Search

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats. Nine-week-old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross-sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three-point bending and microcomputer tomography were measured in the femur. Follow-up experiments in human primary muscle cells were used to explore supra-physiological effects of ACE. Data were analyzed using a two-way ANOVA for treatment (ACE or placebo) and condition (exercise or non-exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment-by-condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated-AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho-4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post-exercise., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Acetaminophen is used clinically in horses with musculoskeletal pain; however, no studies have been performed in horses with chronic lameness., Objectives: To determine the pharmacokinetics, safety and efficacy of chronic dosing of acetaminophen in horses with naturally occurring chronic lameness., Study Design: Longitudinal., Methods: Twelve adult horses with chronic lameness were treated with acetaminophen (30 mg/kg PO) every 12 h for 21 days. Plasma concentrations of acetaminophen were analysed on days 7 and 21 via LC-MS/MS and noncompartmental pharmacokinetic analysis. Lameness was evaluated by body-mounted inertial sensor (BMIS) and 10-point subjective lameness score on day 21 and compared to untreated baseline evaluation on day 35. Clinicopathological analysis (n = 12), hepatic biopsy (n = 6) and gastroscopy (n = 6) were evaluated on days -1 and 22., Results: Maximum plasma acetaminophen concentration (C max ) was 20.83 ± 10.25 μg/mL at time (T max ) 0.40 ± 0.22 h on day 7. The C max on day 21 was 17.33 ± 6.91 μg/mL with a T max of 0.67 ± 0.26 h. Subjective lameness scores significantly improved at 2 and 4 h post-treatment; Significant percent improvement was detected in PD max for horses with hindlimb lameness at 1, 2 and 8 h post-treatment. There were no significant differences in gastroscopy or hepatic biopsy scores between days -1 and 22., Main Limitations: Small sample size, multi-limb lameness of varying severity and aetiology, lack of intermediary lameness evaluation., Conclusions: In horses with naturally occurring chronic lameness, acetaminophen at 30 mg/kg produced a transient improvement in subjective lameness and BMIS evaluation. Acetaminophen may not be effective as a monotherapy. Acetaminophen was safe following 21 days of 30 mg/kg PO every 12 h, with no evidence of clinically significant changes in clinicopathological analysis, hepatic biopsy or gastric ulceration scores., (© 2023 EVJ Ltd.)

Background: Acetaminophen (paracetamol) is increasingly used to treat painful conditions in horses but its ocular penetration has not been studied., Objectives: To determine whether orally administered acetaminophen penetrates the aqueous humour of the normal equine eye and report an aqueous humour:serum acetaminophen concentration ratio in horses., Study Design: In vivo experiment., Methods: Six privately owned horses with normal ophthalmic examinations weighing 568 ± 65 kg (mean ± standard deviation) and aged 11 ± 4 years were given 20 mg/kg acetaminophen orally every 12 h for a total of six doses. Physical exam parameters were recorded prior to, during, and after the dosing period. One hour after the final dose, horses were sedated and simultaneous aqueous humour and serum samples were collected and analysed for acetaminophen concentrations and selected eicosanoids. An aqueous humour:serum acetaminophen concentration ratio was calculated. A second aqueous humour sample was taken and analysed for eicosanoid concentrations 3 months after acetaminophen dosing. Physical exam data were compared between time points using a mixed model analysis (significance p < 0.05)., Results: Acetaminophen was detected in both serum and aqueous humour of all horses and mean ± standard deviation aqueous humour:serum acetaminophen concentration ratio was 44.9 ± 15.9%. No significant changes in physical exam parameters occurred during or after dosing. Eicosanoids were not detected in aqueous humour at any sampling point., Main Limitations: Presence of acetaminophen in the aqueous humour may not relate to clinical effect. A therapeutic level of acetaminophen has not been determined in horses, and the absence of ocular inflammation does not reflect conditions in which acetaminophen may be used., Conclusions: Acetaminophen readily penetrates the aqueous humour of the normal equine eye after consecutive oral dosing. Further study is required to determine whether acetaminophen is useful in the treatment of ocular pain and inflammation., (© 2022 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Background: Acetaminophen is a common analgesic and antipyretic drug used in human medicine and might be an alternative to nonsteroidal anti-inflammatory drugs for treating pain and pyrexia in foals. The pharmacokinetics and safety of differing doses of acetaminophen have not been investigated in foals., Objectives: To determine the plasma pharmacokinetics and any changes in haematology and biochemistry profiles following oral administration of single doses of acetaminophen at 10, 20, and 40 mg/kg to foals., Study Design: Randomised cross-over pharmacokinetic study., Methods: Six Quarter Horse (two colts and four fillies) foals received 10, 20, and 40 mg/kg acetaminophen orally once. Haematology and biochemistry profiles were performed before and 7 days after each drug administration. Blood samples were collected over 64 h after drug administration and were used to quantify plasma acetaminophen concentrations by liquid chromatography. Pharmacokinetic parameters were determined using compartmental analysis., Results: Median (range) acetaminophen plasma concentrations were 4.4 (1.8-5.1), 6.3 (2.6-12.6), and 14 (7.3-18) μg/ml for the 10, 20, and 40 mg/kg doses, respectively. Median acetaminophen area under the concentration versus time curve (AUC) 0-∞ ranged from 25 (11-32), 41 (22-74), and 105 (82-142) h × μg/ml for the 10, 20, and 40 mg/kg doses, respectively. Dose-normalised maximal concentrations and AUC 0-∞ values were similar across dose concentrations (p > 0.05). Median terminal half-life for all doses was 2.7-2.8 h. Haematology and biochemistry profiles were normal except for blood urea nitrogen and alkaline phosphatase concentrations., Main Limitations: Foals were growing throughout the study, starting at 1 month and ending at 3 months. Deposition of drugs changes with age. The sample size was small and only single doses were evaluated. No liver biopsies were performed., Conclusion: Plasma disposition of acetaminophen after a single oral dose of 10, 20, and 40 mg/kg to 1-3-month-old foals varies greatly with the dose. The analgesic and antipyretic effect in foals is unknown., (© 2022 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd.)

Pharmaceuticals are significant environmental stressors, since they are utilized around the world; they are usually released in to the aquatic system without adequate treatment and several non-target species can be harmed because of their intrinsic properties. Paracetamol is one of the most widely prescribed analgesics in human medical care. Consequently, this compound is systematically reported to occur in the wild, where it may exert toxic effects on non-target species, which are mostly uncharacterized so far. The objective of the present work was to assess the acute (control, 5, 25, 125, 625 and 3125 μg/L) and chronic (control, 5, 10, 20, 40 and 80 μg/L) effects of paracetamol on behavioural endpoints, as well as on selected oxidative stress biomarkers [superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRed)] and the anti-inflammatory activity biomarker cyclooxygenase (COX), in the polychaete Hediste diversicolor (Annelida: Polychaeta). Exposure to paracetamol caused effects on behavioural traits, with increased burrowing time (96 h) and hypoactivity (28 days). In addition, exposure to paracetamol resulted also in significant increases of SOD activity, but only for intermediate levels of exposure, but for both acute and chronic exposures. Both forms of GPx had their activities significantly increased, especially after chronic exposure. Acutely exposed organisms had their GRed significantly decreased, while chronically exposed worms had their GRed activity augmented only for the lowest tested concentrations. Effects were also observed in terms of COX activity, showing that paracetamol absorption occurred and caused an inhibition of COX activity in both exposure regimes. It is possible to conclude that the exposure to concentrations of paracetamol close to the ones in the environment may be deleterious to marine ecosystems, endangering marine life by changing their overall redox balance, and the biochemical control of inflammatory intermediaries. Behaviour was also modified and the burrowing capacity was adversely affected. This set of effects clearly demonstrate that paracetamol exposure, under realistic conditions, it not exempt of adverse effects on marine invertebrates, such as polychaetes.

