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Estimates of Acetaminophen-Associated overdoses in the United States
Abstract
To estimate the number of acetaminophen-associated overdoses in the United States and identify possible risk factors for intervention.
The investigators obtained estimates of acetaminophen-associated overdoses using different national databases. Two emergency room databases, a hospital discharge database, a national mortality file, and a poison surveillance database were used to identify cases. The FDA's spontaneous reporting system was searched to identify possible root causes for overdoses.
Analysis of national databases show that acetaminophen-associated overdoses account for about 56,000 emergency room visits and 26,000 hospitalizations yearly. Analysis of national mortality files shows 458 deaths occur each year from acetaminophen-associated overdoses; 100 of these are unintentional. The poison surveillance database showed near-doubling in the number of fatalities associated with acetaminophen from 98 in 1997 to 173 in 2001. AERS data describe a number of possible causes for unintentional acetaminophen-associated overdoses.
Each year a substantial numbers of Americans experience intentional and unintentional acetaminophen-associated overdoses that, in severe cases, lead to serious illness and possible death. This summary of a series of analyses highlights the need for strategies to reduce this public health burden.
... Because of the presence of APAP in numerous prescription and over-the-counter medications, intentional and unintentional overdosing occurs regularly. In fact, 60,000-80,000 emergency department visits, 30,000-40,000 hospitalizations with > 5,000 patients developing severe liver injury, and 300-500 patients die annually in the United States due to APAP overdose [2,4,5]. APAP overdose is the most frequent etiology of acute liver failure in the United States, the United Kingdom, and many other mainly western countries [6]. ...
... Another factor overlooked by using young mice is that age may affect toxicity. However, the age distribution of patients with self-harm intent indicates a substantial peak between 15 and 24 years of age with the lowest number of cases in the > 50-year age group [4,171]. In contrast, unintentional overdosing appears to be relatively equally distributed between all age groups [4,171]. ...
... However, the age distribution of patients with self-harm intent indicates a substantial peak between 15 and 24 years of age with the lowest number of cases in the > 50-year age group [4,171]. In contrast, unintentional overdosing appears to be relatively equally distributed between all age groups [4,171]. Thus, using younger mice replicates the clinical scenario for a large group of patients. ...
Acetaminophen (APAP)-induced liver injury and acute liver failure is a significant clinical problem worldwide; in addition, APAP overdoses in animals or in cell culture are used as popular models to study drug-induced liver injury mechanisms and test therapeutic interventions. Early assumptions that APAP toxicity is caused by a single mechanism resulting in a defined mode of cell death in hepatocytes had to be questioned when over the years many different mechanisms and modes of cell death were reported. Although many of the contradictory results and conclusions reported over the years can be attributed to lack of understanding of established mechanisms, methodological problems, and misinterpretation of data, it is increasingly recognized that some of the reported differences in signaling mechanisms and even a switch in the mode of cell death can be caused by variations in the experimental conditions. In this review, examples will be discussed how experimental conditions (dose, solvent, etc.), the experimental system (species, strain, and substrain in vivo, cell type, and in vitro conditions), and also adaptive responses and off-target effects of genetic manipulations and chemical interventions, can impact the mechanisms of cell death. Given that the conditions will determine the results, it is therefore of critical importance to keep in mind the translational aspect of the experiments, i.e., the conditions relevant to the human pathophysiology. Only the full appreciation of these issues will lead to reproducible and clinically relevant results that advance our understanding of all facets of the human pathophysiology and identify clinically relevant therapeutic targets.
... On the other hand, in overdose scenarios, these pathways become saturated and N-acetyl-p-benzoquinone imine (NAPQI), An unsafe metabolite, is formed. NAPQI can bind to cellular macromolecules when glutathione supplies are low, causing permanent damage and hepatic necrosis (55). Because paracetamol is frequently mixed with other drugs in prescription prescriptions and many over-the-counter products, there is an increased risk of inadvertent overdose. ...
... Many people are not aware that the cumulative dosage from various sources can easily surpass the adult guideline limits of 4 grammes per day (53). Doses as low as 7.5 g/day to 10 g/day can cause toxicity, and N-acetylcysteine is frequently needed for immediate medical attention in cases of severe liver damage (55). Healthcare providers and patients alike must be aware of the dangers of paracetamol, particularly the possibility of severe hepatotoxicity and overdosage. ...
Fever; characterized by an increased core temperature; is a complex physiological reaction to illness involving acute-phase reactants and many physiological; endocrinological; and immunological systems. Antipyretics; chiefly non-steroidal anti-inflammatory Drugs (NSAIDs) and paracetamol; are essential for the management of fever and related discomfort. These medicines primarily function by inhibiting cyclooxygenase enzymes; so diminishing the production of prostaglandin E2 in the hypothalamus and subsequently decreasing the thermal set point. Although paracetamol is acknowledged for its safety when utilized correctly; it presents concerns of hepatic toxicity and overdose; requiring vigilant monitoring; especially in pediatric patients or those with concomitant conditions. Conversely; ibuprofen typically has greater antipyretic efficacy; particularly in pediatric populations; although its application may be constrained by gastrointestinal adverse effects and renal considerations. Recent breakthroughs in this domain concentrate on improving the safety and efficacy of antipyretic drugs; particularly for at-risk populations such as the elderly and children. Innovations like COX-2 selective inhibitors and advanced delivery technologies; including nanomedicine; offer exciting opportunities for enhancing pain management and fever therapy. Future study should emphasize the customization of therapy according to pharmacodynamics; possible drug interactions; and patient attributes to enhance therapeutic results. An interdisciplinary approach is crucial for the appropriate management of fever and pain; enhancing patient welfare and progressing clinical practices in antipyretic and antinociceptive therapies.
... Такой подход приводит к нерациональному применению жаропонижающих препаратов. Стоит также отметить, что применение антипиретиков может быть вредным: в 2006 году случайная передозировка парацетамола привела к 100 смертям только в США [15]. Поэтому целью данного обзора являются анализ существующих клинических исследований, сравнивающих парацетамол и ибупрофен, для последующей разработки рекомендаций практикующим врачам по ведению пациентов детского возраста с лихорадкой. ...
... При этом не существует оснований для того, чтобы парацетамол был единственным лекарственным средством или жаропонижающим средством первой линии, поскольку абсолютное большинство систематических обзоров и рандомизированных клинических исследований, сравнивающих его с ибупрофеном, не показали превосходящего жаропонижающего эффекта или профиля безопасности [25]. В связи с этим возникает вопрос о том, следует ли отнести парацетамол ко второй линии жаропонижающей терапии, поскольку, несмотря на эквивалентность профилей безопасности обоих препаратов в терапевтических дозах, токсический уровень парацетамола достигается гораздо раньше, чем при приёме супратерапевтических доз ибупрофена, и чаще приводит к летальным исходам [15,18]. ...
Fever accounts for a significant proportion of pediatric emergency consultations, with up to 40% of children under the age of five see a doctor for this condition. Fever is usually the result of acute respiratory viral infection, is short-lived and resolves on its own. However, in the hyperergic variant or with depletion of compensatory mechanisms, fever can be the cause of the development of pathological conditions. Therefore, timely and effective control of fever has always been a subject of interest to parents and pediatricians. Current guidelines define fever above 38.5°C as a condition in which the use of antipyretics is indicated. Paracetamol (acetaminophen) and ibuprofen are the most widely prescribed and available over-the-counter antipyretics in children. Despite the widespread use of these drugs, recommendations for the treatment of young children remain varied, leading to irrational use of antipyretics. Therefore, the aim of this review is to analyze existing clinical trials comparing paracetamol and ibuprofen to develop guidelines for pediatricians on the management of febrile pediatric patients.
... The commercially available dosage form of paracetamol includes tablets, caplets, capsules, effervescent tablets, suppositories, suspensions, parenteral injections, chewable tablets, oral drops, syrups, elixirs and extended release tablets [36]. The recommended doses of paracetamol in different age groups are listed in Table 1.1. ...
Quality management, quality control, and quality assurance are three interrelated concepts that are essential for ensuring the quality of products and services. Quality management is the overall approach that an organization takes to managing and improving the quality of its products or services. It encompasses both quality control and quality assurance, as well as other activities such as training employees, engaging with customers, and setting quality goals and objectives. According to World Health Organization, the term quality control refers to the sum of all procedures undertaken to ensure the identity and purity of a particular pharmaceutical. Quality control is an essential operation of the pharmaceutical industry. In addition to the apparent features of tablets, tablets must meet other physical specifications and quality standards. These include criteria for weight, weight variation, content uniformity, thickness, hardness, disintegration, and dissolution. Thus in this project, five types of paracetamol tablets from different companies which are widely used in the private pharmacies in Hilla city were subjected to quality control tests to indicate whether these products will fit to the standard criteria of the United States Pharmacopeia or not. The data indicated that all brands succeeded to pass most quality control tests with some exceptions.
... Acetaminophen (N-acetyl-para-aminophenol; APAP) is one of the most extensively used analgesic and antipyretic agents worldwide. Although it is considered a safe drug when used properly, an overdose is known to cause acute liver failure, which may be fatal [1]. APAPinduced liver injury is attributed to the formation of the reactive metabolite N-acetyl-para-benzo-quinone-imine (NAPQI) upon its biotransformation by cytochrome P450 enzymes, which subsequently depletes cellular glutathione (GSH) and forms protein adducts with mitochondrial proteins [2]. ...
