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Despite pathophysiological similarities to alcoholic liver disease, susceptibility to acetaminophen hepatotoxicity in metabolic syndrome-related nonalcoholic steatohepatitis (NASH) has not been well elucidated. In this study, therefore, we investigated acetaminophen-induced liver injury in KK-[A.sup.y] mice, an animal model of metabolic syndrome. Twelve-week-old male KK-[A.sup.y] and C57B1/6 mice were injected intraperitoneally with 300 or 600 mg/kg acetaminophen, and euthanized 6 h later. Liver histology was assessed, and hepatic expression of 4-hydroxy-2-nonenal was detected by immunohistochemistry. Levels of reduced glutathione were determined spectrophotometrically. Phosphorylation of c-Jun N[H.sub.2]-terminal kinase (JNK) was analyzed by Western blotting. Hepatocytes were isolated from both strains by collagenase perfusion, and cell death and oxidative stress were measured fluorometrically by use of propidium iodide and 5-(and-6)-chloromethyl-2'7'-dichlorodihydrofluorescein diacetate acetyl ester, respectively. Acetaminophen induced more severe necrosis and apoptosis of hepatocytes in KK-[A.sup.y] mice than in C57B1/6 mice and significantly increased serum alanine aminotransferase levels in KK-[A.sup.y] mice. Acetaminophen-induction of 4-hydroxy-2-nonenal in the liver was potentiated, whereas the levels of reduced glutathione in liver were lower in KK-[A.sup.y] mice. Acetaminophen-induced phosphorylation of JNK in the liver was also enhanced in KK-[A.sup.y] mice. Exposure to 20 [micro]M tert-butyl hydroperoxide did not kill hepatocytes isolated from C57B1/6 mice but induced cell death and higher oxidative stress in hepatocytes from KK-[A.sup.y] mice. These results demonstrated that acetaminophen toxicity is increased in diabetic KK-[A.sup.y] mice mainly due to enhanced oxidative stress in hepatocytes, suggesting that metabolic syndrome-related steatohepatitis is an exacerbating factor for acetaminophen-induced liver injury. drug-induced liver injury; metabolic syndrome; steatohepatitis; oxidative stress; hepatotoxicity doi: 10.1152/ajpgi.00361.2009.

Summary Paracetamol and ibuprofen are safe and effective medications for reducing a fever in children and young people and they are often administered together with a view to reducing a [...]

Hemoproteins, hemoglobin and myoglobin, once released from cells can cause severe oxidative damage as a consequence of heine redox cycling between ferric and ferryl states that generates radical species that induce lipid peroxidation. We demonstrate in vitro that acetaminophen inhibits hemoprotein-induced lipid peroxidation by reducing ferryl heme to its ferric state and quenching globin radicals. Severe muscle injury (rhabdomyolysis) is accompanied by the release of myoglobin that becomes deposited in the kidney, causing renal injury. We previously showed in a rat model of rhabdomyolysis that redox cycling between ferric and ferryl myoglobin yields radical species that cause severe oxidative damage to the kidney. In this model, acetaminophen at therapeutic plasma concentrations significantly decreased oxidant injury in the kidney, improved renal function, and reduced renal damage. These findings also provide a hypothesis for potential therapeutic applications for acetaminophen in diseases involving hemoprotein-mediated oxidative injury. isoprostanes | oxidative damage | hemoglobin | myoglobin www.pnas.org/cgi/doi/10.1073/pnas.0910174107

The clinical aspects of acetaminophen poisoning and its treatment with acetylcysteine are discussed with reference to the case study of a 25-year-old man presenting to a hospital emergency department with a toothache that he attempted to treat with over-the-counter acetaminophen.

Byline: A. Bhagyashree, Shyamjith. Manikkoth, Melinda. Sequeira, Roopa. Nayak, S. Rao Objective: Even after 100 years of discovery, the exact mechanisms for the analgesic action of paracetamol are under scanner. [...]

