Oral N-acetylcysteine Treatment Research Articles

N-acetylcysteine protects neonatal mice from ventricular hypertrophy induced by maternal obesity in a sex-specific manner

BackgroundMaternal obesity induces adverse cardiac programming in offspring, and effective interventions are needed to prevent cardiovascular ill-health. Herein we hypothesized that exposure to maternal obesogenic diet-induced obesity in mice results in left ventricular remodelling and hypertrophy in early childhood, and that maternal N-acetylcysteine (NAC) treatment alleviates these effects in a sex-dependent manner. Methods and ResultsThe maternal obesity was induced in mice by the consumption of a Western diet accompanied by a 20 % sucrose solution. To determine the effect of NAC on the cardiac outcomes induced by maternal obesity, obese dams were continuously exposed to the obesogenic diet, with or without the oral NAC treatment during pregnancy. Left ventricular remodelling and hypertrophy occurred as early as 7 days after birth in the male offspring of obese dams (O-OB) compared with controls (O-CO). An over-expression of key genes and markers related to cardiac fibrosis accompanied by more disorganized myofibrils was observed in the hearts of neonatal male O-OB mice. When we next evaluated the level of oxidative stress in the hearts of neonatal mice, the activity of enzymatic antioxidants declined and expression of NOX enzyme complex was up-regulated in O-OB offspring hearts, but was normal in the offspring of NAC treated mice (O-OB/NAC). Maternal obesity also activated cardiac Akt and mammalian target of rapamycin (mTOR) signalling in offspring, and NAC treatment restored offspring cardiac Akt-mTOR signalling to normal irrespective of sex. NAC treatment did not prevent cardiomyocyte hypertrophy but did alleviate increased heart weight, interventricular septal thickness, and collagen content in male O-OB/NAC pups. ConclusionsCollectively, our results indicated that NAC blunted cardiac fibrosis and related ventricular hypertrophy of male neonatal offspring in the setting of maternal obesity, potentially acting by reducing oxidative stress. The present study provides a basis for investigating the role of NAC in nutrition-related cardiac programming.

Effect of Intravenous and Oral N-Acetylcysteine Treatment in a Patient with Sickle Cell Disease at Disease Baseline

Background: We previously showed that patients with sickle cell disease (SCD) have elevated levels of von Willebrand factor (VWF) with high adhesive activity and the level of total active VWF correlated with hemolysis at disease baseline. These findings suggest that VWF plays a role in the pathophysiology of SCD [Chen et al, Blood. 2011; 117:3680‐3]. We also showed that N-acetylcysteine (NAC), a mucolytic and antioxidant drug, can reduce the level of large VWF multimers and platelet adhesion in human plasma in vitro and in mice in vivo [Chen et al, JCI, 2011, 121:522]. Based on these findings, we hypothesized that administration of NAC in SCD patients might reduce VWF multimers in vivo and reduce oxidative stress by scavenging reactive oxygen species (ROS). We started a pilot study to evaluate the effects of intravenous (IV) and oral NAC administration in SCD patients at disease baseline (NCT01800526). In this report, we administered NAC to one patient by IV and orally and compared the effect on biomarkers by the two routes of NAC administration.Patient and protocol: The subject is a 51-year-old male with SS genotype, a history of leg ulcers and acute chest syndrome, and who was not taking hydroxyurea at the time of the study. NAC was infused at a low dose (150 mg/kg over 8 hours) and infusion was repeated at high dose (300 mg/kg over 8 hrs) after 4 weeks. Blood samples were collected before (0), during (4 hr) and after the NAC infusions (8, 24 and 72 hr). Five months after the high dose IV infusion, during which parameters returned to baseline levels, oral NAC was administered for 4 weeks at 2.4g/day. Weekly blood samples were collected four weeks before the start of oral NAC, during oral NAC, and one week after oral NAC administration. We measured RBC parameters and RBC fragments, dense cells and percentage of platelet-monocyte complexes (PMC) by flow cytometry. We also analyzed VWF antigen, VWF multimers, ADAMTS13 antigen and activity levels in plasma. We also measured total, oxidized and reduced forms of NAC, cysteine and glutathione levels in plasma and whole blood by mass spectrometry.Results: 1) The subject did not experience adverse side effect during and after the treatment period. 2) RBC, hemoglobin and hematocrit levels did not significantly change with either IV or oral NAC treatment. Oral and IV NAC decreased dense cell and RBC fragments. NAC reduced the number of dense cells 13% during low dose IV, 79% during high dose IV and 73% with the oral administration. Compared to baseline, RBC fragments decreased 40% during low dose IV, 28% during high dose IV, and 27% with the oral NAC treatment. 3) NAC reduced formation of PMC from 71% to 24% (low dose IV), from 72% to 35% (high dose IV), and from 62% to 27% (oral). 4) VWF multimer size significantly decreased during low and high dose NAC infusions but did not change with oral NAC administration. VWF antigen and ADAMTS13 activity levels did not change with either routes of NAC administration. 5) The concentration of NAC in whole blood increased during treatments: elevated to 0.5 mM and 1 mM at the end of low- and high-dose IV infusions, respectively. At the conclusion of oral administration, the NAC concentration was 4 µM. Total glutathione concentrations in whole blood did not change significantly during and after NAC treatment at either dose or by either route. Free Cys concentrations in plasma increased compared to respective baseline levels 10-fold for low dose infusion (from 10 µM to 101 µM), 20-fold for high dose infusion (from 9 µM to 200 µM), but the level did not change significantly for oral administration (from 5 µM to 7 µM). Protein-bound Cys levels in plasma as markers of oxidative stress were significantly decreased with low- and high-dose IV infusion. However, the level did not change significantly with oral NAC administration.Summary: Both IV and oral administration of NAC were safe and well tolerated in the patient with SCD. Both IV and oral administration reduced the number of dense cells, RBC fragmentation, and formation of PMCs. IV, but not oral NAC, reduced VWF multimer size. These finding suggest that IV administration resulted in higher concentration and had more biologic effects; however both approaches may have a role in treatment of patients with SCD. DisclosuresKonkle:Sangamo: Research Funding; Gilead: Consultancy; Shire: Research Funding; Genentech: Consultancy; CSL Behring: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Spark: Consultancy, Research Funding; Pfizer: Research Funding.