Abstract
The use of N-acetylcysteine against acetaminophen(APAP)-induced hepatotoxicity, a leading cause of liver injury, has several drawbacks, including short therapeutic windows. Khaya grandifoliola (Meliaceae) has been traditionally used to manage liver-related diseases, and many reports have confirmed its hepatoprotective properties. However, its therapeutic potential as an antidote against APAP-induced hepatotoxicity has yet to be proven in a clinically relevant model. This study aimed to verify the efficacy of delayed treatment with the hydroethanolic extract of K. grandifoliola (KgE) in suppressing the early injury phase of APAP pathophysiology. KgE was analyzed using HPLC/UV. Acute oral toxicity tests were conducted in mice to determine the therapeutic dose of KgE. Mice were treated with 300 mg/kg APAP; 1h and 12h later, they were treated with either predetermined doses of KgE or 20 mg/kg c-Jun N-Terminal Kinase (JNK) inhibitor SP600125, which served as a reference
antidote. At 6h and 24h after APAP treatment, the parameters of liver damage and mitochondrial dysfunction, phosphorylation of JNK, and mitochondrial translocation were assessed. KgE at a dose of 5000 mg/kg was safe for mice. Accordingly, 100, 200, and 400 mg/kg were selected as curative treatments. Delayed administration of KgE reversed the histopathological changes in the liver, inhibited serum levels of alanine aminotransferase, reduced the liver content of nitric oxide and malondialdehyde, and restored hepatic glutathione pools and superoxide dismutase and catalase activities in APAP-intoxicated mice. Moreover, KgE prevented APAP-induced JNK phosphorylation and p-JNK mitochondrial translocation and rescued the activities of mitochondrial enzyme complexes II and V. HPLC/UV analysis revealed the presence of gallic acid, Quercetin and Silibinin, with retention times of 3.77, 11.63 and 11.95 min as the major active ingredients present in KgE. Our findings demonstrate that post-treatment with KgE protects the mouse liver from APAP-hepatotoxicity through the inhibition of JNK activation and mitochondrial dysfunction.
Keywords: Acetaminophen-hepatotoxicity; K. grandifoliola; Hydro-ethanolic extract; Inhibition JNK Phosphorylation; Mitochondrial dysfunction.
... Currently, paracetamol also used as combination drug with opioids for severe cancer pain [3]. Although typically safe when used at recommended therapeutic doses, the excessive ingestion of this over-the-counter drug can potentially cause hepatotoxicity, which may lead to acute liver failure (ALF) [4,5]. Along with ALF, acetaminophen overdose also associated with acute kidney injury, gastrointestinal ulceration, bronchospasm, and ductus arteriosus, etc. [3]. ...
Background and aim
N-acetyl-p-benzoquinoneimine (NAPQI), a toxic byproduct of paracetamol (Acetaminophen, APAP), can accumulate and cause liver damage by depleting glutathione and forming protein adducts in the mitochondria. These adducts disrupt the respiratory chain, increasing superoxide production and reducing ATP. The goal of this study was to provide computational proof that succinate dehydrogenase (SDH), a subunit of complex II in the mitochondrial respiratory chain, is a favorable binding partner for NAPQI in this regard.
Method
Molecular docking, molecular dynamics simulation, protein-protein interaction networks (PPI), and KEGG metabolic pathway analysis were employed to identify binding characteristics, interaction partners, and their associations with metabolic pathways. A lipid membrane was added to the experimental apparatus to mimic the natural cellular environment of SDH. This modification made it possible to develop a context for investigating the role and interactions of SDH within a cellular ecosystem that was more realistic and biologically relevant.
Result
The molecular binding affinity score for APAP and NAPQI with SDH was predicted −6.5 and −6.7 kcal/mol, respectively. Furthermore, RMSD, RMSF, and Rog from the molecular dynamics simulations study revealed that NAPQI has slightly higher stability and compactness compared to APAP at 100 ns timeframe with mitochondrial SDH.
Conclusion
This study serves to predict the mechanistic process of paracetamol toxicity by using different computational approaches. In addition, this study will provide information about the drug target against APAP hepatotoxicity.
... Acetaminophen (APAP) is a common analgesic and antipyretic that is used globally, including by an estimated 60 million Americans every week (Agrawal and Khazaeni 2023). While generally well tolerated at therapeutic doses, overdoses of APAP can cause severe acute liver injury which can progress to liver failure and possibly death (Yoon et al. 2016) and account for over 56,000 annual emergency room visits in the US (Nourjah et al. 2006). APAP overdose is the leading cause of drug-induced liver injury and acute liver failure in the US, accounting for nearly 50% of cases of the latter (Larson et al. 2005;Lee 2017). ...
Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42–48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.
... APAP-related adverse events continue to be a public health burden (Lee, 2004). APAP overdose is the leading cause for calls to Poison Control Centers (>100 000/year) and accounts for more than 50 000 emergency room visits, 2600 hospitalizations, and nearly 500 deaths per year as a result of APAP-associated acute liver failure (Major et al., 2016;Nourjah et al., 2006). ...
Acetaminophen (APAP)-induced liver injury is one of the most frequent causes of acute liver failure worldwide. Significant increases in the levels of miRNA-21 in both liver tissues and plasma have been observed in APAP-overdosed animals and in humans. However, the mechanistic effect of miRNA-21 on acute liver injury remains unknown. In this study, we generated a new hepatocyte-specific miRNA-21 knockout (miR-21-HKO) mouse line. miR-21-HKO and the background matched sibling wild-type (WT) mice were treated with a toxic dose of APAP. Compared to WT mice, miR-21 HKO mice showed an increased survival, a reduction of necrotic hepatocytes, and an increased expression of light chain 3B (LC3B), which suggested an autophagy activation. The expression of PPARγ was highly induced in livers of miR-21-HKO mice after a 2 h APAP treatment, which preceded the activation of LC3B at the 12 h APAP treatment. miR-21 negatively regulated PPARγ protein expression by targeting its 3’-UTR. When PPARγ function was blocked by a potent antagonist GW9662 in miR-21-HKO mice, the autophage activation was significantly diminished, suggesting an indispensable role of PPARγ signaling pathway in miR-21-mediated hepatotoxicity. Taken together, hepatocyte-specific depletion of miRNA-21 alleviated APAP-induced hepatotoxicity by activating PPARγ and autophagy, demonstrating a crucial new regulatory role of miR-21 in APAP-mediated liver injury.
... It is noteworthy that in the United States, overdoses involving acetaminophen are the primary cause of calls made to Poison Control Centers, with an annual incidence exceeding 100,000 [1]. These overdoses lead to more than 56,000 emergency room visits, resulting in approximately 2,600 hospitalizations and, tragically, around 450 deaths attributed to ALF each year [1,2]. Such cases of ALF attributed to acetaminophen may stem from intentional overdoses or unintentional ingestions, often influenced by various factors, including the concurrent use of alcohol and specific medications known to promote the formation of reactive and harmful metabolites [3]. ...
This case report explores the intricate diagnostic challenges encountered in a 30-year-old male patient with abdominal pain, jaundice, and a history of acetaminophen use. Initially presenting as a potential case of drug-induced hepatitis due to acetaminophen overdose, the diagnosis took an unexpected turn when the patient tested positive for hepatitis B surface antigen. The case highlights the complexity of diagnosing acute hepatitis, considering multiple potential etiologies, including viral and drug-induced factors. Differential diagnoses for this case involve considering drug-induced hepatitis, autoimmune hepatitis, various viral hepatitis types, and the potential contribution of cocaine-induced hepatitis as individual possibilities or in combination.
This case emphasizes the need for a comprehensive evaluation, the consideration of multiple potential causes, and the importance of ongoing monitoring and follow-up to ensure optimal patient care in cases of acute hepatitis.
... Clinicians and patients should be cautious when using combination products containing acetaminophen, as it may lead to unintentional acetaminophen overdose if other medications are consumed concurrently. developed countries [11]. Acetaminophen overdosages may be intentional, with suicidal ideation, and are more common in patients with underlying psychiatric diseases. ...
Acetaminophen, or paracetamol, ranks among the most extensively utilized analgesic and antipyretic medications globally. The administration of acetaminophen to individuals with underlying liver disease has long sparked concerns regarding the potential risk of hepatotoxicity. However, the available literature and recommendations consider it a safe option in all forms of liver diseases and is deemed safe when used at recommended doses. This article aims to offer a concise review of the pharmacokinetics, toxicity profile, and the intricate considerations surrounding the safety of acetaminophen in patients with liver disease. By delving into the liver-acetaminophen interactions, we seek to provide a nuanced perspective on the use of acetaminophen in this critical patient population.
... However, acetaminophen overdose is reported among the leading causes of AHF in Europe and North America [4,5]. Acetaminophen could cause almost 50% of AHF worldwide in case of overdose [6,7], which can affect around 60,000 individuals annually [8]. More than 90% of acetaminophen is metabolized in the liver to non-toxic compounds, and only 5-10% is converted to N-acetyl-p-benzoquinonemine (NAPQI) toxic metabolite through the CYP2E1 isoform of cytochrome P 450 , the major contributing enzyme in this biochemical reaction [9]. ...
Background:
Acetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity.
Methods:
We have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model.
Results:
Data demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment.
Conclusion:
The results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration.
... become very high, peaking at approximately 72 hours. 15 Acetylcysteine can prevent liver injury when administered within 12 hours of acetaminophen overdose, but whether it is effective at later time points is controversial. 16 ...
Drug-induced liver injury (DILI) is a major cause of acute liver injury, liver failure, and liver transplantation worldwide. In recent years, immune checkpoint inhibitors have become widely used. This has led to an increase in DILI, for which pathophysiology and management methods differ significantly from the past. As the number of cases of acute liver injury and liver transplantation due to DILI is expected to increase, information about a DILI is becoming more valuable. DILI is classified into two types according to its etiology: intrinsic DILI, in which the drug or its metabolites cause liver damage that is dose-dependent and predictable; and idiosyncratic DILI, in which liver damage is also dose-independent but unpredictable. In addition, depending on the course of the disease, chronic DILI or drug-induced autoimmune hepatitis may be present. The number of DILI cases caused by antimicrobial agents is decreasing, whereas that caused by drugs for malignant tumors and health foods is increasing. The Roussel Uclaf Causality Assessment Method is widely used to assess causality in DILI. Liver injury is a type of immune-related adverse event. The pattern of hepatic injury in immune-related adverse events is mostly hepatocellular, but mixed type and bile stasis have also been reported. Sclerosing cholangitis caused by immune checkpoint inhibitors has also been reported as a unique type of injury. Treatment mainly comprises withdrawal of immune checkpoint inhibitors and steroid administration; however, mycophenolate mofetil may be considered if the disease is refractory to steroids.
