n-monoacetylcystine and Chemical-and-Drug-Induced-Liver-Injury

Acetaminophen (APAP) toxicity is the most common cause of acute liver failure in the US and Europe. Massive hepatocyte necrosis is the predominant feature of APAP-induced acute liver injury (ALI). Liver regeneration is a vital process for survival after a toxic insult, it occurs at a relative late time point after the injurious phase. Currently, N-acetylcysteine (NAC), a glutathione precursor, is the antidote for acetaminophen overdose. However, NAC is effective only for patients who present within hours of an acute overdose, and is less effective for late-presenting patients. It is possible that in delayed patients, previously reduced endogenous glutathione (GSH) level has restored and prolonged treatment with NAC might be toxic and impair liver regeneration. Therefore, we hypothesize that prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.. ALI was induced in C57BL/6 male mice by a single dose of APAP (350 mg/kg) by intraperitoneal injection. After two hours of APAP challenge, the mice were given 100 mg/kg NAC dissolved in 0.6 mL saline, or saline treatment every 12 hours for a total of 72 hours.. Seventy-two hours after APAP challenge, compared with saline treatment, NAC treatment significantly increased serum transaminases (alanine transaminase/aspartate aminotransferase), induced evident hepatocyte vacuolation in the periportal area and delayed liver regeneration seen in histopathology. This detrimental effect was associated with reduced hepatic nuclear factor (NF)-kappaB DNA binding and decreased expression of cell cycle protein cyclin D1, two important factors in liver regeneration.. Prolonged treatment with NAC impairs liver regeneration in ALI induced by APAP.

Topics: Acetaminophen; Alanine Transaminase; Analgesics, Non-Narcotic; Animals; Antidotes; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cystine; Disease Models, Animal; Drug Overdose; Glutathione; Male; Mice; Mice, Inbred C57BL; Time Factors; Treatment Outcome

Two cases of unintentional paracetamol overdose are presented. Over a one month period these patients presented to an Accident and Emergency (A&E) department with symptoms of paracetamol toxicity, following the ingestion of large quantities of analgesia for the self treatment of dental pain. In one case the patient had no access to a dentist. Both patients required admission under the care of the medical on-call team and required anti-toxicity treatment to prevent permanent liver injury. Subsequent referrals were made to the oral and maxillofacial surgery team who provided emergency dental treatment and advice on further dental care. This paper highlights the significant signs and symptoms of paracetamol overdose about which dental practitioners should be aware. It also describes the management principles required to prevent potentially life threatening liver damage. Discussion is also made of the potential impact on patients struggling to cope with pulpal pain without access to a general dental practitioner.

Topics: Acetaminophen; Adult; Analgesics, Non-Narcotic; Analgesics, Opioid; Antidotes; Chemical and Drug Induced Liver Injury; Cystine; Drug Overdose; Female; Humans; Male; Nerve Block; Pulpitis; Toothache

A 1-year-old child with severe acetaminophen (APAP) poisoning after ingestion of 10 gm APAP demonstrated central nervous system depression, shock, hypothermia, and metabolic acidosis. There was dramatic improvement during treatment with intravenously administered N-acetylcysteine (NAC) and hemodialysis, and the patient recovered without sequelae. A detailed study of APAP metabolism was carried out during the initial 72 hours after ingestion. APAP-sulfate and APAP-glucuronide accounted for 29% and 33%, respectively, of total drug in urine, whereas cysteine and NAC conjugates accounted for only 12%. The low incidence of severe toxicity in children after overdoses of APAP may be related to greater capacity to metabolize APAP via a nontoxic pathway.

Topics: Acetaminophen; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Cystine; Hepatomegaly; Humans; Hypothermia; Infant; Kinetics; Liver Function Tests; Male

Topics: Acetaminophen; Adult; Chemical and Drug Induced Liver Injury; Cystine; Humans; Male; Necrosis