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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 -
ACS Biomaterials Science & Engineering Mar 2023With respect to sensor application investigations, hollow mesoporous carbon sphere-based materials of the spinel type of cobalt oxide (CoO) and heteroatom-doped...
With respect to sensor application investigations, hollow mesoporous carbon sphere-based materials of the spinel type of cobalt oxide (CoO) and heteroatom-doped materials are gaining popularity. In this contribution, dopamine hydrochloride (DA) and cobalt phthalocyanine (CoPc) precursors were employed to construct a highly homogeneous CoO-embedded N-doped hollow carbon sphere (CoO@NHCS) by a straightforward one-step polymerization procedure. The resulting CoO@NHCS materials may effectively tune the surface area, defect sites, and doping amount of N and Co elements by altering the loading amount of CoPc. The relatively high surface area, greater spherical wall thickness, enriched defect sites, and better extent of N and Co sites are all visible in the best 200 mg loaded CoO@NHCS-2 material. This leads to significant improvement in pyridine and graphitic N site concentrations, which offers exceptional electrochemical performance. Electrochemical analysis was used to study the electrocatalytic activity of CoO@NHCSs towards the sensing of pharmacologically active significant compounds (acetaminophen). Excellent sensor properties include the linear range (0.001-0.2 and 1.0-8.0 mM), sensitivity, limit of detection (0.07 and 0.11 μM), and selectivity in the modified CoO@NHCSs/GCE. The authentic sample (acetaminophen tablet) produces a satisfactory result when used practically.
Topics: Carbon; Acetaminophen; Nitrogen
PubMed: 36840727
DOI: 10.1021/acsbiomaterials.2c01248 -
Journal of Pain & Palliative Care... Sep 2020The use of acetaminophen is recommended in pain management, particularly acute pain management, to reduce opioid utilization and opioid related adverse drug events....
The use of acetaminophen is recommended in pain management, particularly acute pain management, to reduce opioid utilization and opioid related adverse drug events. Acetaminophen's role in chronic pain conditions is understudied. This cross-sectional study was performed in a pain management office to explore how chronic pain patients use acetaminophen. The final study sample included 100 patients. Current users of acetaminophen were most likely to report that a doctor had recommended acetaminophen to them (86.4%) compared to ever (66.7%) and never (55.6%) users ( < .001). Patients who were recommended taking acetaminophen by a physician were 3.60 times as likely (95% CI 1.58, 8.25) to be a current or ever user of acetaminophen as compared to those who did not receive such a recommendation from their physician. There were no significant differences between current, ever, and never users on their knowledge of the maximum daily dose of acetaminophen of 4 g ( = .925). The study suggests that patients are often unaware of acetaminophen's role in the treatment of their chronic pain.
Topics: Acetaminophen; Adult; Aged; Aged, 80 and over; Attitude; Chronic Pain; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Pain Management; Patient Medication Knowledge; Physicians; Surveys and Questionnaires; Young Adult
PubMed: 32186424
DOI: 10.1080/15360288.2020.1734139 -
The Veterinary Record May 2019
Topics: Acetaminophen; Animals; Dog Diseases; Dogs; England; Massive Hepatic Necrosis
PubMed: 31073006
DOI: 10.1136/vr.l2060 -
American Journal of Obstetrics &... May 2019Proper pain control after cesarean delivery is of high clinical importance to the recovery and relief of patients after surgical delivery. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Proper pain control after cesarean delivery is of high clinical importance to the recovery and relief of patients after surgical delivery.
OBJECTIVE
We aimed to compare fixed time interval to on-demand regimens of nonopioid analgesics and to assess whether a protocol that is based on intravenous administration is superior to oral administration.
STUDY DESIGN
This was a randomized controlled trial performed between April 2017 and May 2018. Patients who underwent elective cesarean delivery were assigned randomly to receive 1 of 3 pain relief protocols for the first 48 hours after surgery: (1) the fixed intravenous protocol included intravenous paracetamol (acetaminophen) 3 times daily with oral ibuprofen twice daily, (2) the fixed oral protocol included oral paracetamol 3 times daily with oral ibuprofen twice daily; if the patient requested additional analgesia, tramadol hydrochloride or dipyrone were given as rescue treatments, (3) the on-demand protocol included oral paracetamol or ibuprofen or dipyrone (based on visual analog scale). Pain intensity was measured and compared with the use of the visual analog scale (range, 0 ([no pain] to 10 [worst pain]). Total doses of pain relief analgesia and maternal and neonatal adverse effects were compared between the groups.