Background: Acetaminophen has been used clinically in horses alone or combined with traditional non-steroidal anti-inflammatory drugs for treatment of musculoskeletal pain in horses., Objectives: To determine the pharmacokinetics and efficacy of acetaminophen at two doses in horses with mechanically induced lameness compared with phenylbutazone or placebo control., Study Design: In vivo experiment., Methods: Nine healthy mares with mechanical lameness induced via a reversible sole pressure horseshoe model were treated with acetaminophen (20 mg/kg PO; A20), acetaminophen (30 mg/kg PO; A30), phenylbutazone (2.2 mg/kg, PO; PB) and oral placebo (C) in a randomised four-way Latin square model. Plasma concentrations for A20 and A30 were analysed via LC-MS/MS and noncompartmental pharmacokinetic analysis. Heart rate and heart rate variability were measured using a portable telemetry. Lameness was scored by three blinded boarded equine surgeons using the AAEP and 10-point scales., Results: Mean maximum plasma concentration (C max ) for A20 was 20.01 μg/ml within 0.66 h (T max ) after administration; The mean C max for A30 was 30.02 μg/ml with a T max of 0.43 h. Post-treatment heart rate for A30 was significantly lower than A20 at 1 and 7 h; lower than PB at 2, 3, 4.5 and 7 h; lower than C at 2, 3.5, 4.5, 6, 7 and 8 h. 10-point Lameness scores were significantly improved for A30 than C at 2 and 4 h post-treatment; PB was significantly improved than C at 8 h post treatment. There were no significant differences in lameness between A20, A30 and PB., Main Limitations: Small sample size, lack of objective lameness measurement., Conclusions: Acetaminophen at 30 mg/kg produced a more rapid improvement in lameness scores and heart rate compared with other treatments in this model. Further evaluation of the pharmacokinetics and safety of repeated oral dosing of acetaminophen at 30 mg/kg is needed to determine clinical utility., (© 2022 EVJ Ltd.)

Paracetamol is used worldwide for its analgesic and antipyretic actions. It has a spectrum of action similar to that of NSAIDs and resembles particularly the COX-2 selective inhibitors. Paracetamol is, on average, a weaker analgesic than NSAIDs or COX-2 selective inhibitors but is often preferred because of its better tolerance. Despite the similarities to NSAIDs, the mode of action of paracetamol has been uncertain, but it is now generally accepted that it inhibits COX-1 and COX-2 through metabolism by the peroxidase function of these isoenzymes. This results in inhibition of phenoxyl radical formation from a critical tyrosine residue essential for the cyclooxygenase activity of COX-1 and COX-2 and prostaglandin (PG) synthesis. Paracetamol shows selectivity for inhibition of the synthesis of PGs and related factors when low levels of arachidonic acid and peroxides are available but conversely, it has little activity at substantial levels of arachidonic acid and peroxides. The result is that paracetamol does not suppress the severe inflammation of rheumatoid arthritis and acute gout but does inhibit the lesser inflammation resulting from extraction of teeth and is also active in a variety of inflammatory tests in experimental animals. Paracetamol often appears to have COX-2 selectivity. The apparent COX-2 selectivity of action of paracetamol is shown by its poor anti-platelet activity and good gastrointestinal tolerance. Unlike both non-selective NSAIDs and selective COX-2 inhibitors, paracetamol inhibits other peroxidase enzymes including myeloperoxidase. Inhibition of myeloperoxidase involves paracetamol oxidation and concomitant decreased formation of halogenating oxidants (e.g. hypochlorous acid, hypobromous acid) that may be associated with multiple inflammatory pathologies including atherosclerosis and rheumatic diseases. Paracetamol may, therefore, slow the development of these diseases. Paracetamol, NSAIDs and selective COX-2 inhibitors all have central and peripheral effects. As is the case with the NSAIDs, including the selective COX-2 inhibitors, the analgesic effects of paracetamol are reduced by inhibitors of many endogenous neurotransmitter systems including serotonergic, opioid and cannabinoid systems. There is considerable debate about the hepatotoxicity of therapeutic doses of paracetamol. Much of the toxicity may result from overuse of combinations of paracetamol with opioids which are widely used, particularly in USA.

The heme peroxidase enzyme myeloperoxidase (MPO) is released by activated neutrophils and monocytes, where it uses hydrogen peroxide (H(2)O(2)) to catalyze the production of the potent oxidants hypochlorous acid (HOCl), hypobromous acid (HOBr) and hypothiocyanous acid (HOSCN) from halide and pseudohalide (SCN(-)) ions. These oxidants have been implicated as key mediators of tissue damage in many human inflammatory diseases including atherosclerosis, asthma, rheumatoid arthritis, cystic fibrosis and some cancers. It is shown here that acetaminophen (paracetamol), a phenol-based drug with analgesic and antipyretic actions, is an efficient inhibitor of HOCl and HOBr generation by isolated MPO-H(2)O(2)-halide systems. With physiological halide concentrations, acetaminophen concentrations required for 50% inhibition of oxidant formation (IC(50)) were 77+/-6microM (100mMCl(-)) and 92+/-2microM (100mMCl(-) plus 100microMBr(-)), as measured by trapping of oxidants with taurine. The IC(50) for inhibition of HOCl generation by human neutrophils was ca. 100microM. These values are lower than the maximal therapeutic plasma concentrations of acetaminophen (< or =150microM) resulting from typical dosing regimes. Acetaminophen did not diminish superoxide generation by neutrophils, as measured by lucigenin-dependent chemiluminescence. Inhibition of HOCl production was associated with the generation of fluorescent acetaminophen oxidation products, consistent with acetaminophen acting as a competitive substrate of MPO. Inhibition by acetaminophen was maintained in the presence of heparan sulfate and extracellular matrix, materials implicated in the sequestration of MPO at sites of inflammation in vivo. Overall, these data indicate that acetaminophen may be an important modulator of MPO activity in vivo., (2009 Elsevier Inc. All rights reserved.)

Hepatotoxicity from paracetamol is of great concern because of the considerable number of patients who develop severe toxicity from this drug. A group of senior medical practitioners, academics and scientists were brought together on June 29 and 30, 2009 by the Food and Drug Administration of USA (FDA) with the aim of providing advice on how to limit the number of cases of hepatotoxicity due to paracetamol in USA. The most contentious recommendations were the reduction in the dose of paracetamol to 650 mg and the elimination of prescription combination products of paracetamol and opiates. The first recommendation indicates that many members of the committee consider, despite much evidence to the contrary, that therapeutic doses of paracetamol (up to 4 g daily) are associated with a significant incidence of hepatotoxicity. The second recommendation, if accepted by FDA, will require major changes in the therapeutic use of paracetamol and opiates. Adoption of these two recommendations may lead to the increased use of NSAIDs with the potential of increasing incidence of NSAIDs-related adverse reactions.

