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PubMed1988

Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985)

During the investigational use of oral N-acetylcysteine as an antidote for poisoning with acetaminophen, 11,195 cases of suspected acetaminophen overdose were reported. We describe the outcomes of 2540 patients with acetaminophen ingestions treated with a loading dose of 140 mg of oral N-acetylcysteine per kilogram of body weight, followed four hours later by 70 mg per kilogram given every four hours for an additional 17 doses. Patients were categorized for analysis on the basis of initial plasma acetaminophen concentrations and the interval between ingestion and treatment. Hepatotoxicity developed in 6.1 percent of patients at probable risk when N-acetylcysteine was started within 10 hours of acetaminophen ingestion and in 26.4 percent of such patients when therapy was begun 10 to 24 hours after ingestion. Among patients at high risk who were treated 16 to 24 hours after an acetaminophen overdose, hepatotoxicity developed in 41 percent--a rate lower than that among historical controls. When given within eight hours of acetaminophen ingestion, N-acetylcysteine was protective regardless of the initial plasma acetaminophen concentration. There was no difference in outcome whether N-acetylcysteine was started zero to four or four to eight hours after ingestion, but efficacy decreased with further delay. There were 11 deaths among the 2540 patients (0.43 percent); in the nine fatal cases in which aminotransferase was measured before treatment, values were elevated before N-acetylcysteine was started. No deaths were clearly caused by acetaminophen among patients in whom N-acetylcysteine therapy was begun within 16 hours. We conclude that N-acetylcysteine treatment should be started within eight hours of an acetaminophen overdose, but that treatment is still indicated at least as late as 24 hours after ingestion. On the basis of available data, the 72-hour regimen of oral N-acetylcysteine is as effective as the 20-hour intravenous regimen described previously, and it may be superior when treatment is delayed.

Acetaminophen↗
PubMed2001

Nephrotoxicity after acute severe acetaminophen poisoning in adolescents.

OBJECTIVE: To determine the rate of acetaminophen related nephrotoxicity in adolescents who present after acute severe acetaminophen intoxication and to identify potential predictors of this outcome. STUDY DESIGN: Retrospective analysis of consecutive patients between the ages of 12 and 18 years who were admitted at a tertiary care children's hospital for treatment of acute severe acetaminophen intoxication with N-acetylcysteine. The main outcome measure was the frequency of acetaminophen-related nephrotoxicity, defined as abnormal blood urea nitrogen (>6.4 mmol/L or > 18 mg/dL) and/or elevated creatinine (97.2 micromol/L or > 1.1 mg/dL) in association with one or both of the following: elevated blood pressure (systolic blood pressure > 140 mm Hg/diastolic blood pressure >85) or abnormal urinalysis (urinalysis with hematuria or proteinuria). Statistical analyses used were measures of central tendency, Student's t-test, Mann-Whitney, and multivariate logistic regression. RESULTS: Fourty-five patients were included. Acetaminophen-related nephrotoxicity occurred in 4 (8.9%) cases. One victim developed severe renal injury in association with elevated hepatic transaminases. Intergroup analyses revealed no statistically significant association between acetaminophen-related nephrotoxicity and amount/kg of acute severe acetaminophen ingested, delay in treatment with N-acetylcysteine, or measures of hepaticfunction. CONCLUSIONS: Acetaminophen-related nephrotoxicity occurred in 8.9% [95% CI: 4.52, 20.48] of children with severe overdose. There are no obvious predictors of this complication of acetaminophen overdose. Because the occurrence of renal injury can not be predicted, serial blood pressure, blood urea nitrogen/creatinine, and urinalysis should be considered an integral part of the management of children with acute, severe acetaminophen intoxication.

Acetaminophen↗
PubMed2001

Vascular and hepatocellular peroxynitrite formation during acetaminophen toxicity: role of mitochondrial oxidant stress.