RESULTS
The study included 127 women who were assigned randomly to the intravenous protocol group (n=41), oral protocol group (n=43), and on-demand protocol group (n=43). There were no between group differences in maternal and pregnancy characteristics, cesarean delivery indications, or surgical technique. The average visual analog scale score was 6.2±0.8 in the intravenous group, 7.0±1.1 in the oral group, and 7.5±0.7 in the on-demand group, in the first 24 hours (P=.01) and 6.4±0.7, 6.8±0.9, and 7.4±0.7 for the total 48 hours, respectively (P<.001). Mean pain score reduction was higher in the intravenous protocol compared with the fixed oral protocol group (4.7±1.2 vs 4.0±1.4; P=.02). The median doses of pain relief analgesia in the intravenous group were 5 (interquartile range, 5-7), 6 in the oral group (interquartile range, 4-6), and 4 in the on-demand group (interquartile range, 3-6; P=.001) in the first 24 hours and 9 (interquartile range, 7-10), 9 (interquartile range, 7-10), and 7 (interquartile range, 4-9), respectively, for the total 48 hours (P<.001). There were no "between group" differences in neonatal birthweight or maternal and neonatal adverse outcomes.
CONCLUSION
Administration of pain relief analgesia (ibuprofen and acetaminophen) in fixed time intervals (intravenous or oral) after cesarean delivery yielded reduced visual analog scale pain scores compared with an on-demand protocol, despite fewer pain relief drugs consumed in the on-demand group.
Topics: Acetaminophen; Administration, Intravenous; Administration, Oral; Adult; Analgesia; Analgesics; Analgesics, Non-Narcotic; Cesarean Section; Drug Therapy, Combination; Female; Humans; Ibuprofen; Pain Management; Pain, Postoperative; Pregnancy; Treatment Outcome
PubMed: 33345816
DOI: 10.1016/j.ajogmf.2019.04.002 -
CPT: Pharmacometrics & Systems... Jun 2018Paracetamol (acetaminophen (APAP)) is one of the most commonly used analgesics in the United Kingdom and the United States. However, exceeding the maximum recommended...
Paracetamol (acetaminophen (APAP)) is one of the most commonly used analgesics in the United Kingdom and the United States. However, exceeding the maximum recommended dose can cause serious liver injury and even death. Promising APAP toxicity biomarkers are thought to add value to those used currently and clarification of the functional relationships between these biomarkers and liver injury would aid clinical implementation of an improved APAP toxicity identification framework. The framework currently used to define an APAP overdose is highly dependent upon time since ingestion and initial dose; information that is often highly unpredictable. A pharmacokinetic/pharmacodynamic (PK/PD) APAP model has been built in order to understand the relationships between a panel of biomarkers and APAP dose. Visualization and statistical tools have been used to predict initial APAP dose and time since administration. Additionally, logistic regression analysis has been applied to histology data to provide a prediction of the probability of liver injury.
Topics: Acetaminophen; Animals; Biomarkers; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Drug Overdose; Humans; Logistic Models; Male; Mice; Models, Statistical; Models, Theoretical
PubMed: 29667370
DOI: 10.1002/psp4.12298 -
Microbial Pathogenesis Sep 2021The current failure of antimicrobials in treating life-threatening diseases, the high rate of multidrug resistant pathogens and the slow progress in the development of...
The current failure of antimicrobials in treating life-threatening diseases, the high rate of multidrug resistant pathogens and the slow progress in the development of new antibiotics directed scientists to develop antivirulence drugs that targets quorum sensing (QS). In many microbes, QS acts as a communication system which control pathogenicity of microbes. Analgesics can be beneficial in controlling virulence traits of microbes and hence they may augment the efficacy of antimicrobials. In this study, two analgesics were screened for the inhibition of QS in Chromobacterium violaceum CV026 and their effects on virulence production in Pseudomonas aeruginosa PAO1 strain and clinical isolates of Acinetobacter baumannii were evaluated. The traits investigated were biofilm formation, pyocyanin and rhamnolipid production, twitching, swarming or surface associated motilities, production of protease, phospholipase and gelatinase enzymes and sensitivity to oxidative stress. Relative expression of abaI gene was calculated by performing qRT-PCR. Docking analysis of paracetamol as QSI (quorum sensing inhibitor) of AbaI and AbaR proteins was performed. Paracetamol inhibited QS in CV026, but indomethacin devoids anti-QS activity. Paracetamol inhibited virulence factors of PAO1. It strongly inhibited biofilm formation, and swarming by 66.4% and 57.1%, respectively. While, it moderately to slightly inhibited rhamnolipid, pyocyanin, gelatinase, resistance to oxidative stress, protease and twitching motility by 33.3%, 33.1% 17.5%, 9.1%, 8.7% and 7.7%, respectively. For A. baumannii, paracetamol strongly inhibited biofilm by 39.7-93% and phospholipase enzyme by 8.7-100%, reduced twitching and surface motility by 6.7-82.5% and 7.7-29.4%, respectively, And slightly reduced sensitivity to oxidative stress by 3.3-36.4%. Paracetamol at sub-MIC suppressed the expression of abaI gene by 32% in A. baumannii. Docking studies suggested that paracetamol can bind to AbaR and AbaI proteins and bind more to AbaR, hence it may act by inhibiting AHL signal reception. As a conclusion, paracetamol, beside its analgesic activity, has anti-QS activity and could be used in the eradication of P. aeruginosa and A. baumannii infections in combination with antibiotics.
