomized clinical trial (RIPENACTB study), use of NAC as adjunct therapy during the first two months of anti-TB treatment was safe. Whether adjunct NAC therapy of patients with TB-HIV coinfection in the context of anti-TB treatment could directly affect pro-oxidation and systemic inflammation has not been yet formally demonstrated. To test this hypothesis, we leveraged existing data and biospecimens from the RIPENACTB trial to measure a number of surrogate markers of oxidative stress and of immune activation in peripheral blood of the participants at pre-treatment and at the day 60 of anti-TB treatment. Upon initiation of therapy, we found that the group of patients undertaking NAC exhibited significant increase in GSH levels and in total antioxidant status while displaying substantial reduction in lipid peroxidation compared to the control group. Only small changes in plasma concentrations of cytokines were noted. Pharmacological improvement of the host antioxidant status appears to be a reasonable strategy to reduce TB-associated immunopathology.
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Effect of single dose N-acetylcysteine administration on resting state functional connectivity in schizophrenia.
McQueen, G, Lay, A, Lally, J, Gabay, AS, Collier, T, Lythgoe, DJ, Barker, GJ, Stone, JM, McGuire, P, MacCabe, JH, et al
Psychopharmacology. 2020;(2):443-451
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Abstract
RATIONALE There is interest in employing N-acetylcysteine (NAC) in the treatment of schizophrenia, but investigations of the functional signatures of its pharmacological action are scarce. OBJECTIVES The aim of this study was to identify the changes in resting-state functional connectivity (rs-FC) that occur following administration of a single dose of NAC in patients with schizophrenia. A secondary aim was to examine whether differences in rs-FC between conditions were mediated by glutamate metabolites in the anterior cingulate cortex (ACC). METHODS In a double-blind, placebo-controlled crossover design, 20 patients with schizophrenia had two MRI scans administered 7 days apart, following oral administration of either 2400 mg NAC or placebo. Resting state functional fMRI (rsfMRI) assessed the effect of NAC on rs-FC within the default mode network (DMN) and the salience network (SN). Proton magnetic resonance spectroscopy was used to measure Glx/Cr (glutamate plus glutamine, in ratio to creatine) levels in the ACC during the same scanning sessions. RESULTS Compared to the placebo condition, the NAC condition was associated with reduced within the DMN and SN, specifically between the medial pre-frontal cortex to mid frontal gyrus, and ACC to frontal pole (all p < 0.04). There were no significant correlations between ACC Glx/Cr and rs-FC in either condition (p > 0.6). CONCLUSIONS These findings provide preliminary evidence that NAC can reduce medial frontal rs-FC in schizophrenia. Future studies assessing the effects of NAC on rs-FC in early psychosis and on repeated administration in relation to efficacy would be of interest.
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Prophylactic oral NAC reduced poor hematopoietic reconstitution by improving endothelial cells after haploidentical transplantation.
Kong, Y, Wang, Y, Zhang, YY, Shi, MM, Mo, XD, Sun, YQ, Chang, YJ, Xu, LP, Zhang, XH, Liu, KY, et al
Blood advances. 2019;(8):1303-1317
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Abstract
Poor graft function (PGF) and prolonged isolated thrombocytopenia (PT) remain life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Endothelial cells (ECs) play a crucial role in regulating hematopoiesis in the bone marrow (BM) microenvironment. However, whether the impaired BM ECs are responsible for defective hematopoiesis in PGF and PT patients requires clarification, and clinical management is challenging. Two prospective clinical trials were included in the current study. In the first trial (N = 68), PGF and PT patients demonstrated defective BM ECs pre-HSCT and impaired BM EC dynamic reconstitution at early time points post-HSCT, which was positively correlated with reactive oxygen species (ROS) levels. Receiver operating characteristic curves showed that BM EC < 0.1% pre-HSCT could identify high-risk patients with PGF and PT. The second trial enrolled patients (N = 35) with EC < 0.1% who accepted oral N-acetyl-l-cysteine (NAC; 400 mg 3 times per day) from -14 days pre-HSCT to +2 months post-HSCT continuously, whereas the remaining EC ≥ 0.1% patients (N = 39) received allo-HSCT only. Prophylactic NAC intervention was safe and effective in preventing the occurrence of PGF and PT in EC < 0.1% patients by promoting the dynamic reconstitution of BM ECs and CD34+ cells, along with reducing their ROS levels, which was further confirmed by in situ BM trephine biopsy analyses. These findings suggest that the impaired BM ECs pre-HSCT are responsible for the defective hematopoiesis in PGF and PT patients. Therefore, improvement of BM ECs through prophylactic NAC intervention may be a promising therapeutic approach to promote hematopoietic reconstitution post-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT03236220 and #NCT02978274.
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Principal results of a randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with a 12 h regimen of N-acetylcysteine for paracetamol overdose (POP trial).
