Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases.

N-acetylcysteine (NAC) has shown beneficial effects in both acute kidney disease and chronic kidney disease (CKD) in preclinical and clinical studies. Different dosage and administration forms of NAC have specific pharmacokinetic properties that determine the temporal pattern of plasma concentrations of NAC and its active metabolites. Especially in acute situations with short-term NAC administration, appropriate NAC and glutathione (GSH) plasma concentrations should be timely ensured. For oral dosage forms, bioavailability needs to be established for the respective NAC formulation. Kidney function influences NAC pharmacokinetics, including a reduction of NAC clearance in advanced CKD. In addition, mechanisms of action underlying beneficial NAC effects depend on kidney function as well as comorbidities, both involving GSH deficiency, alterations in nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent signaling, oxidative stress, mitochondrial dysfunction, and disturbed mitochondrial bioenergetics. This also applies to nonrenal NAC mechanisms. The timing of preventive NAC administration in relation to potential injury is important. NAC administration seems most effective either preceding, or preceding and paralleling conditions that induce tissue damage. Furthermore, studies suggest that very high concentrations of NAC should be avoided because they could exert reductive stress. Delayed administration of NAC might interfere with endogenous repair mechanisms. In conclusion, studies on NAC treatment regimens need to account for both NAC pharmacokinetics and NAC molecular effects. Kidney function of the patient population and pathomechanisms of the kidney disease should guide rational NAC trial design. A targeted trial approach and biomarker-guided protocols could pave the way for the use of NAC in precision medicine.

Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.

N-acetylcysteine (NAC) is a medicine widely used to treat paracetamol overdose and as a mucolytic compound. It has a well-established safety profile, and its toxicity is uncommon and dependent on the route of administration and high dosages. Its remarkable antioxidant and anti-inflammatory capacity is the biochemical basis used to treat several diseases related to oxidative stress and inflammation. The primary role of NAC as an antioxidant stems from its ability to increase the intracellular concentration of glutathione (GSH), which is the most crucial biothiol responsible for cellular redox imbalance. As an anti-inflammatory compound, NAC can reduce levels of tumor necrosis factor-alpha (TNF-α) and interleukins (IL-6 and IL-1β) by suppressing the activity of nuclear factor kappa B (NF-κB). Despite NAC's relevant therapeutic potential, in several experimental studies, its effectiveness in clinical trials, addressing different pathological conditions, is still limited. Thus, the purpose of this chapter is to provide an overview of the medicinal effects and applications of NAC to human health based on current therapeutic evidence.

Administration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans.

This was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150 mg/kg) followed by a 4-hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pm and discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8 am.

Twenty-two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171 ± 247 pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538 ± 392 pg/mL) (clamp 3 to clamp 1 NAC: P = .0013). The symptom response during clamp 3 (7 ± 5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16 ± 10) (clamp 3 to clamp 1 NAC: P = .0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion.

We found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.

The primary objective of this study was to evaluate potential interference of Trinder-based chemistry assays by N-acetylcysteine (NAC). A secondary objective was to look for evidence of interference in patients treated with NAC for acetaminophen (APAP) overdose.

Dilutions of NAC in plasma were tested for interference using the following Roche Diagnostics Trinder-based assays on a cobas 8000 system: enzymatic creatinine (Cr), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-C), triglycerides (TRIG), and uric acid (UA). Two non-Trinder Roche assays - urea nitrogen (BUN) and glucose (GLUC) - were tested as controls. Sekisui N-geneous® low-density lipoprotein cholesterol (LDL-C) reagent was also evaluated. Retrospective chart review of APAP overdose cases over 49months was conducted to look for differences in plasma Cr before and after intravenous (IV) NAC administration.

NAC concentrations (shown in parentheses) that caused ≥10% inhibition for individual assays were (in order of sensitivity to interference): TRIG (570mg/L)>CHOL (740mg/L)≈Cr (790mg/L)>UA (1100mg/L)>HDL-C (1760mg/L)>LDL-C (2900mg/L). Neither BUN nor GLUC achieved significant inhibition up to 10,000mg/L NAC. Evidence for relatively minor inhibition of Cr was observed in patients after NAC administration.

NAC inhibition of the assays investigated typically occurs at concentrations higher than expected during IV and oral NAC therapy.

Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies.

Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations.

Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose.

There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.

