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The development of nitric oxide-donating antiphlogistics is intended to improve the tolerability of the parent compounds. The aim of the present study was to explore the potency and tolerability of nitric oxide-donating acetaminophen (NCX 701) in healthy volunteers and to test the hypothesis that NCX 701 could have additional anti-inflammatory efficacy in an experimental model of low-grade human endotoxemia. In this prospective, double-blind, placebo-controlled trial with parallel group design 40 healthy male volunteers were randomized to single oral treatment with NCX 701 (1–2 g), acetaminophen (1 g paracetamol) or placebo before lipopolysaccharide (2ng/kg) infusion. NCX 701 dose-dependently increased plasma and urine nitric oxide concentrations. Pooled analysis of both NCX 701 doses showed a significant, but obviously clinically irrelevant lowering effect on systolic and diastolic blood pressure during the first 5 h. Overall, peak levels of tumor necrosis factor-alpha correlated well with interleukin-6, interleukin-8, monocyte chemoattractant protein-1 and von Willebrand Factor release across all cohorts. There was no major difference between NCX 701 and acetaminophen with respect to their effect on the lipopolysaccharide-induced secretion of inflammation and endothelium activation markers. Overall, a total of 61 adverse events were reported in all treatment arms, mainly related to lipopolysaccharide. Both acetaminophen and NCX 701 effectively reduced the proportion of subjects experiencing headache. Despite substantial nitric oxide release by NCX 701, which reduced arterial blood pressure, nitric oxide did not result in relevant inhibition of lipopolysaccharide-induced inflammation. ISRCTN registry number: ISTCTN-13,358,268.

Introduction Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. Methods Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106–193.1 kg] and body mass index [BMI] of 45.1 kg/m 2 [40–55.2 kg/m 2 ]) and eight non-obese patients (with a TBW of 69.4 kg [53.4–91.7] and BMI of 21.8 kg/m 2 [19.4–27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. Results In morbidly obese patients, the median area under the plasma concentration–time curve from 0 to 8 h (AUC 0–8h ) of acetaminophen was significantly smaller ( P  = 0.009), while the AUC 0–8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher ( P  = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P  < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW ( P  < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW ( P  < 0.001). Conclusion Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.

Background Persistent patency of the ductus arteriosus (PDA) has challenged neonatologists for more than 40 years. Controversies persist about the management of PDA in extremely preterm infants. PDA is associated with morbidities, but no therapeutic strategy has resulted in an improved neonatal outcome. Acetaminophen appears to be a promising alternative with possibly fewer adverse effects. The primary objective is to determine whether a prophylactic pharmacological intervention with acetaminophen may increase the survival without severe morbidity at postmenstrual age of 36 weeks. Methods and analysis TREOCAPA phase III is a randomized, multicenter, double-blind, stratified, placebo-controlled superiority trial, two arms in a 1:1 ratio performed in 43 NICUs of 14 European countries, evaluating whether the intervention increases the survival without severe morbidity by 10%, from 50% in control arm to 60% in treatment arm, until the age of 36 postmenstrual weeks. To detect this difference, 794 patients were required using a group sequential design. Recruitment has been closed, with 803 patients enrolled. Patients eligible for inclusion are preterm infants with a gestational age between 23 and 28 weeks. In the acetaminophen group, 20 mg/kg loading dose within 12 h after birth, followed by 7.5 mg/kg quarter in die (QID) for 5 days, will be administered to the 27–28 weeks gestational age group, and 25 mg/kg loading dose then 10 mg/kg QID will be administered to the 23–26 weeks gestational age group. The severe morbidities include severe bronchopulmonary dysplasia (BPD grade 3) according to NIH consensus, necrotizing enterocolitis (NEC) of Bell’s stage II or III, intraventricular hemorrhage (IVH) grade III–IV according to Papile classification, or cystic leukomalacia. Discussion Whatever the results, the conclusions of this study should be informative for the neonatal scientific community. The results will either confirm the benefit of treatment in increasing survival without severe morbidity, or indicate a worsening of outcomes with prophylactic acetaminophen treatment, or show no difference in the primary outcome. In the latter case, ultrasonographic assessments of ductus arteriosus status on day 7 may help explain the absence of a difference. This could indicate that acetaminophen is ineffective in promoting ductal closure or that early closure of the ductus arteriosus is inconsequential if, despite more frequent closures, there is no associated improvement in outcomes. Ethics and dissemination Ethical approval of the trial has been performed in each of the 14 countries after approval, at the European level, by the Voluntary Harmonization Procedure committee on 04/07/2020. Results will be disseminated through articles in peer-reviewed journals. Trial registration European Clinical Trials Database: EudraCT Number: 2019–004297-26. ClinicalTrials.gov: NCT04459117, registered on July 7, 2020.

