High-dose Acetaminophen Research Articles

Which psychotropic medications induce hepatotoxicity?

Objective Safe prescribing practices to minimize pharmaceutically induced liver damage or worsening of preexisting conditions require knowledge about medicines with hepatotoxic potential. This paper reviews psychotropic medications and their effects on the liver. Methods A MEDLINE search was performed utilizing the phrase “drug-induced liver injury” with various categories of psychiatric drugs. Only articles written in English were utilized. Results Hepatotoxicity can be acute or chronic in nature. Medication discontinuation is necessary in acute forms, while close monitoring is required in milder forms of medication-induced chronic liver damage. Nefazodone, pemoline and/or tacrine are the highest offenders. Carbamazepine and valproate products (e.g., divalproex) can lead to this adverse event and should be avoided in patients with liver disease, persons with alcohol misuse or those consuming high doses of acetaminophen. Conclusion Knowing the risk levels associated with various medicines is important; prescribing multiple drugs with hepatotoxic effects should be avoided. One should educate patients about early warning signs of liver injury. Always provide clinical and laboratory monitoring before and during the use of hepatotoxic drugs. Clinical features and laboratory results govern medication prescribing with ongoing risk-to-benefit ratio assessment during pharmacotherapy.

Running in Place: The Challenge of Prescribing Medications Today

Running in Place: The Challenge of Prescribing Medications Today

Humanizing π-Class Glutathione S-Transferase Regulation in a Mouse Model Alters Liver Toxicity in Response to Acetaminophen Overdose

BackgroundGlutathione S-transferases (GSTs) metabolize drugs and xenobiotics. Yet despite high protein sequence homology, expression of π-class GSTs, the most abundant of the enzymes, varies significantly between species. In mouse liver, hepatocytes exhibit high mGstp expression, while in human liver, hepatocytes contain little or no hGSTP1 mRNA or hGSTP1 protein. π-class GSTs are known to be critical determinants of liver responses to drugs and toxins: when treated with high doses of acetaminophen, mGstp1/2+/+ mice suffer marked liver damage, while mGstp1/2−/− mice escape liver injury.Methodology/Principal FindingsTo more faithfully model the contribution of π-class GSTs to human liver toxicology, we introduced hGSTP1, with its exons, introns, and flanking sequences, into the germline of mice carrying disrupted mGstp genes. In the resultant hGSTP1+mGstp1/2−/− strain, π-class GSTs were regulated differently than in wild-type mice. In the liver, enzyme expression was restricted to bile duct cells, Kupffer cells, macrophages, and endothelial cells, reminiscent of human liver, while in the prostate, enzyme production was limited to basal epithelial cells, reminiscent of human prostate. The human patterns of hGSTP1 transgene regulation were accompanied by human patterns of DNA methylation, with bisulfite genomic sequencing revealing establishment of an unmethylated CpG island sequence encompassing the gene promoter. Unlike wild-type or mGstp1/2−/− mice, when hGSTP1+mGstp1/2−/− mice were overdosed with acetaminophen, liver tissues showed limited centrilobular necrosis, suggesting that π-class GSTs may be critical determinants of toxin-induced hepatocyte injury even when not expressed by hepatocytes.ConclusionsBy recapitulating human π-class GST expression, hGSTP1+mGstp1/2−/− mice may better model human drug and xenobiotic toxicology.

Acetaminophen Injection: A Review of Clinical Information

ABSTRACTAcetaminophen injection is an antipyretic and analgesic agent recently marketed in the United States as Ofirmev. Five published trials directly compare acetaminophen injection to drugs available in the United States. For management of pain in adults, acetaminophen injection was at least as effective as morphine injection in renal colic, oral ibuprofen after cesarean delivery, and oral acetaminophen after coronary artery bypass surgery. In children (3 to 16 years old), single-dose acetaminophen injection was similar to meperidine intramuscular (IM) for pain after tonsillectomy; readiness for discharge from the recovery room was shorter with acetaminophen injection (median 15 minutes) compared with meperidine IM (median 25 minutes), P = .005. In children (2 to 5 years old) postoperative adenotonsillectomy or adenoidectomy, the time to rescue analgesia was superior with high-dose acetaminophen rectal suppository (median 10 hours) compared with acetaminophen injection (median 7 hours), P = .01. One published trial demonstrated acetaminophen injection is noninferior to propacetamol injection for fever related to infection in pediatric patients. Dosing adjustments are not required when switching between oral and injectable acetaminophen formulations in adult and adolescent patients. Acetaminophen injection represents another agent for multimodal pain management.

