Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning.

Prescott, L. F.; Illingworth, R. N.; Critchley, J. A. J. H.; Stewart, M J; Adam, R D; Proudfoot, A. T.

doi:10.1136/bmj.2.6198.1097

Cited by 643 publications

(314 citation statements)

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“…The Plasma compartment represents systemic circulation. Creation of the Intermediate compartment was required to optimize serum ALT dynamics observed in clinical response to several hepatotoxic compounds15, 23, 24, 25 and may represent the ALT in the interstitial space, the Space of Disse, or the liver sinusoids. The clearance of ALT is driven by a specified half‐life 26.…”

Section: Methodsmentioning

confidence: 99%

“…In this SimPops, variability was introduced in the parameters relevant to ALT dynamics and hepatocyte regeneration. The range and variance of each parameter was obtained from the literature, and simulated hepatocyte loss and plasma ALT levels in the SimPops were validated using clinical data from the literature 17, 24. A list of parameters varied and their upper and lower bounds in the SimPops are presented in Supplementary Table S2 .…”

Section: Methodsmentioning

confidence: 99%

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Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo

Generaux

Howell

et al. 2017

Clin Pharma and Therapeutics

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Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa‐treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., “Hy's Law”). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug‐induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

Longo

Generaux

Howell

et al. 2017

Clin Pharma and Therapeutics

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“…15 In clinical trials following acetaminophen poisoning, early NAC administration is highly effective in preventing hepatocellular necrosis, by acting as an antidote through glutathione uplifting. 16,17 Harrison et al 18 showed significant improvement of the outcome of acetaminophen-induced ALF even when NAC was administered after 24 hours and they suggested that this was due to the antioxidant effect of NAC rather than its antidote effect. Further prospective studies have shown the valuable effect of NAC on the survival and final outcome of patients with late acetaminophen-induced ALF.…”

Section: See Editorial On Pagementioning

confidence: 99%

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

et al. 2007

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Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminopheninduced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) Ͼ 2 and abnormal liver function or INR Ͼ1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989)(1990)(1991)(1992)(1993)(1994), standard care (n ϭ 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), standard care and NAC administration (n ϭ 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR Ͻ 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P ϭ not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P ϭ ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P ϭ 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P ϭ 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P ϭ 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P ϭ ns; and LT was performed in 32 (54%) vs. 42 (38%), P ϭ ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P ϭ 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation. Liver Transpl 14: [25][26][27][28][29][30] 2008 See Editorial on Page 7Acute liver failure (ALF) in children is a rare but often fatal condition without liver transplantation (LT). [1][2][3] Multiorgan dysfunction in ALF is believed to derive from oxidative stress due to reactive oxygen species and reactive nitrogen species 4 and from immunological injury mediated by cytokines. 5-8 N-acetylcysteine (NAC) is a thiol-containing agent that scavenges free oxygen radicals and replenishes cellular mitochon...

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“…3,4 NAC is thought to be of benefit in APAP-induced ALF primarily through repletion of hepatocellular glutathione stores, which are severely depleted following an acute toxic ingestion. Interestingly, even when NAC is administered later than 24 hours post-APAP ingestion, at a time when glutathione stores are likely no longer depleted, there is significant improvement in clinical outcome.…”

mentioning

confidence: 99%