Peroxynitrite may be involved in acetaminophen-induced liver damage. However, it is unclear if peroxynitrite is generated in hepatocytes or in the vasculature. To address this question, we treated C3Heb/FeJ mice with 300 mg/kg acetaminophen and assessed nitrotyrosine protein adducts as indicator for peroxynitrite formation. Vascular nitrotyrosine staining was evident before liver injury between 0.5 and 2 h after acetaminophen treatment. However, liver injury developed parallel to hepatocellular nitrotyrosine staining between 2 and 6 h after acetaminophen. The mitochondrial content of glutathione disulfide, as indicator of reactive oxygen formation determined 6 h after acetaminophen, increased from 2.8 +/- 0.6% in controls to 23.5 +/- 5.1%. A high dose of allopurinol (100 mg/kg) strongly attenuated acetaminophen protein-adduct formation and prevented the mitochondrial oxidant stress and liver injury after acetaminophen. Lower doses of allopurinol, which are equally effective in inhibiting xanthine oxidase, were not protective and had no effect on nitrotyrosine staining and acetaminophen protein adduct formation. In vitro experiments showed that allopurinol is not a direct scavenger of peroxynitrite. We conclude that there is vascular peroxynitrite formation during the first 2 h after acetaminophen treatment. On the other hand, reactive metabolites of acetaminophen bind to intracellular proteins and cause mitochondrial dysfunction and superoxide formation. Mitochondrial superoxide reacts with nitric oxide to form peroxynitrite, which is responsible for intracellular protein nitration. The pathophysiological relevance of vascular peroxynitrite for hepatocellular peroxynitrite formation and liver injury remains to be established.

Acetaminophen↗
PubMed2002

Acetaminophen-induced proliferation of estrogen-responsive breast cancer cells is associated with increases in c-myc RNA expression and NF-kappaB activity.

Studies reported here tested the hypothesis that acetaminophen stimulates proliferation of E2-responsive cells by inducing expression of E2-regulated genes. Ribonuclease protection assays compared the effects of acetaminophen and E2 on expression of selected genes (c-myc, c-fos, cyclin D1, bcl-2, bax, gadd45, mcl-1, p53, p21(CIP1/WAF1), and bcl-xL) in E2-responsive breast cancer (MCF-7) and endometrial adenocarcinoma (Ishikawa) cells as well as in E2-nonresponsive (MDA-MB-231) breast cancer cells. Acetaminophen and E2 increased c-myc RNA levels in MCF-7 cells, consistent with a mitogenic activity of these compounds in MCF-7 cells. However, the magnitude and time course of acetaminophen and E2 induction of c-myc differed. Neither acetaminophen nor E2 induced c-myc in MDA-MB-231 cells, whereas E2, but not acetaminophen, weakly induced c-myc expression in Ishikawa cells. Furthermore, in these 3 cell types, the expression patterns of the other genes differed dramatically in response to acetaminophen and to E2, indicating that acetaminophen does not activate ER as a transcription factor in the same manner as does E2. Additionally, gel shift assays demonstrated that in MCF-7 cells, acetaminophen increased NF-kappaB activity approximately 40% and did not alter AP-1 activity, whereas E2 increased AP-1 activity approximately 50% and did not increase NF-B activity. These studies indicate that acetaminophen effects on gene expression and cell proliferation depend more on cell type/context than on the presence of ER.

Acetaminophen↗
PubMed2005

Cellular mechanisms of acetaminophen: role of cyclo-oxygenase.

Acetaminophen is one of the most commonly used drugs for the safe and effective treatment of pain and fever. Acetaminophen works by lowering cyclo-oxygenase products preferentially in the central nervous system, where oxidant stress is strictly limited. However, the precise mechanism of action for acetaminophen on cyclo-oxygenase activity is debated. Two theories prevail. First, it is suggested that acetaminophen selectively inhibits a distinct form of cyclo-oxygenase, cyclo-oxygenase-3. Second, it is suggested that acetaminophen has no affinity for the active site of cyclo-oxygenase but instead blocks activity by reducing the active oxidized form of cyclo-oxygenase to an inactive form. Here, we have used an in vitro model of cyclo-oxygenase-2 activity (A549 cells stimulated with IL-1beta) to show that acetaminophen is an effective inhibitor of cyclo-oxygenase activity in intact cells. However, acetaminophen, unlike nonsteroidal anti-inflammatory drugs (NSAIDs), cannot inhibit activity in broken cell preparations. The inhibitory effects of acetaminophen were abolished by increasing intracellular oxidation conditions with the cell-permeable hydroperoxide t-butylOOH. Similarly the inhibitory effects of the cyclo-oxygenase-2 selective inhibitor rofecoxib or the mixed cyclo-oxygenase-1/cyclo-oxygenase-2 inhibitors ibuprofen and naproxen were significant reduced by t-butylOOH. By contrast, the inhibitory effects of indomethacin or diclofenac, which also inhibit both cyclo-oxygenase-1 and cyclo-oxygenase-2, were unaffected by t-butylOOH. These observations dispel the notion that cyclo-oxygenase-3 is involved in the actions of acetaminophen and provide evidence that supports the theory that acetaminophen interferes with the oxidation state of cyclo-oxygease. Moreover, they suggest for the first time that the inhibitory effects of some NSAIDs, including the newly introduced cyclo-oxygenase-2 selective inhibitor rofecoxib, owe part of their inhibitory actions to effects on oxidation state of cyclo-oxygenase. Our data with t-butylOOH and NSAIDs illustrates an, as yet, undeveloped therapeutic window for the "cyclo-oxygenase inhibitor". Specifically, combining active site selectively with actions on enzyme oxidation state would allow for a broader range of tissue selective drugs.

