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Early acetaminophen-protein adducts predict hepatotoxicity following overdose (ATOM-5).
Chiew, AL, James, LP, Isbister, GK, Pickering, JW, McArdle, K, Chan, BSH, Buckley, NA
Journal of hepatology. 2020;(3):450-462
Abstract
BACKGROUND & AIMS Acetaminophen-protein adducts are specific biomarkers of toxic acetaminophen (paracetamol) metabolite exposure. In patients with hepatotoxicity (alanine aminotransferase [ALT] >1,000 U/L), an adduct concentration ≥1.0 nmol/ml is sensitive and specific for identifying cases secondary to acetaminophen. Our aim was to characterise acetaminophen-protein adduct concentrations in patients following acetaminophen overdose and determine if they predict toxicity. METHODS We performed a multicentre prospective observational study, recruiting patients 14 years of age or older with acetaminophen overdose regardless of intent or formulation. Three serum samples were obtained within the first 24 h of presentation and analysed for acetaminophen-protein adducts. Acetaminophen-protein adduct concentrations were compared to ALT and other indicators of toxicity. RESULTS Of the 240 patients who participated, 204 (85%) presented following acute ingestions, with a median ingested dose of 20 g (IQR 10-40), and 228 (95%) were treated with intravenous acetylcysteine at a median time of 6 h (IQR 3.5-10.5) post-ingestion. Thirty-six (15%) patients developed hepatotoxicity, of whom 22 had an ALT ≤1,000 U/L at the time of initial acetaminophen-protein adduct measurement. Those who developed hepatotoxicity had a higher initial acetaminophen-protein adduct concentration compared to those who did not, 1.63 nmol/ml (IQR 0.76-2.02, n = 22) vs. 0.26 nmol/ml (IQR 0.15-0.41; n = 204; p <0.0001), respectively. The AUROC for hepatotoxicity was 0.98 (95% CI 0.96-1.00; n = 226; p <0.0001) with acetaminophen-protein adduct concentration and 0.89 (95% CI 0.82-0.96; n = 219; p <0.0001) with ALT. An acetaminophen-protein adduct concentration of 0.58 nmol/ml was 100% sensitive and 91% specific for identifying patients with an initial ALT ≤1,000 U/L who would develop hepatotoxicity. Adding acetaminophen-protein adduct concentrations to risk prediction models improved prediction of hepatotoxicity to a level similar to that obtained by more complex models. CONCLUSION Acetaminophen-protein adduct concentration on presentation predicted which patients with acetaminophen overdose subsequently developed hepatotoxicity, regardless of time of ingestion. An adduct threshold of 0.58 nmol/L was required for optimal prediction. LAY SUMMARY Acetaminophen poisoning is one of the most common causes of liver injury. This study examined a new biomarker of acetaminophen toxicity, which measures the amount of toxic metabolite exposure called acetaminophen-protein adduct. We found that those who developed liver injury had a higher initial level of acetaminophen-protein adducts than those who did not. CLINICAL TRIAL REGISTRATION Australian Toxicology Monitoring (ATOM) Study-Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
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An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.
Gelotte, CK
Regulatory toxicology and pharmacology : RTP. 2018;:333-338
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Abstract
Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.
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Effects of acetaminophen and ibuprofen in children with migraine receiving preventive treatment with magnesium.
Gallelli, L, Avenoso, T, Falcone, D, Palleria, C, Peltrone, F, Esposito, M, De Sarro, G, Carotenuto, M, Guidetti, V
Headache. 2014;(2):313-24
Abstract
AIM: The purpose of this study was to evaluate both the effects of ibuprofen and/or acetaminophen for the acute treatment of primary migraine in children in or out prophylactic treatment with magnesium. METHODS Children ranging from the ages of 5 to 16 years with at least 4 attack/month of primary migraine were eligible for participation the study. A visual analog scale was used to evaluate pain intensity at the moment of admission to the study (start of the study) and every month up to 18 months later (end of the study). RESULTS One hundred sixty children of both sexes aged 5-16 years were enrolled and assigned in 4 groups to receive a treatment with acetaminophen or ibuprofen without or with magnesium. Migraine pain endurance and monthly frequency were similar in the 4 groups. Both acetaminophen and ibuprofen induced a significant decrease in pain intensity (P < .01), without a time-dependent correlation, but did not modify its frequency. Magnesium pretreatment induced a significant decrease in pain intensity (P < .01) without a time-dependent correlation in both acetaminophen- and ibuprofen-treated children and also significantly reduced (P < .01) the pain relief timing during acetaminophen but not during ibuprofen treatment (P < .01). In both acetaminophen and ibuprofen groups, magnesium pretreatment significantly reduced the pain frequency (P < .01). CONCLUSIONS Magnesium increased the efficacy of ibuprofen and acetaminophen with not age-related effects.
