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Journal of Clinical Pharmacology Jun 2019Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the... (Observational Study)
Observational Study
Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92-944], body weight, 6.1 kg [4.0-12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8-hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.
Topics: Acetaminophen; Administration, Intravenous; Analgesics, Non-Narcotic; Biological Variation, Population; Body Weight; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child, Preschool; Down Syndrome; Female; Humans; Infant; Infusions, Intravenous; Male; Metabolic Clearance Rate; Models, Biological; Pain, Postoperative; Prospective Studies
PubMed: 30633373
DOI: 10.1002/jcph.1373 -
JPMA. the Journal of the Pakistan... Dec 2022
Topics: Pregnancy; Female; Humans; Acetaminophen; Autism Spectrum Disorder; Prenatal Exposure Delayed Effects
PubMed: 37246699
DOI: 10.47391/JPMA.6267 -
Journal of Veterinary Internal Medicine Mar 2023Acetaminophen has been evaluated in horses for treatment of musculoskeletal pain but not as an antipyretic.
BACKGROUND
Acetaminophen has been evaluated in horses for treatment of musculoskeletal pain but not as an antipyretic.
OBJECTIVES
To determine the pharmacokinetics and efficacy of acetaminophen compared to placebo and flunixin meglumine in adult horses with experimentally induced endotoxemia.
ANIMALS
Eight university owned research horses with experimentally induced endotoxemia.
METHODS
Randomized placebo controlled crossover study. Horses were treated with acetaminophen (30 mg/kg PO; APAP), flunixin meglumine (1.1 mg/kg, PO; FLU), and placebo (PO; PLAC) 2 hours after administration of LPS. Plasma APAP was analyzed via LC-MS/MS. Serial CBC, lactate, serum amyloid A, heart rate and rectal temperature were evaluated. Serum IL-1β, IL-6, IL-8, IL-10, and TNF-α were evaluated by an equine-specific multiplex assay.
RESULTS
Mean maximum plasma APAP concentration was 13.97 ± 2.74 μg/mL within 0.6 ± 0.3 hour after administration. At 4 and 6 hours after treatment, both APAP (P = <.001, P = .03, respectively) and FLU (P = .0045 and P < .001, respectively) had a significantly greater decrease in rectal temperature compared to placebo. FLU caused greater heart rate reduction than APAP at 4 and 6 hours (P = .004 and P = .04), and PLAC at 4 hours (P = .05) after treatment.
CONCLUSIONS AND CLINICAL IMPORTANCE
The pharmacokinetics of acetaminophen in endotoxemic horses differ from those reported by previous studies in healthy horses. Acetaminophen is an option for antipyresis in clinical cases, particularly when administration of traditional NSAIDs is contraindicated.
Topics: Horses; Animals; Acetaminophen; Endotoxemia; Cross-Over Studies; Chromatography, Liquid; Tandem Mass Spectrometry; Horse Diseases
PubMed: 36840424
DOI: 10.1111/jvim.16663 -
British Journal of Clinical Pharmacology Jul 2015Paracetamol poisoning is the commonest overdose seen in the UK. The management of patients with paracetamol poisoning has been little changed for the past 40 years,... (Review)
Review
Paracetamol poisoning is the commonest overdose seen in the UK. The management of patients with paracetamol poisoning has been little changed for the past 40 years, with a weight related dose of antidote (acetylcysteine) and treatment based on nomograms relating paracetamol concentration to time from ingestion. In 2012 the UK Commission on Human Medicines recommended a revision of the nomogram, following the death of a young woman, lowering the treatment threshold for all patients. As a result many more patients were treated. This has resulted in a large increase in admissions and in the proportion suffering adverse reactions to the antidote acetylcysteine since, interestingly, higher paracetamol concentrations inhibit anaphylactoid reactions to the antidote. New approaches to assessing the toxicity of paracetamol are now emerging using new biomarkers in blood. This article discusses new approaches to risk assessment and treatment for paracetamol overdose based on recent research in this area.
Topics: Acetaminophen; Acetylcysteine; Analgesics, Non-Narcotic; Biomarkers; Drug Overdose; Humans; Nomograms; Risk Assessment
PubMed: 26099917
DOI: 10.1111/bcp.12604 -
BMJ (Clinical Research Ed.) Mar 2015
Topics: Acetaminophen; Analgesics, Non-Narcotic; Back Pain; Humans; Osteoarthritis
PubMed: 25828857
DOI: 10.1136/bmj.h1352 -
Acta Obstetricia Et Gynecologica... Jun 2023Paracetamol is used by more than 50% of women worldwide during pregnancy; headache representing the most frequent indication. Several studies report that long-term...