Protective effects of goldenseal (Hydrastis canadensis L.) on acetaminophen-induced hepatotoxicity through inhibition of CYP2E1 in rats

Background:Goldenseal (Hydrastis canadensis L.) inhibits various cytochrome P450 (CYP) isoforms such as CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A in vitro. High doses of acetaminophen (APAP) generate the highly reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI), catalyzed mainly by CYP2E1. The aim of this study was to investigate the hepatoprotective effects of orally administrated goldenseal against APAP-induced acute liver failure (ALF) via inhibition of CYP2E1.Materials and Methods:Male Wistar rats were treated orally with goldenseal (300 and 1000 mg/kg) 2, 18, and 26 h before and 6 h after oral APAP (400 mg/kg) administration. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as serum APAP concentration were evaluated.Results:Goldenseal extract inhibited CYP1A2, CYP2D6, CYP2E1, and CYP3A activity, and the inhibitory effect on CYP2E1 was the strongest (IC50 4.32 μg/mL). Treatment with goldenseal (300 mg/kg) significantly attenuated the APAP-induced increase in serum AST and ALT, and the hepatoprotective effect of goldenseal was stronger than that of silymarin (200 mg/kg). Moreover, serum APAP concentration was increased by goldenseal treatment, presumably as a result of the inhibitory effect of goldenseal on the metabolism of APAP to NAPQI.Conclusion:These results suggest that goldenseal ameliorates APAP-induced ALF and that this protection can likely be attributed to the inhibition of CYP2E1 activity, which generates the highly reactive intermediate of APAP.

Comment: A Population Study of the Frequency of High-Dose Acetaminophen Prescribing and Dispensing

Comment: A Population Study of the Frequency of High-Dose Acetaminophen Prescribing and Dispensing

The role of prostaglandin E2 in acute acetaminophen hepatotoxicity in mice

Prostaglandin E2 (PGE2), which is synthesized by many cell types, has a cytoprotective effect in the gastrointestinal tract and in several other tissues and cells. On the other hand, overdose or chronic use of a high dose of acetaminophen (Paracetamol, APAP) is a major cause of acute liver failure in the western world. These observations prompted us to investigate whether PGE2 plays a role in host defence to toxic effect of APAP. (CBAT6T6xC57Bl/6)F1 hybrid mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. Stabile analogue of PGE2, 16,16-dimethyl PGE2 (dmPGE2), or inhibitor of its production, CAY10526, were given intraperitoneally (i.p.) 30 minutes before or 2 hours after APAP administration. The toxicity of APAP was determined by observing the survival of mice during 48 hours, by measuring concentration of alanine-aminotransferase (ALT) in plasma 20-22 hours after APAP administration and by liver histology. The results have shown that PGE2 exhibits a strong hepatoprotective effect when it is given to mice either before or after APAP, while CAY10526 demonstrated mainly the opposite effect. Immunohistochemical or immunofluorescent examinations in the liver tissue generally support these findings, suggesting that PGE2 inhibited APAP-induced activation of nuclear factor kappa B (NF-kappaB). Similarly, PGE2 down regulated the activity of inducible nitric oxide synthase (iNOS), which was up regulated by APAP. Thus, by these and perhaps by other mechanisms, PGE2 contributes to the defence of the organism to noxious effects of xenobiotics on the liver.

A Population Study of the Frequency of High-Dose Acetaminophen Prescribing and Dispensing

Recurrent intake of 4 g/day or more of acetaminophen has been associated with elevation of serum alanine aminotransferase (ALT) levels in 30-40% of the exposed population and may result in hepatotoxicity. To describe the frequency that patients are prescribed acetaminophen doses that exceed 4 g/day across a large population. Using California's Medicaid (Medi-Cal) fee-for-service population, pharmacy claims including over-the-counter (OTC) medications were examined for prescriptions that could result in acetaminophen doses of 4 g/day or more. The period studied, October 2004 through September 2005, was before the Part D pharmacy benefit was available to dually eligible Medicare patients when all prescriptions were covered by the Medi-Cal claims process. During the pre-Part D evaluation period, approximately 3.27 million beneficiaries were enrolled in the fee-for-service Medi-Cal program. A total of 192,716 (5.9%) were potentially exposed to at least 1 day of 4 g/day or more of acetaminophen. Of those, 769 patients were potentially exposed to at least 1 day of 16 g/day or more. A total of 2664 beneficiaries were dispensed prescriptions and OTC products that, if taken as directed, would have resulted in more than 100 days of acetaminophen doses of 4 g/day or more during the study year. Despite electronic systems designed to warn dispensing pharmacists of duplications of drug class and cumulative excessive doses, potentially toxic amounts of acetaminophen are commonly prescribed and dispensed to this population. Better systems, increased awareness, and education of patients, prescribers, and pharmacists are needed to reduce this potential toxic exposure.