Evaluating the effect of N-acetylcysteine on residual renal function in chronic hemodialysis patients treated with low-flux dialysis membrane; a randomized clinical trial

Introduction: The goal of any physician who cares about dialysis patients is to increase their quality of life. Many studies have shown that residual renal function (RRF) in dialysis patients, especially those undergoing peritoneal dialysis (PD), is an important prognostic factor for mortality. Objectives: In the present study, we aimed to investigate the effect of N-acetylcysteine (NAC) as an antioxidant on increasing RRF in chronic hemodialysis (HD) patients. Patients and Methods: Ninety-eight chronic HD patients who have urinary output greater than 100 cc in 24 hours participated in this study and were divided into two groups of treatment and control (49 patients each). Subsequently, the oral NAC treatment group received 600 mg tablets twice a day before meals. The control group received placebo tablets again twice a day before meals. The duration of the study was 4 weeks. Results: The RRF significantly improved in the treatment group during the study period, but no significant changes were observed in the control group. Residual glomerular filtration rate (GFR) rose from 1.7±0.73 to 2.7±1.1 mL/min/1.73 m2 (P<0.0001) in the treatment group, while in the control group, there was a slight increase from 2.1±0.94 to 2.2±1.19 mL/min/1.73 m2 (P=0.26). Additionally, the average daily volume of urine in the treatment group increased from 594±436 to 953±540 mL/24 h (P<0.0001) in the treatment group and from 809±573 to 771±552 mL/24 h (P=0.11) in the control group. Finally, the calculation of residual renal Kt/V per week showed an increase from 0.21±0.06 to 0.31±0.08 (P<0.0001) in the treatment group and a decrease from 0.23±0.08 to 0.22±0.08 (P=0.22) in the control group. Conclusion: Our study showed that a 4-week NAC treatment improves RRF in chronic HD patients.

Oral N-acetylcysteine and exercise tolerance in mild chronic obstructive pulmonary disease.