... Acetaminophen (APAP) is a drug commonly used for relief from pain and fever; safety is ensured when APAP is used in limited doses with a narrow margin, but at overdose, APAP causes acute liver injury (ALI). 1 Excess APAP, when ingested, is metabolized by phase I cytochrome P450 (CYP) enzymes (CYP2E1, CYP3A4, and CYP1A2) in the liver, resulting in the production of reactive N-acetyl-p-benzoquinone imine (NAPQI). 2 Generally, NAPQI is detoxified through covalent binding to glutathione (GSH) and is then excreted in urine as mercapturic acid, which is less toxic and more water-soluble. However, excess NAPQI can not only deplete GSH but also directly bind to other thiol molecules in cells, which affects APAP therapeutic efficacy and leads to hepatotoxicity. ...
Overdose acetaminophen (APAP) can cause acute liver injury (ALI), but the underlying mechanism remains undetermined. This study explored the role of hepatic Zinc Finger And BTB Domain Containing 22 (ZBTB22) in defense against APAP-mediated hepatotoxicity. The results showed that hepatic ZBTB22 expression was significantly reduced in patients with ALI and mice. In mouse primary hepatocytes (MPHs), ZBTB22 deletion aggravated APAP overdose-induced ALI, whereas ZBTB22 overexpression attenuated that pathological progression. The results were further verified in ZBTB22 over-express or knockout mice models. In parallel, hepatocyte-specific ZBTB22 knockout also enhanced ALI. Furthermore, ZBTB22 decreased pregnane X receptor (PXR) expression, and the PXR activator pregnane-16α-carbonitrile suppressed the protective effect of ZBTB22 in APAP-induced ZBTB22-overexpressing mice. Collectively, our findings highlight the protective effect of ZBTB22 against APAP-induced ALI and unravel PXR signaling as the potential mechanism. Strategies to increase hepatic ZBTB22 expression represent a promising therapeutic approach for APAP overdose-induced ALI.
... This study proposed that some subgroups of patients like young females were at a greater risk and educational and preventive operations may be practical in this area (26). In a similar study in the United States, the incidence of acetaminophen overdose was estimated approximately 20 per 100 000 population (27). ...
Background: The aim of this study was to evaluate the serum levels of acetaminophen in patients with unknown poisoning and loss of consciousness, and to assess whether measuring serum acetaminophen level in all patients with drug overdose or decreased level of consciousness changes outcome. Methods & Materials: In a descriptive-analytical study, 300 patients with loss of consciousness and a history of drug toxicity with an unknown drug that referred to the emergency unit constituted the study sample. Serum acetaminophen levels of patients, the outcome, mortality, and morbidity of patients were evaluated. Results: The mean age of patients was 28.88±8.67 years. The minimum age of patients was 15 years and the maximum age of patients was 58 years. The mean serum level of acetaminophen in patients was 0.62±0.55 μg/ml. The highest level and the lowest level of acetaminophen in patients were 2.8 μg/ml and 0.2 μg/ml respectively. Serum acetaminophen level in patients was less than the toxic level (less than 30 μg/ml). Conclusion: Based on the findings of this study, acetaminophen as a widely used and available drug is not a common cause of poisoning in patients with loss of consciousness in our region.
... In the U.S., 26000 patients with APAP-associated ALI are hospitalized yearly and approximately 500 of them die from APAPassociated ALI. Therefore, it is of clinical significance to unravel the underlying mechanism and explore prevention and treatment strategies for APAP-associated ALI [4]. Although the precise mechanisms remain elusive, inflammatory reactions [5], oxidative stress [6], mitochondrial autophagy [7], and endoplasmic reticulum stress (ERS) [8] are implicated. ...
Background:
Excessive acetaminophen (APAP) use can lead to acute liver injury (ALI) by inducing endoplasmic reticulum stress (ERS). We previously found that pretreatment with the peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand rosiglitazone (RSG) alleviated ALI in APAP-treated mice.
Objective:
To examine if RSG-mediated hepatoprotection is associated with ERS suppression.
Methods:
Forty-eight male CD-1 mice were randomly divided into control, RSG, APAP 4 h, APAP 24 h, RSG + APAP 4 h, and RSG + APAP 24 h groups. The RSG and RSG + APAP groups received RSG (20 mg/kg) by gavage 48, 24, and 1 h before intraperitoneal injection of 300 mg/kg APAP, while the APAP group received APAP alone and the control group received only normal saline. Animals were sacrificed immediately (RSG and control groups), 4 h (APAP 4 h and RSG + APAP 4 h), or 24 h (APAP 24 h and RSG + APAP 24 h) post-APAP injection. Liver tissues were collected for hematoxylin-eosin staining, TUNEL staining, and Western blotting for ERS-associated proteins. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were also measured. A second cohort received APAP or RSG + APAP as described and were monitored for survival over one week.
Results:
At 4 and 24 h following APAP injection alone, serum ALT and AST levels were significantly elevated, and central lobular necrosis of the liver was observed. Necrosis area reached 21.7% at 4 h and 32.1% at 24 h post-APAP, while apoptotic fractions reached 25.6% and 32.4%. Further, 50% of mice in the survival analysis cohort died within one week post-APAP. At 4 h post-APAP, the ERS marker glucose-regulated protein-78 (GRP78) and ERS-associated proteins pJNK, GRP78, p-eIF2α, pPERK, and pIRE were all significantly upregulated. Pretreatment with RSG significantly reduced serum ALT and AST, liver necrosis area, apoptosis rate, and expression of ERS-associated proteins compared to APAP alone, while increasing survival to 80%.
Conclusions:
Rosiglitazone pretreatment can alleviate APAP-induced ALI by suppressing three branches of ERS signaling.
... Acetaminophen (APAP) overdose is a common cause of acute liver failure (ALF) in North American and European countries [131,132]. The increase in the hepatic O-GlcNacylated protein leads to the dysregulation of the hepatic glutathione (GSH) supplement response and increases the APAP-induced hepatic injury, while reduced O-GlcNacylation causes rapid GSH replenishment and the subsequent inhibition of APAP-induced liver injury [133]. ...
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.
... 4 Acetaminophen (APAP) is safely used by millions of people every day, but it is the most common cause of drug-induced liver injury in the United States. 5 The APAP can cause acute pericentral liver injury when greater than 6 to 10 g/d is ingested. Federal changes have been enacted to limit toxic ingestions, including labeling of all over-the-counter products that contain APAP with additional warnings and limiting the dose of APAP to 325 mg per tablet. ...
Objectives
Social disruption due to COVID-19 has detrimentally affected American adolescents’ emotional well-being. Within our system, pediatric acetaminophen ingestions increased in 2020, compared with previous years. We sought to evaluate the rate of hospitalizations for acetaminophen self-harm ingestions and self-harm of adolescents during the COVID-19 pandemic.
Study Design
We identified patients (aged 0-23) from billing data with diagnosis of acetaminophen ingestion with self-harm intent (ICD-10 code T391X2A), from a multicenter urban, quaternary health care system. We performed retrospective chart review from 2016 to 2020 and performed statistics using a generalized estimating equation (GEE) logistic regression model.
Results
From 2016 to 2020, there were 25 790 discharges of adolescents with 65 acetaminophen self-harm ingestion and 148 self-harm discharges. Of the 65 acetaminophen patients, 75% identified as female and 54% identified as non-white; 71% with Medicaid insurance. The proportion of acetaminophen ingestion and self-harm admissions increased from 0.13% in 2016 to 0.46% by 2020 and 0.42% in 2016 to 0.73% by 2020, respectively. The odds of acetaminophen ingestion admission increased by 28% each additional year (odds ratio = 1.28; 95% confidence interval: 1.08, 1.53; P = .006). There was not enough evidence to conclude that the log-odds of a self-harm ingestion were linearly related to time (P = .06).
Conclusions
Acetaminophen ingestion for self-harm has significantly increased, while overall self-harm has increased to a lesser, nonsignificant degree. Primarily females of color and those with Medicaid insurance are affected. It is important to note this growing, disturbing trend, and to continue to screen for depression in our adolescent community and ensure access to mental health resources.
... In North America, APAP overdose is believed to result in 100,000 calls to poison control centers, 50,000 emergency room visits, and at least 500 deaths annually. [159] The annual number of ALF cases from APAP dwarfs the number of ALF cases associated with all idiosyncratic reactions combined. [160] The reason for this widespread toxicity is that, unlike drugs associated with idiosyncrasy, APAP is a dose-related hepatotoxin, with all mammalian species susceptible to liver injury in doses only 2 to 3 times therapeutic dosing. ...
... Intake at this dose commonly does not produce toxic influences while overdose cause severe hepatic damage and even acute liver failure in humans [3]. In the USA, over 60 million people regularly consumed APAP every week and APAP overdose caused 68,000 emergency department visits, 30,000 hospitalizations, and 500 deaths [4][5][6][7][8]. Several preclinical studies have been conducted on the effects of phytochemicals and Chinese herbal medicine on APAP-induced liver injury in animal models [9][10][11]. ...
This study aimed to investigate the hepatoprotective effects of lyophilized powder of goji ferment (LPGF) against acetaminophen (APAP)-induced hepatic damage in Hep3B cells and in mice. Eleven strains of lactic acid bacteria (LAB) were selected and their hepatoprotection against APAP-induced cellular damage in Hep3B cell line was evaluated. Four strains of LAB, including BCRC11652 (Leuconostoc mesenteroides subsp. mesenteroides), BCRC14619 (Lactobacillus gasseri), KODA-1 (Pediococcus acidilactici), and KODA-2 (Limosilactobacillus fermentum), have hepatoprotective potential against APAP in vitro. Goji significantly stimulated the growth of individual and combined strains of LAB and the optimal fermented condition was the treatment of goji at 10% (w/w) for 24 h. The prepared lyophilized powder of goji ferment (LPGF) containing fifteen combinations of LAB strains was used to explore their hepatoprotection in vitro. LPGF containing all combinations of LAB strains, except for KODA-2, significantly restored APAP-reduced cell viability and improved APAP-increased cellular levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In mice model, LPGF containing BCRC11652, BCRC14619, and KODA-2 was chosen to evaluate its hepatoprotection against APAP-induced liver injury. LPGF at diverse doses have a tendency but no significant improvement on APAP-reduced body weight gain and liver weight. LPGF significantly decreased APAP-increased serum ALT and AST levels in a dose-dependent manner. At the end of experiment, LPGF significantly and dose-dependently reversed APAP-reduced activities of GSH and antioxidant enzymes, including glutathione peroxidase, superoxide dismutase, and catalase in hepatic tissue. Overall, LPGF was demonstrated to exhibit hepatoprotection against APAP-induced liver injury in vitro and in vivo.