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Dose-finding studies of ketoprofen in the management of fever in children: report on two randomized, single-blind, comparator-controlled, single-dose, multicentre, phase II studies.
Kokki, H, Kokki, M
Clinical drug investigation. 2010;(4):251-8
Abstract
BACKGROUND Ketoprofen is a highly effective NSAID with antipyretic and analgesic properties for the symptomatic management of pain and fever in both adults and children. OBJECTIVE To compare three dose levels of ketoprofen with paracetamol (acetaminophen) in the management of fever in children. METHODS Two prospective, randomized, single-blind, comparator-controlled, single-dose, multicentre, phase II studies with four parallel groups in each study were conducted in primary-care outpatient clinics. Children aged 6-24 months and 2-6 years presenting with a febrile condition (rectal body temperature > or =39 degrees C) were included in the studies. Patients were treated with either ketoprofen syrup 0.25 mg/kg, 0.5 mg/kg or 1 mg/kg, or paracetamol drinkable solution 15 mg/kg, both administered orally. The primary outcome measure was the maximal reduction in body temperature before re-medication compared with baseline during the 6-hour study period. RESULTS In the ketoprofen groups, the mean maximal temperature decreases in the younger/older age groups were 1.6/1.6 degrees C, 2.0/1.9 degrees C and 1.9/2.2 degrees C with doses of 0.25 mg/kg, 0.5 mg/kg and 1 mg/kg of ketoprofen, respectively, compared with 1.8/1.8 degrees C with paracetamol 15 mg/kg. In the older children, ketoprofen provided antipyretic efficacy in a dose-dependent manner. CONCLUSION Ketoprofen was found to have a significant antipyretic efficacy in children. The lowest dose of ketoprofen syrup that provided a meaningful antipyretic effect in both groups was 0.5 mg/kg. At this dose the antipyretic efficacy was equal to that of paracetamol 15 mg/kg. Based on these data, a dose of 0.5 mg/kg of ketoprofen was selected for future evaluation in phase III studies in the symptomatic management of fever in children.
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A randomized, double-blind, parallel-group study comparing the analgesic effect of etoricoxib to placebo, naproxen sodium, and acetaminophen with codeine using the dental impaction pain model.
Malmstrom, K, Kotey, P, Coughlin, H, Desjardins, PJ
The Clinical journal of pain. 2004;(3):147-55
Abstract
OBJECTIVE To compare the overall analgesic effect, including time to onset, peak and duration of effect for etoricoxib 120 mg, a new COX-2 selective inhibitor, in patients with acute pain to that of placebo. Naproxen sodium 550 mg and acetaminophen/codeine 600/60 mg were the active comparators. METHODS A total of 201 patients with moderate to severe pain following surgical extraction of > or = 2 third molars, of which at least the mandibular tooth was impacted, were randomly allocated to receive single oral doses of placebo (n = 50), etoricoxib 120 mg (n = 50), naproxen sodium 550 mg (n = 51), or acetaminophen/codeine 600/60 mg (n = 50). The endpoints included total pain relief over 8 hours (TOPAR8, primary end point), sum of pain intensity difference over 8 hours, patient's global evaluation, onset, peak, and duration of analgesia. RESULTS Etoricoxib 120 mg had a significantly greater least squares (LS) mean TOPAR8 score than placebo (20.9 vs 5.4; P < 0.001) and acetaminophen/codeine 600/60 mg (20.9 vs 11.5; P < 0.001), and a similar LS mean TOPAR8 score to naproxen sodium 550 mg (20.9 vs 21.3). All three active treatments had rapid onset of analgesia, median time approximately 30 minutes. The duration of analgesic effect, defined as median time to rescue medication use, was >24 hours for etoricoxib, 20.8 hours for naproxen sodium, 3.6 hours for acetaminophen/codeine, and 1.6 hours for placebo. DISCUSSION Etoricoxib is a new COX-2 selective inhibitor under development for treatment of osteoarthritis, rheumatoid arthritis, and acute pain. In this study, etoricoxib 120 mg provided rapid and long-lasting pain relief to patients with moderate-to-severe postdental surgery pain. Etoricoxib was generally well tolerated.
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Ibuprofen vs. acetaminophen vs. ibuprofen and acetaminophen after arthroscopically assisted anterior cruciate ligament reconstruction.