Heightened oxidative stress is implicated in the progressive impairment of skeletal muscle vascular and mitochondrial function in chronic obstructive pulmonary disease (COPD). Whether accumulation of reactive oxygen species contributes to exercise intolerance in the early stages of COPD is unknown. The purpose of the present study was to determine the effects of oral antioxidant treatment with N-acetylcysteine (NAC) on respiratory, cardiovascular, and locomotor muscle function and exercise tolerance in patients with mild COPD. Thirteen patients [forced expiratory volume in 1 s (FEV1)-to-forced vital capacity ratio < lower limit of normal (LLN) and FEV1 ≥ LLN) were enrolled in a double-blind, randomized crossover study to receive NAC (1,800 mg/day) or placebo for 4 days. Severe-intensity constant-load exercise tests were performed with noninvasive measurements of central hemodynamics (stroke volume, heart rate, and cardiac output via impedance cardiography), arterial blood pressure, pulmonary ventilation and gas exchange, quadriceps muscle oxygenation (near-infrared spectroscopy), and estimated capillary blood flow. Nine patients completed the study with no major adverse clinical effects. Although NAC elevated plasma glutathione by ~27% compared with placebo (P < 0.05), there were no differences in exercise tolerance (placebo: 325 ± 47 s, NAC: 336 ± 51 s), central hemodynamics, arterial blood pressure, pulmonary ventilation or gas exchange, locomotor muscle oxygenation, or capillary blood flow from rest to exercise between conditions (P > 0.05 for all). In conclusion, modulation of plasma redox status with oral NAC treatment was not translated into beneficial effects on central or peripheral components of the oxygen transport pathway, thereby failing to improve exercise tolerance in nonhypoxemic patients with mild COPD.NEW & NOTEWORTHY Acute antioxidant treatment with N-acetylcysteine (NAC) elevated plasma glutathione but did not modulate central or peripheral components of the O2 transport pathway, thereby failing to improve exercise tolerance in patients with mild chronic obstructive pulmonary disease (COPD).

The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis

Patients with end-stage renal disease (ESRD) are at an increased risk of cardiovascular disease due to many factors including inflammation and oxidative stress. N-acetylcysteine (NAC) is a thiol-containing anti-oxidant with anti-inflammatory properties. We aimed to assess the effect of three months treatment with oral NAC on the plasma levels of inflammatory mediators like interleukin-6 (IL-6) and C-reactive protein (hs-CRP) in patients on hemodialysis (HD). Twenty-four patients (nine males and 15 females) on maintenance HD were recruited in the study. Their mean age was 55.3 years. All the patients received oral NAC (600 mg twice a day) for a period of three months. The serum levels of biomedical parameters and IL-6 and hs-CRP were measured at baseline and three months after initiation of treatment. A significant decrease in serum levels of hs-CRP (22.4 vs. 5.2), IL-6 (8.1 vs. 3.6), parathyroid hormone (iPTH) (257.2 vs. 158.8), ferritin (632.0 vs. 515.1) and erythrocyte sedimentation rate (ESR) (54.2 vs. 38.3) was observed following NAC treatment. Female subjects presented with a significantly higher change in serum levels of hs-CRP compared with males (23 vs. 5.4). In three subjects who were less than 40 years old, the hs-CRP and IL-6 levels showed an increase following NAC treatment. Our study found that short-term oral NAC treatment might result in the reduction of IL-6 and hs-CRP in patients who are on regular HD. This suggests that patients with ESRD may benefit from the anti-inflammatory effects of NAC.

Effects of oral treatment with N-acetylcysteine on the viscosity of intrauterine mucus and endometrial function in estrous mares

Persistent breeding-induced endometritis is ranked as the third most common medical problem in the adult mare and leads to enormous economic loss in horse breeding. In mares suffering from persistent breeding-induced endometritis, increased amounts of intrauterine (i.u.) fluid or viscous mucus in estrus or after breeding may act as a barrier for sperm and can contribute to low fertility. Current therapies of these mares aim to eliminate i.u. fluid and mucus by uterine lavage and/or administration of ecbolic drugs. Recently, i.u. administration of N-acetylcysteine (NAC) has been shown to support therapy in mares with endometritis. It was the objective of the present study to investigate effects of an oral administration of NAC on the viscosity of i.u. fluid in estrous mares. It was hypothesized that oral treatment with NAC reduces the viscosity of i.u. fluid and has a positive effect on the inflammatory response of the endometrium. Mares (n = 12) were included in the study as soon as estrus was detected (ovarian follicle >3.0 cm and endometrial edema), which was defined as Day 1. They were randomly assigned to a treatment (10 mg/kg NAC on Days 1–4) or a control group (no treatment). On days 1 and 5 i.u. mucus was collected and its rheologic properties were accessed. On Day 5, endometrial biopsies were obtained and evaluated for integrity of the luminal epithelium, number of polymorphonuclear neutrophils (PMN), staining for cyclooxygenase 2 (COX2), staining with Kiel 67 antigen (Ki-67), lectins and periodic acid Schiff (PAS). In the treatment group, viscosity of i.u. mucus increased significantly between Days 1 and 5 (P < 0.05), while no differences were found in control mares (n.s.). At no time were significant differences between treated and control mares seen. Integrity of epithelium was not affected. After NAC treatment the mean number of PMN in endometrial biopsies was significantly lower compared to mares of the control group (1.9 ± 0.3 vs. 4.8 ± 0.4; P < 0.05). Nuclear immunostaining for COX2 was significantly lower after NAC treatment compared to control mares (P < 0.05). Score for PAS and Alcain staining of mucus in deep uterine glands differed significantly between groups (both P < 0.05). We conclude that oral NAC treatment does not reduce viscosity of uterine mucus but has an antiinflammatory effect on the equine endometrium.

