High-dose Acetaminophen Research Articles

Postoperative pain management using high-dose oral acetaminophen for enhanced recovery after colorectal cancer surgery.

Postoperative pain management is important for enhanced recovery. High-dose oral acetaminophen is effective; however, the safety of its long-term use has not been established in gastrointestinal surgeries. This study aimed to investigate drug-induced liver injury (DILI) in patients with colorectal cancer using high-dose acetaminophen. One hundred sixty-eight consecutive colorectal cancer using high-dose oral acetaminophen (3600mg/day between postoperative day 1 and 7) were enrolled. One hundred forty-nine patients (88.7%) completed the administration of high-dose oral acetaminophen. DILI occurred in 58 patients (34.5%), and the cumulative incidence rates were 20.4% and 37.9% on postoperative 6 and 7, respectively. The severity of liver injury was grade 1 in all cases and returned to normal without treatment. Patients with DILI had a higher frequency of dyslipidemia (44.8% vs. 23.6%, P = 0.0047) and M1 staging (10.3% vs. 1.0%, P = 0.0036). A multivariate analysis showed that the presence of dyslipidemia (OR 2.61, P = 0.0067) and M1 stage (OR 12.4, P = 0.0053) were independent risk factors for DILI. The long-term use of high-dose oral acetaminophen in colorectal cancer patients enrolled in enhanced recovery protocols is feasible. Moreover, the presence of dyslipidemia and M status are risk factors for DILI.

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice.

Introduction: Administration of high doses of acetaminophen (APAP) results in liver injury. Oxidative stress and iron overload play roles in the pathogenesis of APAP-induced hepatotoxicity. The present study assessed the potential hepatoprotective effects of phytic acid (PA), a natural antioxidant and iron chelator, on APAP-induced hepatotoxicity and the possible underlying mechanism through its effects on CYP2E1 gene expression, iron homeostasis, oxidative stress, and SIRT-1 expression levels. Methods: Twenty-four adult male albino mice were used in this study. Mice were divided into four groups (six mice in each group): control, APAP-treated, PA-treated and APAP + PA-treated groups. Liver function tests, serum and liver tissue iron load were evaluated in all the study groups. Hepatic tissue homogenates were used to detect oxidative stress markers, including malondialdehyde (MDA) and reduced glutathione (GSH). Histological hepatic evaluation and immunohistochemistry of SIRT-1 were performed. Quantitative real-time PCR was used for the assessment of CYP2E1 and SIRT-1 gene expressions. APAP-induced biochemical and structural hepatic changes were reported. Results: PA administration showed beneficial effects on APAP-induced hepatotoxicity through improvements in liver functions, decreased CYP2E1 gene expression, decreased serum and liver iron load, decreased MDA, increased GSH, increased SIRT-1 expression level and improvement in hepatic architecture. Conclusion: Conclusively, PA can be considered a potential compound that can attenuate acetaminophen-induced hepatotoxicity through its role as an iron chelator and antioxidant, as well as the up-regulation of SIRT-1 and down-regulation of CYP2E1.

High-Dose Acetaminophen as a Treatment for Cancer

The use of high-dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue was studied as an anti-cancer treatment in phase I trials with promising signals of anti-tumor efficacy. Correlative analysis suggested that AAP has a free-radical-independent mechanism of anti-tumor activity—in contrast to the well-established mechanism of AAP hepatotoxicity. Subsequent “reverse translational” studies in the pre-clinical setting have identified novel mechanisms of action of high-dose AAP, including modulation of JAK-STAT signaling in both the tumor cell and the tumor immune microenvironment. Importantly, these effects are free-radical-independent and not reversed by concurrent administration of the established AAP rescue agents fomepizole and NAC. By administering high-dose AAP concurrently with fomepizole and NAC, 100-fold higher AAP levels than those of standard dosing can be achieved in mice without detected toxicity and with substantial anti-tumor efficacy against commonly used mouse models of lung and breast cancer that are resistant to standard first-line anti-cancer therapies. With these recent advances, additional clinical trials of high-dose AAP with concurrent NAC and fomepizole-based rescue are warranted.