The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of paracetamol is its hepatotoxicity after an overdose. Hepatotoxicity has also been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Importantly, prospective studies indicate that therapeutic doses of paracetamol are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol. Controlled clinical trials have found that paracetamol is very well tolerated by the gastrointestinal tract. While variable results have been found in case control studies, most studies have shown no change or a small increase in the relative risk of perforations, ulcer or bleeding in the upper gastrointestinal tract. However, associations between the use of paracetamol and gastrointestinal toxicity, as well as with chronic renal disease and asthma, are very likely to reflect biases in some case control studies. In particular, such biases may be caused by the perceived high tolerability of paracetamol in these diseases. The consequent use of paracetamol in these diseases states then leads to an apparent association between paracetamol and the disease. Despite metabolism of paracetamol to reactive compounds, hypersensitivity reactions are rare, although urticaria occurs in occasional patients. Paracetamol appears to be well tolerated during pregnancy although prospective studies are required.

Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.

Paracetamol (acetaminophen) is a well-tolerated drug at therapeutic doses and this safety profile is a major factor in the very wide use of the drug. It is well known that paracetamol is converted by the hepatic cytochrome P450 system to reactive compounds. Less well known is that paracetamol is also metabolized to the same reactive compounds by myeloperoxidase and the peroxidase function of cycloxygenase (COX)-1. The reactive metabolites lead to hepatotoxicity following overdosage. Similar hepatotoxicity has been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Associations between the use of paracetamol and chronic renal diseases, gastrointestinal toxicity and asthma may be due to biases in case-control studies. In particular, biases may be caused by the perceived safety of paracetamol in these diseases. Selective inhibition of the delayed pathway of prostaglandin synthesis is consistent with the gastrointestinal safety of paracetamol and its safety in the majority of aspirin-sensitive asthmatics. Despite the conversion of paracetamol to reactive compounds, hypersensitivity reactions are rare, although urticaria is produced in occasional patients.

Comparisons are made between the specific COX-2 inhibitors, celecoxib and rofecoxib, and acetaminophen. The specific COX-2 inhibitors are a significant advance in therapy because their anti-inflammatory, analgesic and antipyretic activities are associated with a high degree of gastrointestinal safety. Acetaminophen is often not considered to be a potent inhibitor of COX-2 but it is a potent inhibitor of prostaglandin synthesis in intact cells after stimulation by cytokines. Its weak activity on the pathway of prostanoid synthesis involving COX-1 is shown by its weak anti-platelet activity and good gastrointestinal safety. The specific COX-2 inhibitors and acetaminophen are analgesic after dental surgery, orthopedic surgery and in osteoarthritis although acetaminophen appears to be a slightly weaker agent. The apparent analgesic activity of both the COX-2 inhibitors and acetaminophen may, in part, be due to their anti-inflammatory properties. Both groups of drugs also decrease the urinary excretion of prostacyclin metabolites consistent with inhibition of the systemic and renal activity of the COX-2 system. During repeated dosage with the specific COX-2 inhibitors, the 24 hour urinary excretion of sodium is only inhibited for the first day of treatment while the excretion of sodium is still decreased over the first 3 hours after the individual doses. Therapeutic doses of the COX-2 inhibitors and overdoses of acetaminophen have been associated with the development of occasional cases of acute renal failure. Acetaminophen also may decrease the excretion of sodium and the reason for its greater renal safety at therapeutic doses is unclear. Myocardial infarction has also been attributed to the specific COX-2 inhibitors from meta-analysis of large scale clinical trials and examination of reports of adverse drug reactions although this is still a topic of considerable discussion. No such associations have been made with acetaminophen, possibly because it is a weak inhibitor of COX-1 in platelets.

Background: Intravenous propacetamol is commonly used to control fever and pain in neurocritically ill patients in whom oral administration is often difficult. However, several studies reported that intravenous propacetamol may cause blood pressure drop. Thus, we aimed to investigate the occurrence and risk factors for intravenous propacetamol-induced blood pressure drop in neurocritically ill patients., Methods: This retrospective study included consecutive patients who were administered intravenous propacetamol in a neurointensive care unit at a single tertiary academic hospital between April 2013 and June 2020. The exact timing of intravenous propacetamol administration was collected from a database of the electronic barcode medication administration system. Blood pressure drop was defined as a systolic blood pressure below 90 mm Hg or a decrease by 30 mm Hg or more. Blood pressure, pulse rate, and body temperature were collected at baseline and within 2 h after intravenous propacetamol administration. The incidence of blood pressure drop was evaluated, and multivariable logistic regression analysis was performed to identify risk factors for blood pressure drop events., Results: A total of 16,586 instances of intravenous propacetamol administration in 4916 patients were eligible for this study. Intravenous propacetamol resulted in a significant decrease in systolic blood pressure (baseline 131.1 ± 17.8 mm Hg; within 1 h 124.6 ± 17.3 mm Hg; between 1 and 2 h 123.4 ± 17.4 mm Hg; P < 0.01). The incidence of blood pressure drop events was 13.5% within 2 h after intravenous propacetamol. Older age, lower or higher baseline systolic blood pressure, fever, higher Acute Physiology and Chronic Health Evaluation II score, and concomitant administration of vasopressors/inotropes or analgesics/sedatives were significant factors associated with the occurrence of blood pressure drop events after intravenous propacetamol administration., Conclusions: Intravenous propacetamol can induce hemodynamic changes and blood pressure drop events in neurocritically ill patients. This study identified the risk factors for blood pressure drop events. On the basis of our results, judicious use of intravenous propacetamol is warranted for neurocritically ill patients with risk factors that make them more susceptible to hemodynamic changes., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