Dahl, V, Dybvik, T, Steen, T, Aune, AK, Rosenlund, EK, Raeder, JC
European journal of anaesthesiology. 2004;(6):471-5
Abstract
BACKGROUND AND OBJECTIVE The analgesic potency of non-steroidal anti-inflammatory drugs and acetaminophen are still being debated. We have assessed the relative analgesic effect of ibuprofen, acetaminophen or the combination of both after orthopaedic surgery. METHODS Sixty-one ASA I patients, scheduled for an elective anterior cruciate ligament reconstruction under general anaesthesia were randomized, in a double blind fashion, into one of three groups. The ibuprofen group (n = 17) received ibuprofen 800 mg orally 1 h before operation and again at 6 and 12 h after the initial dose. The acetaminophen group (n = 20) received of acetaminophen 1 g orally at the same time intervals. The combination group (n = 24) received both ibuprofen 800 mg and acetaminophen 1 g. Surgery was performed under general anaesthesia with propofol and fentanyl for induction and maintenance with propofol and nitrous oxide in oxygen. The patients were monitored for 24 h thereafter, and the following variables were assessed: pain by visual analogue and verbal scales, need for rescue intravenous opioid analgesia (i.e. ketobemidone) and adverse events. RESULTS The ibuprofen group and the combination group experienced significantly less pain during the first 6 h after surgery than the acetaminophen group using the visual analogue and the verbal scales. The acetaminophen group also had a significantly higher average consumption of opioids during the first 6 and 24 h. There were no significant differences between the ibuprofen group and the combination group in respect of experienced pain or consumption of rescue analgesia. The incidence of side-effects, postoperative haemoglobin concentration and renal function, judged by creatinine clearance, were identical between the groups. CONCLUSION Ibuprofen 800 mg thrice daily reduced pain to a greater degree than acetaminophen 1 g thrice daily, after anterior cruciate ligament reconstruction under general anaesthesia. The combination of acetaminophen and ibuprofen did not provide any superior analgesic effect.
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Analgesic efficacy and safety of nonprescription doses of naproxen sodium compared with acetaminophen in the treatment of osteoarthritis of the knee.
Golden, HE, Moskowitz, RW, Minic, M
American journal of therapeutics. 2004;(2):85-94
Abstract
Nonprescription doses of naproxen sodium, acetaminophen, and placebo were compared to determine their efficacy and safety in osteoarthritis of the knee. In two identical multicenter, randomized, double-blind, placebo-controlled, multidose, parallel-design studies, patients with osteoarthritis aged (mean +/- SD) 60.6 +/- 12.8 years were randomized to daily doses of 660 mg naproxen sodium (440 mg naproxen sodium in patients >or=65 years), 4000 mg acetaminophen, or placebo for 7 days. Naproxen sodium (440/660 mg) provided significantly greater improvements in pain at rest, on passive motion, on weight-bearing, stiffness after rest (morning), day and night pain compared with placebo, and significantly greater relief from resting pain than acetaminophen (P < 0.05). Acetaminophen provided significantly greater improvements in day pain compared with placebo. Daily evaluations showed naproxen sodium (440/660 mg) provided superior pain relief to acetaminophen and was significantly better than acetaminophen at reducing difficulties experienced in walking several blocks and difficulties in bending, lifting, and stooping. Naproxen sodium (440/660 mg) and acetaminophen (4000 mg) were significantly more effective than placebo in improving mobility level, household tasks, and walking and bending. Patient and investigator evaluation scores were significantly higher in naproxen sodium and acetaminophen groups compared with placebo; no differences were observed between active treatments. Naproxen sodium and acetaminophen had similar safety profiles to placebo. Nonprescription doses of naproxen sodium (440/660 mg) effectively relieve pain and other symptoms of osteoarthritis. Naproxen sodium is an alternative in the initial treatment of osteoarthritis and may be preferred to acetaminophen as first-line therapy in patients with moderate or severe pain.
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A double-blind randomised controlled clinical trial of the effect of preoperative ibuprofen, diclofenac, paracetamol with codeine and placebo tablets for relief of postoperative pain after removal of impacted third molars.
Joshi, A, Parara, E, Macfarlane, TV
The British journal of oral & maxillofacial surgery. 2004;(4):299-306
Abstract
We conducted a randomised double-blind placebo-controlled single-centre study to compare the effect of preoperative ibuprofen 600 mg, diclofenac 100 mg, paracetamol 1 g with codeine 60 mg or placebo (Vitamin C 50 mg) tablets for relief of postoperative pain in 119 patients who had day case operations under general anaesthesia for removal of impacted third molars. Patients were given the tablets 1 h before operation. Pain was assessed using visual analogue scales and verbal rating scales preoperatively at 15 and 30 min and 1 and 3 h postoperatively. After they had gone home, patients were contacted by telephone at 6 and 24 h postoperatively to find out whether they had any adverse effects from the analgesics. There was no significant difference in the extent of postoperative pain among the four groups, but the placebo group had significantly shorter times before their first request for postoperative analgesics (median 17 min, range 14-90) than the diclofenac group (median 32, range 15-150). Preoperative analgesics at the stated doses are effective in providing immediate postoperative pain control after operations on third molars. There were, however, some side-effects including nausea, vomiting, headaches, and gastrointestinal discomfort, but there were no significant differences among the active analgesic groups with respect to adverse events either shortly after operation or at 6 or 24 h.
