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Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC's impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Evidence for the treatment of patients with mild-to-moderate chronic obstructive pulmonary disease (COPD) is limited. The efficacy of N-acetylcysteine (an antioxidant and mucolytic agent) for patients with mild-to-moderate COPD is uncertain. In this multicentre, randomised, double-blind, placebo-controlled trial, we randomly assigned 968 patients with mild-to-moderate COPD to treatment with N-acetylcysteine (600 mg, twice daily) or matched placebo for two years. Eligible participants were 40-80 years of age and had mild-to-moderate COPD (forced expiratory volume in 1 second [FEV 1 ] to forced vital capacity ratio <0.70 and an FEV 1  ≥ 50% predicted value after bronchodilator use). The coprimary outcomes were the annual rate of total exacerbations and the between-group difference in the change from baseline to 24 months in FEV 1 before bronchodilator use. COPD exacerbation was defined as the appearance or worsening of at least two major symptoms (cough, expectoration, purulent sputum, wheezing, or dyspnoea) persisting for at least 48 hours. Assessment of exacerbations was conducted every three months, and lung function was performed annually after enrolment. The difference between the N-acetylcysteine group and the placebo group in the annual rate of total exacerbation were not significant (0.65 vs. 0.72 per patient-year; relative risk [RR], 0.90; 95% confidence interval [CI], 0.80–1.02; P  = 0.10). There was no significant difference in FEV 1 before bronchodilator use at 24 months. Long-term treatment with high-dose N-acetylcysteine neither significantly reduced the annual rate of total exacerbations nor improved lung function in patients with mild-to-moderate COPD. Chinese Clinical Trial Registration: ChiCTR-IIR-17012604. Evidence for the treatment of patients with mild-to-moderate COPD is limited. Here, the authors show that long-term treatment with high-dose N-acetylcysteine neither significantly reduced the annual rate of total exacerbations nor improve lung function in patients with mild-tomoderate COPD.

Cannabis use disorder is particularly prevalent and impairing among young people, and evidence-based treatments are limited. Prior trials of N-acetylcysteine, added to contingency management as a platform behavioral intervention, yielded positive findings in youth but not in adults. This trial sought to rigorously evaluate whether N-acetylcysteine is efficacious in youth when not paired with a robust behavioral treatment platform. Treatment-seeking youth with cannabis use disorder ( N  = 192, ages 14–21) were randomized to receive a double-blind 12-week course of oral N-acetylcysteine 1200 mg or placebo twice daily; all received weekly medical management and brief behavioral counseling. The primary efficacy outcome was the proportion of negative urine cannabinoid tests during treatment, compared between groups. An array of self-report and urine testing measures were examined secondarily to assess cannabis use reduction and cessation outcomes. The N-acetylcysteine and placebo groups did not differ in proportion of negative urine cannabinoid tests (RR = 0.93, 95% CI = 0.53, 1.64; p  = 0.80) or self-reported cannabis abstinence (RR = 1.02, 95% CI = 0.63, 1.65; p  = 0.93) during treatment. The mean percentage of cannabis use days and grams of cannabis used per using day decreased over time during treatment but did not differ between groups. More N-acetylcysteine than placebo treated participants reported gastrointestinal adverse events (63/98 versus 37/94, χ 2 1  = 11.9 p  < 0.001); adverse events were otherwise similar between groups. Findings indicate that N-acetylcysteine is not efficacious for youth cannabis use disorder when not paired with contingency management, highlighting the potentially crucial role of a robust behavioral treatment platform in facilitating prior positive efficacy findings with N-acetylcysteine. Trial Registration: Clinicaltrials.gov identifier NCT03055377

Paracetamol poisoning is common worldwide. It is treated with intravenous acetylcysteine, but the standard regimen is complex and associated with frequent adverse effects related to concentration, which can cause treatment interruption. We aimed to ascertain whether adverse effects could be reduced with either a shorter modified acetylcysteine schedule, antiemetic pretreatment, or both. We undertook a double-blind, randomised factorial study at three UK hospitals, between Sept 6, 2010, and Dec 31, 2012. We randomly allocated patients with acute paracetamol overdose to either the standard intravenous acetylcysteine regimen (duration 20·25 h) or a shorter (12 h) modified protocol, with or without intravenous ondansetron pretreatment (4 mg). Masking was achieved by infusion of 5% dextrose (during acetylcysteine delivery) or saline (for antiemetic pretreatment). Randomisation was done via the internet and included a minimisation procedure by prognostic factors. The primary outcome was absence of vomiting, retching, or need for rescue antiemetic treatment at 2 h. Prespecified secondary outcomes included a greater than 50% increase in alanine aminotransferase activity over the admission value. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov (identifier NCT01050270). Of 222 patients who underwent randomisation, 217 were assessable 2 h after the start of acetylcysteine treatment. Vomiting, retching, or need for rescue antiemetic treatment at 2 h was reported in 39 of 108 patients assigned to the shorter modified protocol compared with 71 of 109 allocated to the standard acetylcysteine regimen (adjusted odds ratio 0·26, 97·5% CI 0·13–0·52; p<0·0001), and in 45 of 109 patients who received ondansetron compared with 65 of 108 allocated placebo (0·41, 0·20–0·80; p=0·003). Severe anaphylactoid reactions were recorded in five patients assigned to the shorter modified acetylcysteine regimen versus 31 who were allocated to the standard protocol (adjusted common odds ratio 0·23, 97·5% CI 0·12–0·43; p<0·0001). The proportion of patients with a 50% increase in alanine aminotransferase activity did not differ between the standard (13/101) and shorter modified (9/100) regimens (adjusted odds ratio 0·60, 97·5% CI 0·20–1·83); however, the proportion was higher with ondansetron (16/100) than with placebo (6/101; 3·30, 1·01–10·72; p=0·024). In patients with paracetamol poisoning, a 12 h modified acetylcysteine regimen resulted in less vomiting, fewer anaphylactoid reactions, and reduced need for treatment interruption. This study was not powered to detect non-inferiority of the shorter protocol versus the standard approach; therefore, further research is needed to confirm the efficacy of the 12 h modified acetylcysteine regimen. Chief Scientist Office of the Scottish Government.