In recent years, studies have explored the effects of paracetamol (acetaminophen) ingestion on exercise performance. However, due to the contrasting findings, there is still no consensus on this topic. This article provides an overview of the effects of paracetamol on endurance, sprinting, and resistance exercise performance. Studies have reported that paracetamol ingestion may be ergogenic for endurance performance. These effects occur when paracetamol is ingested 45-60 min before exercise and appear to be more pronounced in time-to-exhaustion versus time-trial tests. Besides endurance, paracetamol ingestion 30 min before exercise increases mean power during repeated cycling sprints in interval training involving repeated 30-s all-out bouts. Preliminary data on paracetamol ingestion also suggest: (a) improved endurance performance in the heat; (b) an improvement in single sprint performance, at least when paracetamol is ingested following exercise-induced fatigue; and (c) attenuation of the decline in muscular strength that occurs with repeated maximum contractions. An ergogenic effect of paracetamol is most commonly observed when a dose of 1500 mg is ingested 30-60 min before exercise. Despite these performance-enhancing effects, the aim of this article is not to promote paracetamol use, as side effects associated with its consumption and ethical aspects need to be considered before utilizing paracetamol as an ergogenic aid. Future research on this topic is still needed, particularly related to paracetamol dosing, timing of ingestion, and the effects of paracetamol in females and elite athletes., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: To conduct an umbrella review collating the existing evidence to determine whether there is an association between exposure of Paracetamol in-utero or in infancy and the development of childhood Asthma., Methods: In this review, systematic reviews with or without meta-analysis that reported the association between paracetamol and asthma in children were included. To identify relevant reviews, a search was performed in the electronic databases PubMed, the Cochrane Library, and Ovid MEDLINE. The protocol was registered in PROSPERO CRD42020156023. A separate search was conducted for primary studies from the last 5 years not yet included in systematic reviews reporting the association from January 2016 to March 2021., Results: The electronic searches identified 1966 review titles. After the removal of 493 duplicates, 1475 titles and abstracts were screened against the eligibility criteria. Full-text screening yielded six systematic reviews to be included in this review. The search for primary studies in the last 5 years yielded 1214 hits, out of which 5 studies were found suitable for inclusion. Three of them, that were not included in the systematic reviews, and have been summarised in this paper. The odds ratios (ORs) for the outcome of asthma in offspring of mothers with prenatal paracetamol consumption in any trimester were 1.28 (1.13-1.39) and 1.21 (1.02-1.44). For first trimester exposures, they were 1.12 (0.99-1.27), 1.39 (1.01-1.91), and 1.21 (1.14-1.28), for the second or third trimester, they were 1.49 (1.37-1.63) and 1.13 (1.04-1.23). For the third trimester only, the figure was 1.17 (1.04-1.31). Of the six reviews included, 1 had a low risk of bias, 2 had an unclear risk while 3 had a high risk of bias assessed using the ROBIS tool. There was no significant increased risk of asthma with early infancy exposure. The inter-study heterogeneity varied from I 2  = 41% to I 2  = 76% across reviews. In the primary studies, the OR for prenatal exposure ranged from 1.12 (0.25-4.98) to 4.66 (1.92-11.3) and for infancy exposure was 1.56 (1.06-2.30). All three included primary studies were adjudged to be of high quality using the Newcastle Ottawa scale., Conclusions: There is a modest association between paracetamol exposure in-utero and the future development of asthma. Exposure in infancy has a less consistant association. All the studies done thus far are observational in nature, with their inherent biases. Further research, preferably randomized controlled trials are recommended to answer this pertinent question., (© 2021 Wiley Periodicals LLC.)

Objectives: Acetaminophen (paracetamol) and alcohol are widely consumed as analgesic/antipyretic and recreational agent, respectively. High doses of both agents induce liver and male reproductive toxicities. This study investigated the toxicological outcome of concurrent administration of paracetamol and ethanol in the liver and testis in mice., Methods: Animals were gavaged paracetamol (250 mg/kg), ethanol (3 g/kg) or paracetamol + ethanol for 2 d. Some groups were sacrificed 12 h after the last dose, while others were sacrificed 21 d posttreatment for reversibility study. Control group received carboxymethylcellulose sodium (0.2%). Serum levels of liver biochemical indices and epididymal sperm were analysed. Histopathological analysis of the liver and testis were also performed., Results: Alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin in serum were elevated (p<0.001); whereas albumin and total protein were reduced (p<0.001) in paracetamol or ethanol groups compared to control. In the combination group, only mild elevation of ALT (p<0.05) was observed. Additionally, hepatocyte necrosis occurred in the livers of paracetamol and ethanol groups, while only mild inflammatory changes were seen in the combination group. All liver indices were normal in reversibility study animals. Furthermore, sperm count, motility, viability and morphology did not change in all treated animals, except that sperm count was decreased (p<0.05) in paracetamol group. Testis histology of all animal groups were normal., Conclusions: The results demonstrated that simultaneous treatment with acute paracetamol and ethanol doses will possibly minimize hepatotoxicity and reduction of epididymal sperm reserve by the individual agents, and the toxicities are reversible., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

For several years, the scientific community has been concerned about the presence of pharmaceuticals in the wild, since these compounds may have unpredictable deleterious effects on living organisms. Two examples of widely used pharmaceuticals that are present in the environment are paracetamol and ciprofloxacin. Despite their common presence in the aquatic environment due to their poor removal by sewage treatment plants, knowledge concerning their putative toxic effects is still scarce. This work aimed to characterize the effects of paracetamol (0.005, 0.025, 0.125, 0.625, and 3.125 mg/L) and ciprofloxacin (0.005, 0.013, 0.031, 0.078, 0.195, and 0.488 μg/L) in zebrafish embryos and larvae, exposed to environmentally relevant levels, close to the real concentrations of these pharmaceuticals in surface waters and effluents. The adopted toxic end points were developmental, a behavioral parameter (total swimming time), and a biomarker-based approach (quantification of the activities of catalase, glutathione-S-transferase, cholinesterases, glutathione peroxidase, and lipid peroxidation levels) combined with epigenetic analysis (immunohistochemical detection of 5-methylcytidine). Exposure to paracetamol had effects on all of the adopted toxic end points; however, ciprofloxacin only caused effects on behavioral tests and alterations in biomarkers. It is possible to ascertain the occurrence of oxidative stress following exposure to both drugs, which was more evident regarding paracetamol, an effect that may be related to the observed epigenetic modifications., (© 2019 Wiley Periodicals, Inc.)

Joint inflammation is present in a subpopulation of knee osteoarthritis (OA) patients. Proinflammatory cytokines are known to sensitize the peripheral and central pain pathways. This can be mechanistically assessed by pressure pain thresholds and temporal summation of pain (TSP). Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with paracetamol are recommended as OA treatment. The current study hypothesized that evidence of central sensitization would predict poor responses to peripherally directed therapies in knee OA and therefore aimed to investigate the value of mechanistic pain profiling for predicting pain outcome of treatment with NSAIDs plus paracetamol. One hundred thirty-two patients received ibuprofen 1200 mg/daily, paracetamol 3 g/daily, and pantoprazole 20 mg/daily for 3 weeks. Before administration, cuff pain detection, tolerance threshold, and TSP were assessed. Worst pain within the last 24 hours and pain during activity (visual analogue scales) were assessed before and after treatment. Facilitated TSP was found at baseline in the nonresponders to the 3-weeks treatment as compared to responders for both the 30% and 50% pain alleviation criteria (P < 0.02). Linear regression models identified facilitated TSP (P < 0.01) and low clinical pain scores (P < 0.001) as independent factors for prediction of poor pain alleviation by the treatment. In conclusion, this study found that mechanistic pain profiling can predict pain alleviation of NSAIDs and paracetamol. Facilitated TSP and low clinical pain scores before treatment are independent predictors of poor pain alleviation after NSAIDs and paracetamol. This study adds to the growing evidence that a subgroup of knee OA patients with manifested central sensitization may require special management attention.

Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.