Wolfberry, Yam, and Chrysanthemum polysaccharides increased intestinal Akkermansia muciniphila abundance and hepatic YAP1 expression to alleviate DILI.

Drug-induced liver injury (DILI) is frequently induced by high dose of acetaminophen (APAP) and is concomitant with disturbances of gut flora. Akkermansia muciniphila is beneficial for the repair of liver injury. Lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide all have anti-inflammatory and antioxidation effects. The objective of this study is to investigate the potential of lycium barbarum polysaccharide, yam polysaccharide, and chrysanthemum polysaccharide (LYC) in improving DILI by increasing the abundance of A. muciniphila. Initially, screening for the optimal concentrations of wolfberry, yam, and chrysanthemum (WYC) or LYC to promote A. muciniphila proliferation invitro and validated in antibiotic (ATB)-treated KM mice. Subsequently, APAP-induced DILI model in BALB/c mice were constructed to examine the treatment effects of LYC. Our findings indicate that the optimal concentration ratio of WYC was 2:3:2, and LYC was 1:1:1. WYC increased A. muciniphila proliferation invitro and in ATB-treated mice under this ratio. Meanwhile, LYC increased A. muciniphila abundance invitro and the combination LYC with A. muciniphila promoted the proliferation of A. muciniphila in ATB-treated mice. The overdose of APAP resulted in the impairment of the intestinal barrier function and subsequent leakage of lipopolysaccharide (LPS). Moreover, LYC increased A. muciniphila abundance, reduced intestinal inflammation and permeability, and upregulated the expression of the tight junction protein zonula occludens protein 1 (ZO-1) and occludin contents in the gut. Lastly, LYC inhibited LPS leakage and upregulated hepatic YAP1 expression, ultimately leading to the repair of DILI.

High-Dose Acetaminophen with Concurrent CYP2E1 Inhibition Has Profound Anticancer Activity without Liver Toxicity.

Acetaminophen (AAP) is metabolized by a variety of pathways such as sulfation, glucuronidation, and fatty acid amide hydrolase-mediated conversion to the active analgesic metabolite AM404. CYP2E1-mediated metabolism to the hepatotoxic reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine) is a minor metabolic pathway that has not been linked to AAP therapeutic benefits yet clearly leads to AAP liver toxicity. N-acetylcysteine (NAC) (an antioxidant) and fomepizole (a CYP2E1 inhibitor) are clinically used for the treatment of AAP toxicity. Mice treated with AAP in combination with fomepizole (plus or minus NAC) were assessed for liver toxicity by histology and serum chemistry. The anticancer activity of AAP with NAC and fomepizole rescue was assessed in vitro and in vivo. Fomepizole with or without NAC completely prevented AAP-induced liver toxicity. In vivo, high-dose AAP with NAC/fomepizole rescue had profound antitumor activity against commonly used 4T1 breast tumor and lewis lung carcinoma lung tumor models, and no liver toxicity was detected. The antitumor efficacy was reduced in immune-compromised NOD-scid IL2Rgammanull mice, suggesting an immune-mediated mechanism of action. In conclusion, using fomepizole-based rescue, we were able to treat mice with 100-fold higher than standard dosing of AAP (650 mg/kg) without any detected liver toxicity and substantial antitumor activity. SIGNIFICANCE STATEMENT: High-dose acetaminophen can be given concurrently with CYP2E1 inhibition to allow for safe dose escalation to levels needed for anticancer activity without detected evidence of toxicity.

High-Dose Acetaminophen with N-acetylcysteine Rescue Inhibits M2 Polarization of Tumor-Associated Macrophages.

