Comparison of Oral Loading Dose to Intravenous Acetaminophen in Children for Analgesia After Tonsillectomy and Adenoidectomy: A Randomized Clinical Trial.

BACKGROUND: Acetaminophen is a frequently used adjunct analgesic in pediatric patients undergoing tonsillectomy and adenoidectomy. We compared opioid administration following preoperative intravenous (IV) or oral acetaminophen in addition to a standard multimodal regimen to test the hypothesis that 1 loading dose approach would provide superior opioid sparing effects among pediatric surgical patients undergoing tonsillectomy and adenoidectomy. METHODS: This single-center, double-blind, double-dummy prospective randomized study was conducted in patients ages 3 to 15 years undergoing tonsillectomy and adenoidectomy with or without myringotomy and tube placement between September 2017 and July 2019. Subjects received 1 dose of either oral acetaminophen 30 mg/kg with IV placebo (oral group) or IV acetaminophen 15 mg/kg with oral placebo (IV group). Acetaminophen plasma levels were measured at 2 timepoints to evaluate safety and determine plasma levels attained by each dosing regimen. Intraoperative opioid administration and postoperative analgesia were standardized. Standardized postoperative multimodal analgesia included opioid if needed to control pain assessed by standardized validated pediatric pain scales. The primary outcome measure was total opioid administration in the first 24 hours after surgery. Continuous data were not normally distributed and were analyzed using the Wilcoxon rank sum test and the Hodges-Lehman estimator of the median difference. Clinical significance was defined as a 100 µg/kg IV morphine equivalents per day difference. RESULTS: Sixty-six subjects were randomized into and completed the study (29 women, 37 men; age 5.9 ± 3.0 years; percentile weight for age 49.5 ± 30.2; no differences between groups). There was no opioid dose difference between oral (median 147.6; interquartile range [IQR], 119.6-193.0 µg/kg) and IV groups (median 125.4; IQR, 102.8-150.9 µg/kg; median difference 21.3; 95% confidence interval [CI] -2.5 to 44.2 µg/kg IV morphine equivalents; P = .13). No acetaminophen levels exceeded the predefined safety threshold (40 mg/L). No difference was found in the percentage of patients with severe pain: 50.0% oral group, 47.2% IV group; relative risk of severe pain in IV 0.94; 95% CI, 0.57-1.6; P = .82. Postoperative plasma acetaminophen levels were higher in oral (22; IQR, 16-28 mg/L) than IV (20; IQR, 17-22 mg/L) group (median difference 7.0; 4.0-8.0 mg/L; P = .0001). CONCLUSIONS: Opioid-sparing effects did not differ following an oral or standard IV acetaminophen loading dose with no identified acetaminophen toxicity in pediatric patients undergoing tonsillectomy and adenoidectomy who received standardized multimodal postoperative analgesia. An oral loading dose may provide more consistent serum acetaminophen levels at lower cost compared to a standard IV dose.

Application of the DILIsym® Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen.

In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g. baseline glutathione (GSH) levels, pharmacokinetics, and capacity of hepatic antioxidants) leads to potential differences in carcinogenic hazard potential at different dosing schemes: maximum labeled doses of 4 g/day, repeated doses above the maximum labeled dose (>4-12 g/day), and acute overdoses of acetaminophen (>15 g). This was achieved by performing simulations of acetaminophen exposure in thousands of diverse virtual patients scenarios using the DILIsym® Quantitative Systems Toxicology (QST) model. Simulations included assessments of the dose and exposure response for toxicity and mode of cell death based on evaluations of the kinetics of changes of: GSH, N-acetyl-p-benzoquinone-imine (NAPQI), protein adducts, mitochondrial dysfunction, and hepatic cell death. Results support that, at therapeutic doses, cellular GSH binds to NAPQI providing sufficient buffering capacity to limit protein adduct formation and subsequent oxidative stress. Simulations evaluating repeated high-level supratherapeutic exposures or acute overdoses indicate that cell death precedes DNA damage that could result in carcinogenicity and thus acetaminophen does not present a carcinogenicity hazard to humans at any dose.

A critical review of the acetaminophen preclinical carcinogenicity and tumor promotion data and their implications for its carcinogenic hazard potential.

