Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.

BACKGROUND: Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI). METHODS: Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21. RESULTS: Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p < 0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by > 50% (p < 0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p < 0.05), approximately 20-fold greater platelet adhesion (p < 0.05), and increased staining for markers of platelet transforming growth factor-ß1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology. CONCLUSIONS: Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.

[Nephroprotective value of N-acetylcysteine for patients with concomitant trauma, as well as other aspects of the use of this drug in clinical practice].

An analysis and review of domestic and foreign literature on the role of N-acetylcysteine in the correction of oxidative stress, as well as the problem of oxidative stress, and protection against free radicals are presented in the article. The important role of N-acetylcysteine in replenishing the intracellular glutathione level, which is the main cell antioxidant, has been shown, as well as the potential use of N-acetylcysteine for various pathological conditions and diseases. The relevance of concomitant injury and renal dysfunction, and the experience of the clinical use of N-acetylcysteine as a nephroprotector in patients with concomitant injury in the clinic of the Department of Faculty and Endoscopic Surgery of KBSU named after Kh.M. Berbekov are also described. After reviewing the literature, based on the results of many experimental studies, we can conclude that this pharmacological substance is a very promising for replenishing the intracellular glutathione pool, and it becomes possible to include it in the combined therapy of a number of human diseases.

Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field.

Acetaminophen (APAP), the most frequently used mild analgesic and antipyretic drug worldwide, is implicated in causing 46% of all acute liver failures in the USA and between 40% and 70% in Europe. The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine (NAC); however, its efficacy is limited in cases of advanced liver injury or when administered at a late stage. In the current study, we discovered that treatment with a moderate intensity static magnetic field (SMF) notably reduced the mortality rate in mice subjected to high-dose APAP from 40% to 0%, proving effective at both the initial liver injury stage and the subsequent recovery stage. During the early phase of liver injury, SMF markedly reduced APAP-induced oxidative stress, free radicals, and liver damage, resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione (GSH). During the later stage of liver recovery, application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation. Moreover, the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery, even 24 h post overdose, when the effectiveness of NAC alone substantially declines. Overall, this study provides a non-invasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose. Of note, this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP, and potentially other toxic overdoses.

Update on ischemic hepatitis.

PURPOSE OF REVIEW: Ischemic hepatitis (IH) refers to diffuse liver injury secondary to hypoperfusion. The condition is usually seen in the critical care setting and is associated with significant mortality. IH typically occurs in the setting of systemic hypotension superimposed on some form of underlying cardiac dysfunction. This review aims to report what is known and what is new about the etiology, pathophysiology, and clinical features associated with IH. RECENT FINDINGS: In recent years, studies on IH have largely confirmed earlier reports regarding etiologies, comorbid conditions, and associated mortality. Recent study has also shed light on the potential treatment of IH with N -acetyl-cysteine (NAC). SUMMARY: IH is typically associated with underlying cardiac disease, and patients with IH have a very high mortality rate. Treatment remains largely supportive, although the utility of agents such as NAC are being explored.

Assessing the impact of a new medical toxicology service on the treatment of paracetamol overdose at a large tertiary care hospital.

BACKGROUND: Paracetamol overdose is the most common cause of acute liver failure in the United States. Administration of acetylcysteine is the standard of care for this intoxication. Laboratory values and clinical criteria are used to guide treatment duration, but decision-making is nuanced and often complex and difficult. The purpose of this study was to evaluate the effect of the introduction of a medical toxicology service on the rate of errors in the management of paracetamol overdose. METHODS: This was a single center, retrospective, cohort evaluation. Patients with suspected paracetamol overdose were divided into two groups: those attending in the 1 year period before and those in the 1 year after the introduction of the medical toxicology service. The primary outcome was the frequency of deviations from the established management of paracetamol intoxication, using international guidelines as a reference. RESULTS: Fifty-four patients were eligible for the study (20 pre-toxicology-service, 34 post-toxicology-service). The frequency of incorrect therapeutic decisions was significantly lower in the post-toxicology service implementation versus the pre-implementation group (P = 0.005). DISCUSSION: Our study suggests that a medical toxicology service reduces the incidence of management errors, including the number of missed acetylcysteine doses in patients with paracetamol overdose. The limitations include the retrospective study design and that the study was conducted at a single center, which may limit generalizability. CONCLUSIONS: The implementation of a medical toxicology service was associated with a decrease in the number of errors in the management of paracetamol overdose.