Abstract B20: Acetaminophen enhances the cytotoxicity of cisplatin in vitro and in a subcutaneous tumor xenograft model of human ovarian carcinoma

Abstract Background: High dose acetaminophen causes hepatotoxicity by depleting glutathione and increasing production of toxic metabolites. The objective of this study was to examine if these mechanisms of acetaminophen can enhance the cytotoxicity of cisplatin in human ovarian cancer cells both in vitro and in vivo. Methods: In vitro studies (glutathione concentration, cell viability and immunoblotting assays) were performed using SKOV3 human ovarian cancer cells cultured in combinations of acetaminophen and cisplatin. For the tumor model, female nude rats were pre-treated with cyclophosphamide (i.p. 100 mg/kg) one day prior to subcutaneous inoculation of SKOV3 cells with matrigel on the left flank. At 7 days after implantation, rats were randomly assigned into vehicle, cisplatin, and acetaminophen plus cisplatin treatment groups (n=3–5 per group). Subcutaneous tumor volume was measured by dial caliper. Acetaminophen pharmacology and the toxicity of treatments were monitored. Results: In vitro, acetaminophen decreased SKOV3 cellular glutathione level by approximately 30% over 2 hr time frame. Acetaminophen combined with cisplatin decreased cell growth and viability and enhanced apoptosis compared to cisplatin alone in vitro. In vivo, high dose acetaminophen showed uniform tissue distribution, but only decreased glutathione in the liver but not in the serum, brain, or subcutaneous tumor of nude rats. Acetaminophen pretreatment 2–4 hr prior to cisplatin enhanced cisplatin chemotherapeutic effect as determined by a reduction in subcutaneous tumor volume by 15–25% (55–85% vs 40–60%). Serum BUN and creatinine levels were elevated by the combination of acetaminophen with cisplatin treatment when compared to cisplatin alone (48.2±10.9 vs 24.4±4.1 mg/dL; 0.65±0.06 vs 0.30±0.04 mg/dL; p<0.01). Conclusions: Our results suggested that a chemotherapeutic regimen containing both high dose acetaminophen and cisplatin could be applied not only in hepatic tumors but also in ovarian or other tumor malignancies as a potentially promising approach for pre-clinical trial. Citation Information: Cancer Res 2009;69(23 Suppl):B20.

Comparative Impacts of Knockouts of Two Antioxidant Enzymes on Acetaminophen-Induced Hepatotoxicity in Mice

We have previously shown a more potent impact of knockout of Cu,Zn-superoxide dismutase (SOD1) than that of Se-dependent glutathione peroxidase-1 (GPX1) on murine hepatotoxicity induced by an intraperitoneal (ip) injection of a high dose of acetaminophen (APAP, 600 mg/kg). The objective of this experiment was to compare the temporal impacts of knockouts of GPX1 and SOD1 alone or together on mouse susceptibility to an injection of a low dose of APAP (300 mg/kg). The APAP-mediated rises in plasma alanine aminotransferase activity and nitrate/nitrite concentrations, hepatic GSH depletion, and hepatic protein nitration at 5 and (or) 24 h were nearly abolished (P < 0.05) in SOD1-/- or GPX1 and SOD1 double-knockout (DKO) mice, while GPX1-/- mice exerted only moderate or no change compared with the WT. Despite an increased (P < 0.05) APAP-N-acetylcysteine and decreased APAP-glucuronide (P < 0.05) relative to the total APAP metabolites in urine collected for 24 h after the APAP injection, the SOD1-/- mice displayed no shift in urinary APAP-cysteine compared with the WT mice. Knockout of SOD1 prevented the APAP-induced hepatic GPX inactivation (P < 0.05), whereas knockout of GPX1 aggravated the APAP-induced hepatic SOD activity loss (P < 0.05). However, the APAP-mediated activity changes of these enzymes in liver accompanied no protein alterations. In conclusion, knockout of GPX1 or SOD1 exerted differential impact on mouse susceptibility to this low dose of APAP, but neither shifted urinary APAP-cysteine formation.