Acetaminophen↗
PubMed2002

The efficacy of premedication with celecoxib and acetaminophen in preventing pain after otolaryngologic surgery.

UNLABELLED: Non-opioid analgesics are often used to supplement opioids for the management of perioperative pain. In this randomized, double-blinded, placebo-controlled study, we examined the effects of acetaminophen and a cyclooxygenase type-2 inhibitor, celecoxib, when administered alone or in combination, before elective otolaryngologic surgery in 112 healthy outpatients. Subjects were assigned to 1 of 4 study groups: Group 1, placebo (vitamin C, 500 mg per os [PO]); Group 2, acetaminophen 2000 mg PO; Group 3, celecoxib 200 mg PO; or Group 4, acetaminophen 2000 mg and celecoxib 200 mg PO. All patients received a standardized anesthetic technique. During the postoperative period, pain was assessed using a 10-point verbal rating scale. Recovery times, the need for rescue analgesics, side effects, and patient satisfaction scores were also recorded. The combination of acetaminophen and celecoxib was significantly more effective than placebo in reducing postoperative pain. Celecoxib, when administered alone or in combination with acetaminophen, improved patients' satisfaction with their postoperative analgesia. With the combination of acetaminophen and celecoxib, an additional expenditure of $6.16 would be required to obtain complete satisfaction with postoperative pain management in one additional patient who would not have been completely satisfied if he/she had received the placebo. However, oral celecoxib or acetaminophen alone was not significantly more effective than placebo in reducing postoperative pain when administered before surgery. We conclude that oral premedication with a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was highly effective in decreasing pain and improving patient satisfaction after outpatient surgery. IMPLICATIONS: Oral premedication with a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was effective in decreasing pain and improving patient satisfaction after otolaryngologic surgery. However, acetaminophen (2000 mg) or celecoxib (200 mg) alone was not significantly more effective than placebo in reducing postoperative pain.

Acetaminophen↗
PubMed1999

Acetaminophen inhibits spinal prostaglandin E2 release after peripheral noxious stimulation.

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.

Acetaminophen↗
PubMed2003

The role of 5-HT1A/B autoreceptors in the antinociceptive effect of systemic administration of acetaminophen.

BACKGROUND: It has been proposed that serotonin participates in the central antinociceptive effect of acetaminophen. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. In the presence of serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei leads to an increase in serotonin release in terminal areas, thus improving serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors in the antinociceptive effect of acetaminophen in mice. METHODS: The effects of acetaminophen (600 mg/kg intraperitoneal) followed by different doses of antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129 [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively, were determined in the hot-plate test in mice. RESULTS: Acetaminophen (300-800 mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B antagonist) induced a dose-related increase in the antinociceptive effect of acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased the antinociceptive effect of acetaminophen. CONCLUSIONS: These results suggest that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B antagonist properties could be a new strategy to improve the analgesia of acetaminophen, thanks to its mild serotonergic properties.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMedDate not supplied

Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee.