Activating mutations of the interleukin-7 receptor (IL7R) occur in approximately 10% of patients with T cell acute lymphoblastic leukaemia (T-ALL). Most mutations generate a cysteine at the transmembrane domain leading to receptor homodimerization through disulfide bond formation and ligand-independent activation of STAT5. We hypothesized that the reducing agent N-acetylcysteine (NAC), a well-tolerated drug used widely in clinical practice to treat acetaminophen overdose, would reduce disulfide bond formation, and inhibit mutant IL7R-mediated oncogenic signalling. We found that treatment with NAC disrupted IL7R homodimerization in IL7R-mutant DND-41 cells as assessed by non-reducing Western blot, as well as in a luciferase complementation assay. NAC led to STAT5 dephosphorylation and cell apoptosis at clinically achievable concentrations in DND-41 cells, and Ba/F3 cells transformed by an IL7R-mutant construct containing a cysteine insertion. The apoptotic effects of NAC could be rescued in part by a constitutively active allele of STAT5. Despite using doses lower than those tolerated in humans, NAC treatment significantly inhibited the progression of human DND-41 cells engrafted in immunodeficient mice. Thus, targeting leukaemogenic IL7R homodimerization with NAC offers a potentially effective and feasible therapeutic strategy that warrants testing in patients with T-ALL.

Chronic hepatitis C (CHC) infection affects almost 3% of the global population and can lead to cirrhosis, liver failure, and hepatocellular carcinoma in a significant number of those infected. Until recently, the only treatments available were pegylated interferon and ribavirin, which traditionally were not very effective and have considerable side effects. For this reason, interest in complementary and alternative medications (CAM) in the management of hepatitis C has been investigated. Some CAM has demonstrated therapeutic potential in chronic hepatitis C treatment. Unfortunately, some CAM has been shown to have the potential to cause drug-induced liver injury. This article will review and evaluate many of the natural molecules that interact with the hepatitis C virus (HCV) life cycle and discuss their potential use and safety in HCV therapy, as well as highlight some important interactions between medical and complementary treatments.

Haemodialysis is sometimes used for patients with massive acetaminophen overdose when signs of "mitochondrial paralysis" (lactic acidosis, altered mental status, hypothermia and hyperglycaemia) are present. The role of haemodialysis is debated, in part because the evidence base is weak and the endogenous clearance of acetaminophen is high. There is also concern because the antidote acetylcysteine is also dialyzable. We prospectively measured serum acetylcysteine concentrations during haemodialysis in three such cases.

Three adults each presented comatose and acidemic 10 to ~18 h after ingesting > 1000mg/kg of acetaminophen. Two were hypothermic and hyperglycaemic. Serum lactate concentrations ranged from 7 mM to 12.5 mM. All three were intubated, and initial acetaminophen concentrations were as high as 5980 μM (900 μg/mL). An intravenous loading dose of 150 mg/kg acetylcysteine was initiated between 10.8 and ~18 h post ingestion, and additional doses were empirically administered during haemodialysis to compensate for possible antidote removal. A single run of 3-4 h of haemodialysis removed 10-20 g of acetaminophen (48-80% of remaining body burden), reduced serum acetaminophen concentrations by 56-84% (total clearance 3.4-7.8 mL/kg/min), accelerated native acetaminophen clearance (mean elimination half-life 580 min pre-dialysis, 120 min during and 340 min post-dialysis) and corrected acidemia. Extraction ratios of acetylcysteine across the dialysis circuit ranged from 73% to 87% (dialysance 3.0 to 5.3 mL/kg/min). All three patients recovered fully, and none developed coagulopathy or other signs of liver failure.

When massive acetaminophen ingestion is accompanied by coma and lactic acidosis, emergency haemodialysis can result in rapid biochemical improvement. As expected, haemodialysis more than doubles the clearance of both acetaminophen and acetylcysteine. Because acetylcysteine dosing is largely empirical, we recommend doubling the dose during haemodialysis, with an additional half-load when dialysis exceeds 6 h.