Hepatotoxicity in an infant following supratherapeutic dosing of acetaminophen for twenty-four hours

Severe hepatotoxicity in acute acetaminophen overdose in children is uncommon. This apparent protection does not extend to chronic or repeated high dose acetaminophen administration. The Illinois Poison Center (IPC) was consulted on a case involving a 7 month old 17 lb infant, who had presented the day prior to an emergency department with complaint of febrile illness. Patient had been prescribed acetaminophen for symptoms, and the mother called IPC when she realized that she had been incorrectly giving the patient concentrated infant acetaminophen (80 mg per 0.8 mL) totalling 42.3 mg/kg/dose or 234 mg/kg/24 hours instead of children's acetaminophen (160 mg/5 ml). Per recently published national triage guidelines, the patient was referred to an acute care facility for evaluation. The patient presented with significantly elevated aspartate aminotransferrase (AST) and alanine aminotransferrase (ALT) levels of 1339 and 907 U/L respectively, and was initiated on i.v. n-acetylcysteine therapy. The patient responded well to therapy, with AST and ALT declining to 145 and 479 U/L respectively over the next 48 hours. This case represents one of the shortest durations of chronic acetaminophen therapy to cause hepatic injury in an infant. Further, while the level was only slightly above the national triage guideline recommended referral dose per 24 hours, significant hepatotoxicity was observed.

Endoscopic and histopathological evaluation of acute gastric injury in high-dose acetaminophen and nonsteroidal anti-inflammatory drug ingestion with suicidal intent

To evaluate endoscopic and histopathologic aspects of acute gastric injury due to ingestion of high-dose acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) with respect to some risk factors and patient characteristics. The study group consists of 50 patients admitted to emergency department with high dose analgesic ingestion (group I) with suicidal intent. Thirty patients with or without mild complaints of dyspepsia (group II) were selected as the control group. The study group was stratified according to the use of type and number of analgesics. Endoscopic findings were evaluated according to the Lanza score (LS), expressing the severity of the gastroduodenal damage and biopsies according to a scoring system based on histopathologic findings of acute erosive gastritis. Gastroduodenal damage was signifi-cantly more severe in group I compared to group II (P < 0.01). The LS was similar in both groups Ia and Ib. However LS was significantly higher in patients who had ingested multiple NSAIDs (group Ic) compared to other patients (P < 0.01). The LS was correlated to age (P < 0.01) and total amount of drug ingested (P < 0.05) in group I; but it was not correlated with Helicobacter pylori (H pylori) infection or duration of exposure (P > 0.05). The biopsy score (BS) was higher in group I than group II (P < 0.01), and higher in group Ib than group Ia (P < 0.05). The histopathologic damage was more severe among NSAID ingesting patients compared to those ingesting only acetaminophen and there is no significant difference in the endoscopic findings between the groups. There is no significant difference in the LS between the groups. This lack of significance is remarkable in terms of the gastric effects of high-dose acetaminophen.

High-Dose Acetaminophen Inhibits the Lethal Effect of Doxorubicin in HepG2 Cells: The Role of P-glycoprotein and Mitogen-Activated Protein Kinase p44/42 Pathway

Doxorubicin (DOX) is a widely used chemotherapeutic drug for human hepatocellular carcinoma (HCC). A major limitation to its effectiveness is the development of multidrug resistance of cancer cells. In clinical trials, patients with advanced HCC were treated with high-dose acetaminophen (HAAP) in an effort to improve the antitumor activity of chemotherapeutics. In this study, we investigated the effect of concomitant treatment of DOX and HAAP on hepatoma-derived HepG2 cells. Viability, cell cycle distribution, and ultrastructure were examined. Unexpectedly, HAAP, when added to DOX-exposed cells, increased cell viability, released cell cycle arrest, and decreased apoptosis. To elucidate the mechanisms by which HAAP reduces the DOX lethal effect to HepG2 cells, we investigated the multidrug resistance P-glycoprotein (P-gp) and p44/42-mitogen-activated protein kinase (MAPK) pathways. The P-gp function was enhanced by DOX and HAAP, and it was further stimulated during combined treatment, leading to decreased DOX retention. Verapamil (VRP), when added to DOX + HAAP exposure, increased DOX accumulation and restored DOX-induced toxicity. The increased phospho-p44/42-MAPK level in DOX-exposed cells was inhibited by HAAP. In addition, suppression of p44/42 activation by the p44/42-MAPK inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked DOX-induced apoptosis. These findings suggest that the antagonistic effect of concomitant DOX + HAAP treatment occurs as a result of interactive stimulation of P-gp, generating decreased intracellular drug concentrations. Furthermore, inhibition of the p44/42-MAPK phosphorylation by HAAP could abolish the DOX-induced cell death pathway. Thus, combined treatment by DOX + HAAP, intended to improve chemotherapeutic efficacy, could have an opposite effect facilitating cancer cell survival.