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

Hepatic Adaptation to Therapeutic Doses of Acetaminophen: An Exploratory Study in Healthy Individuals.

PURPOSE: 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. METHODS: 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. FINDINGS: 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). IMPLICATIONS: 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.

Emulsion Droplet Crystallinity Attenuates Short-Term Satiety in Healthy Adult Males: A Randomized, Double-Blinded, Crossover, Acute Meal Study.

BACKGROUND: The influence of triacylglycerol (TAG) physical properties on satiety remains poorly understood. OBJECTIVES: The objective was to investigate if and how TAG digestion and absorption, modulated only by differences in TAG crystallinity, would differentially affect short-term satiety in healthy men. METHODS: We tempered 500 mL 10% palm stearin oil-in-water emulsions such that the lipid droplets were either undercooled liquid (LE) or partially crystalline solid (SE). Fifteen healthy men (mean ± SD age: 27.5 ± 5.7 y; BMI: 24.1 ± 2.5 kg/m2; fasting TAG: 0.9 ± 0.3 mmol/L) consumed each beverage at two 6-h study visits separated by ≥6 d after an overnight fast, along with 1500 mg acetaminophen suspended in water. The participants characterized the emulsion sensory properties, completed satiety visual analog scale ratings, and had serial blood samples collected for 6-h analysis of plasma peptide YY (PYY), glucagon-like peptide-1 (GLP-1), ghrelin, leptin, glucose-dependent insulinotropic polypeptide (GIP), insulin, and acetaminophen (for assessing gastric emptying). Repeated-measures ANOVAs and 2-tailed paired t tests were used to analyze the changes from baseline and incremental area under the curve (iAUC) values, respectively. RESULTS: With consumption of LE compared with SE, there was a 358% higher fullness (P = 0.015) and a 103% lower average appetite (P = 0.041) score, along with higher iAUC values for PYY (P = 0.011) and GLP-1 (P = 0.028) (103% and 66% higher, respectively), but not for ghrelin (P = 0.39), based on change from baseline values. Acetaminophen response trended toward significance (P = 0.08) and was 15% higher with LE. SE was rated as 44% thicker (P = 0.034) and 24% creamier (P = 0.05) than LE. CONCLUSIONS: The suppression of TAG digestion by the presence of partially crystalline lipid droplets blunted the appetite-suppressing effects of an oil-in-water emulsion.This trial was registered at clinicaltrials.gov as NCT03990246.

In vivo assessment of the drug interaction between sorafenib and paracetamol in rats.

PURPOSE: Sorafenib is a multi-targeted tyrosine kinase inhibitor (TKI) used for the treatment of advanced renal cell carcinoma, hepatocellular carcinoma and radioactive iodine resistant thyroid carcinoma. Neoplastic diseases are the cause of pain, which may occur regardless of the stage of the disease. Paracetamol is a non-opioid analgesic used alone or in combination with opioids for the treatment of cancer pain. Numerous studies have pointed out changes in the pharmacokinetic parameters of TKIs when co-administered with paracetamol. The aim of the study was to assess drug-drug interactions (DDIs) between sorafenib and paracetamol. METHODS: Rats were divided into three groups, each consisting of eight animals. The first group received sorafenib (IIS), the second group received sorafenib + paracetamol (IS+PA), whereas the third group received only paracetamol (IIIPA). A single dose of sorafenib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. The plasma concentrations of sorafenib and its metabolite-N-oxide as well as paracetamol and its glucuronide and sulphate metabolites were measured using validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. RESULTS: The co-administration of sorafenib and paracetamol increased the maximum concentration (Cmax) of paracetamol by 33% (p = 0.0372). In the IS+ PA group the Cmax of paracetamol glucuronide was reduced by 48% (p = < 0.0001), whereas the Cmax of paracetamol sulphate was higher by 153% (p = 0.0012) than in the IIIPA group. Paracetamol increased sorafenib and sorafenib N-oxide Cmax by 60% (p = 0.0068) and 83% (p = 0.0023), respectively. CONCLUSIONS: A greater knowledge of DDI between sorafenib and paracetamol may help adjust dose properly and avoid toxicity effects in individual patients.