N-acetylcysteine for the prevention of stricture after circumferential endoscopic submucosal dissection of the esophagus: a randomized trial in a porcine model

BackgroundCircumferential endoscopic submucosal dissection (CESD) of the esophagus would allow for both the eradication of Barrett’s esophagus and its related complications, such as advanced neoplasia. However, such procedures generally induce inflammatory repair resulting in a fibrotic stricture. N-acetylcysteine (NAC) is an antioxidant that has shown some efficacy against pulmonary and hepatic fibrosis. The aim of our study was to evaluate the benefit of NAC in the prevention of esophageal cicatricial stricture after CESD in a swine model.Animals and methodsTwo groups of six pigs each were subjected to general anesthesia and CESD: after randomization, a first group received an oral NAC treatment regimen of 100 mg/kg/day, initiated one week before the procedure, whereas a second group was followed without any prophylactic treatment. Follow-up endoscopies took place seven, fourteen, twenty-one, and twenty-eight days after CESD. Necropsy, histological assessment of esophageal inflammation, and fibrosis were performed on day 28.ResultsThe median esophageal lumen diameter on day 21 (main judgment criterion) was 4 mm (range 2 to 5) in group 1 and 3 mm (range 1 to 7) in group 2 (P = 0.95). No significant difference was observed between the two groups regarding clinical evaluation (time before onset of clinically significant esophageal obstruction), number of dilations, esophageal inflammation and fibrosis, or oxidative stress damage on immunohistochemistry.ConclusionsDespite its antioxidant effect, systemic administration of NAC did not show significant benefit on esophageal fibrosis in our animal model of esophageal wound healing within the experimental conditions of this study. Since the administered doses were relatively high, it seems unlikely that NAC might be a valuable option for the prevention of post-endoscopic esophageal stricture.

An Analysis ofN-Acetylcysteine Treatment for Acetaminophen Overdose Using a Systems Model of Drug-Induced Liver Injury

N-acetylcysteine (NAC) is the treatment of choice for acetaminophen poisoning; standard 72-h oral or 21-h intravenous protocols are most frequently used. There is controversy regarding which protocol is optimal and whether the full treatment course is always necessary. It would be challenging to address these questions in a clinical trial. We used DILIsym, a mechanistic simulation of drug-induced liver injury, to investigate optimal NAC treatment after a single acetaminophen overdose for an average patient and a sample population (n = 957). For patients presenting within 24 h of ingestion, we found that the oral NAC protocol preserves more hepatocytes than the 21-h intravenous protocol. In various modeled scenarios, we found that the 21-h NAC infusion is often too short, whereas the full 72-h oral course is often unnecessary. We found that there is generally a good correlation between the time taken to reach peak serum alanine aminotransferase (ALT) and the time taken to clear N-acetyl-p-benzoquinone imine (NAPQI) from the liver. We also found that the most frequently used treatment nomograms underestimate the risk for patients presenting within 8 h of overdose ingestion. V(max) for acetaminophen bioactivation to NAPQI was the most important variable in the model in determining interpatient differences in susceptibility. In conclusion, DILIsym predicts that the oral NAC treatment protocol, or an intravenous protocol with identical dosing, is superior to the 21-h intravenous protocol and ALT is the optimal available biomarker for discontinuation of the therapy. The modeling also suggests that modification of the current treatment nomograms should be considered.