N-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates (i) alcohol cue-elicited activation, and (ii) intrinsic functional connectivity compared to placebo in patients with AUD. In this preliminary study, twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day, n  = 9), or a placebo ( n  = 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 377 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by-time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC-treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. However, the absence of cue reactivity findings may result from low power, rather than the absence of cue reactivity findings associated with NAC. These results provide preliminary evidence that NAC treatment may modulate intrinsic functional connectivity brain activation in patients with alcohol use disorder, but replication in larger studies are required to determine the strength of this effect and any associations with clinical outcomes. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT03879759.

Cognitive deficits are predictors of functional outcome in patients with psychosis. While conventional antipsychotics are relatively effective on positive symptoms, their impact on negative and cognitive symptoms is limited. Recent studies have established a link between oxidative stress and neurocognitive deficits in psychosis. N-acetylcysteine (NAC), a glutathione precursor with glutamatergic properties, has shown efficacy on negative symptoms and functioning in patients with schizophrenia and bipolar disorder, respectively. However, there are few evidence-based approaches for managing cognitive impairment in psychosis. The present study aims to examine the cognitive effects of adjunctive NAC treatment in a pooled subgroup of participants with psychosis who completed neuropsychological assessment in two trials of both schizophrenia and bipolar disorder. A sample of 58 participants were randomized in a double fashion to receive 2 g/day of NAC (n = 27) or placebo (n = 31) for 24 weeks. Attention, working memory and executive function domains were assessed. Differences between cognitive performance at baseline and end point were examined using Wilcoxon's test. The Mann-Whitney test was used to examine the differences between the NAC and placebo groups at the end point. Participants treated with NAC had significantly higher working memory performance at week 24 compared with placebo (U = 98.5, p = 0.027). NAC may have an impact on cognitive performance in psychosis, as a significant improvement in working memory was observed in the NAC-treated group compared with placebo; however, these preliminary data require replication. Glutamatergic compounds such as NAC may constitute a step towards the development of useful therapies for cognitive impairment in psychosis.

Idiopathic pulmonary fibrosis is a progressive disorder characterized by loss of lung function; there is no effective treatment. In this multinational, randomized, placebo-controlled trial with all patients receiving azathioprine and prednisone, acetylcysteine was shown to slow the rate of deterioration of lung function. There was no effect on survival. In patients receiving azathioprine and prednisone, acetylcysteine was shown to slow the rate of deterioration of lung function. There was no effect on survival. Idiopathic pulmonary fibrosis is a chronic progressive interstitial pneumonia with a poor prognosis. 1 – 4 It has been proposed that a pathogenetic mechanism of idiopathic pulmonary fibrosis is repeated lung injury, with aberrant progressive fibrotic reaction. 5 – 9 If this is the case, it may explain why treatment with corticosteroids and immunosuppressive agents results in only slight therapeutic benefit. 3 , 10 – 12 An oxidant–antioxidant imbalance may contribute to the disease process in idiopathic pulmonary fibrosis. 13 – 20 Acetylcysteine, a precursor of the major antioxidant glutathione, given at a daily dose of 1800 mg, has been shown to restore depleted pulmonary glutathione levels 16 – 19 and . . .

