Modulation of serum growth factor signal transduction in Hepa 1-6 cells by acetaminophen: an inhibition of c-myc expression, NF-kappaB activation, and Raf-1 kinase activity.
(17/1789)
Acetaminophen (APAP) is a widely used analgesic and antipyretic that can lead to severe liver damage when taken at excessive doses. APAP toxicity results when cytochrome P450-generated APAP metabolites trigger an oxidative stress and covalently modify target proteins. APAP has also been reported to inhibit cells from completing S-phase through a cytochrome P450-independent mechanism, raising the possibility that APAP may directly suppress liver regeneration and repair. Here we show that APAP also inhibits entrance of Hepa 1-6 cells into the cell cycle by blocking a number of events associated with the G0-G1 transition. We have found that APAP inhibits serum growth factor activation of c-myc expression, NF-kappaB DNA binding, and Raf kinase. Therefore, the ability of APAP to inhibit passage of cells through both G1 and S phases might interfere with organ regeneration and thus exacerbate acute liver damage caused by APAP. (+info)
Who gives pain relief to children?
(18/1789)
OBJECTIVE: To compare pre-hospital parental administration of pain relief for children with that of the accident and emergency (A&E) department staff and to ascertain the reason why pre-hospital analgesia is not being given. DESIGN/METHODS: An anonymous prospective questionnaire was given to parents/guardians of children < 17 years. The children were all self referred with head injuries or limb problems including burns. The first part asked for details of pain relief before attendance in the A&E department. The second part of the questionnaire contained a section for the examining doctor and triage nurse to fill in. The duration of the survey was 28 days. RESULTS: Altogether 203 of 276 (74%) of children did not receive pain relief before attendance at the A&E department. Reasons for parents not giving pain relief included 57/203 (28%) who thought that giving painkillers would be harmful; 43/203 (21%) who did not give painkillers because the accident did not happen at home; and 15/203 (7%) who thought analgesia was the responsibility of the hospital. Eighty eight of the 276 (32%) did not have any painkillers, suitable for children, at home. A&E staff administered pain relief in 189/276 (68%). CONCLUSIONS: Parents often do not give their children pain relief before attending the A&E department. Parents think that giving painkillers may be harmful and often do not have simple analgesics at home. Some parents do not perceive that their child is in pain. Parents require education about appropriate pre-hospital pain relief for their children. (+info)
BACKGROUND: Prostaglandin play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E2 (PGE2) in antinociception produced by intraperitoneally administered acetaminophen. METHODS: The PGE2 concentrations in the dorsal horn of the spinal cord were measured after formalin was injected into the hind paw of rats. The effect of antinociceptive doses of acetaminophen (100, 200, and 300 mg/kg given intraperitoneally) on PGE2 levels and flinching behavior was monitored Spinal PGE2 and acetaminophen concentrations were obtained by microdialysis using a probe that was implanted transversely through the dorsal horn of the spinal cord at L4. Furthermore, the effects of acetaminophen on urinary prostaglandin excretion were determined. RESULTS: Intraperitoneal administration of acetaminophen resulted in a significant decrease in spinal PGE2 release that was associated with a significant reduction in the flinching behavior in the formalin test Acetaminophen was distributed rapidly into the spinal cord with maximum dialysate concentrations 4560 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was not significantly altered after acetaminophen administration. CONCLUSIONS: The data confirm the importance of PGE2 in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE2 release. The mechanism, however, remains unknown. The finding that urinary excretion of prostaglandins was not affected might explain why acetaminophen is antinociceptive but does not compromise renal safety. (+info)
Morphine-sparing effect of acetaminophen in pediatric day-case surgery.
(20/1789)
BACKGROUND: Postoperative pain is a major problem in day-case surgery in children. Nonsteroidal antiinflammatory drugs have gained popularity in management of pediatric surgical patients to reduce the need for opioids. The aim of this study was to evaluate the efficacy of different doses of rectal acetaminophen in day-case surgery in children. METHODS: A randomized, double-blinded, placebo-controlled study design was used. Patients (n = 120) were randomized to receive a single dose of 0, 20, 40, or 60 mg/kg of rectal acetaminophen after induction of anesthesia. General anesthesia was induced by mask ventilation with sevoflurane (7%) in nitrous oxide and oxygen and maintained with 2.5-4.0% end-tidal sevoflurane. Opioids or local anesthetics were not used. Postoperative pain was evaluated by behavioral assessment and physiologic measurements every 10 min after arrival at the postanesthesia care unit. The pain intensity was scored using a 0-100 visual analog scale used in the authors' clinic. The need for rescue medication, intravenous morphine 0.1 mg/kg, was decided by the nurse, who was unaware of the rectal acetaminophen dose. The parents were interviewed by phone after 24 h regarding pain and its treatment, nausea, and vomiting. Rescue analgesia at home was rectal ibuprofen, 10 mg/kg. RESULTS: In the postanesthesia care unit pain scores were significantly lower in the 40- and 60-mg/kg groups compared with placebo and 20-mg/kg groups. Acetaminophen resulted in a dose-related reduction in the number of children who required postoperative rescue opioid, with significance reached with 40 or 60 mg/kg doses. Calculated dose of acetaminophen at which 50% of the children not requiring a rescue opioid was 35 mg/kg. The need for rescue analgesia at home during the first 24 h after surgery was also significantly less in patients in the 40- or 60-mg/kg groups than in the 0- or 20-mg/kg groups (20-17 vs. 80-63%). Thirty-three percent of patients receiving placebo had postoperative nausea and vomiting, compared with 0-3% in groups receiving 40 or 60 mg/kg acetaminophen. CONCLUSIONS: A single dose of 40 or 60 mg/kg of rectal acetaminophen has a clear morphine-sparing effect in day-case surgery in children if administered at the induction of anesthesia. Moreover, children with adequate analgesia with acetaminophen have less postoperative nausea and vomiting. (+info)
Role of CYP1A2 in the toxicity of long-term phenacetin feeding in mice.