It has been documented that medical prosthetic alloys release metal ions into surrounding tissues and cause cytotoxicity, but the mechanisms remain undefined. In that regard the cellular oxidative stress may be a common pathway in cellular responses to metal ions. The objective of this study was to approach the hypothesis that oxidative stress mediates chromium-induced cytotoxicity in rat calvarial osteoblasts. Osteoblasts were exposed to different concentrations of Cr6+ or Cr3+ (5-20 microM) in the presence or absence of the antioxidant N-acetyl-cysteine (NAC; 1-5 mM). Cellular viability, differentiation, and intracellular ultrastructural alterations were evaluated by MTT assay, alkaline phosphatase (ALP) activity assay, and transmission electron microscopy. Cellular oxidative stress was evaluated by intracellular reactive oxygen species (ROS) production. ROS production was monitored by the oxidation-sensitive fluorescent probe 2'7'-dichlorofluorescin diacetate (DCFH-DA). A time- and concentration- dependent increased cytotoxicity, time-dependent increased intracellular ROS production were indicated on exposure to Cr6+. Pretreatment of osteoblasts with 1-5 mM NAC afforded dose-dependent cytoprotective effects against Cr6+-induced cytotoxicity in osteoblasts. NAC decreased the level of intracellular ROS induced by Cr6+, too. While Cr3+ and NAC did not have any significant effects on osteoblasts (5-20 microM). These results suggest that oxidative stress is involved in Cr6+-induced cytotoxicity in osteoblasts, and NAC can provide protection for osteoblasts against Cr6+-induced oxidative stress. Cr3+ (5-20 microM) have no significant cytotoxicity in osteoblasts based on the results of this study.

Studies evaluating the role of N-acetylcysteine in patients undergoing coronary angiography have yielded inconsistent data. Less is known about patients with normal renal function at baseline.

Prospective, double-blind, placebo-controlled trial to determine the benefits of intravenous N-acetylcysteine as an adjunct to hydration in this kind of population. Patients were randomly assigned to receive either N-acetylcysteine (600 mg twice daily) or placebo, in addition to 0.45% intravenous saline. The primary end point was development of contrast-induced nephropathy, defined as an acute increase in the serum creatinine concentration > or = 0.5 mg/dl and/or > 25% increase above baseline level at 48 h after contrast dosing.

A total of 216 patients were studied: N-acetylcysteine = 107 and placebo = 109. Treatment groups were similar with respect to baseline clinical characteristics. Overall incidence of contrast-induced nephropathy was 10.2%, 10.3% in the N-acetylcysteine group and 10.1% in the placebo group. Furthermore, no significant differences were observed when considering the non-diabetic population, although there was a trend towards a protective effect of N-acetylcysteine in the subgroup of 47 patients with both hypertension and diabetes. There were no significant changes in serum urea nitrogen concentrations. The incidence of in-hospital adverse clinical events was low: no patient with contrast-induced nephropathy required dialysis, the median Coronary Unit stay was 4.5 vs. 4 days, and the mortality rate was 2.8% vs. 4.6% in the N-acetylcysteine and placebo groups, respectively (p=NS).

The prophylactic administration of intravenous N-acetylcysteine provides no additional benefit to saline hydration in high-risk coronary patients with normal renal function.

N-acetylcysteine (NAC) is a mucolytic agent with anti-oxidant properties. It might have potential positive effects in renal patients and, therefore, its pharmacokinetics and safety in haemodialysis was investigated.

Twelve dialysis patients received 2 g NAC (10 ml NAC 20% solution i.v.) mixed with 500 ml saline during the first 3 h of the session for six dialysis sessions. A bolus of heparin was injected intravenously as LWH-heparin. In six patients, one session was repeated with NAC mixed with heparin and infused through the heparin pump.

Baseline NAC was on average 454 ng ml(-1); its concentration increased to 9,253 ng ml(-1) at the second infusion and attained a steady state between 14,000 ng ml(-1) and 17,000 ng ml(-1) at the fourth dose. We observed a C (max) of 53,458 ng ml(-1) with a t (max) of 3.0 h. Plasma clearance was 1.25 l h(-1) and dialytic clearance 5.52 l h(-1). No side effects were observed.

In the case of repeated doses, the NAC pre-dose concentration after repeated infusion of 2 g of the drug during the first 3 h of a dialysis session reached the steady state at the fourth infusion, without further accumulation. The dialytic clearance is effective, the total body clearance being reduced to 1.25 l h(-1). In dialysis patients, 2 g NAC given intravenously over 3 h is a safe dosage, with no short-term side effects.

Hepatitis C is an escalating global health problem. The recommended treatment regimen is associated with considerable expense, adverse effects and poor efficacy in some patients. Complementary therapies are widely promoted for and used by patients with hepatitis C. The aim is to systematically assess the efficacy of complementary therapies in treating chronic hepatitis C.

Systematic searches were conducted in six databases, reference lists of all papers were checked for further relevant publications and information was requested from experts. No language restrictions were imposed.