Because the mechanism underlying the analgesic action of acetaminophen remains unclear, we investigated the possible interaction of acetaminophen with central serotonergic pathways. The effects of acetaminophen, tropisetron, the combination of both drugs, and saline on pain perception and central sensitization in healthy volunteers were compared. Sixteen healthy volunteers were included in this randomized, double-blind, placebo-controlled crossover study. Intracutaneous electrical stimulation (46.1 ± 19.1 mA) induced acute pain (numeric rating scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia and allodynia were regularly assessed before, during, and after a 15-min infusion of acetaminophen, tropisetron, the combination of both drugs, and saline. Acetaminophen concentrations were measured to rule out any pharmacokinetic interaction. Both acetaminophen and tropisetron led to decreased pain ratings as compared to saline. However, when acetaminophen and tropisetron were administered simultaneously, the pain ratings were not affected. There was no significant difference in the evolution of the hyperalgesic and allodynic areas during the study period between the study groups (P = .06 and P = .33, respectively). Acetaminophen serum levels were not significantly different when associated with tropisetron (P = .063), although we observed a trend toward lower acetaminophen concentrations when both drugs were concurrently administered. In summary, while the combination of acetaminophen and tropisetron showed no analgesic action, each drug administered alone led to decreased pain ratings as compared to saline. In an electrically evoked human pain model, the combination of acetaminophen with tropisetron was free of any analgesic potential. However, when administered on its own, both acetaminophen and tropisetron were mildly analgesic., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

Copyright of Agri: Journal of the Turkish Society of Algology / Türk Algoloji (Ağrı) Derneği'nin Yayın Organıdır is the property of KARE Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The pharmacokinetic profile of paracetamol in koalas is described when administered orally at 15 mg/kg; followed by the same dose, administered every 12 hours (hrs), repeated five times. After the initial oral administration, the median (range) maximal plasma concentration (Cmax), the time Cmax was reached (Tmax) and elimination half-life (t1/2) were 16.93 μg/mL (13.66 to 20.25 μg/mL); 4 hrs (4 to 8 hrs) and 5.54 hrs (4.66 to 7.67 hrs), respectively. When paracetamol was administered orally at 15 mg/mL every 12 hrs, the trough total plasma concentration range remained comparable to the therapeutic range in humans i.e. 4 to 20 μg/mL that is known to provide some analgesia. However, there is a smaller proportion of free drug (i.e. not bound to plasma proteins; and the active form) available in koala plasma (approximately 40% unbound) compared to human plasma (approximately 80% unbound). Consequently, even when there are similar total drug plasma concentrations in both koala and human plasma, the therapeutic efficacy may be reduced in koalas compared to humans. The initial oral dose and subsequent twice daily doses resulted in no obvious adverse effects in any koala. Haematology, plasma electrolyte and biochemical analyte values remained within their reference ranges eight hrs after the last dose but there was a significant change in alanine transaminase (ALT) levels (an increase), and in total protein (a decrease) (both p = 0.03). A dose of 15 mg/kg was also administered as a subcutaneous injection, diluted 50:50 with saline, to two koalas. As the oral formulation and the subcutaneous administration resulted in comparable absorption, the study focused on the oral profile. Based on these results there is an argument to recommend a slight increase in the oral paracetamol dose for the koala, however further investigation is required to confirm whether repeated administration of a slightly higher dose may be associated with more severe or additional significant changes in haematology, electrolytes or biochemical analytes. However, a preferable recommendation would be to administer this dosage of paracetamol in combination with another analgesic such as tramadol, as a subcutaneous injection, to improve efficacy. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) is a widely used drug known for its analgesic and antipyretic properties. However, its exact mechanism of action is still unclear and has been primarily associated with its effects on COX enzymes and serotonergic pathways. Till date, the immunological mechanisms affected by APAP has gained only inadequate attention. A distinct group of immune cells called Group 2 Innate Lymphoid Cells (ILC2s) are known to play an important role in type 2 cytokine-mediated immunity and their regulatory dysfunction is associated with numerous type 2 pathologies, such as allergy. Conversely, another class of recently characterized Innate Lymphoid Cells called Innate Regulatory Cells (ILCregs) suppress the activation of ILC2s. Maintaining a balance between ILC2s and ILCregs is vital for achieving a well-controlled immune response and tissue homeostasis. Recent studies have highlighted the critical role of prostaglandin D2 (PGD2) in the maturation and development of ILC2 functions. Since APAP also suppresses PGD2 synthesis, it was speculated that APAP treatment could reduce the number of ILC2s while potentially increasing the number of ILCregs. To investigate this hypothesis, here, we administered therapeutic doses of APAP to OVA-sensitized mice, a well-established model of type 2 pathological inflammation. The mice received oral doses of 200 mg/kg body wt. of APAP twice weekly, along with weekly OVA sensitizations for six weeks. The mice were sacrificed at different time points (days 14, 28 and 42) to assess the kinetics of ILC2s, ILCregs and immunoglobulins (IgE and IgG1). The results demonstrated that APAP treatment effectively suppressed OVA-induced ILC2s while significantly increasing the number of IL-10+ ILCregs. APAP exposure also led to decreased levels of serum PGD2, OVA-specific IgE and IgG1, and enhanced the level of IL-10 in OVA sensitized mice. Moreover, OVA sensitized mice treated with APAP did not develop pathological changes in spleen, when compared to OVA sensitized mice. Additionally, APAP treatment did not cause any adverse effects on mice liver in treatment groups. These preliminary findings suggest that APAP exhibits the capacity to modulate type 2 immune responses by suppressing ILC2s and inducing the expansion of IL-10+ ILCregs. [ABSTRACT FROM AUTHOR]

Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV1, a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain for healthy adults, children, and patients with health concerns. However, safety concerns remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis. Centrally acting paracetamol/p-aminophenol derivatives could potentiate the analgesic effect of paracetamol without increasing the risk of hepatoxicity. Moreover, the specific central MoA of paracetamol allows its combination with other analgesics, including NSAIDs, with a different MoA. Future experiments to better explain the central actions of paracetamol could pave the way for discovering new central analgesics with a better benefit-to-risk ratio. [ABSTRACT FROM AUTHOR]

Background: Needle pain due to routine vaccination is an important factor contributing to low vaccine adherence and immunization coverage. Prophylactic oral analgesics can address this important issue of needle pain related to vaccination. Paracetamol and mefenamic acid are commonly used nonsteroidal anti-inflammatory drugs for pain relief, but there is little published literature on whether the same can be used for needle pain related to vaccination. Objectives: This study was planned to compare the efficacy of oral mefenamic acid and paracetamol over placebo as a prophylactic analgesic during vaccination and prophylactic antipyretic during the post-vaccination period. Designs: Three-arm, triple-blind, randomized controlled trial. Methods: This study was conducted at the outpatient department of a tertiary-level medical college in South India from January 2021 to June 2022. In this three-arm interventional trial, each arm had either a single dose of placebo or mefenamic acid (4 mg/kg/dose) or paracetamol (10 mg/kg/dose). These medicines were administered orally 30 min before vaccination to reduce needle pain. Main outcome and measures: Outcome was measured with the change of FLACC (Face, Leg, Activity, Cry, Consolability) scoring at the time of vaccination, subsequently at 15 and 30 min of vaccination in all three groups. Appearance of fever, grade of fever, and need for antipyretics 24 h after vaccination were also noted. Results: There was a significant difference in FLACC scores at the time of administration (p = 0.010) and at 15 min (p = 0.014) with mefenamic acid compared to placebo. Although the paracetamol group showed a difference when compared to the placebo, it was not significant at the time of administration (p = 0.401), at 15 min (p = 0.451), or 30 min (p = 0.892) post-vaccination. The appearance of fever, grade of fever, and use of antipyretic up to 24 h post-vaccination had no significant difference among any of the three groups. Conclusion: Mefenamic acid was more potent than placebo for pre-vaccination pain prophylaxis in children. There was no difference in the appearance of fever and its grade among the three groups. The promising results from this trial warrant further large-scale studies to recommend a single oral dose of mefenamic acid to tackle needle pain related to vaccination in children to improve vaccine adherence and coverage. Trial registration: CTRI (Clinical trials registry-India) (CTRI/2021/01/030239). [Date of Commencement: 13 Jan 2021, Date of last recruitment: 30 June 2022 (now closed for new participants)] [ABSTRACT FROM AUTHOR]

