Acetaminophen/paracetamol: A history of errors, failures and false decisions

Brune, Kay; Renner, Bertold; Tiegs, Gisa

doi:10.1002/ejp.621

Cited by 174 publications

(104 citation statements)

References 87 publications

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“…In addition, reasons for the limited use of paracetamol in GER could be recent concerns and public discussions about the safety of paracetamol and its risks for hepatotoxicity [25]. At that time, the maximum quantity of paracetamol per package that can be purchased over-the-counter was limited in Germany and partially put under prescription-only medicine due to those discussions [26].…”

Section: Discussionmentioning

confidence: 99%

Analgesic Drug Prescription Patterns on Five International Paediatric Wards

et al. 2016

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Key points• Use of analgesic and anti-inflammatory drugs was in line with local recommendations and WHO guidelines • Oral paracetamol and oral ibuprofen are the most commonly used analgesic drugs on general paediatric wards • Differences regarding dose and frequency of ibuprofen and paracetamol use were observed, indicating that safety concerns for individual drugs are perceived differently among countries BOTZENHARDT et al. 2/1 2016-09-16 ABSTRACT AimAnalgesic and anti-inflammatory drugs are frequently prescribed in paediatrics. Prescribing and dosing patterns in hospitalised children are not well known. This study explores analgesic drug utilisation on five paediatric wards and discusses its findings in comparison with WHO guidelines. MethodA sub-analysis of a prospective, multi-centre, observational cohort study was undertaken. Prescription data of children aged up to ≤18 years were collected between October 2008 and December 2009 on paediatric general medical wards in five hospitals in Australia, Germany, the United Kingdom (UK), Hong Kong (HK) and Malaysia. Analgesic drug prescriptions were analysed for prescribing patterns in terms of dosing, frequency and route of administration. Dosing data were compared with local recommendations and WHO guidelines for children. ResultsIn the study cohort 56.8% (726/1,278) of paediatric patients received at least one analgesic drug prescription (1,227 prescriptions). Median age of patients with analgesics was 2.2 years (IQR 0.8-7.3) and median number of prescriptions per patient was 1 (IQR 1-2). Most commonly prescribed drugs were oral paracetamol (45.9%, 563/1,227) and oral ibuprofen (19.9%, 244/1,227). Daily doses of paracetamol ranged from 30 mg/kg/day in Germany to 67-68 mg/kg/day in UK and HK (p<0.05). For ibuprofen, single doses ranged from 5-6 mg/kg in HK and UK to 10 mg/kg in GER and AUS (p<0.001). Opioid use prevalence was statistically different between the centres and ranged from 0% to 17.6% (p<0.001). ConclusionThis study provides a comprehensive overview of analgesic drug use of hospitalised children. Similar to primary care data, paracetamol is the most commonly used analgesic. As recommended by WHO guidelines, oral medication was favoured and opioids used in addition to paracetamol and ibuprofen. Overall drug utilisation was in line with local recommendations and WHO guidelines. Differences in use of paracetamol and ibuprofen among countries was seen indicating that safety concerns are perceived differently. More large-scale safety studies are needed. BOTZENHARDT et al.

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Section: Discussionmentioning

confidence: 99%

Analgesic Drug Prescription Patterns on Five International Paediatric Wards

et al. 2016

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“…At appropriate dose of APAP, NAPQI is generally eliminated through the conjugation with GSH. However, in overdosing conditions it depletes the systemic GSH levels causing hepato- and renal- toxicity [118]. Interestingly, a recent report demonstrated that even normal dose of APAP is linked to APAP-associated acute liver failure [119].…”