Twenty-seven eligible randomised clinical trials were located involving herbal products and supplements. No randomised clinical trials were identified for any other complementary therapy. In 14 of the trials, patients received interferon-alpha in combination with the complementary therapy. Less than half the trials (11/27) were of good methodological quality. Compared with the control group, significant improvements in virological and/or biochemical response were seen in trials of vitamin E, thymic extract, zinc, traditional Chinese medicine, Glycyrrhiza glabra and oxymatrine.

We identified several promising complementary therapies, although extrapolation of the results is difficult due to methodological limitations. More research is warranted to establish the role of these and other therapies in the treatment of hepatitis C.

A high-performance liquid chromatographic assay was developed for the quantitative determination of the sulfur-containing amino acids N-acetyl-L-cysteine (NAC) and L-cysteine (Cys) in rat plasma. The thiols were separated by reverse-phase ion-pair chromatography, and the column eluent was continuously mixed with an iodoplatinate-containing solution. The substitution of sulfur of the thiol compound with iodide was quantitatively determined by measuring changes in the absorption at 500 nm. The low-molecular-weight disulfides and mixed disulfide conjugates of thiols with proteins were entirely reduced to the original reduced compounds by dithiothreitol. By reducing these two types of disulfides separately during sample pretreatment, the reduced, protein-unbound, and total thiol concentrations could also be determined. Validation testing was performed, and no problems were encountered. The limit of detection was approximately 20 pmol of thiol on the column. The present method was used to measure the plasma concentrations of NAC and Cys in the rat after a bolus intravenous administration of NAC, focusing on disulfide formation. The binding of NAC to protein through mixed disulfide formation proceeds in a time-dependent and reversible manner. Moreover, this "stable" covalent binding might limit total drug elimination, while the unbound NAC is rapidly eliminated. Consequently, the analytical method described in this study is very useful for the determination of plasma NAC and Cys, including disulfide conjugates derived from them.

Capillary electrophoresis has been applied to separate and determine N-acetylcysteine (NAC) and related impurities. Determination conditions were found to be optimum with 100 mmol/l borate as the buffer, pH 8.40. The limit of detection was established for each substance examined. The method has been validated by examining linearity ranges, precision and repeatability. The method was used to determine the content of NAC in, and purity of, pharmaceutical preparations. The major impurities (N,N-diacetylcystine, N,S-diacetylcysteine and cystine) were determined at levels of 0.1%.

The mechanism of action of N-acetylcysteine in early acetaminophen poisoning is well understood, but much remains to be learned of the mechanism of its possible benefit in acetaminophen poisoning presenting beyond 15 hours.

Selective review of medical literature. N-acetylcysteine should be used in all cases of early acetaminophen poisoning where the plasma acetaminophen concentration lies "above the line;" which line is chosen depends on individual preference and whether enzyme induction is suspected. Particular care should be taken with the use of the nomogram for patients with chronic excess ingestion of acetaminophen or for those who have taken slow-release formulations.

While there is a trend suggesting a beneficial effect of N-acetylcysteine in some patients presenting beyond 15 hours, further research is necessary to establish just how effective N-acetylcysteine is, particularly in patients presenting with fulminant hepatic failure. Candidate mechanisms for a beneficial effect in-clude improvement of liver blood flow, glutathione replenishment, modification of cytokine production, and free radical or oxygen scavenging. Hemody-namic and oxygen delivery and utilization parameters must be monitored carefully during delayed N-acetylcysteine treatment of patients with fulminant hepatic failure, as unwanted vasodilation may be deleterious to the maintenance of mean arterial blood pressure.

To examine the possibility of immunotherapy for activating liver-associated mononuclear cells (liver MNC) in hepatocellular carcinoma (HCC), we evaluated the cytotoxicity of liver MNC and peripheral blood mononuclear cells (PBMNC) in HCC patients and examined how they can be activated by cytokines and how this activation is modulated by reduction/oxidation. Cytotoxicity of liver MNC but not PBMNC in HCC patients was significantly decreased compared with that of controls, despite no alteration in the subpopulation of liver MNC between the two groups. We next measured intracellular glutathione (GSH), which is required for the enhancement of the cytotoxicity by interleukin-2 (IL-2). Intracellular GSH levels of liver MNC in HCC were significantly lower than that of controls. In vitro administration of N-acetylcysteine (NAC) not only restored intracellular GSH levels but also enhanced the IL-2-stimulated cytotoxicity of liver MNC in HCC patients. This suggests that intracellular GSH of liver MNC in HCC may participate in the modulation of cytotoxicity of liver MNC in vitro and that NAC may be effective as an adjunct to immunotherapy for HCC.