The kinetic study of ruthenium(III) chloride catalyzed oxidation of paracetamol by N‐chloro‐p‐toluene sulfonamide (chloramine‐T) in the alkaline medium has been performed. The reaction exhibits second order nature and the effect of the catalyst indicates the occurrence of uncatalyzed reaction simultaneously. Rate is decelerated by hydroxide ions. A plausible reaction mechanism has been suggested and the rate law is derived to account for such experiential observations. The activation parameters have been calculated. No evidence of the participation of free radicals is observed. [ABSTRACT FROM AUTHOR]

Background: Malaria remains a major public health challenge in Africa where annually, ~250,000 children with malaria experience a neurologic injury with subsequent neuro-disability. Evidence indicates that a higher temperature during the acute illness is a risk factor for post-infectious neurologic sequelae. As such, aggressive antipyretic therapy may be warranted among children with complicated malaria at substantial risk of brain injury. Previous clinical trials conducted primarily in children with uncomplicated malaria and using only a single antipyretic medication have shown limited benefits in terms of fever reduction; however, no studies to date have examined malaria fever management using dual therapies. In this clinical trial of aggressive antipyretic therapy, children hospitalized with central nervous system (CNS) malaria will be randomized to usual care (acetaminophen every 6 hours for a temperature ≥ 38.5°C) vs. prophylactic acetaminophen and ibuprofen every 6 hours for 72 hours. Methods: In this double-blinded, placebo controlled, two-armed clinical trial, we will enroll 284 participants from three settings at Queen Elizabeth Central Hospital in Blantyre, Malawi; at the University Teaching Hospitals Children's Hospital in Lusaka, Zambia and at Chipata Central Hospital, Chipata, Zambia. Parents or guardians must provide written informed consent. Eligible participants are 2–11 years with evidence of P. falciparum malaria infection by peripheral blood smear or rapid diagnostic test with CNS symptoms associated with malaria. Eligible children will receive treatment allocation randomization either to standard of care for fever management or to prophylactic, scheduled treatment every 6 hours for 72 hours with dual antipyretic therapies using acetaminophen and ibuprofen. Assignment to treatment groups will be with 1:1 allocation using blocked randomization. The primary outcome will be maximum temperature in the 72 hours after enrolment. Secondary outcomes include parasite clearance as determined by quantitative Histidine Rich Protein II and seizures through 72 hours after enrolment. Discussion: This clinical trial seeks to challenge the practice paradigm of limited fever treatment based upon hyperpyrexia by evaluating the fever-reduction efficacy of more aggressive antipyretic using two antipyretics and prophylactic administration and will elucidate the impact of antipyretics on parasite clearance and acute symptomatic seizures. If aggressive antipyretic therapy is shown to safely reduce the maximum temperature, a clinical trial evaluating the neuroprotective effects of temperature reduction in CNS malaria is warranted. [ABSTRACT FROM AUTHOR]

Introduction: The use of paracetamol for pain relief in pregnancy is common. However, the influence of paracetamol on the perinatal adaptation of high‐risk infants has not been studied. These data are important for safety, since another inhibitor of prostaglandin synthesis is harmful to infants born very preterm and increases serious morbidity. We studied whether the use of paracetamol had an adverse influence on neonatal adaptation and the outcomes of infants during the first hospitalization. Material and Methods: We studied the patient records of high‐risk mothers and their infants born before 32 weeks of gestation for multiple variables over a period of 84 months in Oulu University Hospital, a regional tertiary care hospital caring for high‐risk deliveries and providing neonatal intensive care. In a matched cohort setting, the exposition was defined as paracetamol use <24 h before childbirth. The controls had consumed no paracetamol up to 1 week before delivery. Infants with major anomalies were excluded. The primary outcome was defined as the need for early interventional treatments for the preterm infants. Outcomes during the first hospitalization were also studied. Results: Altogether, 170 fetuses from 149 mothers were exposed to paracetamol during the study period. The control population, delivering during the same period, consisted of 118 non‐exposed fetuses from 104 mothers. Among them, the mothers were pairwise matched according to their medications, amniotic fluid leakage time, clinical infections, and delivery mode. After matching, 72 mothers/group remained, resulting in 88 paracetamol‐exposed infants and 85 controls. No perinatal adverse reactions were detected. There were no differences in either circulatory support during the first postnatal day or in the risk for major diseases during the first hospitalization. Paracetamol‐exposed infants needed fewer acute delivery room therapies (51.1% vs 65.9%, mean difference −14.89; 95% confidence interval −0.29 to −0.003). Maternal total paracetamol dose in the 1 week before delivery correlated positively with Apgar scores. Conclusions: Antenatal paracetamol given within 24 h before birth had no adverse effects on extremely or very preterm infants. The long‐term safety of paracetamol and the potential acute benefits for preterm infants during perinatal transition remain to be proven in larger, prospective settings. [ABSTRACT FROM AUTHOR]

Background: Several supplementary approaches have been used to increase the patient's comfort during phacoemulsification under topical anesthesia. Objective: This study aimed to compare the effects of lidocaine/paracetamol (LP) and midazolam/fentanyl (MF) administration on pain intensity and hemodynamic changes in patients undergoing cataract surgery using phacoemulsification. Methods: This study was designed and implemented as a pilot randomized double-blinded clinical trial. A total number of 80 patients with cataracts scheduled for phacoemulsification were randomly assigned to two groups (40 subjects in each group) to receive lidocaine at a dose of 1.5 mg/kg and then infused with 1 g of paracetamol in 100 cc of normal saline (LP group) or midazolam 0.2 mg/kg and fentanyl 1.5 µg/kg (MF group). Hemodynamic parameters and sedation scores were measured before, 5, and 15 minutes after surgery, and then during recovery. Furthermore, pain (VAS), patient-surgeon satisfaction, propofol, and opioid consumption were all assessed. Findings: The sedation scores during recovery in the LP group were significantly lower (P= 0.04) than those in the MF group. Respiratory depression was also significantly lower (P<0.001) in the LP group compared to that infused by MF. According to other findings, no significant difference was observed between both study groups. Conclusion: The use of lidocaine-paracetamol as a supplementary approach for patients undergoing cataract surgery under topical anesthesia can cause better sedation scores with lower respiratory depression compared to the use of midazolam-fentanyl. [ABSTRACT FROM AUTHOR]