INTRODUCTION. The main action of paracetamol (acetaminophen) is presumed to be in the central nervous system. The central nervous system penetration of paracetamol has been described in children with intracranial pathologies but not in children with an intact blood-brain barrier. OBJECTIVE. We investigated the cerebrospinal fluid penetration of paracetamol in 32 healthy children, aged 3 months to 12 years, who were undergoing surgery in the lower body using spinal anesthesia. MATERIALS AND METHODS. In this open-label prospective study, children were given a single intravenous injection of paracetamol (15 mg/kg). Cerebrospinal fluid and venous blood samples were obtained between 5 minutes and 5 hours after injection. Paracetamol concentrations were determined from the cerebrospinal fluid and plasma by using a fluorescence polarization immunoassay. RESULTS. Paracetamol was detected in cerebrospinal fluid from the earliest sample at 5 minutes, although in this sample paracetamol concentration was below the limit of quantification of 1.0 mg/L. Subsequent paracetamol concentrations in cerebrospinal fluid ranged between 1.3 and 18 mg/L (median: 7.2 rag/L), plasma concentrations ranged between 2.4 and 33 mg/L, and cerebrospinal fluid/plasma ratios ranged between 0.06 and 2.0. The highest CSF paracetamol concentration was detected at 57 minutes. CONCLUSIONS. Paracetamol permeates readily into the cerebrospinal fluid of children. This fast and extensive transfer enables the rapid central analgesic and antipyretic action of intravenous paracetamol. Key Words acetaminophen, paracetamol, cerebrospinal fluid, pharmacokinetics, child, infant, PARACETAMOL (acetaminophen) is the most commonly used antipyretic analgesic in children for the symptomatic treatment of acute pain and fever. At sufficient enteral dosage, paracetamol is effective alone for the [...]

We aimed to determine whether nitroparacetamol (NO-paracetamol) and paracetamol exhibit cardioprotective effects. Myocardial infarction (MI) was induced in rats, and drug treatment was started 1 wk before surgery. Mortality rate and infarct size at 2 days after MI were compared. Treatment groups included vehicle (saline), paracetamol (5 mg * [kg.sup.-1] * [day.sup.-1]) and NO-paracetamol (15 mg * [kg.sup.-1] * [day.sup.-1]). Mortality rates for vehicle (n = 80), paracetamol (n = 79), and NOparacetamol (n = 76) groups were 37.5%, 21.5%, and 26.3%, respectively. Infarct size for the vehicle group was 44.8% ([+ or -] 6.1%) of the left ventricle (LV). For the paracetamol and NO-paracetamol groups, infarct size was 31.3% ([+ or -]5.6%) and 30.7% ([+ or -] 8.1%) of the LV, respectively. Both paracetamol- and NO-paracetamol-treated groups showed increased activities of catalase and SOD compared with the vehicle group. They could attenuate endothelial, inducible, and neuronal nitric oxide synthase and cyclooxygenase-1 and -2 gene expression after MI. The observation indicates the potential clinical significance of the cardioprotective effects of these drugs. infarct size; cardioprotection

Purpose. Bone metastasis is one of the major causes of cancer-related pain, and not all bone cancer pain can be effectively treated. Recently, a mouse model of bone cancer pain [...]

ABSTRACT: Medications are useful in the treatment of patients with acute low back pain (LBP). Acetaminophen, a first-line agent for osteoarthritis pain, can be used as an analgesic for acute [...]

Objectives. To compare the defervescent effect of high-dose rectal suppository acetaminophen with the recommended oral and rectal dosages and to evaluate acceptability of rectal acetaminophen. Methods. A randomized, controlled trial was performed in 70 patients aged 6 months to 6 years with fever [greater than or equal to] 39[degrees]C. Group A received rectal acetaminophen 15 mg/ kg, group B received rectal acetaminophen 30 mg/kg, and group C received oral acetaminophen 15 mg/kg. Primary outcome was maximal change in temperature during the 3-hour study period after initial treatment. Results. There were 24 patients in group A, 23 in group B, and 23 in group C. There was no significant difference in temperature change between the groups during the 3 hours or in the maximum drop in temperature or final temperature. Visual analog scores for satisfaction of parents did not reveal any significant differences between the oral and rectal routes. Conclusions. There was no difference between the temperature decrement in patients treated with 15 mg/kg oral acetaminophen and the same or double dose rectally. Thus, there seems to be no evidence to support the use of higher doses of rectal acetaminophen for the treatment of fever in children. The rectal route proved to be as acceptable as the oral among parents. Pediatrics 2002;110:553-556; acetaminophen, fever, rectal, dose., Acetaminophen is the most commonly used drug in pediatrics. (1) For routine clinical use, it is administered in oral and rectal forms, as a tablet, liquid, or suppository. The rectal [...]