Kronik Böbrek Yetmezliği ile İlişkili Psödoporfiri: Üç Olguda Oral N-Asetilsistein Tedavisinin Sonuçları

Kronik Böbrek Yetmezliği ile İlişkili Psödoporfiri: Üç Olguda Oral N-Asetilsistein Tedavisinin Sonuçları

Effect of Oral N-Acetylcysteine Treatment on Plasma Inflammatory and Oxidative Stress Markers in Peritoneal Dialysis Patients: A Placebo-Controlled Study

Inflammation and oxidative stress (OS) are cardiovascular risk factors in patients with chronic kidney disease. N-acetylcysteine (NAC) is a thiol-containing antioxidant with anti-inflammatory properties and has been shown to reduce the number of cardiovascular events in hemodialysis patients. The current study aimed to determine the effect of oral NAC (2 x 600 mg/daily) on plasma levels of inflammatory and OS markers in peritoneal dialysis (PD) patients. We performed a placebo-controlled study over 8 weeks in 30 patients (40% males, age 52 +/- 13 years) on regular PD. Before the study was started, the patients were divided into 2 groups of 15 patients matched for age and gender. 22 patients completed the study (12 on NAC, 10 on placebo). Proinflammatory cytokines [high-sensitivity C-reactive protein, interleukin-6 (IL-6), tumor necrosis factor-alpha, and pentraxin 3] and markers of OS (pentosidine, advanced oxidation protein products, homocysteine, glutathione, asymmetric dimethylarginine, and free sulfhydryls) were measured before and after treatment with NAC. Treatment with NAC for 8 weeks increased mean baseline plasma NAC levels from 2.6 to 24.8 mumol/L (p = 0.007). This intervention, which caused no side effects, significantly diminished IL-6 levels, from 9.4 (4.5 - 31) to 7.6 (4.9 - 13.5) pg/mL (p = 0.006), whereas no such changes were observed in the placebo group. NAC treatment did not significantly affect the other inflammatory and OS markers. Short-term oral NAC treatment resulted in reduction of circulating IL-6, suggesting that such treatment could be a useful strategy in blunting the inflammatory response in PD patients.

A retrospective evaluation of shortened-duration oral N-acetylcysteine for the treatment of acetaminophen poisoning

The use of less than the traditional 72-hour course of oral N-acetylcysteine has been an alternative treatment option following potentially toxic acute and chronic acetaminophen ingestions felt to be at low risk of developing hepatotoxicity. While clinical experience with shortened treatment duration is extensive, there are few studies evaluating the effectiveness and extent to which these regimens may be used. A large statewide poison center database was reviewed for all acetaminophen exposures involving potentially toxic acute and chronic ingestions, in addition to those taking place at unknown times. Patients were identified who met laboratory criteria for early N-acetylcysteine (NAC) discontinuation (APAP>10 micro/mL, INR<or=1.3, and AST/ALT<or=60 IU) after a minimum of a 140-mg/kg oral NAC loading dose and 5 additional 70-mg/kg doses over 20 hours. A further search of the poison center database was conducted for individuals who received shortened-course (20-48 hours) oral NAC treatment who developed subsequent hepatotoxicity or death. Of 3303 individuals with potentially toxic acetaminophen ingestions, 1932 met criteria for early NAC discontinuation. Mean treatment duration was 36.4+/-7.7 hours (acute=37.3+/-7.6 hours; chronic=34.8+/-7.4 hours; unknown=35.2+/-7.6 hours). The poison center database search identified no short-course eligible subjects who developed subsequent hepatotoxicity or death following<or=48 hours of oral NAC. Treatment with shortened-course oral NAC in patients meeting criteria for early discontinuation may be an effective treatment option in a sizeable proportion of individuals with potentially toxic acetaminophen ingestions.