Paracetamol is used by more than 50% of women worldwide during pregnancy; headache representing the most frequent indication. Several studies report that long-term exposure to paracetamol in utero is associated with adverse neurodevelopmental outcomes in children, indicating a dose-response effect. However, less or no risk is found to be associated with short-term exposure. Paracetamol most likely crosses the placenta through passive diffusion, and there are several possible mechanisms for how paracetamol might affect fetal brain development. Although the literature suggests an association between prenatal paracetamol exposure and neurodevelopmental outcomes, the role of confounders cannot be ruled out. Consequently, as a precaution, we believe that pregnant women should be recommended ideally to only use paracetamol to treat conditions that might harm the fetus, such as severe pain or a high fever. This Comment aims to put focus on the potential fetal risks of paracetamol exposure in utero.
Topics: Child; Female; Humans; Pregnancy; Acetaminophen; Prenatal Exposure Delayed Effects; Placenta; Fetus; Fetal Development
PubMed: 36941046
DOI: 10.1111/aogs.14557 -
F1000Research 2020Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as "safe" by regulatory authorities. Clinically relevant doses of paracetamol were...
Paracetamol (acetaminophen) is widely used in pregnancy and generally regarded as "safe" by regulatory authorities. Clinically relevant doses of paracetamol were administered intraperitoneally to pregnant rats twice daily from embryonic day E15 to 19 (chronic) or as a single dose at E19 (acute). Control samples were from un-treated age-matched animals. At E19, rats were anaesthetised, administered a final paracetamol dose, uteruses were opened and fetuses exposed for sample collection. For RNA sequencing, placentas and fetal brains were removed and flash frozen. Fetal and maternal plasma and cerebrospinal fluid were assayed for α-fetoprotein and interleukin 1β (IL1β). Brains were fixed and examined (immunohistochemistry) for plasma protein distribution. Placental permeability to a small molecule ( C-sucrose) was tested by injection into either mother or individual fetuses; fetal and maternal blood was sampled at regular intervals to 90 minutes. RNA sequencing revealed a large number of genes up- or down-regulated in placentas from acutely or chronically treated animals compared to controls. Most notable was down-regulation of three acute phase plasma proteins (α-fetoprotein, transferrin, transthyretin) in acute and especially chronic experiments and marked up-regulation of immune-related genes, particularly cytokines, again especially in chronically treated dams. IL1β increased in plasma of most fetuses from treated dams but to variable levels and no IL1β was detectable in plasma of control fetuses or any of the dams. Increased placental permeability appeared to be only from fetus to mother for both C-sucrose and α-fetoprotein, but not in the reverse direction. In the fetal brain, gene regulatory changes were less prominent than in the placenta of treated fetuses and did not involve inflammatory-related genes; there was no evidence of increased blood-brain barrier permeability. Results suggest that paracetamol may induce an immune-inflammatory-like response in placenta and more caution should be exercised in use of paracetamol in pregnancy.
Topics: Acetaminophen; Animals; Blood-Brain Barrier; Brain; Female; Gene Expression; Inflammation; Permeability; Placenta; Pregnancy; Rats
PubMed: 32934805
DOI: 10.12688/f1000research.24119.2 -
Drug Discovery Today. Technologies Aug 2015One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to... (Review)
Review
One aim of systems toxicology is to deliver mechanistic, mathematically rigorous, models integrating biochemical and pharmacological processes that result in toxicity to enhance the assessment of the risk posed to humans by drugs and other xenobiotics. The benefits of such 'in silico' models would be in enabling the rapid and robust prediction of the effects of compounds over a range of exposures, improving in vitro-in vivo correlations and the translation from preclinical species to humans. Systems toxicology models of organ toxicities that result in high attrition rates during drug discovery and development, or post-marketing withdrawals (e.g., drug-induced liver injury (DILI)) should facilitate the discovery of safe new drugs. Here, systems toxicology as applied to the effects of paracetamol (acetaminophen, N-acetyl-para-aminophenol (APAP)) is used to exemplify the potential of the approach.
Topics: Acetaminophen; Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Computer Simulation; Drug Design; Drug Discovery; Glutathione; Humans; Models, Biological; Toxicology; Xenobiotics
PubMed: 26464084
DOI: 10.1016/j.ddtec.2015.06.003 -
BMJ (Clinical Research Ed.) Dec 1996
Topics: Acetaminophen; Drug Labeling; Drug Overdose; Health Education; Humans; United Kingdom
PubMed: 8973219
DOI: 10.1136/bmj.313.7070.1417 -
Postgraduate Medical Journal Jan 1993A 29 year old man with a significant paracetamol overdose was found to have an abnormal electrocardiograph which, in the absence of hepatic encephalopathy, was...
A 29 year old man with a significant paracetamol overdose was found to have an abnormal electrocardiograph which, in the absence of hepatic encephalopathy, was considered due to a direct cardiotoxic effect of the drug. A functional coronary insufficiency resulting from inhibition of endothelium-derived relaxing factor secondary to depletion of sulphydryl groups is postulated, and it is suggested that in paracetamol poisoning evidence of cardiotoxicity alone may be sufficient justification for treatment with acetylcysteine.
Topics: Acetaminophen; Adult; Arrhythmia, Sinus; Drug Overdose; Electrocardiography; Humans; Male
PubMed: 8446552
DOI: 10.1136/pgmj.69.807.52