High-dose acetaminophen (AAP) with N-acetylcysteine (NAC) rescue is among the few treatments that has shown activity in phase I trials without achieving dose-limiting toxicity that has not progressed to evaluation in later line studies. While the anti-tumor effects of AAP/NAC appear not to be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized. In vitro, the effects of AAP/NAC were evaluated on bone marrow derived macrophages. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling and downstream gene and protein expression were studied. NAC reversed the AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes and proteins but did not inhibit the IFN/LPS induction of M1-associated genes and proteins. In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple-negative breast tumors. Flow cytometry of tumor-associated macrophages revealed that AAP/NAC selectively inhibited M2 polarization. The anti-tumor activity of high-dose AAP/NAC is lost in macrophage-depleted mouse syngeneic tumor models, suggesting a macrophage-dependent mechanism of action. In conclusion, our study is the first to show that high-dose AAP/NAC has profound effects on the tumor immune microenvironment that facilitates immune-mediated inhibition of tumor growth.

Abstract 6388: High dose acetaminophen with n-acetylcysteine rescue inhibits M2 polarization of tumor associated macrophages

Abstract Background: High dose acetaminophen (AAP) with n-acetylcysteine (NAC) rescue is among the few treatments that has shown a signal of activity in phase I trials (21% response rate, 3/14 assessable patients) without achieving dose limiting toxicity that has not progressed to evaluation in later line studies. We have previously shown that high dose AAP selectively depletes glutathione in the liver but not the tumor, suggesting that NAC, the FDA-approved antidote for AAP toxicity and a glutathione precursor, may selectively rescue the normal liver but not the tumor from high dose AAP. While the anti-tumor effects of AAP/NAC appear to not be mediated by glutathione depletion and free radical injury, the mechanism of anti-tumor effects of AAP/NAC has not been definitively characterized. Methods: In vitro the effects of Vehicle, AAP, or AAP/NAC was evaluated on bone marrow derived macrophages polarized to M2 and M1 phenotypes using IL-4 or IFN/LPS, respectively. Tumor cell viability was assessed with MTT assay. Effects of AAP on IL-4/STAT6 (M2) or IFN/LPS/STAT1 (M1) signaling, and downstream gene and protein expression was studied. In vivo, effects of AAP/NAC on tumor size and tumor associated macrophage polarization were characterized in orthotopic triple negative breast tumor models 4T1 and EF43.fgf4 using cytokine elisa of tumor lysate and flow cytometry. Results: NAC reversed AAP toxicity in the normal liver but did not reverse AAP cytotoxicity against tumor cells in vitro. AAP/NAC selectively inhibited IL-4-induced STAT6 phosphorylation but not IFN/LPS-induced STAT1 phosphorylation. Downstream, AAP/NAC inhibited IL-4 induction of M2-associated genes (such as CCL24, YM1 and arginase) and proteins (arginase, PD-L2, and CD206). However, AAP/NAC did not inhibit IFN/LPS induction of M1-associated genes (IL-6, TNF, IL-12) and proteins (INOS, PD-L1, MHC I, and CD64). In vivo, AAP/NAC inhibited tumor growth in EF43.fgf4 and 4T1 triple negative breast tumors. Flow cytometry of tumor associated macrophages revealed that AAP/NAC selectively inhibited M2 but not M1 polarization. ELISA of tumor lysate demonstrated relatively stable expression of IFN gamma but markedly suppressed expression of IL-10 in the tumor immune microenvironment. Conclusion: Our study is the first to show that at high doses AAP/NAC has profound effects on the tumor immune microenvironment that may facilitate immune-mediated inhibition of tumor growth. Citation Format: Alexander Neuwelt, Allyn Bryan, Won Lee, Pavani Pingali, Howard Li, Bhaumik Patel. High dose acetaminophen with n-acetylcysteine rescue inhibits M2 polarization of tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6388.