Nonprescription doses of naproxen sodium, acetaminophen, and placebo were compared to determine their efficacy and safety in osteoarthritis of the knee. In two identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients with osteoarthritis aged (mean +/- SD) 60.6 +/- 12.8 years were randomized to daily doses of 660 mg naproxen sodium (440 mg naproxen sodium in patients >or=65 years), 4000 mg acetaminophen, or placebo for 7 days. Naproxen sodium (440/660 mg) provided significantly greater improvements in pain at rest, on passive motion, on weight-bearing, stiffness after rest (morning), day and night pain compared with placebo, and significantly greater relief from resting pain than acetaminophen (P < 0.05). Acetaminophen provided significantly greater improvements in day pain compared with placebo. Daily evaluations showed naproxen sodium (440/660 mg) provided superior pain relief to acetaminophen and was significantly better than acetaminophen at reducing difficulties experienced in walking several blocks and difficulties in bending, lifting, and stooping. Naproxen sodium (440/660 mg) and acetaminophen (4000 mg) were significantly more effective than placebo in improving mobility level, household tasks, and walking and bending. Patient and investigator evaluation scores were significantly higher in naproxen sodium and acetaminophen groups compared with placebo; no differences were observed between active treatments. Naproxen sodium and acetaminophen had similar safety profiles to placebo. Nonprescription doses of naproxen sodium (440/660 mg) effectively relieve pain and other symptoms of osteoarthritis. Naproxen sodium is an alternative in the initial treatment of osteoarthritis and may be preferred to acetaminophen as first-line therapy in patients with moderate or severe pain.

Acetaminophen↗
PubMed2003

Acetaminophen-induced hepatotoxicity.

The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1beta is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.

Acetaminophen↗
PubMed1995

In vivo murine studies on the biochemical mechanism of acetaminophen cataractogenicity.

C57BL/6 and DBA/2 mice are, respectively, susceptible and resistant both to the induction of aryl hydrocarbon hydroxylase (cytochrome P450 1A1, or CYP1A1) and to the cataractogenicity of acetaminophen, which may involve its bioactivation to a toxic reactive intermediate, catalysed by P450 and (or) prostaglandin H synthase (PHS). Following induction of P450 using beta-naphthoflavone, the cataractogenicity of acetaminophen (400 mg/kg ip) in C57BL/6 mice was reduced by pretreatment with the P450 inhibitors SKF 525A and metyrapone, the glutathione precursor N-acetylcysteine, the antioxidant vitamin E, and the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (p < 0.05). Acetaminophen (200 mg/kg) cataractogenicity was enhanced by pretreatment with the glutathione depletor diethyl maleate (DEM) and the gamma-glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) (p < 0.05). No significant effect on acetaminophen cataractogenicity was observed using the PHS cyclooxygenase inhibitors aspirin or naproxen, or the glutathione reductase inhibitor 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Accordingly, acetaminophen cataractogenicity in C57BL/6 mice does not appear to be dependent upon bioactivation by PHS. In DBA/2 mice treated with beta-naphthoflavone, a high dose of acetaminophen (750 mg/kg ip) was not cataractogenic, even after pretreatment with DEM, BSO, or BCNU. The resistance of DBA/2 mice to acetaminophen cataractogenesis, despite concomitant pretreatments with an inducer of P450 and several agents that interfere with glutathione-dependent detoxifying pathways, suggests differences in this strain involving cytoprotective pathways subsequent to acetaminophen bioactivation and detoxification of the cataractogenic reactive intermediate. These results indicate that acetaminophen cataractogenicity in C57BL/6 mice results from P450-catalysed bioactivation of acetaminophen to a reactive intermediate, possibly a benzoquinone imine and (or) a free radical, the toxicity of which is reduced by glutathione-dependent reactions.

Acetaminophen↗
PubMed2006

Role of acetaminophen in acute myocardial infarction.