Topics: Acetaminophen; Analgesics; Anti-Bacterial Agents; Biofilms; Chromobacterium; Indomethacin; Pseudomonas aeruginosa; Quorum Sensing; Virulence Factors
PubMed: 34284088
DOI: 10.1016/j.micpath.2021.105097 -
Talanta Dec 2019In this study, a capillary electrophoresis-tandem mass spectrometry method combining efficient separation and sensitive detection has been developed and validated, for...
In this study, a capillary electrophoresis-tandem mass spectrometry method combining efficient separation and sensitive detection has been developed and validated, for the first time, to quantify acetaminophen and five of its metabolites in urine samples. Optimization of the method has led us to perform detection in positive ESI mode using MeOH-ammonium hydroxide (0.1%) (50:50, v/v) as sheath liquid. Moreover, optimal separation has been obtained in less than 9 min after anodic injection, using an ammonium acetate solution (40 mM, pH 10) as BGE. It was shown that the dilution solvent and the dilution factor to use for sample preparation are critical parameters to avoid peak splitting, to gain in sensitivity and then to obtain an effective analysis method. While a 200-fold factor dilution was shown to be suitable for quantitation of acetaminophen, acetaminophen mercapturate, acetaminophen sulfate and acetaminophen glucuronide, a 20-fold dilution was finally selected for methoxy-acetaminophen and 3-methylthioacetaminophen analysis, thus requiring two successive analyses to be carried out in order to quantify all metabolites. Hyphenation of CE with MS/MS versus UV permits to improve LOQ (10-20-fold factor with respect to previous works for acetaminophen, acetaminophen sulfate and acetaminophen glucuronide). Moreover, use of CE versus HPLC, permits to quantify two additional metabolites, i.e. 3-methylthio-acetaminophen and methoxy-acetaminophen. The method has been validated using the accuracy profile approach with a total error (accuracy) included in the ± 20% range. Thereby, the method allows the quantitation of acetaminophen and acetaminophen mercapturate in the range (0.1-1 mg mL), and of acetaminophen sulfate, methoxy-acetaminophen, acetaminophen glutathione and 3-methylthio-acetaminophen in the ranges (0.5-5 mg mL), (0.025-0.4 mg mL), (9.22-30 mg mL) and (0.073-0.4 mg mL), respectively. The method was finally applied to the analysis of urine samples of eighteen patients belonging to three different inclusion groups of the ongoing clinical trial, demonstrating that the method is suitable to highlight different metabolic profiles. This work will be subsequently extended to the analysis two hundred and seventy urine samples from patients included in a clinical trial dedicated to the study of acetaminophen metabolism changes after hepatic resection.
Topics: Acetaminophen; Electrophoresis, Capillary; Humans; Tandem Mass Spectrometry
PubMed: 31450387
DOI: 10.1016/j.talanta.2019.07.003 -
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 -
Biological Trace Element Research Jan 2023Acetaminophen (APAP) is one of the popular and safe pain medications worldwide. However, due its wide availability, it is frequently implicated in intentional or...
Acetaminophen (APAP) is one of the popular and safe pain medications worldwide. However, due its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure. Boron is a bioactive trace element, found naturally as boric acid (BA) and borate. In this study, the effects of boric acid on the acute renal toxicity induced by APAP in rats were researched in comparison with N-acetyl cysteine (NAC). In the study, 7 groups were formed and 2 g/kg dose of paracetamol per rat was prepared by suspending in 1% Carboxy Methyl Cellulose (CMC) solution of phosphate buffer saline (PBS). Boric acid dissolved in saline was administered to experimental animals by gavage at doses of 50, 100, and 200 mg/kg. In this study, ER stress and apoptosis formed by paracetamol-induced nephrotoxicity were investigated. This purpose determined iNOS, PERK, ATF6, NFkB p53, caspases 3, 12, bcl-2, and bcl-xL gene mRNA expression kidney tissue. Also, the levels of kidney injury molecule-1 (KIM-1), Cysteine (Cys), and IL-18 levels, which are mentioned today as kidney damage markers were compared with BUN and creatine levels. The effect of boron on kidney damage was determined by histopathologic. Data were statistically analyzed by using SPSS-20 ANOVA and stated as means and standard deviation. According to the data obtained in our study, we believe that boric acid has a protective effect on the negative effects of paracetamol on the kidney. We believe that our study will provide useful data to the literature on the possibility of a supplement to be used as an active compound in paracetamol for the prophylaxis of boric acid and it can also be converted into a useful product.
Topics: Rats; Animals; Acetaminophen; Boron; Acetylcysteine; Apoptosis; Kidney Diseases; Endoplasmic Reticulum Stress
PubMed: 35020164
DOI: 10.1007/s12011-022-03114-9