Responses of gut and pancreatic hormones, bile acids, and fibroblast growth factor-21 differ to glucose, protein, and fat ingestion after gastric bypass surgery.

Postprandial gut hormone responses change after Roux-en-Y gastric bypass (RYGB), and we investigated the impact of glucose, protein, and fat (with and without pancreas lipase inhibition) on plasma responses of gut and pancreas hormones, bile acids, and fibroblast growth factor 21 (FGF-21) after RYGB and in nonoperated control subjects. In a randomized, crossover study 10 RYGB operated and 8 healthy weight-matched control subjects were administered 4 different 4-h isocaloric (200 kcal) liquid meal tests containing >90 energy (E)% of either glucose, protein (whey protein), or fat (butter with and without orlistat). The primary outcome was glucagon-like peptide-1 (GLP-1) secretion (area under the curve above baseline). Secondary outcomes included responses of peptide YY (PYY), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), glicentin, neurotensin, ghrelin, insulin, glucagon, bile acids, and FGF-21. In the RYGB group the responses of GLP-1, GIP, glicentin, FGF-21, and C-peptide were increased after glucose compared with the other meals. The neurotensin and bile acids responses were greater after fat, while the glucagon and CCK responses were greater after protein ingestion. Furthermore, compared with control subjects, RYGB subjects had greater responses of total PYY after glucose, glucagon after glucose and fat, glicentin after glucose and protein, and GLP-1 and neurotensin after all meals, while GIP and CCK responses were lower after fat. Ghrelin responses did not differ between meals or between groups. Orlistat reduced all hormone responses to fat ingestion, except for ghrelin in the RYGB group. In conclusion, after RYGB glucose is a more potent stimulator of most gut hormones, especially for the marked increased secretion of GLP-1 compared with fat and protein.NEW & NOTEWORTHY We investigated the impact of glucose, protein, and fat meals on intestinal and pancreatic hormones, bile acid, and fibroblast growth factor 21 (FGF-21) secretion in gastric bypass-operated patients compared with matched nonoperated individuals. The fat meal was administered with and without a pancreas lipase inhibitor. We found that the impact of the different meals on gut hormones, bile, and FGF 21 secretion differ and was different from the responses observed in nonoperated control subjects.

Intravenous versus subcutaneous route pharmacokinetics of paracetamol (acetaminophen) in palliative care patients: study protocol for a randomized trial (ParaSCIVPallia).

BACKGROUND: Among palliative care (PC) patients who are administered paracetamol, the subcutaneous (SC) route is often an alternative to the intravenous (IV) route. Yet pharmacological and clinical data on whether these are equivalent pharmacokinetically are lacking. Many French palliative teams are now empirically using paracetamol by the SC route, but there are no data to support this practice. This trial aims to compare the pharmacokinetic (PK) parameters of paracetomol between the IV and SC routes in PC patients. METHODS/DESIGN: This is a randomized, open, crossover study in two PC centers. The primary endpoints are AUC0-t, AUC0-∞, Cmax, Vd, and t1/2. All adverse events will be reported for a safety analysis. Twenty adult PC patients with an IV device having spontaneous pain not related to care, with a numeric pain rate scale > 3/10, or having a systematic prescription of paracetamol as the usual treatment will be included. All patients also have to meet all eligibility criteria. CONCLUSION: This is the first study comparing PK parameters for IV paracetamol versus SC paracetamol in PC patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944044. Registered on 4 June 2019. Committee for the protection of persons (CPP) 18.09.05.58206 approval 4 October 2018. National Drug Safety Agency (ANSM; Agence Nationale de Sécurité Médicament) MEDAECNAT-2018-09-00009 approval 29 November 2018.

Two-bag intravenous N-acetylcysteine, antihistamine pretreatment and high plasma paracetamol levels are associated with a lower incidence of anaphylactoid reactions to N-acetylcysteine.