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Phase I trial of high dose paracetamol and carmustine in patients with metastatic melanoma.
Wolchok, JD, Williams, L, Pinto, JT, Fleisher, M, Krown, SE, Hwu, WJ, Livingston, PO, Chang, C, Chapman, PB
Melanoma research. 2003;(2):189-96
Abstract
Reduced glutathione (GSH) production by tumour cells has been proposed as a mechanism for resistance to alkylating agents. High levels of paracetamol can deplete intracellular GSH. We conducted a phase I trial of high dose paracetamol and carmustine (BCNU) in patients with advanced malignant melanoma to determine the optimal biological dose and the maximum tolerated dose (MTD) with the goal of increasing sensitivity to BCNU by GSH depletion. Groups of three to five patients received escalating doses of paracetamol (10, 15 or 20 g/m(2)) every 3 weeks. Every other cycle, BCNU (10 mg/m(2)) was given 6.5 h after administration of paracetamol and 45 min before a 20 h infusion of N-acetylcysteine. Once the MTD for paracetamol had been determined, the dose of BCNU was sequentially escalated in subsequent cohorts to 150 mg/m(2). GSH levels were measured in peripheral blood mononuclear cells (PBMCs) and, when available, in tumour biopsies. The MTD of paracetamol was 15 g/m(2). The dose of BCNU was safely escalated to 150 mg/m(2). The most common toxicity was grade II nausea/vomiting. At 15 g/m(2), peak paracetamol levels (median 253 microg/ml) were reached between 1 and 4 h. No changes in GSH levels in PBMCs were seen. There were two partial responses, including a dramatic decrease in hepatic metastases. Treatment of melanoma patients with paracetamol (15 g/m(2)) every 3 weeks and BCNU (150 mg/m(2)) every 6 weeks is safe. The observation of two partial responses has led to a phase II study to evaluate treatment with high dose paracetamol alone or in combination with BCNU.
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Lack of efficacy of acetaminophen in treating symptomatic knee osteoarthritis: a randomized, double-blind, placebo-controlled comparison trial with diclofenac sodium.
Case, JP, Baliunas, AJ, Block, JA
Archives of internal medicine. 2003;(2):169-78
Abstract
BACKGROUND Recommendations state that acetaminophen should be used in preference to nonsteroidal anti-inflammatory drugs in the initial treatment of symptomatic osteoarthritis (OA) of the hip or knee, because of lesser toxicity and the pervasive belief that acetaminophen is not only effective in treating OA pain but is of equal analgesic efficacy as nonsteroidal anti-inflammatory drugs. METHODS This was a randomized, double-blind, placebo-controlled trial of diclofenac sodium, 75 mg twice daily, vs acetaminophen, 1000 mg 4 times daily, in 82 subjects with symptomatic OA of the medial knee. Osteoarthritis was quantitated radiographically, and subjects met stringent baseline pain criteria. The primary evaluation of efficacy used the Western Ontario and McMaster Universities Osteoarthritis Index, with evaluations at screening, baseline, and 2 and 12 weeks after treatment. Intention-to-treat analysis was used. RESULTS Twenty-five subjects were randomized to diclofenac, 29 to acetaminophen, and 28 to placebo. The groups were closely matched for age, sex, body mass index, prior use of OA medications, baseline pain, and radiographic features. At 2 and 12 weeks, clinically and statistically significant (P<.001) improvements were seen in the diclofenac-treated group; however, no significant improvements were seen in the acetaminophen-treated group (P =.92 at 2 weeks and.19 at 12 weeks). Stratification of subjects according to baseline pain, prestudy OA medication, and radiographic grade showed no clear pattern of preferential response to diclofenac, and did not reveal a subset of subjects who responded to acetaminophen. CONCLUSIONS Diclofenac is effective in the symptomatic treatment of OA of the knee, but acetaminophen is not. A review of the literature reveals that there is scanty published evidence for a therapeutic effect of acetaminophen relative to placebo in patients with OA of the knee, because most published studies use active comparators (ie, nonsteroidal anti-inflammatory drugs) only. The advocacy of acetaminophen use in subjects with OA of the knee should be reconsidered pending further placebo-controlled studies.