Purpose: Exercise increases core body temperature (TC) due to metabolic heat production. However, the exercise-induced release of inflammatory cytokines including interleukin-6 (IL-6) may also contribute to the rise in TC by increasing the hypothalamic temperature set point. This study investigated whether the exercise-induced increase in TC is partly caused by an altered hypothalamic temperature set point. Methods: Fifteen healthy, active men age 36 ± 14 y were recruited. Subjects performed submaximal treadmill exercise in 3 randomized test conditions: (1) 400 mg ibuprofen and 1000 mg acetaminophen (IBU/APAP), (2) 1000 mg acetaminophen (APAP), and (3) a control condition (CTRL). Acetaminophen and ibuprofen were used to block the effect of IL-6 at a central and peripheral level, respectively. TC, skin temperature, and heart rate were measured continuously during the submaximal exercise tests. Results: Baseline values of TC, skin temperature, and heart rate did not differ across conditions. Serum IL-6 concentrations increased in all 3 conditions. A significantly lower peak TC was observed in IBU/APAP (38.8°C ± 0.4°C) vs CTRL (39.2°C ± 0.5°C, P = .02) but not in APAP (38.9°C ± 0.4°C) vs CTRL. Similarly, a lower ΔTC was observed in IBU/APAP (1.7°C ± 0.3°C) vs CTRL (2.0°C ± 0.5°C, P < .02) but not in APAP (1.7°C ± 0.5°C) vs CTRL. No differences were observed in skin temperature and heart-rate responses across conditions. Conclusions: The combined administration of acetaminophen and ibuprofen resulted in an attenuated increase in TC during exercise compared with a CTRL. This observation suggests that a prostaglandin-E2-induced elevated hypothalamic temperature set point may contribute to the exercise-induced rise in TC. [ABSTRACT FROM AUTHOR]

Objective: Acetaminophen (APAP) is widely used as an analgesic for postoperative pain relief. However, the pharmacokinetic-pharmacodynamic (PK-PD) properties of intravenous APAP administration remain unclear. We developed a PK-PD model in adult volunteers.Methods: APAP (1 g) was intravenously administered to 15 healthy volunteers. The pain equivalent current (PEC) was then measured using the pulse current, corresponding to the quantitative value of pain perception. The PK model was developed using a 2-compartment model, and the PD model was developed using a linear model and an effect compartment model.Results: APAP plasma concentration peaked just administration, whereas PEC significantly increased at 90 minutes and lasted through the experimental period (300 minutes). APAP plasma concentrations and PEC were processed for use in the PK-PD model. The developed PK-PD model delineates the analgesic effect profile, which peaked at 188 minutes and lasted until 327 minutes.Conclusion: We developed the PK/PD model for APAP administered intravenously. The analgesic effect can be expected ∼90 minutes after administration and to last >5 hours. It is suggested that APAP be administered ∼90 minutes prior to the onset of anticipated postoperative pain. [ABSTRACT FROM AUTHOR]

Although widely believed by pediatricians and parents to be safe for use in infants and children when used as directed, increasing evidence indicates that early life exposure to paracetamol (acetaminophen) may cause long-term neurodevelopmental problems. Furthermore, recent studies in animal models demonstrate that cognitive development is exquisitely sensitive to paracetamol exposure during early development. In this study, evidence for the claim that paracetamol is safe was evaluated using a systematic literature search. Publications on PubMed between 1974 and 2017 that contained the keywords "infant" and either "paracetamol" or "acetaminophen" were considered. Of those initial 3096 papers, 218 were identified that made claims that paracetamol was safe for use with infants or children. From these 218, a total of 103 papers were identified as sources of authority for the safety claim. Conclusion: A total of 52 papers contained actual experiments designed to test safety, and had a median follow-up time of 48 h. None monitored neurodevelopment. Furthermore, no trial considered total exposure to drug since birth, eliminating the possibility that the effects of drug exposure on long-term neurodevelopment could be accurately assessed. On the other hand, abundant and sufficient evidence was found to conclude that paracetamol does not induce acute liver damage in babies or children when used as directed. What is Known: • Paracetamol (acetaminophen) is widely thought by pediatricians and parents to be safe when used as directed in the pediatric population, and is the most widely used drug in that population, with more than 90% of children exposed to the drug in some reports. • Paracetamol is known to cause liver damage in adults under conditions of oxidative stress or when used in excess, but increasing evidence from studies in humans and in laboratory animals indicates that the target organ for paracetamol toxicity during early development is the brain, not the liver. What is New: • This study finds hundreds of published reports in the medical literature asserting that paracetamol is safe when used as directed, providing a foundation for the widespread belief that the drug is safe. • This study shows that paracetamol was proven to be safe by approximately 50 short-term studies demonstrating the drug's safety for the pediatric liver, but the drug was never shown to be safe for neurodevelopment. Paracetamol is widely believed to be safe for infants and children when used as directed, despite mounting evidence in humans and in laboratory animals indicating that the drug is not safe for neurodevelopment. An exhaustive search of published work cited for safe use of paracetamol in the pediatric population revealed 52 experimental studies pointing toward safety, but the median follow-up time was only 48 h, and neurodevelopment was never assessed. [ABSTRACT FROM AUTHOR]

Background: Acetaminophen use for pharmacological treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants is becoming more popular with emerging evidence that it is effective as well as safe alternative for other agents used to close hsPDA. Data sources: We performed a narrative review of literature about pharmacological treatment of PDA using acetaminophen. Results: Acetaminophen was used as a prophylaxis, symptomatic, targeted, and a rescue approach. Conclusions: It appears that acetaminophen could be used in different approaches to close the hsPDA. Long-term outcomes of acetaminophen exposure early in life still lack certainty. [ABSTRACT FROM AUTHOR]

Organo-hydrogels were synthesized by using free radical polymerization in the emulsion technique, using agar, glycerol, sesame oil, ammonium persulfate as initiator and N,N'-methylene bisacrylamide or glutaraldehyde as crosslinker. Swelling behaviors, blood compatibility, antioxidant and properties of the organo-hydrogels were investigated thoroughly. The highest swelling value was seen in organo-hydrogel synthesized with the N,N'-methylene bisacrylamide crosslinker containing 0.1 ml of sesame oil. Moreover, drug release behaviors of organo-hydrogels were studied as paracetamol and carboplatin used as model drugs. Release studies were shown that some basic parameters such as medium pH and composition of the polymer structure affect organo-hydrogels drug release behavior. As a result of drug release experiments, it was observed that the release values of organo-hydrogels changed depending on sesame oil and crosslinker content. The highest paracetamol release capacities for the p (AG-m-SO)² and p (AG-g-SO)² organohydrogels were calculated as 45.3 % and 79.8 %. When investigated carboplatin releases, the highest releases also were founded to be 100 % for p (AG-m-SO)² and 85 % for p (AG-g-SO)². [ABSTRACT FROM AUTHOR]