... It is fairly well established that APAP ingestion at doses above the recommended levels causes end-stage renal disease (ESRD) and acute renal failure (Jeffery and Lafferty, 1981;Li and Martin, 2011;Nourjah et al., 2006;Perneger et al., 1994;Mazer and Perrone, 2008;Chen et al., 2015;Kelkar et al., 2012). A dose-response relation between the odds ratio for ESRD and APAP ingestion has been reported (Perneger et al., 1994) and higher median levels of serum alanine aminotransferase (ALT) was observed with reoccurring doses of APAP at 4 g, with or without combinations of pain relievers that also contain opiates (Watkins et al., 2006). ...
... The retrospective design based on administrative databases also impacts the reliability of the findings. Poisoning data identification and analysis in official databases, similar to present effort, are widely used as a surveillance method in other countries (Nourjah et al., 2006;Gedeborg et al., 2017) and are considered valuable sources to assess the magnitude of the problem. Deaths, hospital admissions, and poisoning reports due to paracetamol exposure were predominant among adults, a scenario that is similar to what was observed in Sweden in 2000-2013(Gedeborg et al., 2017, Germany in 2007-2018 (Daly et al., 2020), England in 2004(Casey et al., 2020, and Algeria in 2010-2017 (restricted to one hospital) (Chefirat et al., 2020). ...
Objective: To assess the cases of paracetamol poisoning in Brazil. Methods: Analysis of official records of deaths between 1996 and 2019 from the Brazil Mortality Information System (SIM), admissions between 2008 and 2020 from the Hospital Information System (SIH), and cases of poisoning between 2017 and 2020 in health services, reported to the Brazilian Notifiable Diseases Surveillance System (SINAN). In SIM and SIH, records with ICD-10 were included: F55, T39, X40, X60, and Y10. In SINAN, commercial products containing paracetamol were identified. Records were stratified by age, sex, and intentionality. Mean and standard error were calculated for each stratum based on the annual data, by federation unit. Poisoning reports by 1,000,000 inhabitants were calculated from each state and compared to the national average. Results: In total, 492 deaths, 5,666 hospital admissions, and 17,031 cases of paracetamol poisoning were recorded in the period. Deaths occurred mostly among adults (71.3% ± 3.0) and in suicide attempts (37.3% ± 2.7). Hospital admissions were more frequent in adults (69.7% ± 1.4), women (57.1% ± 2.5), and unintentional poisoning (80.2% ± 4.2). Poisoning reports was more also frequent among adults (71.4% ± 1.2), women (74.2% ± 0.6), and due to accidents (79.6% ± 1.8). The South and Southeast regions of the country presented the highest frequencies in all outcomes, above the national average. Conclusion: Paracetamol exposure is a concern for preventable poisonings, hospital admissions and deaths. More accurate data about paracetamol poisoning are required to support surveillance actions and the development of mechanisms to reduce poisoning, particularly related to adults, women and suicide attempts.
... Long-term drug use or overdose has produced a series of adverse reactions, severe cases can be lifethreatening. Analysis showed that 56,000 emergency department visits, 26,000 hospitalizations and 458 deaths were attributed to acetaminophen-associated overdoses in the United States from 1991 to 1998 (Nourjah et al., 2006). As people's understanding of drugs has improved in the last decades, the number of adverse outcomes caused by ibuprofen and acetaminophen has decreased significantly (Tan et al., 2020). ...
Background: Although kidney injury has been reported as a serious adverse effect in patients treated with ibuprofen or acetaminophen (APAP), there are still few real-world studies to compare the specific differences in the adverse effects of nephrotoxicity.
Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected kidney injury after using ibuprofen and APAP based on the FDA’s Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of ibuprofen-associated kidney injury and APAP-associated kidney injury were also investigated.
Results: 2,453 reports of ibuprofen-associated kidney injury and 1,288 reports of APAP-associated kidney injury were identified. Ibuprofen appeared to affected more middle-aged patients than elderly ones (27.76 vs 16.53%) while APAP appeared to affected more young patients than middle-aged patients (45.24 vs 29.10%) and elderly patients were fewer (13.99%). Compared to ibuprofen, APAP had the higher association with renal injury based on the higher reporting odds ratio (ROR = 2.45, 95% two-sided CI = 2.36–2.56), proportional reporting ratio (PRR = 2.39, χ ² = 2002.94) and empirical Bayes geometric mean (EBGM = 2.38, 95% one-sided CI = 2.3). In addition, APAP-associated kidney injury had earlier onset (32.74 vs 115.82 days, p < 0.0001) and a higher fatality rate (44.43 vs 7.36%, p < 0.001) than those of ibuprofen-associated kidney injury.
Conclusion: The analysis of FAERS data provides a more accurate profile on the incidence and prognosis of kidney injury after ibuprofen and acetaminophen treatment, enabling continued surveillance and timely intervention in patients at risk of kidney injury using these drugs.
... Acetaminophen (APAP) is one of the most widely used antipyretic and analgesic agents in the world and is very effective when take as directed (1)(2)(3). However, overdose of APAP remains the leading cause of acute liver failure (ALF) in the Western world (4)(5)(6). ...
Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the Western world with very limited treatment options. Previous studies from our groups and others have shown that timely activation of liver regeneration is a critical determinant of transplant free survival of APAP-induced acute liver failure (ALF) patients. Here we report that hepatocyte specific deletion of Yes associated protein (Yap), the downstream mediator of the Hippo Kinase signaling pathway results in faster recovery from APAP-induced acute liver injury (ALI). Initial studies performed with male C57BL/6J mice showed a rapid activation of Yap and its target genes within first 24 hours after APAP administration. Treatment of hepatocyte specific Yap knockout mice (Yap-KO) with 300 mg/kg APAP resulted in equal initial liver injury but a significantly accelerated recovery in Yap-KO mice. The recovery was accompanied by significantly rapid hepatocyte proliferation supported by faster activation of Wnt/β-catenin pathway. Furthermore, Yap-KO mice had significantly earlier and higher pro-regenerative inflammatory response following APAP overdose. Global gene expression analysis indicated that Yap-KO mice had a robust activation of transcription factors involved in response to ER stress (XBP1) and maintaining hepatocyte differentiation (HNF4α). In conclusion, these data indicate that inhibition of Yap in hepatocytes results in rapid recovery from APAP overdose due to an earlier activation of liver regeneration.
... Among the causes of poisoning, narcotics and painkillers accounted for the largest share (33). The most common cause of poisoning in the United States was analgesic medication poisoning, including acetaminophen (34). While in our study opium poisoning was the most prevalent. ...
Objective: Acute poisoning is a major health problem and one of the most common causes of emergency visits worldwide. Since most poisoning subjects present with a decreased level of consciousness and due to unreliable disease history, recognizing the etiological cause of the poisoning represents a critical part in arranging the treatment strategy. This study aimed at examining the prevalence of etiological causes of poisoning in Iran in a systematic review and meta-analysis. Method: This systematic review and meta-analysis investigated the cross-sectional studies published from 1990 to 2020, reporting specific poisoning agents among acute poisoning cases in Iran. Persian and English articles on this subject were collected by searching the Scientific Information Database (SID), ScienceDirect, PubMed, Medlib, IranMedex, Scopus, Magiran, and Google Scholar databases. The heterogeneity of the studies was investigated using the I2 index and the probability of bias in the publication was assessed by the Begg and Mazumdar test with a significance level of 0.1. Data analysis was performed by Comprehensive Meta-analysis software version 3 (Biostat, Englewood, NJ, USA). Results: In our review, 19 studies appraising 143,251 cases of poisoning were included. The ranking of the OR of each agent was done; Opium poisoning was the most prevalent poisoning case followed by benzodiazepine, acetaminophen, antipsychotic medications, organophosphates, aluminum phosphide, amphetamine, pesticide, tricyclic antidepressant (TCA), alcohol, chemicals, carbon monoxide (CO), nonsteroidal anti-inflammatory drugs (NSAIDs), and selective serotonin reuptake inhibitors (SSRIs). Conclusion: While proper judgment on the cause of poisoning and selection of suitable treatment manners could be followed by a very good prognosis in patients with acute poisoning; this demands an epidemiological perception of the prevalence of the etiological poisoning agents. Our study ranked the most likely agents leading to the poisoning, to be at the top of the list of differential diagnoses of physicians.
... It is considered safe when used in the recommended therapeutic dose of up to 4 g/day for adults, and has very little side effects. Nonetheless, APAP toxicity is frequently observed due to intentional or unintentional overdoses, and it is the leading cause of acute liver failure in the US and many other western countries, with several hundreds of deaths per year in the US alone [1][2][3]. ...
Paracetamol (acetaminophen, APAP) is the most frequently used analgesic and antipyretic worldwide. Nonetheless, APAP induced hepatotoxicity is the most common cause of acute liver failure in the western world. This hepatotoxicity is related to the metabolism of APAP, via the formation of the electrophilic oxidation product N-acetyl-para-benzoquinone imine. To investigate differences in APAP metabolism in specific patient populations and to optimize dosing regimens, quantification of metabolites from the different metabolic pathways is needed to perform pharmacokinetic (PK) studies. For this purpose, sensitive and short liquid chromatography-tandem mass spectrometry methods were developed for the quantitation of APAP and four of its metabolites (APAP-glucuronide, APAP-sulfate, APAP-mercapturate, and APAP-cysteine) in plasma, whole blood and dried blood microsamples collected via 10 µL volumetric absorptive microsampling (VAMS) devices. The methods were successfully validated based on internationally accepted guidelines (EMA, FDA), encompassing selectivity, evaluation of the calibration model, matrix effect and recovery, accuracy and precision, stability, and dilution integrity. In addition, for the VAMS samples, the effect of the hematocrit on the recovery was evaluated. Successful application on whole blood and plasma, as well as on VAMS samples prepared from venous or capillary blood of patients, demonstrated that the methods were fit-for-purpose and can be used for future PK studies.
