Acetaminophen toxicity. Opposite effects of two forms of glutathione peroxidase. (9/1789)

Acetaminophen is one of the most extensively used analgesics/antipyretics worldwide, and overdose or idiopathic reaction causes major morbidity and mortality in its victims. Research into the mechanisms of toxicity and possible therapeutic intervention is therefore essential. In this study, the response of transgenic mice overexpressing human antioxidant enzymes to acute acetaminophen overdose was investigated. Animals overexpressing superoxide dismutase or plasma glutathione peroxidase demonstrated dramatic resistance to acetaminophen toxicity. Intravenous injection of glutathione peroxidase provided normal mice with nearly complete protection against a lethal dose of acetaminophen. Surprisingly, animals overexpressing intracellular glutathione peroxidase in the liver were significantly more sensitive to acetaminophen toxicity compared with nontransgenic littermates. This sensitivity appears to be due to the inability of these animals to efficiently recover glutathione depleted as a result of acetaminophen metabolism. Finally, the results suggest that glutathione peroxidase overexpression modulates the synthesis of several acetaminophen metabolites. Our results demonstrate the ability of glutathione peroxidase levels to influence the outcome of acetaminophen toxicity.  (+info)

Randomised controlled trial of paracetamol for heel prick pain in neonates. (10/1789)

AIM: To evaluate the effectiveness of paracetamol in decreasing the pain from heel prick. METHODS: A prospective randomised double blind placebo controlled trial was conducted of 75 term neonates undergoing heel prick. Sixty to 90 minutes before the procedure neonates received paracetamol orally in a dose of 20 mg/kg (group 1) or an equal volume of placebo (group 2). Heel prick was performed in a standardised manner. Pain assessments were made using per cent facial action (brow bulge, eye squeeze, and nasolabial fold (range 0-300%) and per cent of time spent crying (range 0-100%). RESULTS: Thirty eight neonates were enrolled in group 1 and 37 neonates in group 2. There were no significant differences in the demographic characteristics between groups. Mean gestational age was 39 (SD 1.4) vs 39.4 (SD 1.2) weeks, p = 0.86, mean birthweight 3.45 (SD 0.45) vs 3.44 (SD 0.42) kg; p = 0.31 for groups 1 and 2, respectively. Facial action pain scores did not differ between groups (143.5 (SD 54.2)% vs 131.1 (SD 59.6)%; p = 0.38). Cry scores also did not differ (29.4 (SD 19.9)% vs 26.8 (SD 20.2)%; p = 0.60). No adverse effects were observed. CONCLUSION: Paracetamol is ineffective for decreasing the pain from heel prick in term neonates.  (+info)

Effects of a drug overdose in a television drama on presentations to hospital for self poisoning: time series and questionnaire study. (11/1789)

OBJECTIVES: To determine whether a serious paracetamol overdose in the medical television drama Casualty altered the incidence and nature of general hospital presentations for deliberate self poisoning. DESIGN: Interrupted time series analysis of presentations for self poisoning at accident and emergency departments during three week periods before and after the broadcast. Questionnaire responses collected from self poisoning patients during the same periods. SETTING: 49 accident and emergency departments and psychiatric services in United Kingdom collected incidence data; 25 services collected questionnaire data. SUBJECTS: 4403 self poisoning patients; questionnaires completed for 1047. MAIN OUTCOME MEASURES: Change in presentation rates for self poisoning in the three weeks after the broadcast compared with the three weeks before, use of paracetamol and other drugs for self poisoning, and the nature of overdoses in viewers of the broadcast compared with non-viewers. RESULTS: Presentations for self poisoning increased by 17% (95% confidence interval 7% to 28%) in the week after the broadcast and by 9% (0 to 19%) in the second week. Increases in paracetamol overdoses were more marked than increases in non-paracetamol overdoses. Thirty two patients who presented in the week after the broadcast and were interviewed had seen the episode-20% said that it had influenced their decision to take an overdose, and 17% said it had influenced their choice of drug. The use of paracetamol for overdose doubled among viewers of Casualty after the episode (rise of 106%; 28% to 232%). CONCLUSIONS: Broadcast of popular television dramas depicting self poisoning may have a short term influence in terms of increases in hospital presentation for overdose and changes in the choice of drug taken. This raises serious questions about the advisability of the media portraying suicidal behaviour.  (+info)

Tenoxicam and paracetamol-codeine combination after oral surgery: a prospective, randomized, double-blind, placebo-controlled study. (12/1789)

We studied 90 adults undergoing surgical removal of at least both lower third molar teeth as day cases under standardized general anaesthesia. Patients were allocated randomly (with stratification for surgeon) to receive tenoxicam 40 mg, tenoxicam 20 mg or placebo i.v. at induction of anaesthesia and orally (effervescent tablets) with food on each of the subsequent 2 days. Panadeine (paracetamol 500 mg-codeine 8 mg) was given before operation and was available as needed for pain thereafter, to a limit of two tablets every 4 h. Nefopam i.v. was also available. Efficacy variables and adverse reactions were assessed over 6 days. Over the 6-day period, patients who received tenoxicam reported less pain on rest (area under the curve; P < 0.05) and less disturbance in sleep (P < 0.01) even though they used fewer Panadeine tablets (P < 0.05). Differences between tenoxicam 40 mg and 20 mg were not significant. There was no significant difference in nefopam requirements or side effects, and no adverse event attributable to the study medication.  (+info)