N-acetylcysteine Treatment in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Bronchitis/Pre-COPD: Distinct Meta-analyses.

INTRODUCTION: N-acetylcysteine (NAC) is a mucolytic agent with antioxidant properties. Oxidative stress is a key pathogenic mechanism in chronic respiratory conditions such as COPD and chronic bronchitis (CB). In these meta-analyses we investigated the efficacy of NAC in subjects with COPD or CB, the latter being a potential pre-COPD condition (CB/pre-COPD). METHODS: The meta-analyses were conducted according to PRISMA guidelines. Exacerbations were assessed using total number of exacerbations. Improvement in patients' respiratory symptoms and/or patients quality of life (QoL) were measured by validated tools or assessed at the end of the study. RESULTS: Twenty studies were included, of which seven evaluated NAC in patients with symptoms of CB/pre-COPD as entry criterion. NAC treated patients showed a significant reduction of the incidence of exacerbations as compared to placebo both in COPD (IRR=0.76; 95% confidence interval (CI) 0.59-0.99) and CB/pre-COPD (IRR=0.81; 95% CI 0.69-0.95). Sensitivity analyses in studies with duration higher than 5 months, confirmed the overall results. CB/pre-COPD patients treated with NAC were significantly more likely to experience an improvement in symptoms and/or QoL compared to placebo (odds ratio (OR)=3.47; 95% CI 1.92-6.26). A similar trend was observed in the few COPD studies evaluable. Sensitivity analyses showed a significant association of NAC with improvement in symptoms and/or QoL both in CB/pre-COPD and COPD patients. CONCLUSIONS: These findings provide novel data of NAC on the improvement in symptoms and QoL in addition to prevention of exacerbations in COPD and CB/pre-COPD. PROSPERO registry no. CRD42023468154.

N-Acetylcysteine Alters Disease Progression and Increases Janus Kinase Mutation Frequency in a Mouse Model of Precursor B-Cell Acute Lymphoblastic Leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent type of cancer in young children and is associated with high levels of reactive oxygen species (ROS). The antioxidant N-acetylcysteine (NAC) was tested for its ability to alter disease progression in a mouse model of B-ALL. Mb1-CreΔPB mice have deletions in genes encoding PU.1 and Spi-B in B cells and develop B-ALL at 100% incidence. Treatment of Mb1-CreΔPB mice with NAC in drinking water significantly reduced the frequency of CD19+ pre-B-ALL cells infiltrating the thymus at 11 weeks of age. However, treatment with NAC did not reduce leukemia progression or increase survival by a median 16 weeks of age. NAC significantly altered gene expression in leukemias in treated mice. Mice treated with NAC had increased frequencies of activating mutations in genes encoding Janus kinases 1 and 3. In particular, frequencies of Jak3 R653H mutations were increased in mice treated with NAC compared with control drinking water. NAC opposed oxidization of PTEN protein ROS in cultured leukemia cells. These results show that NAC alters leukemia progression in this mouse model, ultimately selecting for leukemias with high Jak3 R653H mutation frequencies. SIGNIFICANCE STATEMENT: In a mouse model of precursor B-cell acute lymphoblastic leukemia associated with high levels of reactive oxygen species, treatment with N-acetylcysteine did not delay disease progression but instead selected for leukemic clones with activating R653H mutations in Janus kinase 3.