Background:
Acetaminophen (APAP) is commonly used as an antipyretic and analgesic agent. Excessive APAP can induce liver toxicity, known as APAP-induced liver injury (ALI). The metabolism and pathogenesis of APAP have been extensively studied in recent years, and many cellular processes such as autophagy, mitochondrial oxidative stress, mitochondrial dysfunction, and liver regeneration have been identified to be involved in the pathogenesis of ALI. Caveolin-1 (CAV-1) as a scaffold protein has also been shown to be involved in the development of various diseases, especially liver disease and tumorigenesis. The role of CAV-1 in the development of liver disease and the association between them remains a challenging and uncharted territory.
Summary:
In this review, we briefly explore the potential therapeutic effects of CAV-1 on ALI through autophagy, oxidative stress, and lipid metabolism. Further research to better understand the mechanisms by which CAV-1 regulates liver injury will not only enhance our understanding of this important cellular process, but also help develop new therapies for human disease by targeting CAV-1 targets.
Key messages:
This review briefly summarizes the potential protective mechanisms of CAV-1 against liver injury caused by APAP.
zamanda karaciğerin birçok farklı mekanizma ile hasarlanma-sına da yatkınlık sağlamaktadır. Organizma tarafından yaban-cı olarak karşılanan her türlü maddeye karşı karaciğer hasarı GİRİŞ Karaciğer, ilaçlar ve çevresel toksinler de dahil olmak üzere organizmaya yabancı tüm maddelerin metabolizması ve atı-lımında merkezi bir göreve sahiptir. Bu merkezi görev aynı İletişim: Esra Nur DURMAZER • Ege Üniversitesi Tıp Fakültesi, 35040, Bornova, İzmir, Türkiye • Özet • İlaca bağlı karaciğer hasarı, ilaca maruz kalmaya atfedilen karaciğer hasarını oluşturur. Her yaşta, akut karaciğer yetmezliğinin önemli bir nede-nidir. İlaca bağlı karaciğer hasarı hepatoselüler, kolestatik veya karışık (miks) tip olarak kategorize edilebilir ve immün yanıtları da içerebilir. İlaca bağlı karaciğer hasarı doza bağımlı bir şekilde ortaya çıkarsa bu intrinsik hasar, öngörülemez bir şekilde meydana gelirse de idiyosinkrazik hasar olarak adlan-dırılır. Tedavide benimsenmiş spesifik modaliteler bulunmamaktadır. Patogenezinde birçok immün moleküler mekanizmanın yer aldığı düşünülmektedir. İlaca bağlı karaciğer hasarı için belirlenmiş moleküler mekanizmalar arasında 1) Mitokondri disfonksiyonu, 2) Artan reaktif oksijen seviyeleri, 3) Yüksek apoptoz ve nekroz varlığı ve 4) İmmün aracılı yolaklarla ilişkili safra kanalı hasarları yer alır. Ancak ilaca bağlı karaciğer hasarından sorumlu olan immün mekanizmaların hala büyük çoğunluğunun bilinmediği vurgulanmalıdır. İlaç ilişkili karaciğer hasarı sık meydana geldiğinden ve hasar geliştikten sonra tedavi seçenekleri sınırlı olduğundan önleme stratejileri kritik öneme sahiptir. Bu derlemede, literatürde bugüne kadar yapılmış prospektif ve retrospektif kohort çalışmalardan yararlanılarak, ilaca bağlı karaciğer hasarının altında yatan mekanizmalara ilişkin bilinenler ele alınarak, klinik özellikler ve potansiyel risk faktörleri değerlendirilecek, ayrıca tanı ve tedavide gelecekte potansiyel olarak kullanılabilecek moleküller tartışılacaktır. Anahtar kelimeler: İlaç ilişkili karaciğer hasarı, toksik hepatit, hepatotoksisite Abstract • Drug-induced liver injury constitutes liver damage attributed to exposure to the drugs and is a significant cause of acute liver failure at any age. Drug-induced liver injury can be categorized as hepatocellular, cholestatic, or mixed, and may also involve immune responses. When drug-induced liver injury occurs in a dose-dependent manner, it is termed intrinsic, whereas if the damage occurs unpredictable, it is referred to as idiosyncratic. Specific modalities for the treatment are not currently established. The pathogenesis involves many immunomolecular mechanisms. Among the identified molecular mechanisms for drug-induced liver injury are 1) Mitochondrial dysfunction, 2) Elevated levels of reactive oxygen species, 3) The presence of high apoptosis and necrosis, and 4) Bile duct injuries associated with immune-mediated pathways. However, some mechanisms involved drug-induced liver injury are remained unknown. Frequent occurrence and limited treatment options of drug induced liver injury, prevention strategies have critical importance. In this review, we will discuss the possible mechanisms and clinical features of drug-induced liver injury, potential risk factors, and molecules that may potentially be used in the future in diagnosis and treatment, by prospective and retrospective cohort studies in the literature.
As one of the most widely used drugs, acetaminophen, is the leading cause of acute liver injury. In addition, acetaminophen‐induced liver injury (AILI) has a strong relationship with the overproduced reactive oxygen species, which can be effectively eliminated by nanozymes. To address these challenges, mesoporous PdPt@MnO2 nanoprobes (PPM NPs) mimicking peroxide, catalase, and superoxide dismutase‐like properties are synthesized. They demonstrate nontoxicity, high colloidal stability, and exceptional reactive oxygen species (ROS)‐scavenging ability. By scavenging excessive ROS, decreasing inflammatory cytokines, and inhibiting the recruitment and activation of monocyte/macrophage cells and neutrophils, the pathology mechanism of PPM NPs in AILI is confirmed. Moreover, PPM NPs’ therapeutic effect and good biocompatibility may facilitate the clinical treatment of AILI.
JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity. In the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans.
Nanozymes are artificial enzymes with high catalytic activity, low cost, and good biocompatibility, and have received ever-increasing attention in recent years. Various inorganic and organic nanoparticles have been found to exhibit enzyme-like activities and are used as nanozymes for diverse biomedical applications ranging from tumor imaging and therapeutics to detection. However, their further clinical applications are hindered by the potential toxicity and long-term retention of nanomaterials in vivo. Clarifying the catalytic mechanism of nanozymes and identifying the key factors responsible for their behavior can guide the design of nanozyme structure, enlighten the ways to improve their enzyme-like activities, and minimize the dosage of nanozymes, leading to reduced toxicity to the human body for a real biomedical application prospect. In particular, inflammation occurring in numerous diseases is closely related to reactive oxygen species, and the active oxygen scavenging ability of nanozymes potentially exerts excellent therapeutic effects on inflammatory diseases. In this review, we systematically summarize the structure-activity relationship of nanozymes, including regulation strategies for size and morphology, surface structure, and composition. Based on the structure-activity mechanisms, a series of chemically designed nanozymes developed to target various inflammatory diseases are briefly summarized.
Importance:
Mifepristone (RU-486) is a selective progesterone receptor modulator that has antagonist properties on the uterus and cervix. Mifepristone is an effective abortifacient, prompting limitations on its use in many countries. Mifepristone has many uses outside of induced abortion, but these are less well known and underutilized by clinicians because of challenges in accessing and prescribing this medication.
Objectives:
To provide clinicians with a history of the development of mifepristone and mechanism of action and safety profile, as well as detail current research on uses of mifepristone in both obstetrics and gynecology.
Evidence acquisition:
A PubMed search of mifepristone and gynecologic and obstetric conditions was conducted between January 2018 and December 2021. Other resources were also searched, including guidelines from the American College of Obstetricians and Gynecologists and the Society of Family Planning.
Results:
Mifepristone is approved by the Food and Drug Administration for first-trimester medication abortion but has other off-label uses in both obstetrics and gynecology. Obstetric uses that have been investigated include management of early pregnancy loss, intrauterine fetal demise, treatment of ectopic pregnancy, and labor induction. Gynecologic uses that have been investigated include contraception, treatment of abnormal uterine bleeding, and as an adjunct in treatment of gynecologic cancers.
Conclusions and relevance:
Mifepristone is a safe and effective medication both for its approved use in first-trimester medication abortion and other off-label uses. Because of its primary use as an abortifacient, mifepristone is underutilized by clinicians. Providers should consider mifepristone for other indications as clinically appropriate.
There are numerous prescription drugs and non-prescription drugs that cause drug-induced liver injury (DILI), which is the main cause of liver disease in humans around the globe. Its mechanism becomes clearer as the disease is studied further. For an instance, when acetaminophen (APAP) is taken in excess, it produces N-acetyl-p-benzoquinone imine (NAPQI) that binds to biomacromolecules in the liver causing liver injury. Treatment of DILI with traditional Chinese medicine (TCM) has shown to be effective. For example, activation of the Nrf2 signaling pathway as well as regulation of glutathione (GSH) synthesis, coupling, and excretion are the mechanisms by which ginsenoside Rg1 (Rg1) treats APAP-induced acute liver injury. Nevertheless, reducing the toxicity of TCM in treating DILI is still a problem to be overcome at present and in the future. Accumulated evidences show that hydrogel-based nanocomposite may be an excellent carrier for TCM. Therefore, we reviewed TCM with potential anti-DILI, focusing on the signaling pathway of these drugs' anti-DILI effect, as well as the possibility and prospect of treating DILI by TCM based on hydrogel materials in the future. In conclusion, this review provides new insights to further explore TCM in the treatment of DILI.
Fever is an abnormal increase in body temperature that occurs as part of a specific biologic response mediated and controlled by the central nervous system. Despite the fact that most fevers are viral in origin, approaching a febrile child is always a concern for any physician. There is still a significant gap between current practice and scientific evidence. According to research, we are at a crossroad, with strong research evidence accumulating over the last few decades supporting a positive role for fever and the ongoing pressures of current practice to lower body temperature. Despite the fact that most pediatricians agree that treating a febrile child with antipyretics is primarily for the relief of fever symptoms, many continue to prescribe antipyretics for any child with fever, ignoring important research messages. By prescribing antipyretics to children who are only mildly febrile, pediatricians may contribute to fever phobia. We give parents the impression that fever is harmful and that antipyresis is beneficial when we focus on treating the fever. The purpose of this review is to present the evidence that is currently available regarding the management of the febrile child.