Use of Nonsteroidal Antiinflammatory Drugs

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population

ObjectiveTo evaluate the knowledge of appropriate doses and potential toxicities of acetaminophen and assess the ability to recognize products containing acetaminophen in an adult outpatient setting. DesignCross-sectional, prospective study. SettingUniversity adult general internal medicine (AGIM) clinic. Patients104 adult patients presenting to the clinic over consecutive weekdays in December 2003. InterventionsThree-page, written questionnaire. Main Outcome MeasuresAbility of patients to identify maximum daily doses and potential toxicities of acetaminophen and recognize products that contain acetaminophen. ResultsA large percentage of participants (68.3%) reported pain on a daily or weekly basis, and 78.9% reported use of acetaminophen in the past 6months. Only 2 patients correctly identified the maximum daily dose of regular acetaminophen, and just 3 correctly identified the maximum dose of extra-strength acetaminophen. Furthermore, 28 patients were unsure of the maximum dose of either product. Approximately 63% of participants either had not received or were unsure whether information on the possible danger of high doses of acetaminophen had been previously provided to them. When asked to identify potential problems associated with high doses of acetaminophen, 43.3% of patients noted the liver would be affected. The majority of the patients (71.2%) recognized Tylenol as containing acetaminophen, but fewer than 15% correctly identified Vicodin, Darvocet, Tylox, Percocet, and Lorcet as containing acetaminophen. ConclusionAlthough nearly 80% of this AGIM population reported recent acetaminophen use, their knowledge of the maximum daily acetaminophen doses and potential toxicities associated with higher doses was poor and appeared to be independent of education level, age, and race. This indicates a need for educational efforts to all patients receiving acetaminophen-containing products, especially since the ability to recognize multi-ingredient products containing acetaminophen was likewise poor.

Alterations in the Rat Serum Proteome during Liver Injury from Acetaminophen Exposure

Changes in the serum proteome were identified during early, fulminant, and recovery phases of liver injury from acetaminophen in the rat. Male F344 rats received a single, noninjury dose or a high, injury-producing dose of acetaminophen for evaluation at 6 to 120 h. Two-dimensional gel electrophoresis of immunodepleted serum separated approximately 800 stained proteins per sample from which differentially expressed proteins were identified by mass spectrometry. Serum alanine aminotransferase/aspartate aminotransferase levels and histopathology revealed the greatest liver damage at 24 and 48 h after high-dose acetaminophen corresponding to the time of greatest serum protein alterations. After 24 h, 68 serum proteins were significantly altered of which 23 proteins were increased by >5-fold and 20 proteins were newly present compared with controls. Only minimal changes in serum proteins were noted at the low dose without any histopathology. Of the 54 total protein isoforms identified by mass spectrometry, gene ontology processes for 38 unique serum proteins revealed involvement of acute phase response, coagulation, protein degradation, intermediary metabolism, and various carrier proteins. Elevated serum tumor necrosis factor-alpha from 24 to 48 h suggested a mild inflammatory response accompanied by increased antioxidant capability demonstrated by increased serum catalase activity. Antibody array and enzyme-linked immunosorbent assay analyses also showed elevation in the chemokine monocyte chemoattractant protein-1 and the metalloprotease inhibitor tissue inhibitor of metalloproteinases-1 during this same period of liver injury. This study demonstrates that serum proteome alterations probably reflect both liver damage and a concerted, complex response of the body for organ repair and recovery during acute hepatic injury.