Effects of Acetaminophen on Reproductive Activities in Male Golden Hamsters

Acetaminophen [Paracetamol, N-acetyl-para-aminophenol (APAP)] is a common over-the- counter analgesic agent as nonsteroidal anti-inflammatory drugs (NSAIDs). The high doses or the long-term treatment of acetaminophen via usual gavage feeding resulted in damage of testicles that presented recoverable impairment, as well as liver and kidney. The influence of acetaminophen was examined in male golden hamsters treated with acetaminophen- containing diet feeding. They were divided into 5 groups and subjected to this experiment for 4 weeks: animals housed in long photoperiod (LP) as LP control, animals housed in short photoperiod (SP) for 4 weeks as SP control (SP4), and groups of animals treated with low, middle, and high concentrations of acetaminophen (Low, Middle, High groups). Also animals housed in SP for 8 weeks were included (SP8) to contrast testicular activities, if necessary. As results, spermatozoa filled the seminiferous tubules of the testicles of animals in LP control and SP4 groups. The aspects were seen in the animals taken diets of low and middle doses of acetaminophen. The animals who fed high dose of acetaminophen showed large or small testicles. The large testicles displayed all germ cells at the steps of spermatogenesis. The small testicles presented no sperm as the animals housed in SP for 8 weeks. Thus these results indicate that acetaminophen invokes the antigonadal effects and accelerates the regressing process of the testicles in the animals compared to the animals exposed to SP.

Effects of Acetaminophen on Reproductive Activities in Male Golden Hamsters

Acetaminophen [Paracetamol, N-acetyl-para-aminophenol (APAP)] is a common over-the- counter analgesic agent as nonsteroidal anti-inflammatory drugs (NSAIDs). The high doses or the long-term treatment of acetaminophen via usual gavage feeding resulted in damage of testicles that presented recoverable impairment, as well as liver and kidney. The influence of acetaminophen was examined in male golden hamsters treated with acetaminophen- containing diet feeding. They were divided into 5 groups and subjected to this experiment for 4 weeks: animals housed in long photoperiod (LP) as LP control, animals housed in short photoperiod (SP) for 4 weeks as SP control (SP4), and groups of animals treated with low, middle, and high concentrations of acetaminophen (Low, Middle, High groups). Also animals housed in SP for 8 weeks were included (SP8) to contrast testicular activities, if necessary. As results, spermatozoa filled the seminiferous tubules of the testicles of animals in LP control and SP4 groups. The aspects were seen in the animals taken diets of low and middle doses of acetaminophen. The animals who fed high dose of acetaminophen showed large or small testicles. The large testicles displayed all germ cells at the steps of spermatogenesis. The small testicles presented no sperm as the animals housed in SP for 8 weeks. Thus these results indicate that acetaminophen invokes the antigonadal effects and accelerates the regressing process of the testicles in the animals compared to the animals exposed to SP.

The Hepatoprotective Effects of Ethanolic Extract Noni Fruits (Morinda citrifolia L.) on Rats (Rattus norvegicus) Liver with SGPT and Histopathological Evaluations

The liver is an important organ that plays a role in metabolism in the human body. However, the use of certain types of chemical compounds tends to damage these organs. This study aims to determine the hepatoprotective effectiveness of noni fruit (Morinda citrifolia L.) against exposure to hepatotoxic compounds. This research was conducted by experimental method with Groups I to III treated with noni extract with concentrations of 10, 15, and 20%, respectively. Group IV was treated with acetaminophen, a hepatotoxic substance, as a positive control and group V was treated with Na.CMC as a negative control. Data serum glutamate pyruvate transaminase (SGPT) levels and histopathological examination of the liver of the test animals were then analyzed by One-Way Anova. Histopathological examination results showed hepatotoxicity caused by high doses of acetaminophen 10 g/70 KgBW in the positive control group achieved a score of +4 (severe damage), groups I and II showed a score of +3 (moderate damage), and in group III only showed a score of +3 (moderate damage). +2 (light damage). The results of SGPT examination and histopathology showed that the ethanol extract of noni fruit at a concentration of 20% had a hepatoprotective effect.

High-Dose Acetaminophen Alters the Integrity of the Blood-Brain Barrier and Leads to Increased CNS Uptake of Codeine in Rats.