Introduction:
The Senior Section is a continuation of a previous intervention that aims to address a gap in medication safety, specifically related to older adult selection and use of over-the-counter medications. The purpose of this paper is to describe the protocol of this study.
Methods:
This study will occur in three phases: an adaptation phase, an effectiveness phase using a randomized controlled trial, and a sustainment phase. This study will take place in conjunction with administrative leadership and pharmacy sites of a regional Midwest integrated health system. Eye tracking technology will inform the adaptation of the intervention and demonstrate effectiveness in the randomized controlled trial. Following the randomized controlled trial, the health system will implement the intervention without research team support. Fidelity and long-term effectiveness outcomes will be collected to demonstrate sustainment.
Discussion:
The potential implications of this study are a complete and sustained redesign of the pharmacy setting to include educational and directional materials on medication safety, leading to a decrease in over-the-counter medication misuse in older adults. This project could provide a road map for pharmacy organizations to tailor and adopt the Senior Section, to ultimately reduce inappropriate over-the-counter medication use in older adults.
This study is aimed at establishing the outcome of RSTI exposure to acetaminophen based on a decision tree algorithm for the first time. This study used the National Poison Data System (NPDS) to conduct a six-year retrospective cohort analysis, which included 4522 individuals. The patients had a mean age of 26.75 ± 16.3 years (1-89). 3160 patients (70%) were females. Most patients had intentional exposure to acetaminophen. Almost all the patients had acetaminophen exposure via ingestion. In addition, 400 (8.8%) experienced major outcomes, 1500 (33.2%) experienced moderate outcomes, and 2622 (58%) of the patients experienced mild ones. The decision tree model performed well in the training and test groups. In the test group, the accuracy was 0.813, precision of 0.827, recall being 0.798, specificity 0.898, and an F1 score 0.80. In the training group, accuracy was 0.831, recall was 0.825, precision was 0.837, specificity was 0.90, and F1 score was 0.829. Our results showed that serum liver enzymes being present at elevated levels (Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) greater than 1000 U/L followed by ALT, AST between 100 and 1000 U/L) , prothrombin time (PT) prolongation, bilirubin increase, renal failure, confusion, age, hypotension, other coagulopathy (such as partial thromboplastin time (PTT) prolongation), acidosis, and electrolyte abnormality were the effective factors in determining the outcomes in these patients. The decision tree algorithm is a dependable method for establishing the prognosis of patients who have been exposed to RSTI acetaminophen and can be used throughout the patients' hospitalization period.
Aim
Hepatic encephalopathy (HE) development is crucial in liver transplantation for patients with acute liver injury (ALI) and failure (ALF); to predict HE development, the Japan Hepatic Encephalopathy Prediction (JHEP) model, calculated using age, etiology, prothrombin time (PT), and total bilirubin, was established in 2004, and a referral system to the liver center was implemented using the JHEP model from April 2004.
Methods
The JHEP model’s ability to predict HE development in 460 consecutive patients with ALI between April 2004 and January 2021 using data from the referral system was evaluated, and the JHEP model was revised.
Results
During the observation period, 7.8% patients developed HE. There was no difference in the proportion of HE development among the etiologies. In the Hosmer-Lemeshow test for HE development prediction, the JHEP model, revised JHEP (rJHEP) model, which was calculated without etiology data, and the modified JHEP model, which used the PT international ratio instead of PT in the rJHEP model, were good fitting models. Upon 30% random sampling from the total patients 60 times, the receiver operating curve analysis of both JHEP and rJHEP models for HE development was performed in all the datasets. The area under the curve of the JHEP model was subtracted from that of the rJHEP model ( 95% confidential interval, 0.0002–0.0079).
Conclusions
The referral system using the JHEP model reduced the difference in the risk for HE development among each etiology; the rJHEP model had a better prediction ability for HE development than the JHEP model.
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Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in Western countries. Pirfenidone (PFD), an orally bioavailable pyridone derivative, is clinically used for idiopathic pulmonary fibrosis treatment and has antifibrotic, anti-inflammatory, and antioxidant effects. Here we examined the PFD effect on APAP-induced liver injury.
In a murine model, APAP caused serum alanine aminotransferase elevation attenuated by PFD treatment. We performed terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) and vital propidium iodide (PI) stainings simultaneously. APAP induced TUNEL-positive/PI-negative necrosis around the central vein and subsequent TUNEL-negative/PI-positive oncotic necrosis with hemorrhage and caused the upregulation of hypercoagulation- and hypoxia-associated gene expressions. PFD treatment suppressed these findings. Western blotting revealed PFD suppressed APAP-induced c-Jun N-terminal kinase (JNK) phosphorylation despite no effect on JNK phosphatase expressions.
In conclusion, simultaneous TUNEL and vital PI staining is useful for discriminating APAP-induced necrosis from typical oncotic necrosis. Our results indicated that PFD attenuated APAP-induced liver injury by suppressing TUNEL-positive necrosis by directly blocking JNK phosphorylation. PFD is promising as a new option to prevent APAP-induced liver injury.
The article presents a review of the literature on the side effects of ibuprofen in children. The international guidelines recommend ibuprofen as an antipyretic and analgesic drug in pediatrics. The drug is characterized by a high profile of efficacy and safety in the treatment of children with fever, mild to moderate pain. Ibuprofen in over-the-counter doses has a low probability of serious side effects from the gastrointestinal tract and kidneys. Side effects of ibuprofen are transient and resolve after discontinuation of treatment. Circumstances associated with a higher risk of adverse events are highlighted. The use of ibuprofen is contraindicated in children with dehydration, which is associated with a risk of acute kidney damage. Caution should be exercised when prescribing ibuprofen to children with community-acquired pneumonia due to the risk of purulent complications. Ibuprofen should not be prescribed to patients with chickenpox to avoid bacterial superinfections. Ibuprofen should be used with caution in children with diseases of the gastrointestinal tract, liver, renal failure, hemorrhagic syndrome, anticoagulant therapy. Ibuprofen is allowed in children with bronchial asthma unless a personal or family history of aspirin-induced asthma. Caution should be exercised when treating premature infants or low birth weight infants due to the reduction in nephron mass and, therefore, the increased risk of renal damage. Ibuprofen should not be used in patients who are sensitive to this drug or other non-steroidal anti-inflammatory drugs. Ibuprofen should be taken in the minimum effective dose and discontinued as soon as possible — no more than 3 days for fever and 5 days for pain.
Acetaminophen is one of the most commonly used analgesic drugs in the United States. However, the outcomes of acute acetaminophen overdose might be very serious in some cases. Therefore, prediction of the outcomes of acute acetaminophen exposure is crucial. This study is a six-year retrospective cohort study using National Poison Data System data (NPDS). A decision tree algorithm was used to determine the risk predictors of acetaminophen exposure. The decision tree model had an accuracy of 0.839, an accuracy of 0.836, a recall of 0.72, a specificity of 0.86, and an F1 _ score of 0.76 for the test group and an accuracy of 0.848, a recall of 0.85, a recall of 0.74, a specificity of 0.87 and an F1 _ score of 0.78 for the training group.
Our results showed that elevated serum levels of liver enzymes, other liver function test abnormality, anorexia, acidosis, electrolyte abnormality, increased bilirubin, coagulopathy, abdominal pain, coma, increased anion gap, tachycardia, and hypotension were the most important factors in determining the outcome of acute acetaminophen exposure. Therefore, the decision tree model is a reliable approach in determining the prognosis of acetaminophen exposure cases and can be used in an emergency room or during hospitalization.
Acetaminophen (APAP) or paracetamol, despite its wide and common use for pain and fever symptoms, shows a variety of side effects, toxic effects, and overdose effects. The most common form of toxic effects of APAP is in the liver where phosphatidylcholine is the major component of the cell membrane with additional associated functionalities. Although this is the case, the effects of APAP on pure phospholipid membranes have been largely ignored. Here, we used 1,2-di-(octadecenoyl)-sn-glycero-3-phosphocholine (DOPC), a commonly found phospholipid in mammalian cell membranes, to synthesize large unilamellar vesicles to investigate how the incorporation of APAP changes the pure lipid vesicle structure, morphology, and fluidity at different concentrations. We used a combination of dynamic light scattering, small-angle neutron and X-ray scattering (SANS, SAXS), and cryo-TEM for structural characterization, and neutron spin-echo (NSE) spectroscopy to investigate the dynamics. We showed that the incorporation of APAP in the lipid bilayer significantly impacts the spherical phospholipid self-assembly in terms of its morphology and influences the lipid content in the bilayer, causing a decrease in bending rigidity. We observe a decrease in the number of lipids per vesicle by almost 28% (0.06 wt % APAP) and 19% (0.12 wt % APAP) compared to the pure DOPC (0 wt % APAP). Our results showed that the incorporation of APAP reduces the membrane rigidity by almost 50% and changes the spherical unilamellar vesicles into much more irregularly shaped vesicles. Although the bilayer structure did not show much change when observed by SAXS, NSE and cryo-TEM results showed the lipid dynamics change with the addition of APAP in the bilayer, which causes the overall decreased membrane rigidity. A strong effect on the lipid tail motion showed that the space explored by the lipid tails increases by a factor of 1.45 (for 0.06 wt % APAP) and 1.75 (for 0.12 wt % APAP) compared to DOPC without the drug.
Acetaminophen toxicity, which can lead to hepatotoxicity, is a burden on our health care system and contributes significantly to intensive care unit admissions and cost of hospitalization. The aim of our study was to determine the epidemiology of various types of acetaminophen poisoning and analyze their outcome compared with their admission characteristics.
We identified 93 consecutive patients, hospitalized for acetaminophen toxicity over a 52-month period from 1996 to 1999 in our urban county hospital. Retrospective case-control analysis was carried out using the data obtained from the medical records.