Successful treatment of doxorubicin and cisplatin resistant hepatoblastoma in a child with Beckwith-Wiedemann syndrome with high dose acetaminophen and N -acetylcysteine rescue

High dose acetaminophen (HDAC) with N-acetylcysteine (NAC) has been effective in adults with advanced malignancies. We report HDAC with NAC in a child with progressive hepatoblastoma, confirmed at biopsy of an unresectable hepatic mass. Alpha-fetoprotein (AFP) increased despite four courses of doxorubicin and one course of cisplatin, 5-flurouracil, and vincristine. Following HDAC with NAC, AFP markedly decreased. A continued response without toxicity was observed during four subsequent courses of HDAC with NAC and cisplatin. The residual necrotic tumor was resected. The child is now over 8 years disease free. HDAC and NAC are effective and well tolerated for progressive hepatoblastoma.

Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR

Zhang J, Huang W, Chua SS, et al (Baylor College of Medicine, Houston, TX) Overdoses of acetaminophen are the leading cause of hospital admission for acute liver failure in the United States. Ingestion of only 2 to 3 times the maximum daily recommended dose of acetaminophen can cause hepatotoxicity, and higher doses result in potentially fatal centrilobular necrosis. Acetaminophen toxicity is increased in both human beings and rodents by pretreatment with various inducers of CYP gene expression, including ethanol and phenobarbital. Because the xenobiotic receptor CAR has recently been shown to mediate the effects of phenobarbital and other phenobarbital-like inducers, the effects of phenobarbital and the potent CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on acetaminophen toxicity were examined in wild-type and CAR knockout mice. Both strains of mice were treated with inducers or the vehicle control, followed by acetaminophen (250 mg/kg of body weight). The known CAR activators and the high dose of acetaminophen induced expression of 3 acetaminophen-metabolizing enzymes in wild-type mice but not in the CAR null mice. The CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration by the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild-type but not in CAR null mice. These findings demonstrate that CAR is a central mediator of acetaminophen toxicity in mice and potentially also in human beings. It would appear that CAR is not involved in the toxicity associated with ethanol-dependent induction of CYP2E1 and other targets because CAR activation caused a modest decrease in CYP2E1 mRNA levels. However, activation of either mouse or human CAR by appropriate inducers, including acetaminophen itself, increased the production of APAP-metabolizing enzymes and increased toxicity. Fatal outcomes have been reported to result from the combination of phenobarbital and acetaminophen in human beings. The findings of this study suggest a new strategy for treatment of acetaminophen toxicity based on the use of CAR agonists.

Car Unlikely to Significantly Modulate Acetaminophen Hepatotoxicity in Most Humans

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen–metabolizing enzymes in wild–type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild–type but not CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.

The Cost-Effectiveness of Acetaminophen, NSAIDs, and Selective COX-2 Inhibitors in the Treatment of Symptomatic Knee Osteoarthritis

Objective The objective of this study was to conduct an economic evaluation of rofecoxib and celecoxib compared with high-dose acetaminophen or ibuprofen with and without misoprostol for patients with symptomatic knee osteoarthritis (OA). Methods A decision analysis model was designed over 6 months using two measures of effectiveness: 1) number of upper gastrointestinal (GI) adverse events averted; and 2) number of patients who achieved perceptible pain relief. Separate analyses were conducted for all patients and for those who did not respond to acetaminophen. Outcome probabilities were obtained from a comprehensive review of randomized controlled trials and observational studies. Costs were derived from actual resource utilization of OA patients. Results In terms of averting GI events, acetaminophen dominates the other options for an average risk patient population. For patients who did not respond to acetaminophen, rofecoxib had the lowest incremental cost-effectiveness ratio (ICER) per GI event avoided ($32,000) relative to ibuprofen. In terms of pain control, ibuprofen had an ICER of $610.77 per additional patient achieving minimal perceptible clinical improvement (MPCI) relative to acetaminophen, while rofecoxib had an ICER of $12,000 relative to ibuprofen. For patients who did not respond to acetaminophen and who are at high risk of developing an adverse GI event, rofecoxib dominates ibuprofen as the preferred alternative for both measures of effectiveness. One-way, two-way, and probabilistic sensitivity analyses established that these results were generally robust. Conclusions Our results suggest that for average-risk knee OA patients, acetaminophen dominates the other therapies in terms of cost per GI event averted. In terms of pain relief, cost-effectiveness acceptability curves indicate that if one values pain relief below $275 per patient achieving MPCI, acetaminophen is the therapy most likely to be optimal; between $275 and $14,150, ibuprofen is most likely to be optimal; and above $14,150, rofecoxib is most likely to be optimal.