The consumption of acetaminophen (APAP) can induce neurological changes in human subjects; however, effects of APAP on blood–brain barrier (BBB) integrity are unknown. BBB changes by APAP can have profound consequences for brain delivery of co-administered drugs. To study APAP effects, female Sprague–Dawley rats (12–16 weeks old) were administered vehicle (i.e., 100% dimethyl sulfoxide (DMSO), intraperitoneally (i.p.)) or APAP (80 mg/kg or 500 mg/kg in DMSO, i.p.; equivalent to a 900 mg or 5600 mg daily dose for a 70 kg human subject). BBB permeability was measured via in situ brain perfusion using [14C]sucrose and [3H]codeine, an opioid analgesic drug that is co-administered with APAP (i.e., Tylenol #3). Localization and protein expression of tight junction proteins (i.e., claudin-5, occludin, ZO-1) were studied in rat brain microvessels using Western blot analysis and confocal microscopy, respectively. Paracellular [14C]sucrose “leak” and brain [3H]codeine accumulation were significantly enhanced in rats treated with 500 mg/kg APAP only. Additionally, claudin-5 localization and protein expression were altered in brain microvessels isolated from rats administered 500 mg/kg APAP. Our novel and translational data show that BBB integrity is altered following a single high APAP dose, results that are relevant to patients abusing or misusing APAP and/or APAP/opioid combination products.

The Effects of Nitric Oxide Synthase Inhibitors in Acetaminophen-Induced Hepatic Injury in Mice

(1) Aim of the Study: In this study, we aimed to evaluate the vascular damage and the effects of nitric oxide synthase (NOS) enzyme inhibitors in hepatic damage caused by high doses of acetaminophen (APAP). (2) Material and methods: Fifty-three Swiss albino male mice were used for this study. Hepatic and thoracic aorta toxicity caused by 2 or 6 h exposures to APAP (300 mg/kg intraperitoneally (i.p.)) were evaluated. The general NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME: 25 mg/kg and 50 mg/kg, i.p.) and the neuronal NOS inhibitor 7-nitroindazole (7-NI: 15 mg/kg, i.p.) were administered one hour before APAP exposure. (3) Results: Significant morphological deteriorations were observed after 6 h of APAP exposure in histopathological examinations of hepatic sections. Pre-treatment with L-NAME (at 50 mg/kg) or 7-NI before a 6 h APAP exposure significantly decreased hepatic toxicity (p < 0.05). Significant increases in ALT levels in 6 h of APAP exposure were decreased by both L-NAME (with the 25 mg/kg but not at 50 mg/kg) and 7-NI pre-treatments. No significant change was observed in the measured nitrate/nitrite levels and total antioxidant status in either serum or liver homogenates. No significant deteriorations were observed during either hematoxylin-eosin or immunohistochemical staining in thoracic aorta sections. In the thoracic artery sections, no statistical difference was found in acetylcholine-mediated relaxation, which may indicate endothelial dysfunction. (4) Conclusions: This study demonstrated that APAP-induced hepatic toxicity, especially neuronal NOS inhibitors, may decrease hepatic toxicity. It was also shown that APAP-induced hepatic toxicity was not accompanied by vascular dysfunction.

Morphological changes in the liver of experimental animals in the early stages after correction of exposure to high doses of paracetamol