Acetaminophen, the active ingredient in Tylenol, is a widely used drug that is well known for its analgesic and antipyretic properties. Acetaminophen is a commonly used alternative to nonsteroidal anti-inflammatory drugs, which have recently been demonstrated to increase mortality after acute myocardial infarction (AMI). The safety and potential cardioprotective properties of acetaminophen in the setting of AMI have recently been investigated; however, the results from these studies have been inconclusive. Using both large (ovine) and small (rabbit) collateral-deficient animal models, we studied the effects of acetaminophen in the setting of reperfused AMI. In both species we studied the effects of acetaminophen on myocardial salvage and ventricular function. Additionally, we studied the effects of acetaminophen on myocardial perfusion in sheep and on myocyte apoptosis in rabbits. Sixteen sheep and twenty-two rabbits were divided into two groups and administered acetaminophen or a vehicle before undergoing ischemia and reperfusion. The ischemic period was 60 min in sheep and 30 min in rabbits. All animals were reperfused for 3 h. There were no significant differences observed in myocardial perfusion, myocyte apoptosis, or infarct size in acetaminophen-treated animals. Acetaminophen increased cardiac output and mean arterial pressure before ischemia in sheep but had no effect on any other hemodynamic parameter. In rabbits, no effect on cardiac output or blood pressure was detected. These results support the role of acetaminophen as a safe drug in the postmyocardial infarction setting; however, no significant cardioprotective effect of the drug could be demonstrated.

Acetaminophen↗
PubMed2004

Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells.

Acetaminophen is a widely used antipyretic and analgesic drug whose mechanism of action has recently been suggested to involve inhibitory effects on prostaglandin synthesis via a newly discovered cyclooxygenase variant (COX-3). Because COX-3 expression is high in cerebral endothelium, we investigated the effect of acetaminophen on the prostaglandin production of cultured rat cerebral endothelial cells (CECs). Acetaminophen dose-dependently inhibited both basal and LPS-induced PGE(2) production in CECs with IC(50) values of 15.5 and 6.9 microM, respectively. Acetaminophen also similarly inhibited the synthesis of 6-keto-PGF(1alpha) and thromboxane B(2). LPS stimulation increased the expression of COX-2 but not COX-1 or COX-3. In addition, the selective COX-2 inhibitor NS398 (1 microM) was equally as effective as acetaminophen in blocking LPS-induced PGE(2) production. Acetaminophen did not influence the expression of the three COX isoforms and the inducible nitric oxide synthase. In LPS-stimulated isolated cerebral microvessels, acetaminophen also significantly inhibited PGE(2) production. Our results show that prostaglandin production in CECs during basal and stimulated conditions is very sensitive to inhibition by acetaminophen and suggest that acetaminophen acts against COX-2 and not COX-1 or COX-3. Furthermore, our findings support a critical role for cerebral endothelium in the therapeutic actions of acetaminophen in the central nervous system.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Influence of advanced age on the formation and elimination of acetaminophen metabolites by male rats.

The effects of aging on acetaminophen metabolism and elimination in male Fischer 344 rats were examined after intravenous injection of 300 mg/kg. Age as a variable had only a small effect on the total clearance of acetaminophen. However, the fraction of administered dose recovered from urine as acetaminophen sulfate and the partial clearance to acetaminophen sulfate decreased while the fraction recovered as acetaminophen glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. Renal clearances of acetaminophen and acetaminophen glucuronide were unchanged while that of acetaminophen sulfate decreased. These data point to an age-related decrease in sulfation and increase in glucuronidation of acetaminophen and further emphasize that the major conjugated metabolites are excreted by renal transport processes that operate under separate control. Moreover, they raise the possibility that advancing age may be accompanied by a general decline in processes that govern sulfate conjugate formation and elimination.

Acetaminophen↗
PubMed1999

Acute effects of acetaminophen on renal function and urinary excretion of some proteins and enzymes in patients with kidney disease.

The acute effects of acetaminophen, a commonly used as analgesic drug, upon the urinary excretion of some proteins and enzymes as markers of kidney damage, was investigated. Patients with chronic glomerulonephritis (GN) and Balkan endemic nephropathy (BEN), having kidney vulnerable to toxic drugs, were enrolled in the study. Timed urine specimens were collected: before drug administration, and in 3-hour periods for 24 hours after an oral dose of 2 g of acetaminophen. Urinary excretion of albumin before acetaminophen treatment was significantly higher in patients with GN and BEN than in healthy adults, however, beta 2-microglobulin excretion was increased in BEN patients only. Urinary excretion of creatinine markedly increased immediately after acetaminophen ingestion. Urinary excretion of total protein and albumin was not changed after acetaminophen administration. However, acetaminophen treatment produced a significant increase in beta 2-microglobulin excretion in patient with BEN and GN, and in clinically healthy members of nephropathic families. Excretion of aminopeptidase N (APN) activity before acetaminophen treatment was significantly higher in patients with GN, however, NAGA excretion was higher in both GN and BEN patients than in healthy controls. After acetaminophen administration urinary excretion of APN, dipeptidylpeptidase IV (DPP IV), gamma-glutamyltranspeptidase (GGT) and N-acetyl-beta-D-glucosaminidase (NAGA) did not increase significantly in any group studied. This study has shown that urinary excretion of APN, DPP IV, NAGA and GGT, as markers of kidney brush border and lysosomal damage, did not change after 2 g of acetaminophen taken orally. beta 2-microglobulin was a marker of acute acetaminophen nephrotoxicity in kidney disease patients and in clinically healthy adults from nephropathic families.