Mitigating Methylmercury Exposure: Study Confirms Potential of NAC as Antidote and Biomarker

Vol. 116, No. 1 EnvironewsOpen AccessMitigating Methylmercury Exposure: Study Confirms Potential of NAC as Antidote and Biomarker Kris Freeman Kris Freeman Search for more papers by this author Published:1 January 2008https://doi.org/10.1289/ehp.116-a36aCited by:1AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Researchers have been searching for better ways to quantify and mitigate exposures to the neurotoxicant methylmercury (MeHg). Results from a new animal study confirm that N-acetylcysteine (NAC), already used to treat acetaminophen overdose, may serve as a quick-acting antidote for and biomarker of MeHg exposure [EHP 116:26–31; Aremu et al.].MeHg is created when elemental mercury released through the burning of coal, waste incineration, and other industrial processes is metabolized by aquatic microorganisms such as anaerobic bacteria. It bioaccumulates rapidly, with concentrations in some top marine predators reaching 100,000 times that of surrounding seawater. Fish consumption is the major source of human exposure. MeHg can cause irreversible brain damage, and the developing brain is especially vulnerable to its effects.Treatments to mitigate MeHg exposure involve chelation, the administration of compounds that bind mercury, speeding its elimination from the body and thereby minimizing its toxicity. Current chelation methods can be nonspecific, depleting not only MeHg but also minerals required for normal cell function, such as calcium.In contrast, chelation treatment with NAC does not affect levels of essential minerals. NAC, a derivative of the amino acid l-cysteine and a precursor of the antioxidant glutathione, is itself a potent antioxidant. NAC can be delivered intravenously or orally.In the current study, adult rats were injected with NAC (1 mmol/kg) 2 hours after being exposed to MeHg (0.1 μmol/kg). The treated animals excreted about 5% of their body burden of MeHg within 2 hours, compared with less than 0.1% excreted by untreated animals. The response was transient and dose dependent, with larger doses of NAC resulting in higher rates of MeHg excretion.These effects were not seen in preweaned rats (age 15–19 days) treated with NAC. The researchers speculate that the transporter systems needed to move the MeHg–NAC complex through the kidney do not mature until animals reach adulthood (around 30 days of age). However, oral NAC treatment in pregnant rats (10 mg/mL in drinking water) did protect their fetuses, reducing concentrations in the placenta and the whole fetus by 70–90%. In the dams themselves, NAC also reduced MeHg concentrations by 70–90% in the brain, by about 20% in the kidney, and by 60–80% in the blood and liver.NAC’s short half-life, about 2 hours, may allow it to serve as an accurate real-time biomarker of MeHg exposure. According to the researchers, such a quick-acting biomarker could provide critical early warning of possible acute exposures, where early treatment is critical to prevent neurological damage. In the current study, MeHg excretion in animals treated with NAC was proportionate to MeHg body burden at the time of treatment. In contrast, standard monitoring techniques, which use hair analysis, can provide only a history of exposure and cannot guide immediate treatment for acute exposures. The researchers propose that future studies test NAC in adult humans as a biomarker of exposure and a possible treatment for MeHg exposure, especially for pregnant women whose unborn children are in danger of prenatal MeHg exposure.NAC offers promise as an antidote to acute MeHg exposureFiguresReferencesRelatedDetailsCited by Horowitz S (2014) Chelation Therapy: A Review of Applications and Empirical Evidence, Alternative and Complementary Therapies, 10.1089/act.2014.20101, 20:1, (41-46), Online publication date: 1-Feb-2014. Vol. 116, No. 1 January 2008Metrics About Article Metrics Publication History Originally published1 January 2008Published in print1 January 2008 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Neutral sphingomyelinase inhibition participates to the benefits of N-acetylcysteine treatment in post-myocardial infarction failing heart rats

Deficiency in cellular thiol tripeptide glutathione ( l-γ glutamyl–cysteinyl–glycine) determines the severity of several chronic and inflammatory human diseases that may be relieved by oral treatment with the glutathione precursor N-acetylcysteine (NAC). Here, we showed that the left ventricle (LV) of human failing heart was depleted in total glutathione by 54%. Similarly, 2-month post-myocardial infarction (MI) rats, with established chronic heart failure (CHF), displayed deficiency in LV glutathione. One-month oral NAC treatment normalized LV glutathione, improved LV contractile function and lessened adverse LV remodelling in 3-month post-MI rats. Biochemical studies at two time-points of NAC treatment, 3 days and 1 month, showed that inhibition of the neutral sphingomyelinase (N-SMase), Bcl-2 depletion and caspase-3 activation, were key, early and lasting events associated with glutathione repletion. Attenuation of oxidative stress, downregulation of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) and its TNF-R1 receptor were significant after 1-month NAC treatment. These data indicate that, besides glutathione deficiency, N-SMase activation is associated with post-MI CHF progression, and that blockade of N-SMase activation participates to post-infarction failing heart recovery achieved by NAC treatment. NAC treatment in post-MI rats is a way to disrupt the vicious sTNF-α/TNF-R1/N-SMase cycle.