Acetaminophen accounted for 7.5% of all cases of poisoning admitted during this period. Of the 93 patients, 80 were classified as suicidal and 13 had accidentally poisoned themselves in an attempt to relieve pain. The ratio of females to males was found to be 2:1. Of the 93 patients studied, 88 were admitted to the intensive care unit for initial 24-48 hours of monitoring. Peak acetaminophen levels were higher in the suicidal overdose group (mean 121.7 +/- 97.0 mg/l vs. 64.5 +/- 61.8 mg/l, P < 0.05) than in the accidental group. In spite of this, peak aminotransferase levels >1000 IU/l were more often seen in the latter (39% vs. 12%, P < 0.05). Hepatic coma and death were seen more often in the accidental overdose group (15% vs 0%, P < 0.05). Interestingly chronic alcohol abuse was also more frequent in the accidental overdose category (39% vs 18%, P = 0.05).
Although the peak acetaminophen level in the suicidal group was significantly higher, cases of therapeutic misadventure had higher rates of morbidity and mortality. Peak acetaminophen levels correlate poorly with hepatic dysfunction, morbidity and mortality.
We recommend that the patients with suicidal acetaminophen overdose, without any concomitant poisoning, can safely managed on the medical floors.
Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition.
To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure.
Prospective cohort study.
17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group.
308 consecutive patients with acute liver failure, admitted over a 41-month period.
Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission.
73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not.
Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.
In long-term alcohol users, the syndrome of hepatotoxicity from acetaminophen taken in therapeutic or modestly excessive doses is distinctive. It is characterized by striking elevation of transaminase levels and the potential for acute liver failure with high morbidity and mortality rates. A high index of suspicion should be maintained; in any patient with evidence of acute hepatic injury, a complete history of over-the-counter drug use should be obtained and acetaminophen levels checked. If there is doubt about the dose or time of ingestion, one should err on the side of treatment with acetylcysteine, because it is both effective and safe. Therapy should be initiated as early as possible, but even late administration may be of benefit. Timely contact with a medical center that has liver transplantation capabilities should be made before encephalopathy becomes advanced. Heightened awareness of this preventable and treatable condition is needed by healtcare providers and acetaminophen users alike. Because the minimum safe dose of acetaminophen is not known in the setting of chronic alcohol use, it seems prudent in such situations to avoid acetaminophen altogether, especially during brief periods of abstinence.
We have treated 6 chronic alcoholics and identified an additional 19 reported in the literature who developed severe hepatotoxicity from acetaminophen taken in apparently moderate doses. The clinical disease in these 25 patients had a characteristic pattern: mild to moderate jaundice; mild to severe coagulopathy; and strikingly abnormal aminotransferase levels, values inconsistent with either acute alcoholic hepatitis or viral hepatitis. The possible causes for the injury from ostensibly nontoxic drug levels appear to be either the induction by chronic alcohol intake of the cytochrome P-450 system responsible for converting acetaminophen to a toxic metabolite, or the effect of alcoholism and the associated malnutrition in reducing the glutathione concentration, responsible normally for preventing hepatotoxicity by conjugation with the toxic metabolite. The research data pertaining to the apparent enhanced toxicity from chronic alcoholism are reviewed. Despite the low frequency of ethanol-potentiated acetaminophen hepatotoxicity, alcoholics should be cautioned about the use of acetaminophen while they persist in heavy consumption of alcohol. Language: en
Objectives.
—To evaluate the association of fasting and alcohol use with hepatotoxicity from acetaminophen ingested for therapeutic reasons.Design.
—Retrospective case series.Setting.
—Hospitals of the University of Pittsburgh (Pa) Medical Center.Patients.
—A total of 126779 discharge summaries from January 1987 to July 1993 were reviewed using a comprehensive, whole-text-indexed medical database to identify all patients with acetaminophen ingestion and hepatotoxicity. These patients were categorized according to the intended acetaminophen use and dose of acetaminophen ingested.Main Outcomes Measured.
—The independent variables of chronic alcohol use, recent alcohol use, and recent fasting were determined for all patients.Results.
—Forty-nine patients with acetaminophen hepatotoxicity (aspartate aminotransferase >1000 U/L) were identified. Twenty-one patients (43%) ingested acetaminophen for therapeutic purposes. All patients with hepatotoxicity took more than the recommended limit of 4 g/d. Recent fasting was more common than recent alcohol use among those who suffered hepatotoxicity after a dose of 4 to 10 g of acetaminophen per day (P=.02). Recent alcohol use was more common in the group who took more than 10 g/d than in those who took 4 to 10 g/d (P=.004).Conclusion.
—Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use. Patients who developed hepatoxicity after taking acetaminophen doses of greater than 10 g/d for therapeutic purposes were alcohol users. Acetaminophen hepatotoxicity after an overdose appears to be enhanced by fasting in addition to alcohol ingestion.(JAMA. 1994;272:1845-1850)
PurposeAnalgesics offer many benefits, however, chronic, long-term use may pose risks of adverse drug events. The objective of this study was to estimate frequent monthly non-narcotic analgesic use among U.S. adults, identifying socio-demographic trends and potentially at-risk groups.Methods
Analysis of adult medication use data from the 1999–2000 National Health and Nutrition Examination Survey household interview (n = 4880).ResultsSome 20% of U.S. adults used non-prescription or prescription non-narcotic analgesics on a frequent basis, that is nearly every day for a month, at some point during their lifetime. Also, 14% of U.S. adults were currently using analgesics frequently. Aspirin was most commonly used (8%), followed by non-aspirin non-steroidal anti-inflammatory drugs (NANSAID, 3%) and acetaminophen (3%). Three-quarters of aspirin, 46% of NANSAID and 63% of acetaminophen users were long-term frequent monthly users (1+ years). Seven percent of frequent monthly analgesic users reported using two or more analgesics nearly every day during the month. Frequent analgesic use was most common among older adults and non-Hispanic whites with no differences by gender or education. Use patterns, however, varied by analgesic subgroups.Conclusions
Frequent monthly non-narcotic analgesic use, especially of over-the-counter analgesics, is widely prevalent among U.S. adults. Health-care providers should heighten their awareness of this trend, and routinely monitor both non-prescription and prescription analgesic use in their patients to prevent adverse drug effects and inappropriate use. Published in 2004 by John Wiley & Sons, Ltd.
Acetaminophen overdose is the leading cause for calls to Poison Control Centers (>100,000/year) and accounts for more than 56,000 emergency room visits, 2,600 hospitalizations, and an estimated 458 deaths due to acute liver failure each year. Data from the U.S. Acute Liver Failure Study Group registry of more than 700 patients with acute liver failure across the United States implicates acetaminophen poisoning in nearly 50% of all acute liver failure in this country. Available in many single or combination products, acetaminophen produces more than $1 billion dollars in annual sales for Tylenol products alone. It is heavily marketed for its safety compared to nonsteroidal analgesics. By enabling self-diagnosis and treatment of minor aches and pains, its benefits are said by the Food and Drug Administration to outweigh its risks. It still must be asked: Is this amount of injury and death really acceptable for an over-the-counter pain reliever? (HEPATOLOGY 2004;40:6–9.)
Hepatocytes freshly isolated from diethylmaleate-treated rats have been shown to perform net biosynthesis of intracellular glutathione at approximately an in vivo rate. 35S from |35S| cysteine or |35S | methionine each contributed to the formation of glutathione to about the same extent, up to 75 and 61%, respectively, depending upon the amino acid concentration in the medium. The sulfur atom of methionine makes a significant contribution to the synthesis of the thiol of glutathione probably via the formation of cystathionine.
Persons with alcoholism are at increased risk for acetaminophen liver toxicity. Two complementary theories have been proposed to explain this phenomenon. The first is that the livers of persons with alcoholism are depleted in glutathione and are therefore incapable of detoxifying the electrophilic metabolite of acetaminophen produced by the liver's mixed-function oxidase system. The second theory is that ethanol consumption stimulates, or 'induces,' a mixed-function oxidase enzyme (P-450IIE1) that appears to generate the toxic metabolite. We report the case of a woman who developed life-threatening hepatic and renal toxicity after ingesting not more than 11.5 g of acetaminophen and whose initial acetaminophen blood level was not in the usual toxic range. This patient did not drink ethanol but was being treated with isoniazid. Isoniazid does not appear to deplete liver glutathione stores but does induce P-450IIE1. The data support the hypothesis that induction of P-450IIE1 may predispose patients to acetaminophen toxicity in the absence of glutathione depletion.
We have treated 6 chronic alcoholics and identified an additional 19 reported in the literature who developed severe hepatotoxicity from acetaminophen taken in apparently moderate doses. The clinical disease in these 25 patients had a characteristic pattern: mild to moderate jaundice; mild to severe coagulopathy; and strikingly abnormal aminotransferase levels, values inconsistent with either acute alcoholic hepatitis or viral hepatitis. The possible causes for the injury from ostensibly nontoxic drug levels appear to be either the induction by chronic alcohol intake of the cytochrome P-450 system responsible for converting acetaminophen to a toxic metabolite, or the effect of alcoholism and the associated malnutrition in reducing the glutathione concentration, responsible normally for preventing hepatotoxicity by conjugation with the toxic metabolite. The research data pertaining to the apparent enhanced toxicity from chronic alcoholism are reviewed. Despite the low frequency of ethanol-potentiated acetaminophen hepatotoxicity, alcoholics should be cautioned about the use of acetaminophen while they persist in heavy consumption of alcohol.
Hepatic injury in alcoholics due to intake of acetaminophen (APAP or acetylparaaminophenol) with therapeutic intent has been reported, but the extent of the phenomenon is not clear, pertinent details of the association remain insufficiently clarified, and the importance of the phenomenon is not widely appreciated. The present report describes 67 patients who developed hepatic injury after ingestion of APAP with therapeutic intent. All were regular users of alcohol. Sixty-four percent of the patients were considered to be "alcoholic" or reported intakes greater than 80 g/d, 35% took 60 g/d or less, and the remainder were vague in their reporting. Doses of APAP were in the "nontoxic" range ( < 6 g/d) in 60% of the group, within the recommended range ( < 4 g/d) in 40%, and at 4.1 to 6 g/d in 20%. Characteristic feature was the towering level reached by aspartate transaminase (AST) with figures ranging from 3,000 to 48,000 IU in more than 90% of cases. Almost 20% of the patients died. The data on these patients were similar to 94 cases of injury from APAP taken with therapeutic intent reported in the literature. This study provides further evidence of hepatic injury in regular uses of alcohol, especially chronic alcoholics, who take APAP with therapeutic intent. Susceptibility is presumably caused by induction of cytochrome P-4502EI by ethanol and by depletion of glutathione (GSH) because of the effects of alcohol, the malnutrition often associated with alcoholism, and the depletion associated with chronic use of APAP and impaired glucuronidation caused by fasting perhaps as well. The syndrome of liver injury is distinctive, marked by uniquely elevated levels of AST, and poses a significant threat.(ABSTRACT TRUNCATED AT 250 WORDS)
To evaluate the association of fasting and alcohol use with hepatotoxicity from acetaminophen ingested for therapeutic reasons.