Introduction. Acetaminophen exhibits hepatotoxicity in overdose, which is the leading cause of drug-induced liver failure. The aim of the research was to study early morphological changes in the liver of experimental animals under the influence of high doses of paracetamol and after correction with hepatoprotectors. Materials and methods. The corrective effect of various drugs - ademetionine, ethylmethylhydroxypyridine succinate and oxymethyluracil after exposure to high doses of acetaminophen was studied. Acetaminophen was administered to experimental rats once intragastrically at a dose of 1 g/kg, animals received hepatoprotectors twice (after 1 and 24 hours) or four times (after 1, 24, 48, 72 hours) after the toxicant. Morphological studies of the liver of experimental animals were carried out. Results. Pathomorphological changes were revealed on rat liver preparations after exposure to paracetamol, the most pronounced after 72 hours of exposure. Oxymethyluracil has a protective effect on the structure of the liver during acute exposure to high doses of paracetamol, comparable to the well-known drugs “Heptor” and “Mexidol”. In addition, the protective effect of oxymethyluracil appears earlier. Limitations. Morphological studies of the liver of 90 white male rats were carried out for studying the corrective action of hepatoprotectors after acute exposure to high doses of acetaminophen and after double (after 1 and 24 hours) or quadruple (after 1, 24, 48, 72 hours) administration of ademethionine, ethylmethylhydroxypyridine succinate and oxymethyluracil, which allowed to determine an effective means to reduce the toxic effect of paracetamol on the liver. Conclusion. The data obtained may have a certain practical value in terms of the prospective use of oxymethyluracil as an additional effective agent for reducing the toxic effect of paracetamol.

Rectal diclofenac versus high-dose rectal acetaminophen in children: A randomized clinical trial.

Background:Fever is the most common complaint among the children admitted to health care centers. The aim of this study was to compare the anti-pyretic effect of diclofenac and high dose acetaminophen suppository in 1 to 6 years old children.Methods:This double-blind clinical trial study was performed on 1-6-year-old children hospitalized in 17th Shahrivar Teaching Hospital, Rasht, Iran. Children were divided into two groups of 45 using a block randomization design. The first group received a high dose of acetaminophen suppository at a dose of 30 mg/kg and the second group received a diclofenac suppository at a dose of 1 mg/kg. The rectal temperature of the patients was measured using a digital thermometer at the time of drug administration, and one and three hours after that.Results:90 children were studied in two groups of 45 each. Temperature changes in the diclofenac group were significantly greater than the acetaminophen group, so from zero to 3 hours after administering diclofenac, the temperature decreased to 1.76±0.95°C. This reduction was lower in acetaminophen group (1.26±0.49°C, P=0.019).Conclusion:Both acetaminophen and diclofenac suppositories significantly reduced the rectal temperature. However, the effect of rectal diclofenac on reducing temperature is more than rectal acetaminophen.

High dose acetaminophen inhibits STAT3 and has free radical independent anti-cancer stem cell activity

High-dose acetaminophen (AAP) with delayed rescue using n-acetylcysteine (NAC), the FDA-approved antidote to AAP overdose, has demonstrated promising antitumor efficacy in early phase clinical trials. However, the mechanism of action (MOA) of AAP's anticancer effects remains elusive. Using clinically relevant AAP concentrations, we evaluated cancer stem cell (CSC) phenotype in vitro and in vivo in lung cancer and melanoma cells with diverse driver mutations. Associated mechanisms were also studied. Our results demonstrated that AAP inhibited 3D spheroid formation, self-renewal, and expression of CSC markers when human cancer cells were grown in serum-free CSC media. Similarly, anti-CSC activity was demonstrated in vivo in xenograft models - tumor formation following in vitro treatment and ex-vivo spheroid formation following in vivo treatment. Intriguingly, NAC, used to mitigate AAP's liver toxicity, did not rescue cells from AAP's anti-CSC effects, and AAP failed to reduce glutathione levels in tumor xenograft in contrast to mice liver tissue suggesting nonglutathione-related MOA. In fact, AAP mediates its anti-CSC effect via inhibition of STAT3. AAP directly binds to STAT3 with an affinity in the low micromolar range and a high degree of specificity for STAT3 relative to STAT1. These findings have high immediate translational significance concerning advancing AAP with NAC rescue to selectively rescue hepatotoxicity while inhibiting CSCs. The novel mechanism of selective STAT3 inhibition has implications for developing rational anticancer combinations and better patient selection (predictive biomarkers) for clinical studies and developing novel selective STAT3 inhibitors using AAP's molecular scaffold.

Does high dose intravenous acetaminophen affect liver function for PDA closure in premature neonate?