Delay of gastric emptying by duodenal intubation: sensitive measurement of gastric emptying by the paracetamol absorption test. (13/1789)

AIMS: To examine the influence of duodenal intubation on gastric emptying measured by the paracetamol absorption test using a new algorithm developed to estimate emptying parameters, and to determine the sensitivity of this test. METHODS: A caloric liquid meal with paracetamol as marker of emptying was administered orally to eight healthy volunteers during phase I and phase II of the migrating motor complex (MMC) and without intubation on 3 separate days, and to 10 patients with partial gastrectomy. RESULTS: Healthy subjects: With duodenal tube, time until 25% of the meal had emptied (t25%) was 24+/-7 (phase I, P<0.02) and 21+/-6 min (phase II, P<0.02) compared with 14+/-4 min for meal intake without intubation. Time until 50% of the meal had emptied (t50%) was 45+/-8 (phase I, P<0.001) and 35+/-8 min (phase II, P<0.02) compared with 26+/-9 min for meal intake without intubation. Intraduodenal instillation of 10-20 mL of the liquid meal was reliably detected. PATIENTS: In 9 out of 10 patients with partial gastrectomy t25% was below the lower limit of the range for healthy controls, and t25% detected accelerated emptying with a higher degree of sensitivity than the commonly applied pharmacokinetic parameters Cmax and Tmax. CONCLUSIONS: A duodenal tube delays gastric emptying of a caloric liquid meal. The paracetamol absorption test emerges as a sensitive method suitable for detecting both delayed and accelerated gastric emptying of caloric liquid meals.  (+info)

Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. (14/1789)

AIM: To investigate the pharmacokinetics, metabolism, and dose-response relation of a single rectal dose of paracetamol in preterm infants in two different age groups. METHODS: Preterm infants stratified by gestational age groups 28-32 weeks (group 1) and 32-36 weeks (group 2) undergoing painful procedures were included in this study. Pain was assessed using a modified facies pain score. RESULTS: Twenty one infants in group 1 and seven in group 2 were given a single rectal dose of 20 mg/kg body weight. Therapeutic concentrations were reached in 16/21 and 1/7 infants in groups 1 and 2, respectively. Peak serum concentrations were significantly higher in group 1. Median time to reach peak concentrations was similar in the two groups. As serum concentration was still in the therapeutic range for some infants in group 1, elimination half life (T1/2) could not be determined in all infants: T1/2 was 11.0 +/- 5.7 in 11 infants in group 1 and 4.8 +/- 1.2 hours in group 2. Urinary excretion was mainly as paracetamol sulphate. The glucuronide:sulphate ratio was 0.12 +/- 0.09 (group 1) and 0.28 +/- 0.35 (group 2). The pain score did not correlate with therapeutic concentrations. CONCLUSIONS: A 20 mg/kg single dose of paracetamol can be safely given to preterm infants in whom sulphation is the major pathway of excretion. Multiple doses in 28-32 week old neonates would require an interval of more than 8 hours to prevent progressively increasing serum concentrations.  (+info)

Acetaminophen alters estrogenic responses in vitro: inhibition of estrogen-dependent vitellogenin production in trout liver cells. (15/1789)

The purpose of this study was to determine if acetaminophen altered estrogen-dependent vitellogenin production in isolated trout liver cells. Estrogen-induced vitellogenesis was studied in liver cells isolated from male trout and cultured in defined medium; vitellogenin secreted into culture medium was quantitated using immunological procedures. Vitellogenin production was absolutely dependent on the addition of estradiol (10(-6) M) to liver cells from male trout. Acetaminophen produced a dose-dependent inhibition of vitellogenin production; approximately 50% inhibition was achieved with 0.05 mM acetaminophen, while 0.3 mM acetaminophen inhibited secreted vitellogenin to undetectable levels. In contrast, these concentrations of acetaminophen (< or = 1 mM) did not significantly alter the production of secreted albumin, determined immunologically, or cause detectable toxicity. Higher doses of acetaminophen were toxic, but did not induce DNA fragmentation in the trout liver cells. Acetaminophen reduction of estradiol-induced vitellogenin production was accompanied by a dose-dependent decrease in vitellogenin mRNA, indicating acetaminophen inhibited a step prior to, or during, formation of vitellogenin mRNA. Estrogen receptor-binding assays demonstrated that acetaminophen did not reduce binding of [3H]-estradiol to trout liver estrogen receptor. In addition, catabolism of estradiol to water-soluble metabolites was not significantly altered by acetaminophen. These studies indicate that non-toxic concentrations of acetaminophen specifically inhibit estrogen-dependent vitellogenin synthesis and suggest that this commonly used drug may alter estrogen-regulated processes.  (+info)

The role of biotransformation in chemical-induced liver injury. (16/1789)

The role of drug metabolism in chemical-induced liver injury is reviewed. Parameters for studying the formation of chemically reactive metabolites are discussed and the factors that alter the formation and covalent binding of reactive metabolites are selectively emphasized. Some of the experimental work that led to these concepts is discussed, especially the chemical toxicology of the hepatic injury produced by acetaminophen, bromobenzene, furosemide, isoniazid and iproniazid.  (+info)