The presence of abdominal pain associated with acetaminophen overdose does not predict severity of liver injury.

AIM: Whilst it is known that abdominal pain is a common symptom in patients with acetaminophen overdose, its association with severity of liver injury has not been clearly defined. This study investigates the association between the symptom of abdominal pain on presentation to hospital and the degree of liver injury post-acetaminophen overdose. METHODS: Admissions with acetaminophen poisoning, requiring treatment with acetylcysteine were identified and reviewed from a search of a large Australian tertiary hospital network from February 20th, 2014, to August 30th, 2018. Parameters such as presence of abdominal pain, time post-ingestion and peak ALT were collected. Single acute ingestions, staggered and repeated supratherapeutic ingestions were analysed. RESULTS: 539 cases were identified in the study period, 79% female, with mean age 25 (17-43) years. Patients presenting to the emergency department with abdominal pain post-acetaminophen overdose had a similar risk of developing hepatotoxicity or acute liver injury compared to patients without abdominal pain regardless of time to presentation. Patients presenting <8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (1/46, 2.2%) compared to those without abdominal pain (1/54 [1.9%]; OR = 1.18 [0.07 to 19.4]). Those presenting >8-h post-overdose with abdominal pain were as likely to develop hepatotoxicity (13/92, 14.1%) compared to those without abdominal pain (4/35 [11.4%]; OR = 1.28 [0.39 to 4.21]). CONCLUSIONS: The presence of abdominal pain after acetaminophen overdose was not predictive of the development of liver injury in patients receiving acetylcysteine treatment. Further prospective studies are required to confirm this finding. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Organoids as a biomarker for personalized treatment in metastatic colorectal cancer: drug screen optimization and correlation with patient response.

BACKGROUND: The inability to predict treatment response of colorectal cancer patients results in unnecessary toxicity, decreased efficacy and survival. Response testing on patient-derived organoids (PDOs) is a promising biomarker for treatment efficacy. The aim of this study is to optimize PDO drug screening methods for correlation with patient response and explore the potential to predict responses to standard chemotherapies. METHODS: We optimized drug screen methods on 5-11 PDOs per condition of the complete set of 23 PDOs from patients treated for metastatic colorectal cancer (mCRC). PDOs were exposed to 5-fluorouracil (5-FU), irinotecan- and oxaliplatin-based chemotherapy. We compared medium with and without N-acetylcysteine (NAC), different readouts and different combination treatment set-ups to capture the strongest association with patient response. We expanded the screens using the optimized methods for all PDOs. Organoid sensitivity was correlated to the patient's response, determined by % change in the size of target lesions. We assessed organoid sensitivity in relation to prior exposure to chemotherapy, mutational status and sidedness. RESULTS: Drug screen optimization involved excluding N-acetylcysteine from the medium and biphasic curve fitting for 5-FU & oxaliplatin combination screens. CellTiter-Glo measurements were comparable with CyQUANT and did not affect the correlation with patient response. Furthermore, the correlation improved with application of growth rate metrics, when 5-FU & oxaliplatin was screened in a ratio, and 5-FU & SN-38 using a fixed dose of SN-38. Area under the curve was the most robust drug response curve metric. After optimization, organoid and patient response showed a correlation coefficient of 0.58 for 5-FU (n = 6, 95% CI -0.44,0.95), 0.61 for irinotecan- (n = 10, 95% CI -0.03,0.90) and 0.60 for oxaliplatin-based chemotherapy (n = 11, 95% CI -0.01,0.88). Median progression-free survival of patients with resistant PDOs to oxaliplatin-based chemotherapy was significantly shorter than sensitive PDOs (3.3 vs 10.9 months, p = 0.007). Increased resistance to 5-FU in patients with prior exposure to 5-FU/capecitabine was adequately reflected in PDOs (p = 0.003). CONCLUSIONS: Our study emphasizes the critical impact of the screening methods for determining correlation between PDO drug screens and mCRC patient outcomes. Our 5-step optimization strategy provides a basis for future research on the clinical utility of PDO screens.