ObjectivesThe aim of this study was to collect consistent data on the efficacy and safety and evaluation hepatotoxicity of intravenous acetaminophen for the treatment of PDA in preterm infants.MethodsThis is an observational longitudinal prospective study on 46 preterm infants with PDA who treated with high dose of acetaminophen and evaluated with echocardiography and serum liver enzymes at Hafez and Zeinabiyeh hospitals from January 2016 to December 2019.ResultForty-six preterm infants with PDA treated with intravenous acetaminophen. Rate of closure of PDA was 82.6. There was no significant difference after treatment regarding AST, ALT, Albumin, total and direct bilirubin (P value > 0.05) and no adverse side effects were observed in association with intravenous acetaminophen.ConclusionHigh dose of acetaminophen is not more effective than that with standard doses although without hepatotoxic side effect for PDA closure.

Assessment of the biochemical pathways for acetaminophen toxicity: Implications for its carcinogenic hazard potential

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (≤4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death – thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

National Poison Center Calls Before vs After Availability of High-Dose Acetaminophen (Paracetamol) Tablets in Switzerland

Acetaminophen (paracetamol) is among the most widely used pain medications worldwide; while safe within the therapeutic range, intake exceeding 4000 mg/d can lead to hepatotoxicity. Prior evidence suggests that limiting the availability of large quantities of acetaminophen is associated with decreased acetaminophen-related poisonings and mortality; in Switzerland, 500-mg tablets are available over-the-counter (OTC) and, as of October 2003, 1000-mg tablets are available with prescription. To evaluate the association of adding 1000-mg acetaminophen tablets to the Swiss market with utilization and poisonings. This cross-sectional study used a quasi-experimental interrupted time series analysis to evaluate 15 790 acetaminophen poison records from January 1, 2000, to December 31, 2018. All calls for acetaminophen-related poisonings identified from the National Swiss Poisons Centre and all sales for oral acetaminophen tablets (prescription and OTC) dispensed between January 2000 and December 2018 were included. October 3, 2003 (Q4 2003), was defined as the intervention date, corresponding to the date of market entry for 1000-mg acetaminophen tablets in Switzerland. The primary outcome was the number of quarterly acetaminophen-related poison calls to the National Poison Centre. Additional outcomes included quarterly sales for acetaminophen and change in poisoning circumstances, stratified by preintervention and postintervention periods and by formulation (ie, 500-mg and 1000-mg tablets). Between 2000 and 2018, 15 790 acetaminophen-related poisoning calls were identified, of which 10 628 (67.3%) were regarding women, and the mean (SD) age of patients was 25.2 (18.2) years. The interrupted time series analysis identified a significant increase in the slope for the number of reported poisonings following the intervention point, particularly for accidental circumstances (z score, -3.62; P < .001). In the preintervention period, 120 of 961 poisonings (15.3%) involved a dose greater than 10 000 mg, while for the postintervention period, 1140 of 5696 (30.6%) had a dose larger than 10 000 mg (P < .001). There was a rapid uptake in 1000-mg acetaminophen sales, while sales of the 500-mg tablet decreased slightly. Since 2012, a mean (SD) of 20.7 million (1.4 million) 1000-mg tablets were dispensed quarterly compared with 2.7 million (0.5 million) 500-mg tablets. This study found a significant increase in acetaminophen dispensing and acetaminophen-related poisonings in Switzerland following the approval of 1000-mg tablets in 2003. The availability of 1000-mg acetaminophen should be re-evaluated to minimize the potential for accidental poisonings.