•Nonalcoholic steatohepatitis represents a more severe manifestation of nonalcoholic fatty liver disease.•The effectiveness of pharmaceuticals as a single therapy seems restricted.•We assessed the impacts of N-acetyl cysteine and rosuvastatin (RSV) combination against conventional vitamin E in nonalcoholic steatohepatitis.•Patients treated with combination N-acetyl cysteine/RSV exhibited significant safety profile and efficacy.•N-acetyl cysteine/RSV improves liver steatosis and fibrosis, besides metabolic parameters. There is currently no US Food and Drug Administration–approved remedy for nonalcoholic steatohepatitis (NASH). The present study evaluated the efficacy of N-acetyl cysteine (NAC) and rosuvastatin (RSV) compared with conventional vitamin E in patients with NASH. This study was designed as a parallel, double-blinded, randomized controlled trial. Ninety patients who met the eligibility criteria were enrolled in this study. Subsequently, 45 patients were allocated to each group as follows: group 1 reported consistent administration of vitamin E 400 IUⓇ (PHARCO-Pharmaceuticals) twice daily over a duration of 6 months. Group 2 included patients with NASH who received NAC, Gemacysteine 300 mgⓇ (GEMA-Pharma) at 1200 mg twice daily, along with RSV, Crestor 20 mgⓇ (AstraZeneca). To achieve the study’s objective, FibroScanⓇ examination of liver tissue and fibrosis scores, as well as tests for liver aminotransferases, lipid profile, glycemic parameters, and hepatic and renal functions, besides health-related quality of life using the Short-Form 36 were evaluated before and after 6 months of treatment. In group 1, a statistically significant decrease in the mean value of steatosis was observed after 6 months by 6.05% (P = 0.017), whereas treated group 2 exhibited a reduction of 16.49% (P = 0.001). Group 2 reported a statistically significant decrease in the mean fibrosis value of approximately 19.5% (P = 0.001). Fibrosis-4 Index score’s significance stated a reduction in the mean values within treatment group 2, with decreases of 51.70%. MACK-3 score which is a combination of homeostatic model assessment, aspartate aminotransferase, and cytokeratin-18, exhibited a notable reduction in mean values within treatment group 2 by 25.06% (P = 0.001). Concerning biological markers, malondialdehyde, both groups reported significant reductions in mean values of 11.90% (P = 0.006) and 27.43% (P = 0.001), respectively. Group 2 exhibited substantial reductions in mean levels of all biological markers: NOD-like receptor-associated protein 3 inflammasome decreased by 24.40%, tumor necrosis factor-α by 9.64%, tissue inhibitor of metalloproteinases 1 by 10.28%, N-terminal propeptide of procollagen type III by 14.58%, cytokeratin-18 by 23.44%, and fibroblast growth factor-21 by 15.08% (P < 0.05), whereas group 1 did not demonstrate significant differences. Group 2 has substantial improvement in various metabolic parameters and health-related quality of life with accepted safety profile parameters. Patients in group 2 treated with the combination of NAC/RSV exhibited tolerability and efficacy in improving liver steatosis and fibrosis, besides metabolic parameters, indicating a new combination approach to the management of NASH. ClinicalTrials.gov identifier: NCT06105060.

Background Promoting the absorption of COVID-19 pneumonia is critical for reducing pulmonary sequelae and improving prognosis. This study aimed to evaluate the efficacy and safety of nebulized unfractionated heparin, acetylcysteine, budesonide, and ipratropium bromide (HABIT) in hospitalized patients with COVID-19 pneumonia. Methods This single-center, open-label, randomized, parallel-group trial was conducted at a tertiary hospital in China. Participants were randomized 1:1 to receive either standard of care (SOC) or SOC plus nebulized HABIT. The HABIT protocol included daily quadruple nebulization for seven days, comprising 6000 units heparin sodium, 2 mg budesonide, 0.3 g acetylcysteine, and 0.5 mg ipratropium bromide. The primary outcome was the change in lung lesions assessed by chest CT scans on admission (Day 0) and post-treatment (Day 8). Results A total of 74 patients were randomized to the HABIT group ( n  = 37) or the control group ( n  = 37). Four patients per group were excluded during follow-up, leaving 66 patients for final analysis. Baseline CT scores were comparable between groups (10.55 ± 3.11 vs. 10.76 ± 2.85, p  = 0.774). Post-treatment, the HABIT group showed significantly lower mean CT scores (6.6 ± 2.98 vs. 8.69 ± 2.53, p  = 0.003) and greater lesion absorption (37.5% vs. 20%, p  < 0.001) compared to controls. The HABIT group also exhibited a non-significant improvement in PaO 2 /FiO 2 (75.27 vs. 51.23, p  = 0.113). Safety analysis showed no significant differences in activated partial thromboplastin time or serious adverse events. Conclusion The adjunctive HABIT regimen demonstrates favorable efficacy and safety in treating COVID-19 pneumonia. Trial registration The clinical trial was registered with the Chinese Clinical Trial Registry (ChiCTR; www.chictr.org.cn ; ID: ChiCTR2300073871) on July 24, 2023. Ethical approval was valid from May 2023 to May 2025.

IntroductionIn overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. N-Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the UK receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggest that this dose may be insufficient in some patients (particularly those taking a large overdose).Methods and analysisA multicentre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced on 19 February 2024 and is anticipated to run for approximately 2 years. This is a three-group dose-finding trial, in which participants are assigned in a 1:1:1 ratio to either Standard NAC (300 mg/kg) or higher doses of 450 mg/kg (Group 1) and 600 mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant will HiSNAP Group 1 be tested against Standard NAC.Ethics and disseminationThe HiSNAP trial has been approved by the East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development Department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences and linked on isrctn.com.Trial registration number ISRCTN17516192.