Assessing the frequency and types of errors involved in the use of a modified intravenous N-acetylcysteine protocol for acetaminophen overdose.

BACKGROUND: Acetaminophen overdose is a leading cause of acute liver failure in developing countries. N-acetylcysteine (NAC) is a highly effective antidote for acetaminophen hepatotoxicity, typically initiated in the emergency department. Due to a known high rate of errors with the standard three-bag IV NAC protocol, in 2019, the Ontario Poison Center changed to a modified 3% IV NAC one-bag protocol. This study was undertaken to determine the frequency and types of errors associated with the use of this protocol. METHODS: Data were gathered via chart review of Ontario Poison Centre electronic medical record cases identified as receiving IV NAC for acetaminophen overdose between August 1 and September 30, 2022. 218 total charts were identified, and 188 were deemed eligible based on inclusion and exclusion criteria. RESULTS: Errors were identified in 25% of charts, consisting of dosing errors in 11.7%, stopping errors in 9.0%, initiation errors in 3.7%, and interruptions in therapy in 3.2%. Dosing errors were the most common type of error (44.4%), with overdoses occurring three times more than underdoses. Errors were identified at 39% of geographic locations in the charts reviewed, with similar frequency in Ontario, Manitoba, and Nunavut. Clinical outcomes were similar in charts with and without errors. INTERPRETATION: The rate of errors identified with this 3% IV NAC one-bag protocol is lower than reported for the standard three-bag protocol, but remains high due to dosing errors. Previously reported issues with prolonged interruptions in therapy with the standard three-bag protocol were low with the current 3% one-bag protocol. Although severe outcomes are rare, IV NAC overdose can be fatal. Identifying local factors in emergency departments that can contribute to administration errors (i.e., dose calculation, pump programming issues) can enhance the safety of this important antidote.

RéSUMé: CONTEXTE: La surdose d'acétaminophène est l'une des principales causes d'insuffisance hépatique aiguë dans les pays en développement. La N-acétylcystéine (NAC) est un antidote très efficace contre l'hépatotoxicité de l'acétaminophène, généralement initiée au service des urgences. En raison d'un taux élevé connu d'erreurs avec le protocole NAC standard à 3 sacs IV, en 2019, le Centre antipoison de l'Ontario a adopté un protocole NAC à 1 sac IV modifié à 3 %. Cette étude a été entreprise pour déterminer la fréquence et les types d'erreurs associées à l'utilisation de ce protocole. MéTHODES: Les données ont été recueillies au moyen d'un examen des dossiers médicaux électroniques du Centre antipoison de l'Ontario qui ont reçu une dose IV de NAC pour une surdose d'acétaminophène entre le 1 août et le 30 septembre 2022. 218 cartes au total ont été identifiées, et 188 ont été jugées admissibles en fonction de critères d'inclusion et d'exclusion. RéSULTATS: Des erreurs ont été relevées dans 25 % des dossiers, soit des erreurs de dosage dans 11,7 %, des erreurs d'arrêt dans 9,0 %, des erreurs d'initiation dans 3,7 % et des interruptions du traitement dans 3,2 %. Les erreurs de dosage étaient le type d'erreur le plus courant (44,4 %), les surdoses étant trois fois plus fréquentes que les sous-doses. Des erreurs ont été relevées à 39 % des emplacements géographiques dans les cartes examinées, avec une fréquence similaire en Ontario, au Manitoba et au Nunavut. Les résultats cliniques étaient similaires dans les tableaux avec et sans erreurs. INTERPRéTATION: Le taux d'erreurs identifiées avec ce protocole à un sac NAC IV à 3 % est inférieur à celui du protocole standard à 3 sacs, mais reste élevé en raison d'erreurs de dosage. Les problèmes précédemment rapportés avec les interruptions prolongées du traitement avec le protocole standard à 3 sacs étaient faibles avec le protocole actuel à 3% à un sac. Bien que les résultats graves soient rares, une surdose de NAC IV peut être fatale. L'identification de facteurs locaux dans les services d'urgence qui peuvent contribuer aux erreurs d'administration (c.-à-d. le calcul de la dose, les problèmes de programmation de la pompe) peut améliorer l'innocuité de cet antidote important.

Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.

N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg-1 ). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.

Exploring the role of oxidative stress and the effect of N-acetylcysteine in thiopurine-induced liver injury in inflammatory bowel disease: A randomized crossover pilot study.

Thiopurine treatment is regularly complicated by drug-induced liver injury. It has been suggested that oxidative stress may play a synergistic role. To assess whether thiopurine-induced liver injury coincides with increased oxidative stress and whether co-administration with N-acetylcysteine is protective, we performed a randomized open label crossover pilot study in inflammatory bowel disease patients with thiopurine-induced increased serum liver tests. The study comprised four stages of 4 weeks. Patients received no additional therapy followed by N-acetylcysteine 1200 mg twice a day, or the other way around, alongside ongoing thiopurine treatment. The third and fourth stages comprised a washout period and thiopurine reintroduction period. Nine patients completed the study, and the addition of N-acetylcysteine decreased myeloperoxidase concentrations (33.6-24.5 pmol/L, p = 0.038). The other biomarkers remained unchanged, including thiopurine metabolites, xanthine oxidase activity, thiopurine S-methyltransferase activity and serum liver enzyme activity tests. Reintroduction of thiopurines led to an increase of F2-isoprostanes (101-157 ng/mmol, p = 0.038), but not of serum liver enzyme activity tests. Results suggests that thiopurines may increase oxidative stress and although the addition of N-acetylcysteine led to a decrease in plasma myeloperoxidase concentrations, it does not protect from thiopurine-induced increase of serum liver tests.

The efficacy of N-acetylcysteine in decreasing airway inflammation and mucus accumulation in horses with 18 hours of head confinement.

BACKGROUND: During transportation many horses develop post-transportation infection, which can be life-threatening and end their sport career. Preventing mucus accumulation and inflammation during transportation is vital, emphasizing the need for effective strategies to enhance overall horse health welfare. OBJECTIVES: Assess the impact of N-acetylcysteine (NAC) on mucus accumulation and inflammation in horses subjected to 18 hours of head confinement. ANIMALS: Six healthy crossbred horses, 5.3 ± 2.1 years of age and weighing 387 ± 30 kg. METHODS: Prospective placebo-controlled cross-over design study. The horses' heads were restrained in their stalls for a period of 18 hours. They were studied under 4 conditions: Not confined (NC): before head confinement, placebo (P), and confined head (CH): 18 hours of head confinement without treatment, and N-Acetylcysteine (NAC): 18 hours of head confinement treated with NAC before confinement (15 mg/kg/day NAC PO for 3 days). Bronchoalveolar lavage (BAL) was performed in each condition. Mucus accumulation along the trachea was evaluated by endoscopy. RESULTS: Endoscopic scores were significantly different between CH and other conditions, whereas no significant differences were found among NC, P, and NAC. The BAL cell count (34 291 ± 2624 cells/µL), neutrophil and lymphocyte count (18 601 ± 3193 cells/µL and 3337.4 ± 593 cells/µL, respectively) in CH were significantly higher compared to NAC. Neutrophil percentage was significantly higher in CH (53.8 ± 8%) compared to horses that received NAC (20.08 ± 8%). Conversely, in comparison to NAC (66.33 ± 9%), the percentage of macrophages was significantly lower in CH (35.7 ± 10%). CONCLUSIONS: N-acetylcysteine was found to significantly decrease mucus accumulation and inflammatory cell counts in horses with head confinement.

Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.

Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.