Abstract 2045: Characterization of inpatient opioid use among pediatric neuroblastoma patients during dinutuximab therapy

Abstract Background: Dinutuximab is a chimeric anti-GD-2 (disialoganglioside) antibody approved for use in post-consolidation care of patients with high-risk neuroblastoma. GD-2 receptors are also expressed in cerebellar neurons, melanocytes, and peripheral sensory nerve fibers in normal human tissue. Given this pattern of expression, pain is a common and often infusion rate-limiting adverse effect, with greater than 50% of patients experiencing severe (Grade 3 or above) pain. Standard pain management for dinutuximab infusions at our center includes initiation of continuous infusion of opioid patient-controlled analgesia along with demand, loading, and boluses doses. Little to no data exist in the literature to describe opioid use in pediatric patients with acute, episodic pain. Therefore, this study aims to characterize opioid use in this setting. Methods: Data were collected retrospectively from the electronic medical record under a study protocol approved by the Institutional Review Board at the University of Michigan, C.S. Mott Children's Hospital. Patients were included in the study if they had a clinical diagnosis of metastatic or relapsed high-risk neuroblastoma, received at least one dinutuximab cycle, and were aged 2-14 at the time of admission. Daily amount of opioids, calculated as the oral morphine equivalent daily dose (MEDD), acetaminophen, and gabapentin administered were calculated. Repeated measures ANOVA was used to evaluate within-subjects changes. Results: The average age of patients was 5.7 years [range 2-14 years]. Four of eleven (36.4%) were female and 7/11 (63.6%) were male. All patients received four days of dinutuximab infusions for an average length of 11.8 hours (SD=2.0) per day. All patients received gabapentin prophylactic treatment and an average of 3387 mg (SD=1275.5). Average total MEDD across all patients was 184.7 mg (SD=137.6) during the inpatient hospitalization. Females (p=0.003) and older patients (p=0.04) had significantly increased daily MEDD as compared to their day 1 intake. All patients experienced a fever spike and received acetaminophen (2915 mg, SD=1737.8) Older patients received higher doses of acetaminophen (p=0.007) Only 1 patient met definition of a chronic opioid user and was discharged with an outpatient opioid prescription. The remaining opioid-naïve patients were discontinued on opioid treatment at the time of discharge. Conclusions: Pediatric patients on dinutuximab therapy received a high MEDD parenteral opioids dose alongside adjunctive analgesics. Future studies are needed to determine opioid requirement trends across gender, age, and cycles in a larger cohort of patients, as well as to determine the risk of chronic opioid use in this patient population. Citation Format: Jola Mehmeti, Jae Eun Choi, Ian Wolfe, Juan Cata, Rajen Mody. Characterization of inpatient opioid use among pediatric neuroblastoma patients during dinutuximab therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2045.

Prophylactic Effect of Cyperus Esculentus Milk on High Dose Acetaminophen Model of Hepatic Toxicity in Wistar Rats

Cyperus esculentus is a wholesome nut with notable nutritional and medicinal benefits. This study investigated the prophylactic impact of Cyperus esculentus milk extract (CE) on high dose acetaminophen (APAP)-induced liver impairment in experimental rats. Thirty rats weighing between 180-200 g were randomly distributed into 6 groups (n=5). Groups 1 (control given only distilled water) and 2 (negative control given APAP) were without treatment, while rats in groups 3, 4, 5 and 6 were orally administered 8.57 mg ascorbic acid, 100 mg/kg, 200 mg/kg and 400 mg/kg of body weight CE respectively for 21 days. On the 22nd day of the experiment, 1 g/kg body weight of acetaminophen was administered orally to rats in groups 2, 3, 4, 5 and 6. The serum and liver of sacrificed animals were collected for analyses. CE at selected doses appreciably prevented high dose acetaminophen-induced increase in serum activities (p&lt;0.05) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and concentration of malondialdehyde as seen in the untreated APAP control group. Decreased serum GST activity caused by acetaminophen in untreated group improved significantly (p&lt;0.05) in CE treated groups which was comparable (p &gt; 0.05) to ascorbic acid group. In the liver, acetaminophen decreased the activities of AST, ALT, ALP, however, increased concentration and activity of malondialdehyde and GST respectively (p &lt; 0.05). Pre-administration of CE markedly prevented these effects in the liver of rats that were administered acetaminophen. The present study demonstrated C. esculentus milk extracts prevented hepatic damage caused by high dose acetaminophen in rats.&#x0D; Keywords: Acetaminophen, Cyperus esculentus, biomarkers, hepatoprotective.