Acetaminophen↗
PubMed1999

Protective effect of chlormethiazole, a sedative, against acetaminophen-induced liver injury in mice.

OBJECTIVES: The hepatotoxicity of acetaminophen is not a result of the parent compound but is mediated by its reactive metabolite N-acetyl-p-benzoquinone imine. Cytochrome P4502E1 (CYP2E1) is the principal enzyme of this biotransformation, which accounts for approximately 52% of the bioactivation in human microsomes. Recently, chlormethiazole a sedative drug, is reported to be an efficient inhibitor of CYP2E1 activity in human beings. In this study we wished to evaluate whether chlormethiazole, an inhibitor of CYP2E1, could prevent acetaminophen-induced liver injury in mice. METHODS: Acetaminophen, at doses ranging from 200 to 600 mg/kg, was injected into the peritoneum of female C57BL/6 inbred mice fasted for four hours. Chlormethiazole (60 mg/kg) or 5% dextrose water was given 30 min before or 2 h after acetaminophen. Serum aminotransferase activities, histologic index score, survival rate and hepatic malondialdehyde levels were compared. RESULTS: Pretreatment with chlormethiazole 30 min before 400 mg/kg of acetaminophen completely inhibited acetaminophen-induced liver injury (median 118.5 U/L, range 75 to 142 vs. 14,070 U/L, range 5980 to 27,680 for AST; 49 U/L, range 41 to 64 vs. 15,330 U/L, range 13,920 to 15,940 for ALT). In mice receiving chlormethiazole 2 h after acetaminophen, the mean AST and ALT levels were also less elevated, reaching only 20% of the value of acetaminophen-only group. These protective effects were confirmed histologically. Whereas more than 50% of mice died at 500 mg/kg of acetaminophen, all the mice pretreated with chlormethiazole survived at the same dose. CONCLUSION: Chlormethiazole effectively reduces acetaminophen-induced liver injury in mice. Further studies are needed to assess its role in humans.

Acetaminophen↗
PubMed1990

Glutathione and ascorbate reduction of the acetaminophen radical formed by peroxidase. Detection of the glutathione disulfide radical anion and the ascorbyl radical.

The acetaminophen phenoxyl radical was generated by the oxidation of acetaminophen by horseradish peroxidase in a fast-flow ESR experiment, and its reaction with glutathione and ascorbate was studied. Glutathione reduces the phenoxyl radical of acetaminophen to regenerate acetaminophen and form the thiyl radical of glutathione. This thiyl radical reacts with the thiolate anion of glutathione to form the disulfide radical anion, which was detected and characterized by ESR spectroscopy. In the presence of ascorbate, the ascorbyl radical was produced by the reduction of the acetaminophen phenoxyl radical by ascorbate. This reaction results in the complete reduction of the free radical of acetaminophen, whereas the glutathione reduction of the phenoxyl radical of acetaminophen was not complete on the fast-flow ESR time scale of milliseconds. This suggests that ascorbate rather than glutathione is more likely to react with the acetaminophen phenoxyl free radical in vivo. In the presence of both ascorbate and higher concentrations of glutathione, the reaction with ascorbate is dominant. When cysteine was used in the place of reduced glutathione in the above assay system, the disulfide radical anion of cystine was observed in a manner similar to glutathione. These reactions may have significance in the detoxification of acetaminophen and the free radical metabolites of xenobiotics in general. Only in cells containing low levels of ascorbate can glutathione play a direct role in the detoxification of the acetaminophen phenoxyl radical.

Acetaminophen↗
PubMed1990

Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states.

The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3-methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene-induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.

Acetaminophen↗