Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily

Watkins, Paul B.; Kaplowitz, Neil; Slattery, John T.; Colonese, Connie R.; Colucci, Salvatore V.; Stewart, Paul W.; Harris, Stephen

doi:10.1001/jama.296.1.87

Cited by 587 publications

(400 citation statements)

References 22 publications

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“…Moreover, there is evidence that the maximum recommended dose (i.e., 4 g/day) can induce mild to moderate hepatic cytolysis, even in healthy individuals (Watkins et al. 2006; Winnike et al. 2010).…”

Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

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Section: Introductionmentioning

confidence: 99%

Role of endoplasmic reticulum stress in drug‐induced toxicity

Foufelle

Fromenty

2016

Pharmacology Res & Perspec

194

161

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“…In recent time, the safety of acetaminophen even at therapeutic doses has generated considerable debate (Jalan et al, 2006). Results of recent study by Watkins and co-workers as well as of other studies have reopened the controversies on the therapeutic safety of acetaminophen on long term continuous treatment (Kwan et al, 1995;Yin et al, 2001;Watkins et al, 2006). Acute liver injury has been reported in patients on therapeutic doses of acetaminophen (Critchley et al, 1986;Yin et al, 2001;Watkins et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Results of recent study by Watkins and co-workers as well as of other studies have reopened the controversies on the therapeutic safety of acetaminophen on long term continuous treatment (Kwan et al, 1995;Yin et al, 2001;Watkins et al, 2006). Acute liver injury has been reported in patients on therapeutic doses of acetaminophen (Critchley et al, 1986;Yin et al, 2001;Watkins et al, 2006). Acetaminophen-induced hepatic injury is reported to be mediated through an increased lipid peroxidation in hepatic tissues (Schnellman, 2001;Bessems and Vermeulen, 2001).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Adeneye¹,

Olagunju²

2010

African Journal of Biomedical Research

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The incidence of acetaminophen-induced hepatotoxicity is reported to be on the increase, with limited therapeutic or chemoprophylactic options. In the present in vivo study, single daily oral doses (100 -500 mg/kg) of ascorbic acid (ASC) were investigated for their protective effects against acetaminophen (APAP)-induced hepatotoxicity in 4 groups of rats made up of 6 rats per group for 14 days. Also, effects of the doses on body weights taken on the 1 st , 7 th and 15 th day of the experiment were also investigated. On the 15 th day, blood samples for serum ALT, AST and FBG assay were collected through cardiac puncture under inhaled diethyl ether anaesthesia. Rat livers were also studied for histopathology. Results showed that treatment with APAP intraperitoneal injection induced significant (P<0.001) elevation in the serum levels of ALT and AST while inducing significant (P<0.05) decrease in the serum FBG. The hepatotoxicity was also corroborated by the histopathological lesion of lipid peroxidation characterized by diffuse ballooning degeneration with lymphocytic infiltration. Significant (P<0.01) weight loss and hypoglycaemia were also associated with APAP-induced hepatotoxicity. However, these alterations were attenuated in ASC pretreated rats dose dependently. Also, APAP-induced hypoglycaemia and weight loss were significantly (P<0.01, P<0.001) enhanced by ASC in dose related pattern. Thus, results of this study showed that 100 -500 mg/kg/day was protective against APAP-induced hepatotoxicity, effect which could have been mediated via its inherent free radical scavenging and/or free radicals generation inhibiting activities.

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“…After the addition was completed, the reaction mixture was stirred at room temperature for 2 h. The resulting solid was filtered and recrystallized from ethanol/water (10:1) to furnish the corresponding 5 as a white crystalline solid. (8). Two grams of 5a (6 mmol) was suspended in 10 mL of 10% aqueous NaOH, and after 30 min, suspension turned into a solution.…”

Section: Methods Bmentioning

confidence: 99%

“…1) that interferes with targets involved in pain and thermoregulation, including COX-mediated prostaglandin synthesis, and vanilloid and cannabinoid receptor systems. 7 Although APAP shows low incidence of gastrointestinal and other COX-related adverse effects as compared with most NSAIDs, it is well established that APAP can cause hepatotoxicity 8 and nephrotoxicity. These effects can potentially be lethal, 9,10 particularly after ingestion of large doses or after chronic use of small doses when liver function is already compromised (e.g., in the elderly and in patients with alcoholic liver disease).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

Vaccarino

Paúl

Mukherjee

et al. 2007

Bioorganic & Medicinal Chemistry

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Abstract-A series of acetaminophen (APAP) analogs, 2-(1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-N-(4-hydroxyphenyl)alkanecarboxamides, bearing a heterocyclic moiety linked to the p-acylaminophenol fragment, were prepared in a general project to develop APAP analogs with modulated pharmacokinetic profiles. Unexpectedly, the products described maintained the in vivo analgesic profile, while the characteristic hepatotoxicity of APAP was consistently reduced. One of the products, 5a, was studied in vivo in comparison with APAP. Compound 5a displayed an analgesic efficacy comparable to that of APAP. A relatively high acute oral dose of 5a (6 mmol/kg) produced no measurable toxicity, whereas the equimolar dose of APAP increased transaminase activity, depleted hepatic and renal glutathione, and resulted in mortality. In human hepatocytes (HEPG-2) and in human primary cultures of normal liver cells, APAP, but not 5a, was associated with apoptotic cell death, Fas-ligand up-regulation, and CAR (constitutive androstane receptor) activation, contributing to a favorable safety profile of 5a as an orally delivered analgesic.

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Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of Acetaminophen Daily

Cited by 587 publications

References 22 publications

Role of endoplasmic reticulum stress in drug‐induced toxicity

Role of endoplasmic reticulum stress in drug‐induced toxicity

Protective effect of oral ascorbic acid (vitamin c) against acetaminophen- induced hepatic injury in rats

Synthesis and in vivo evaluation of non-hepatotoxic acetaminophen analogs

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