This randomized, controlled trial shows that acetaminophen reduces kidney dysfunction and risk of developing acute kidney injury, particularly in severe malaria patients who present with high plasma hemoglobin, supporting the hypothesis that acetaminophen inhibits cell-free hemoglobin-mediated renal tubular oxidative damage. Abstract Background Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria. Methods This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin. Results Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to −71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity. Conclusions In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis. Clinical Trials Registration NCT01641289.

In this prospective study, we compared the efficacy and side effects of indomethacin, ibuprofen, and paracetamol in patent ductus arteriosus (PDA) closure in preterm neonates. Three hundred preterm neonates with hemodynamically significant PDA (hs-PDA) admitted at our neonatal intensive care unit were enrolled in the study. They were randomized into three groups. Group I (paracetamol group) received 15 mg/kg/6 h IV paracetamol infusion for 3 days. Group II (ibuprofen group) received 10 mg/kg IV ibuprofen infusion followed by 5 mg/kg/day for 2 days. Group III (indomethacin group) received 0.2 mg/kg/12 h indomethacin IV infusion for three doses. Laboratory investigations such as renal function test, liver function test, complete blood count, and blood gases were conducted in addition to echocardiographic examinations. All investigations were done before and 3 days after treatment. There was no significant difference between all groups regarding efficacy of PDA closure ( P  = 0.868). There was a significant increase in serum creatinine levels and serum blood urea nitrogen (BUN) in the ibuprofen and indomethacin groups ( P  < 0.001). There was a significant reduction in platelet count and urine output (UOP) in both ibuprofen and indomethacin groups ( P  < 0.001). There was a significant increase in bilirubin levels in only the ibuprofen group ( P  = 0.003). No significant difference of hemoglobin (HB) level or liver enzymes in all groups ( P  > 0.05). Ventilatory settings improved significantly in patients with successful closure of PDA than those with failed PDA closure ( P  < 0.001). Conclusion : Paracetamol is as effective as indomethacin and ibuprofen in closure of PDA in preterm neonates and has less side effects mainly on renal function, platelet count, and GIT bleeding. What is Known: • Hemodynamically significant patent ductus arteriosus has many complications for preterm and low birth weight neonates and better to be closed. Many drugs were used for medical closure of PDA e.g. indomethacin, ibuprofen and recently paracetamol. Many studies compare safety and efficacy of paracetamol with either indomethacin or ibuprofen. What is New: • It is the first large study that compares the efficacy and side effects of the three drugs in one study.

ABSTRACT Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.