Section: Das: Protection Against Alcohol Analgesic Drugs and Othmentioning

confidence: 99%

Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1

Rao¹,

Midde²,

Miller³

et al. 2015

CDM

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Diallyl sulfide (DAS) and other organosulfur compounds are chief constituents of garlic. These compounds have many health benefits, as they are very efficient in detoxifying natural agents. Therefore, these compounds may be useful for prevention/treatment of cancers. However, DAS has shown appreciable allergic reactions and toxicity, as they can also affect normal cells. Thus their use as in the prevention and treatment of cancer is limited. DAS is a selective inhibitor of cytochrome P450 2E1 (CYP2E1), which is known to metabolize many xenobiotics including alcohol and analgesic drugs in the liver. CYP2E1-mediated alcohol/drug metabolism produce reactive oxygen species and reactive metabolites, which damage DNA, protein, and lipid membranes, subsequently causing liver damage. Several groups have shown that DAS is not only capable of inhibiting alcohol- and drug-mediated cellular toxicities, but also HIV protein- and diabetes-mediated toxicities by selectively inhibiting CYP2E1 in various cell types. However, due to known DAS toxicities, its use as a treatment modality for alcohol/drug- and HIV/diabetes-mediated toxicity have only limited clinical relevance. Therefore, effort is being made to generate DAS analogs, which are potent and selective inhibitor of CYP2E1 and poor substrate of CYP2E1. This review summarizes current advances in the field of DAS, its anticancer properties, role as a CYP2E1 inhibitor, preventing agent of cellular toxicities from alcohol, analgesic drugs, xenobiotics, as well as, from diseases like HIV and diabetes. Finally, this review also provides insights toward developing novel DAS analogues for chemical intervention of many disease conditions by targeting CYP2E1 enzyme.

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“…While not generally considered an anti-inflammatory drug, acetaminophen (paracetamol, N-acetylpara-aminophenol, APAP) has similar clinical indications to NSAIDs due to its analgesic and antipyretic properties [18] . Acetaminophen inhibits the synthesis of prostaglandin (PG) E2, PGF2, and thromboxane B2 by lipopolysaccharide (LPS)-stimulated microglia, yet has no effect on the levels of pro-inflammatory mediators such as tumor necrosis factor (TNF)-α and NO [19,20] .…”

Section: Introductionmentioning

confidence: 99%

Acetaminophen metabolites p-aminophenol and AM404 inhibit microglial activation

Slattery¹,

Klegeris²

2018

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Aim: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, deposits of amyloid beta and neurofibrillary tangles. Inflammation facilitated by microglia, the resident immune cells of the brain, contribute to the pathogenesis of AD. Epidemiological data indicate that nonsteroidal anti-inflammatory drugs (NSAIDs), which are cyclooxygenase (COX) inhibitors, reduce the risk of developing AD when administered over the course of two or more years. The mechanisms underlying this protective effect are unknown. Acetaminophen (paracetamol), which is not effective as an inhibitor of COX in peripheral tissues, may provide similar protection without the adverse effects of chronic NSAID use. The beneficial effects of acetaminophen have been proposed to stem from its metabolites p-aminophenol and N-arachidonoylaminophenol (AM404), of which, AM404 possesses analgesic and antipyretic properties. The goal of this study was to compare the effects of acetaminophen and its metabolites on microglial immune function and to elucidate the molecular mechanisms engaged by these compounds.Methods: Lipopolysaccharide-stimulated BV-2 murine microglia were used as models. Microglial activation was monitored by their secretion of nitric oxide.Results: P-aminophenol and AM404 suppressed nitric oxide secretion from stimulated microglia more effectively than acetaminophen through pathways that were independent of COX inhibition, cannabinoid receptor type two (CB2) inhibition, and activation of transient receptor potential cation channel subfamily V member 1 (TRPV1). Conclusion:Since AM404 has been previously demonstrated to attenuate NF-kB activation, it is likely that the protective effects of acetaminophen against adverse microglia activation are mediated by its metabolites p-aminophenol and AM404 inhibiting this transcription factor.

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Acetaminophen/paracetamol: A history of errors, failures and false decisions

Cited by 174 publications

References 87 publications

Analgesic Drug Prescription Patterns on Five International Paediatric Wards

Analgesic Drug Prescription Patterns on Five International Paediatric Wards

Diallyl Sulfide: Potential Use in Novel Therapeutic Interventions in Alcohol, Drugs, and Disease Mediated Cellular Toxicity by Targeting Cytochrome P450 2E1

Acetaminophen metabolites p-aminophenol and AM404 inhibit microglial activation

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