Retrospective case series.
Hospitals of the University of Pittsburgh (Pa) Medical Center.
A total of 126,779 discharge summaries from January 1987 to July 1993 were reviewed using a comprehensive, whole-text-indexed medical database to identify all patients with acetaminophen ingestion and hepatotoxicity. These patients were categorized according to the intended acetaminophen use and dose of acetaminophen ingested.
The independent variables of chronic alcohol use, recent alcohol use, and recent fasting were determined for all patients.
Forty-nine patients with acetaminophen hepatotoxicity (aspartate aminotransferase > 1000 U/L) were identified. Twenty-one patients (43%) ingested acetaminophen for therapeutic purposes. All patients with hepatotoxicity took more than the recommended limit of 4 g/d. Recent fasting was more common than recent alcohol use among those who suffered hepatotoxicity after a dose of 4 to 10 g of acetaminophen per day (P = .02). Recent alcohol use was more common in the group who took more than 10 g/d than in those who took 4 to 10 g/d (P = .004).
Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use. Patients who developed hepatoxicity after taking acetaminophen doses of greater than 10 g/d for therapeutic purposes were alcohol users. Acetaminophen hepatotoxicity after an overdose appears to be enhanced by fasting in addition to alcohol ingestion.
We report 2 fatal cases of the acetaminophen-alcohol syndrome and review 51 reported cases in the medical literature. The MEDLINE database from January 1966 to December 1995 and bibliographies of selected articles were used to obtain the case reports. Inclusion criteria were a clear history of alcohol use, a history of acetaminophen use and/or an elevated serum acetaminophen level, peak aspartate aminotransferase (AST) greater than 800 U/L, and exclusion of other causes of hepatotoxicity by negative hepatitis serologies and/or a liver biopsy showing typical findings of acetaminophen toxicity. Demographic characteristics, clinical features, treatment, and outcome were extracted from reports meeting inclusion criteria and our own 2 cases. This syndrome affected relatively young, frequently healthy patients. Acetaminophen was invariably taken for nonsuicidal intent. The mortality rate was 32%. A typical laboratory picture was defined, characterized by an extraordinarily high AST level. Treatment with N-acetylcysteine was not effective due to delayed presentation and diagnosis. Patients who use alcohol and health care providers should be educated about this potentially fatal syndrome. Prevention is the key to reducing its occurrence.
The prevalence and characteristics of acetaminophen-associated liver injury in hospitalized patients are not well defined.
We identified patients hospitalized for excessive acetaminophen ingestion at an urban county hospital over a 40-month period (1992 to 1995) and reviewed their medical records to determine the incidence and clinical features of the ingestions and their outcomes.
Of the 71 patients studied, 50 were classified as having taken acetaminophen during suicide attempts and 21 as having accidentally poisoned themselves while attempting to relieve pain. The suicidal patients had ingested almost twice as much acetaminophen as those in the accidental-overdose group (median, 20 vs. 12 g; P=0.009). Among the patients for whom data were available, 63 percent of those in the accidental-overdose group and 25 percent of those in the suicidal group had chronic alcohol abuse (P=0.009). The patients in the accidental-overdose group more often had severe liver necrosis (aminotransferase levels, >3500 IU per liter; 52 percent vs. 14 percent; P=0.002), and were more likely to have hepatic coma (33 percent vs. 6 percent, P=0.006). There were four deaths (19 percent) in the accidental-overdose group and one (2 percent) in the suicidal group (P=0.04). Five patients -- three in the accidental-overdose group and two in the suicidal group -- had ingested 4 g of acetaminophen or less. Acetaminophen ingestion accounted for 12 percent of all patients hospitalized with overdoses (71 of 589) and 40 percent of patients with acute liver failure (10 of 25) during the study period.
In an urban county hospital, patients hospitalized with acetaminophen toxicity related to accidental misuse had higher rates of morbidity and mortality than those who attempted suicide, even though the latter had taken more acetaminophen. A higher frequency of chronic alcohol abuse among the patients with accidental overdoses may be one explanation.
In long-term alcohol users, the syndrome of hepatotoxicity from acetaminophen taken in therapeutic or modestly excessive doses is distinctive. It is characterized by striking elevation of transaminase levels and the potential for acute liver failure with high morbidity and mortality rates. A high index of suspicion should be maintained; in any patient with evidence of acute hepatic injury, a complete history of over-the-counter drug use should be obtained and acetaminophen levels checked. If there is doubt about the dose or time of ingestion, one should err on the side of treatment with acetylcysteine, because it is both effective and safe. Therapy should be initiated as early as possible, but even late administration may be of benefit. Timely contact with a medical center that has liver transplantation capabilities should be made before encephalopathy becomes advanced. Heightened awareness of this preventable and treatable condition is needed by healthcare providers and acetaminophen users alike. Because the minimum safe dose of acetaminophen is not known in the setting of chronic alcohol use, it seems prudent in such situations to avoid acetaminophen altogether, especially during brief periods of abstinence.
To evaluate the literature regarding the potential of acetaminophen to cause toxicity in adult patients without risk factors, when used chronically in daily doses < or = 4 g.
Key tertiary literature was reviewed, along with searches of MEDLINE (1966-July 2001). International Pharmaceutical Abstracts (1970-May 2001), and PREMEDLINE (July Week 5, 2001). Key search terms included acetaminophen, paracetamol, toxic hepatitis, hepatotoxicity, liver dysfunction, overdose, drug toxicity, and poisoning.
Most tertiary references state that the maximum daily dose of acetaminophen is 4 g. Patients taking more than this amount, especially those with certain risk factors, are more likely to develop toxicity. However, a few patients may develop toxicity regardless of risk. An evaluation of the literature regarding the toxic potential of acetaminophen when given at doses < or = 4 g/d chronically (> or = 4 d) to adult patients without risk factors was conducted.
Acetaminophen should be used cautiously on a chronic basis because several case reports show that it may be hepatotoxic at therapeutic doses.
The Food and Drug Administration (FDA) is responsible not only for approving drugs but also for monitoring their safety after they reach the market. The complete adverse event profile of a drug is not known at the time of approval because of the small sample size, short duration, and limited generalizability of pre-approval clinical trials. This report describes the FDA's postmarketing surveillance system, to which many clinicians submit reports of adverse drug events encountered while treating their patients. Despite its limitations, the spontaneous reporting system is an extremely valuable mechanism by which hazards with drugs that were not observed or recognized at the time of approval are identified. Physicians are strongly encouraged to submit reports of adverse outcomes with suspect drugs to the FDA, and their reports make a difference. The FDA is strengthening its postmarketing surveillance with access to new data sources that have the potential to further improve the identification, quantification, and subsequent management of drug risk.
Kurtovic J, Riordan SM (The Prince of Wales Hospital and University of New South Wales, Sydney, Australia). Paracetamol-induced hepatotoxicity at recommended dosage (Case report). J Intern Med 2003; 253: 240–243.
In patients who develop liver damage following moderate paracetamol overdose in the order of 5–10 g daily, recent fasting and nutritional impairment have been identified as key precipitants. Hepatotoxicity caused by paracetamol at recommended dosage, in the absence of exposure to enzyme-inducing drugs, has recently been described as an idiosyncratic phenomenon. The possible importance of fasting and malnutrition in this setting is uncertain. We report a severely malnourished 53-year-old woman who developed severe hepatotoxicity whilst receiving paracetamol at recommended dosage (4 g daily) following a period of fasting, in the absence of enzyme-inducing agents. Subsequent paracetamol exposure up to 2.6 g daily thrice weekly, in the setting of ongoing malnutrition and fasting as before, did not lead to recurrent liver damage. These findings indicate that paracetamol-related liver damage occurring within recommended dosage guidelines can be a dose-dependent rather than necessarily idiosyncratic phenomenon, at least in the setting of recent fasting and severe malnutrition.
To estimate prescription and non-prescription analgesic use in a nationally representative sample of US adults.
Data collected during the third National Health and Nutrition Examination Survey (1988-1994), for persons 17 years and older were analyzed (n = 20,050). During the household interview, respondents reported use, in the last month, of prescription and non-prescription analgesics.
An estimated 147 million adults reported monthly analgesic use, Prescription analgesic use was 9% while non-prescription use was 76%. Females were more likely than males to use prescription (11 vs. 7%, p < 0.001) and non-prescription (81 vs. 71%, p < 0.001) analgesics. Across race-ethnicity groups, males (approximately 8%) and females (11-13%) had similar age-adjusted prescription analgesic use. Non-prescription analgesic use was higher among non-Hispanic whites than non-Hispanic blacks and Mexican-Americans for males (76 vs. 53% (p < 0.001) and 59% (p < 0.001), respectively) and females (85 vs. 68% (p < 0.001) and 71% (p < 0.001), respectively). With increasing age, prescription analgesic use increased whereas non-prescription use decreased. Approximately 30% of adults used multiple analgesics during a 1-month period. This was more common among females (35%) than males (25%, p < 0.001) and among younger (17-44 years, 33%) rather than older age groups (45+ years, 26%, p < 0.001).
Analgesic use among US adults is extremely high, specifically of non-prescription analgesics. Given this, health care providers and consumers should be aware of potential adverse effects and monitor use closely.
Adverse drug event monitoring at the FDA: Your report can make a difference
- Ahmad Sr
Ahmad SR. Adverse drug event monitoring at the FDA: Your report can make a difference. J Gen Intern Med 2003; 18: 57–60.
Acute Liver Failure Study Group: Lowering the risks of hepatic failure
- Wm Lee
- U S Acetaminophen And
Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: Lowering the risks of hepatic failure. Hepatol-ogy 2004; 40: 6–9.