(21/1789)
The mechanisms underlying phenacetin-induced toxicity and carcinogenicity are not clear. In particular, it is not known whether these effects are mediated by metabolic activation of the drug. CYP1A2 is known to metabolize phenacetin in vitro. To determine the role of this enzyme in vivo, the toxicity and carcinogenicity of phenacetin was examined in Cyp1a2-null mice (that lack CYP1A2). Six- to 8-week-old wild type (+/+) or null (-/-) mice were fed either a control diet, or one containing 1.25% phenacetin, ad libitum for up to 67 weeks. Representative groups of mice were examined for phenacetin-induced toxicity and carcinogenicity after 36, 48, 58, or 67 weeks of feeding. Consistent with the known role of CYP1A2 in phenacetin metabolism, plasma levels of phenacetin were higher and acetaminophen levels lower in the (-/-) mice fed phenacetin compared to phenacetin-fed (+/+) controls. Weight gain was significantly depressed in both groups of phenacetin-fed mice after 4 weeks of feeding, and continued to be lower for the remainder of the experiment, compared to controls. Hepatomegaly and splenomegaly were more severe in (-/-) mice but present in both genotypes fed phenacetin at all time points assessed. Histological analysis of liver, kidney, spleen, and urogenital tract also revealed a differential response in the (-/-) mice fed phenacetin compared to (+/+) mice fed the same diet. Further, mortality was the most severe in the (-/-) mice fed phenacetin than in all other groups. Despite significant toxicity in (-/-) mice fed phenacetin, only one renal carcinoma was found among them. Results from this work demonstrate that, in the absence of CYP1A2, phenacetin is more toxic than in controls. This provides evidence that metabolism of phenacetin by CYP1A2 alters toxicity in vivo, and suggests that alternate CYP1A2-independent metabolic pathways contribute to its toxicity. (+info)
Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells.
(22/1789)
The biochemical influence of flavonolignans from the milk thistle Silybum marianum has been tested on kidney cells of African green monkeys. Two nonmalignant cell lines were selected, with the focus of the work on the fibroblast-like Vero line. Proliferation rate, biosynthesis of protein and DNA, and the activity of the enzyme lactate dehydrogenase (as a measure of the cellular metabolic activity) were chosen as parameters for the effect of the flavonolignans. Silibinin and silicristin show remarkable stimulatory effects on these parameters, mainly in Vero cells; however, isosilibinin and silidianin proved to be inactive. In vitro experiments with kidney cells damaged by paracetamol, cisplatin, and vincristin demonstrated that administration of silibinin before or after the chemical-induced injury can lessen or avoid the nephrotoxic effects. The results warrant in vivo evaluations of the flavonolignan derivatives. (+info)
Novel CXCR2-dependent liver regenerative qualities of ELR-containing CXC chemokines.
(23/1789)
Severe acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELR-containing CXC chemokines such as macrophage inflammatory protein-2 (MIP-2), epithelial neutrophil-activating protein-78 (ENA-78), or interleukin 8. Intravenous administration of ELR-CXC chemokines or N-acetyl-cysteine (NAC) immediately after acetaminophen challenge in mice significantly reduced histological and biochemical markers of hepatic injury. However, when the intervention was delayed until 10 h after acetaminophen challenge, only ELR-CXC chemokines significantly reduced liver injury and mouse mortality. The delayed addition of ELR-CXC chemokines to cultured hepatocytes maintained the proliferation of these cells in a CXCR2-dependent fashion after acetaminophen challenge whereas delayed NAC treatment did not. These observations demonstrate that ELR-CXC chemokines represent novel hepatic regenerative factors that exhibit prolonged therapeutic effects after acetaminophen-induced hepatotoxicity. (+info)
Profound hepatocellular injury is often a consequence of adenovirus-mediated gene therapy or acetaminophen ingestion. The aim of the present study was to examine the role of a CXC chemokine, macrophage inflammatory protein-2 (MIP-2), in the hepatotoxic response by mice infected with adenovirus and challenged with acetaminophen. CD1 mice that received a replication-defective human type 5 adenovirus vector (Ad70-3) intravenously exhibited hepatic injury that peaked at 24 h after infection. In contrast, mice that received a similar adenovirus vector containing a rodent MIP-2 cDNA insert had no hepatic injury at any time after infection. The combination of Ad70-3 infection and an intraperitoneal challenge with 400 mg/kg of acetaminophen was fatal in 50% of the mice, but only 10% of the AdMIP-2 group receiving acetaminophen were similarly affected. Furthermore, AdMIP-2 mice had significantly lower hepatic injury and serum aminotransaminases compared with the Ad70-3 group. However, AdMIP-2 infection in mice lacking the CXC chemokine receptor that binds MIP-2, CXCR2, did not attenuate any of the markers of liver injury after adenovirus and acetaminophen challenge. AdMIP-2 treatment of CD1 mice was also associated with significantly decreased leukocyte infiltration into the liver and an earlier increase in hepatic 3H-thymidine incorporation compared with the control group. Taken together, these data demonstrate that MIP-2 has a protective role in both adenovirus- and acetaminophen-mediated hepatotoxicity, and suggest that MIP-2 may promote rapid hepatic regeneration following acute hepatic injury. (+info)