Morrison, EE, Oatey, K, Gallagher, B, Grahamslaw, J, O'Brien, R, Black, P, Oosthuyzen, W, Lee, RJ, Weir, CJ, Henriksen, D, et al
EBioMedicine. 2019;:423-430
Abstract
BACKGROUND The POP Trial was a phase 1, open-label, rising-dose, randomised study that explored the safety and tolerability of calmangafodipir (superoxide dismutase mimetic) co-treatment with n-acetylcysteine (NAC) for paracetamol overdose. METHODS Patients were recruited at the Royal Infirmary of Edinburgh (8th June 2017-10th May 2018). Inclusion criterion: adults within 24 h of a paracetamol overdose that required NAC. Within each of 3 sequential cohorts, participants were randomly assigned, with concealed allocation, to NAC and a single intravenous calmangafodipir dose (n = 6) or NAC alone (n = 2). Calmangafodipir doses were 2, 5, or 10 μmol/kg. Participants, study and clinical teams were not blinded. The primary outcome was safety and tolerability. Secondary outcomes were alanine transaminase (ALT), international normalised ratio (INR), keratin-18, caspase-cleaved keratin-18 (ccK18), microRNA-122, and glutamate dehydrogenase (GLDH). (Clinicaltrials.gov:NCT03177395). FINDINGS All 24 participants received their allocated drug doses and were analysed. Primary endpoints: all participants experienced ≥1 adverse event (AE), most commonly gastrointestinal. Patients experiencing ≥1 serious adverse event (SAE): NAC alone, 2/6; NAC + calmangafodipir (2 μmol/kg), 4/6; NAC + calmangafodipir (5 μmol/kg), 2/6; NAC + calmangafodipir (10 μmol/kg), 3/6. No AEs or SAEs were probably or definitely calmangafodipir-related. Secondary safety outcomes demonstrated no differences between groups. With NAC alone, 2/6 had ALT > 100 U/L; with NAC + calmangafodipir, 0/18. No INR difference. Keratin-18 and ccK18 increased in the NAC alone group more than with calmangafodipir (baseline to 20 h fold change, NAC + calmangafodipir (5 μmol/kg) compared to NAC alone: 0.48 (95%CI 0.28-0.83)). microRNA-122 changes were similar to K18, GLDH was frequently undetected. INTERPRETATION Calmangafodipir was tolerated when combined with NAC and may reduce biomarkers of paracetamol toxicity.
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N-acetyl-L-cysteine improves mesenchymal stem cell function in prolonged isolated thrombocytopenia post-allotransplant.
Kong, Y, Song, Y, Tang, FF, Zhao, HY, Chen, YH, Han, W, Yan, CH, Wang, Y, Zhang, XH, Xu, LP, et al
British journal of haematology. 2018;(6):863-878
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Abstract
Prolonged isolated thrombocytopenia (PT) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Murine studies and in vitro experiments suggest that mesenchymal stem cells (MSCs) can, not only to support haematopoiesis, but also preferentially support megakaryocytopoiesis in bone marrow (BM). However, little is known about the quantity and function of BM MSCs in PT patients. In a case-control study, we found that BM MSCs from PT patients exhibited significantly reduced proliferative capacities, increased reactive oxygen species and senescence. Antioxidant (N-acetyl-L-cysteine, NAC) treatment in vitro not only quantitatively and functionally improved BM MSCs derived from PT patients through down-regulation of the p38 (also termed MAPK14) and p53 (also termed TP53) pathways but also partially rescued the impaired ability of BM MSCs to support megakaryocytopoiesis. Subsequently, a pilot study showed that the overall response of NAC treatment was obtained in 7 of the enrolled PT patients (N = 10) without significant side effects. Taken together, the results indicated that dysfunctional BM MSCs played a role in the pathogenesis of PT and the impaired BM MSCs could be improved by NAC in vitro. Although requiring further validation, our data indicate that NAC might be a potential therapeutic approach for PT patients after allo-HSCT.
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N-Acetylcysteine rapidly replenishes central nervous system glutathione measured via magnetic resonance spectroscopy in human neonates with hypoxic-ischemic encephalopathy.
Moss, HG, Brown, TR, Wiest, DB, Jenkins, DD
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2018;(6):950-958
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Abstract
Persistent oxidative stress depletes reduced glutathione (GSH), an intracellular antioxidant and an important determinant of CNS injury after hypoxia ischemia. We used standard, short echo time Stimulated Echo Acquisition Mode (STEAM) to detect GSH by magnetic resonance spectroscopy (MRS) in 24 term neonates with hypoxic-ischemic encephalopathy (HIE), on day of life 5-6, after rewarming from therapeutic hypothermia. MRS demonstrated reliable, consistent GSH of 1·64 ± 0·20 mM in the basal ganglia immediately before intravenous infusion of N-acetylcysteine. N-acetylcysteine resulted in a rapid and significant GSH increase to 1·93 ± 0.23 mM within 12-30 min after completion of infusion ( n = 21, p < 0.0001, paired t-test), compared with those who did not receive N-acetylcysteine ( n = 3, GSH = 1.66 ± 0.06 mM and 1.64 ± 0.09 mM). In one perinatal stroke patient, GSH in the diffusion-restricted stroke area was 1.0 mM, indicating significant compromise of intracellular redox potential, which also improved after N-acetylcysteine. For comparison, GSH in healthy term neonates has been reported at 2.5 ± 0.9 mM in the thalamus. This is the first report to show persistent oxidative stress reflected in GSH during the subacute phase in neonates with HIE and rapid response to N-acetylcysteine, using a short echo MRS sequence that is available on all clinical scanners without spectral editing.