Aims: Toxicity in paracetamol overdose with opioid co‐ingestion is poorly understood. We compared outcomes in both paracetamol‐only and paracetamol–opioid overdoses to determine whether toxicity differed significantly between the groups, and to assess the utility of the ratio of measured plasma paracetamol concentration relative to the 4‐hour nomogram‐adjusted level (APAPpl/APAPt). Methods: We conducted a retrospective observational study of all patients (n = 1159) presenting to 2 large UK hospitals between 2005 and 2013 with acute single‐dose ingestion paracetamol overdose, with (n = 221) or without (n = 938) opioid co‐ingestion. Adverse outcomes included biomarkers of hepatotoxicity and the need for extended treatment. Several outcomes were assessed in relation to the APAPpl/APAPt ratio. Results: Median ingested dose of paracetamol was low in both groups (10 g). Statistical comparison of the median APAPpl/APAPt ratios showed a significant difference (0.65 vs. 0.56 for the paracetamol‐only and paracetamol–opioid groups respectively, P =.0329). Although there was a trend towards a lower risk of predefined toxic outcomes with opioid co‐ingestion, statistical analysis did not show a significant difference, with outcomes for the paracetamol‐only and paracetamol–opioid groups including the following: alanine transaminase >2× upper limit of normal, 7.7 vs. 5.7% (P =.6480); alanine transaminase >1000 IU/L, 2.4 vs. 0% (P =.2145); international normalised ratio > 1.3, 8.6 vs. 4.4% (P =.2774); and transfer to tertiary liver unit, 0.2 vs. 0% (P nonsignificant). Conclusion: Our study does not support a change in current clinical practise beyond standard testing at 4 hours or longer post ingestion for mixed low dose paracetamol–opioid overdose. [ABSTRACT FROM AUTHOR]

Objective: Although acetaminophen is one of the most widely used over-the-counter drugs, the mechanisms by which this classical drug exerts analgesic, hepatotoxic, and nephrotoxic effects remain unclear. We hypothesized that acetaminophen might act on cellular membranes of nerves, liver, and kidneys. In order to verify this hypothesis, we studied the interactivity of acetaminophen with biomimetic lipid bilayer membranes by comparing with structurally related phenacetin.Methods: Liposomal membranes (unilamellar vesicles suspended in the buffer of pH 7.4) were prepared with phospholipids and cholesterol to mimic the membrane lipid composition of neuronal cells, hepatocytes, and nephrocytes. They were subjected to reactions with acetaminophen and phenacetin at clinically relevant concentrations, followed by measuring fluorescence polarization to determine their membrane interactivity to modify membrane fluidity.Results: Acetaminophen and phenacetin interacted with neuro-mimetic and hepato-mimetic membranes to increase membrane fluidity at 10-100 μM. Both drugs were more effective in fluidizing hepato-mimetic membranes than neuro-mimetic membranes. Although the relative membrane-interacting potency was phenacetin >> acetaminophen in neuro-mimetic and hepato-mimetic membranes, such membrane effects conflicted with their relative analgesic and hepatotoxic effects. Acetaminophen and phenacetin strongly interacted with nephro-mimetic membranes to increase membrane fluidity at 2-100 μM and 0.1-100 μM, respectively. Phenacetin interacted significantly with nephro-mimetic membranes at lower concentrations (<2 μM) than acetaminophen, which was consistent with their relative nephrotoxic effects.Conclusion: In comparison with phenacetin, lipid composition-dependent membrane interactivity of acetaminophen could be related to nephrotoxicity but not to analgesic activity and hepatotoxicity. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a new simple and cost-effective spectrophotometric method to be used as an alternative to chromatography for the analysis of paracetamol and methocarbamol (PAR-MET) combination. In this regard, a comparative study on the quantitative resolution of PAR and MET mixture using continuous wavelet transform (CWT) and ultra-performance liquid chromatography (UPLC) techniques was performed. In interpretation of the spectrophotometric data, three different wavelet families Biorthogonal3.5 (Bior3.5), Mexican Hat Function (Mexh), and Symlets5 (Sym5) were found suitable to get better transform of zero-order spectra of the samples containing PAR and MET. The concentrations of PAR and MET in the working range of 4.0 – 20.0 μg/mL and 5.0 – 45.0 μg/mL, respectively, were proportional to the wavelet amplitudes. This mathematical relationship was used to construct calibration curves for each compound. After validation of the CWT method, analyses of commercial tablets were successfully performed. A new UPLC method was developed and validated in order to compare the results with those obtained by the CWT method and the data were found comparable. The analysis of results obtained from experimental trials showed that the proposed CWTmethod is suitable for the quality control and quantitative assessment of both active substances in tablet formulations. [ABSTRACT FROM AUTHOR]

When a new coronavirus appeared in the late 2019, identified as the cause of several cases of pneumonia in Wuhan, Paracetamol was initially reported to be the preferable antipyretic medication, choice which was detrimental to the use of other drugs. People have resorted to buying large stocks of Paracetamol and some have used it in large doses, regardless of the consequences. However, the Paracetamol (Acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. This review aims at presenting the pharmacokinetics, the clinical signs, and the risk factors for systemic toxicity associated with Paracetamol overdose, as well as the current therapeutic approach. Paracetamol is primarily metabolized in the liver, by glucuronidation and sulfation. In case of a Paracetamol overdose, a large amount of NAPQI is conjugated with glutathione, and this process is due to a major depletion of glutathione, thus leading to hepatic necrosis, renal failure, and encephalopathy. The evaluation of serum acetaminophen levels by analytical methods is extremely useful both for the diagnosis and the therapy monitoring. [ABSTRACT FROM AUTHOR]

Objectives: Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation. Methods: Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates. Key findings: Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 µM. The index constant 'a' was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6. Conclusions: Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures. [ABSTRACT FROM AUTHOR]

The composite of zeolitic imidazolate frameworks (ZIF-67) and ordered macroporous carbon (OMC) was successfully synthesized via in situ growth from the OMC matrix. The ZIF67–OMC composite was verified by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and electrochemical impedance spectroscopy (EIS) and then evaluated as a modified material for electrochemical sensor. Benefitting from the large surface area and enhanced conductivity of the ZIF67–OMC composite, ZIF67–OMC nanocomposite showed superior electrocatalytic performance toward acetaminophen (AP) oxidation. The redox reaction of AP underwent a quasi-reversible redox reaction with higher anodic current at ZIF67–OMC modified electrode compared with the bare glassy carbon electrode (GCE). In optimal condition, the ZIF67–OMC/GCE was stable, reproducible and had a linear range of 0.05–100 μmol·L−1 AP concentration, with the detection limit of 20 nmol·L−1 (signal-to-noise of S/N = 3). In addition, the prepared sensing platform for the detection of AP was evaluated for the compound paracetamol tablets and urine samples. [ABSTRACT FROM AUTHOR]

Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that in vitro screens demonstrate low potency on the inhibition of COX-1 and COX-2. In vivo data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol. List of Abbreviations: AM404, N-(4-hydroxyphenyl)-arachidonamide; CB1R, Cannabinoid receptor-1; Cmax, Maximum concentration; CNS, Central nervous system; COX, Cyclooxygenase; CSF, Cerebrospinal fluid; ED50, 50% of maximal effective dose; FAAH, Fatty acid amidohydrolase; IC50, 50% of the maximal inhibitor concentration; LPS, Lipopolysaccharide; NSAIDs, Non-steroidal anti-inflammatory drugs; PGE2, Prostaglandin E2; TRPV1, Transient receptor potential vanilloid-1 [ABSTRACT FROM AUTHOR]