Acetaminophen (APAP) has hepatotoxic potential when overdosed. Recent studies have reported serum alanine aminotransferase (ALT) elevations that resolve spontaneously with continued use of the drug, referred to as adaptation, in several individuals receiving therapeutic doses of APAP. However, the clinical significance of these ALT elevations remains unclear. This study was performed to investigate the incidence and characteristics of hepatic adaptation to therapeutic doses of APAP in healthy individuals. In a randomized, single-blind, placebo-controlled study, 242 healthy Japanese individuals were enrolled. Each person received 3 g/d of APAP (n = 202) or placebo (n = 40) for 28 days. All study participants underwent analysis of genetic polymorphisms of CYP2E1 and UGT1A1; measurements of plasma APAP concentration and urine metabolites (glucuronide, sulfate, cysteine, and mercapturate); liver function monitoring, including ALT, microRNA-122, and high-mobility group box 1. Individuals with ALT levels remaining below the upper limit of normal (ULN; 40 U/L) during the study period were defined as tolerant and those with ALT elevations above the ULN as susceptible. Susceptible individuals who developed ALT elevations exceeding 2 × ULN discontinued use of the study drug for tolerability consideration. Susceptible individuals who had ALT elevations that decreased toward the ULN spontaneously with continued use of the study drug were classified as adaptation. In the APAP group, 129 individuals (66%) were classified as tolerant and 65 (34%) as susceptible. Among 65 susceptible individuals, 12 (18%) discontinued use of APAP because of ALT elevations (>2 × ULN), whereas 53 (82%) completed 28-day APAP dosing. Thirty of 65 susceptible individuals (46%) had adaptation within 28 days. In the placebo group, no individuals was withdrawn from the study because of elevated ALT levels, 33 individuals (89%) were classified as tolerant, and 4 (11%) were classified as susceptible. None had clinical signs of liver injury. ALT level correlated significantly with microRNA-122 but not with high-mobility group box 1. No association was found between plasma APAP concentrations and ALT levels. Urinary excretion of APAP mercapturate was higher in susceptible than in tolerant individuals (P = 0.018, Wilcoxon or Kruskal-Wallis test). The frequency of homozygotes and compound heterozygotes for UGT1A1∗28 and UGT1A1∗6 (∗28/∗28, ∗6/∗6, and ∗6/∗28) was higher in susceptible than in tolerant individuals (13.9% vs 3.9%; P = 0.011, χ2 test). These findings indicate that in healthy individuals, APAP at a therapeutic dose can cause transient and self-limiting ALT elevation, reflecting subclinical hepatocellular damage, and these ALT elevations may be associated with the disposition of APAP metabolites and genetic factors. UMIN-CTR identifier: UMIN000019607.

Following publication, concerns were raised regarding the peer-review process related to the publication of this article [...].Following publication, concerns were raised regarding the peer-review process related to the publication of this article [...].

PurposeEffect size estimates of analgesic drugs can be misleading. Ibuprofen (400 mg, 600 mg, 800 mg), paracetamol (1000 mg, 500 mg), paracetamol 1000 mg/codeine 60 mg, and placebo were investigated to establish the multidimensional pharmacodynamic profiles of each drug on acute pain with calculated effect size estimates.MethodsA randomized, double-blind, single-dose, placebo-controlled, parallel-group, single-centre, outpatient, and single-dose study used 350 patients (mean age 25 year, range 18 to 30 years) of homogenous ethnicity after third molar surgery. Primary outcome was sum pain intensity over 6 h. Secondary outcomes were time to analgesic onset, duration of analgesia, time to rescue drug intake, number of patients taking rescue drug, sum pain intensity difference, maximum pain intensity difference, time to maximum pain intensity difference, number needed to treat values, adverse effects, overall drug assessment as patient-reported outcome measure (PROM), and the effect size estimates NNT and NNTp.ResultsIbuprofen doses above 400 mg do not significantly increase analgesic effect. Paracetamol has a very flat analgesic dose–response profile. Paracetamol 1000/codeine 60 mg gives similar analgesia as ibuprofen from 400 mg, but has a shorter time to analgesic onset. Active drugs show no significant difference in maximal analgesic effect. Other secondary outcomes support these findings. The frequencies of adverse effects were low, mild to moderate in all active groups. NNT and NTTp values did not coincide well with PROMs.ConclusionIbuprofen doses above 400 mg for acute pain offer limited analgesic gain. Paracetamol 1000 mg/codeine 60 mg is comparable to ibuprofen doses from 400 mg. Calculated effect size estimates and PROM in our study seem not to relate well as clinical analgesic efficacy estimators.Trial registrationNCT00699114.