Improvement of the chronic failing heart via compensation for glutathione deficiency

Glutathione deficiency in chronic heart failure (CHF) has been overlooked. Glutathione neutralizes reactive oxygen species (ROS) production, and is the biological inhibitor of neutral- sphingomyelinase (N-SMase). ROS and N-SMase are both contributors to tumor necrosis factor alpha -receptor-1 (TNF-R1) signalling, determining the deleterious effects of TNF in heart. Differently, TNF-R2 would mediate beneficial effects of TNF. We examined the glutathione status and TNF-R1 and TNF-R2 signalling components in post-myocardial infarction (MI) rats, non-treated or treated, once CHF was established, with the glutathione precursor, N-acetylcysteine (NAC). Oral NAC treatment (50 mg/ day) was started 2-months after coronary artery ligation. Echocardiographic examination indicated well-established CHF in 2-month post-MI rats, associated with a 44% decrease in left ventricular (LV) glutathione. 3-day NAC treatment replenished glutathione to 75% its control value, without improving LV function. 1-month NAC treatment restored glutathione content and enhanced heart function. These benefits were associated with the blockade of TNF-R1 signalling: inversion of the TNF-R1/TNF-R2 and secreted-TNF/membrane-TNF ratios, inhibition of ROS production, N-SMase activity, cell infiltration, and reduction of fibrosis. In conclusion, glutathione replenishment, via NAC treatment, improves failing heart function through TNF-R1 signalling inhibition.

Shorter duration of oral N -Acetylcysteine therapy for acute acetaminophen overdose

Study objective: We sought to evaluate the safety and efficacy of a shorter N -acetylcysteine (NAC) regimen in the treatment of acute acetaminophen overdose. Methods: We performed a retrospective case series in a large urban county hospital. Of 305 patients identified through the emergency department, 75 patients met the criteria inclusion: an acute overdose ingestion, serum acetaminophen concentration in toxic range according to the Rumack-Matthew nomogram, and oral NAC treatment initiated within 24 hours of the ingestion. The regional poison control center recommended oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours until the serum acetaminophen level was no longer detectable, rather than the standard 72-hour treatment regimen. Results: The primary outcome measure was the development of hepatotoxicity. Twenty-five (33.3%) patients were treated for a period of less than 24 hours, 25 (33.3%) were treated for 24 to 36 hours, and 25 (33.3%) were treated for 37 to 64 hours; the mean and median duration of treatment was 31 hours. None of the patients treated for less than 24 hours had evidence of hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level >1,000 IU/L); hepatotoxicity developed in 2 (8%) patients treated for 24 to 36 hours and 4 (16%) patients treated for 37 to 64 hours. There were no deaths or patients who received liver transplantation. The overall incidence of hepatotoxicity in our patients was similar to that found in other protocols with administration of oral NAC for 72 hours or intravenous NAC for 20 or 48 hours. Conclusion: This observational study suggests that a shorter course of oral NAC therapy in patients who do not show evidence of hepatotoxicity within 36 hours of an acute acetaminophen overdose is safe and effective. [Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY. Shorter duration of oral N -acetylcysteine therapy for acute acetami-nophen overdose. Ann Emerg Med . April 2000;35:363-368.]

No effect of oral N-acetylcysteine on the bioavailability of erythromycin and bacampicillin

In vitro studies with N-acetylcysteine (NAC) solutions used for inhalation treatment have demonstrated inactivation of some antibiotics by NAC. Oral NAC treatment is increasingly common for long-term prophylaxis in chronic bronchitis. During exacerbations, treatment with oral antibiotics will often be given simultaneously. We assessed the effect of simultaneous oral administration of NAC on the bioavailability of two antibiotics in ten healthy volunteers. No effect of NAC was found on the bioavailability of ampicillin, after administration of the prodrug bacampicillin. A slight, but not significant statistical increase in erythromycin serum levels was seen with NAC. Acetylator phenotype did not influence the absorption of NAC, which seemed slightly reduced by bacampicillin, but significantly increased by erythromycin. No decrease of antibacterial activity of sera was found in vitro after the addition of NAC or the related thiol glutathione, employing micrococcus luteus and staphylococcus aureus as indicator organisms.