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Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury.
Hagos, FT, Empey, PE, Wang, P, Ma, X, Poloyac, SM, Bayir, H, Kochanek, PM, Bell, MJ, Clark, RSB
Critical care medicine. 2018;(9):1471-1479
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OBJECTIVES To employ metabolomics-based pathway and network analyses to evaluate the cerebrospinal fluid metabolome after severe traumatic brain injury in children and the capacity of combination therapy with probenecid and N-acetylcysteine to impact glutathione-related and other pathways and networks, relative to placebo treatment. DESIGN Analysis of cerebrospinal fluid obtained from children enrolled in an Institutional Review Board-approved, randomized, placebo-controlled trial of a combination of probenecid and N-acetylcysteine after severe traumatic brain injury (Trial Registration NCT01322009). SETTING Thirty-six-bed PICU in a university-affiliated children's hospital. PATIENTS AND SUBJECTS Twelve children 2-18 years old after severe traumatic brain injury and five age-matched control subjects. INTERVENTION Probenecid (25 mg/kg) and N-acetylcysteine (140 mg/kg) or placebo administered via naso/orogastric tube. MEASUREMENTS AND MAIN RESULTS The cerebrospinal fluid metabolome was analyzed in samples from traumatic brain injury patients 24 hours after the first dose of drugs or placebo and control subjects. Feature detection, retention time, alignment, annotation, and principal component analysis and statistical analysis were conducted using XCMS-online. The software "mummichog" was used for pathway and network analyses. A two-component principal component analysis revealed clustering of each of the groups, with distinct metabolomics signatures. Several novel pathways with plausible mechanistic involvement in traumatic brain injury were identified. A combination of metabolomics and pathway/network analyses showed that seven glutathione-centered pathways and two networks were enriched in the cerebrospinal fluid of traumatic brain injury patients treated with probenecid and N-acetylcysteine versus placebo-treated patients. Several additional pathways/networks consisting of components that are known substrates of probenecid-inhibitable transporters were also identified, providing additional mechanistic validation. CONCLUSIONS This proof-of-concept neuropharmacometabolomics assessment reveals alterations in known and previously unidentified metabolic pathways and supports therapeutic target engagement of the combination of probenecid and N-acetylcysteine treatment after severe traumatic brain injury in children.
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The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis.
Teskey, G, Cao, R, Islamoglu, H, Medina, A, Prasad, C, Prasad, R, Sathananthan, A, Fraix, M, Subbian, S, Zhong, L, et al
Frontiers in immunology. 2018;:2069
Abstract
Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.
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N-acetylcysteine (NAC) in schizophrenia resistant to clozapine: a double blind randomised placebo controlled trial targeting negative symptoms.
Rossell, SL, Francis, PS, Galletly, C, Harris, A, Siskind, D, Berk, M, Bozaoglu, K, Dark, F, Dean, O, Liu, D, et al
BMC psychiatry. 2016;(1):320
Abstract
BACKGROUND Clozapine is an effective treatment for a proportion of people with schizophrenia (SZ) who are resistant to the beneficial effects of other antipsychotic drugs. However, anything from 40-60 % of people on clozapine experience residual symptoms even on adequate doses of the medication, and thus could be considered 'clozapine resistant'. Agents that could work alongside clozapine to improve efficacy whilst not increasing the adverse effect burden are both desired and necessary to improve the lives of individuals with clozapine-resistant SZ. N-Acetylcysteine (NAC) is one such possible agent. Previous research from our research group provided promising pilot data suggesting the efficacy of NAC in this patient population. The aim of the study reported here is to expand this work by conducting a large scale clinical trial of NAC in the treatment of clozapine-resistant SZ. METHODS This study is an investigator initiated, multi-site, randomised, placebo-controlled trial. It aims to include 168 patients with clozapine-resistant SZ, divided into an intervention group (NAC) and a control group (placebo). Participants in the intervention group will receive 2 g daily of NAC. The primary outcome measures will be the negative symptom scores of the Positive and Negative Syndrome Scale (PANSS). Secondary outcome measures will include: changes in quality of life (QoL) as measured by the Lancashire Quality of Life Profile (LQoLP) and cognitive functioning as measured by the total score on the MATRICS. Additionally we will examine peripheral and cortical glutathione (GSH) concentrations as process outcomes. DISCUSSION This large scale clinical trial will investigate the efficacy of NAC as an adjunctive medication to clozapine. This trial, if successful, will establish a cheap, safe and easy-to-use agent (NAC) as a 'go to' adjunct in patients that are only partly responsive to clozapine. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registration Number: Current Randomised Controlled Trial ACTRN12615001273572 . The date of registration 23 November 2015.