Context:N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or discontinuations. In Denmark in 2013, the NAC treatment regimen was simplified from a three-bag to a two-bag NAC regimen. Factors of importance for the development of anaphylactoid reaction to this new regimen are poorly explored. Previous studies have suggested a protective effect of high plasma levels of paracetamol on the development of anaphylactoid reactions. Likewise, exposure to antihistamines prior to NAC treatment may protect against these reactions.Methods: This is a retrospective cohort study of patients treated with NAC and with at least one plasma paracetamol sample performed in the Capital Region of Denmark from 2010 to 2017. The primary outcome was the incidence of anaphylactoid reactions to NAC requiring intravenous treatment with antihistamines and/or glucocorticoids. Logistic regression analyses were carried out to identify the risk of developing an anaphylactoid reaction to NAC affected by influencing factors.Results: Of 4315 admissions included in the study, 259 (6.0%) developed an anaphylactoid reaction to NAC. The two-bag regimen (adjusted OR 0.44 [95%CI: 0.32-0.60]), increasing age (adjusted OR 0.84 [95%CI: 0.78-0.90] per 10-year increase) or children <10 years (adjusted OR 0.14 [95%CI: 0.04-0.36]) and antihistamine co-ingestion in overdose (adjusted OR 0.17 [95%CI: 0.02-0.64]) were associated with significantly fewer anaphylactoid reactions. High plasma paracetamol concentrations protected against development of anaphylactoid reactions during the two-bag regimen (adjusted OR 0.59 [95%CI: 0.47-0.71] and three-bag regimen 0.82 [95%CI: 0.72-0.94] per doubling of paracetamol concentration). The effect differed between the two regimens (p = .004 for interaction).Conclusion: In this retrospective cohort, a high peak plasma paracetamol concentration, age, antihistamine co-ingestion and use of the two-bag NAC regimen were associated with fewer anaphylactoid reactions to NAC.

Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women.

BACKGROUND AND OBJECTIVE: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy. METHODS: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated. RESULTS: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8-5.1] mg/L), while Css,avg was 6.7 [5.9-7.4], 5.6 [4.7-6.3], and 4.9 [4.1-5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1-13.4%]), followed by the second (9.0% [7.5-11.0%]) and third trimester (8.2% [6.8-10.1%]), compared with non-pregnant women (7.7% [6.4-9.4%]). CONCLUSION: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.

Effects of serum from breast cancer surgery patients receiving perioperative dexmedetomidine on breast cancer cell malignancy: A prospective randomized controlled trial.

Adrenergic receptors (ARs) have gained attention for their involvement in breast cancer (BC) progression. Dexmedetomidine, a selective α2 -AR agonist, has been reported to increase the malignancy of BC cells in vitro or stimulate tumor growth in mice. However, clinical evidence is lacking. Clinical research in this area is important as dexmedetomidine is widely used in BC surgery patients. Here we allocated 24 women with primary BC to the dexmedetomidine group (who received a total dose of 2 µg kg-1 dexmedetomidine perioperatively) or to the control group (who received the same volume of normal saline). Venous blood was obtained from all patients immediately upon entering the operating room and 24 hours postoperatively. Serum was then exposed to MCF-7 cells at a concentration of 10% for 24 hours. Cell proliferation, migration, and invasion were analyzed using EdU, Transwell, and Matrigel methods, respectively. We found that postoperative serum from those who received dexmedetomidine was associated with significantly increased cell proliferation, migration, and invasion compared with preoperative serum when used to culture MCF-7 cells. The mean percentage change from post to preoperative values in these cell functions was significantly larger in the dexmedetomidine group than in the control group (proliferation, 30.44% vs 8.45%, P = .0024; migration, 15.90% vs 3.25%, P = .0015; invasion, 8.17% vs 2.13%, P = .04). In conclusion, these findings suggest that in patients undergoing surgery for primary BC, perioperative administration of dexmedetomidine might influence the serum milieu in a way that favors the malignancy of MCF-7 cells. Clinical trial registration: NCT03108937.

A case of accidental neonatal paracetamol overdose with prolonged half-life and measured metabolites.

Introduction: Limited data exist regarding paracetamol metabolism after overdose in the neonate. We report a case of repeated supratherapeutic overdose in a neonate with paracetamol metabolite concentrations.Case report: A 10-day-old male neonate presented to hospital after repeated supratherapeutic dosing of paracetamol. Paracetamol concentration 19.5 h post-last dose was 381 µmol/L and 236 µmol/L, 9 h later. Initial alanine aminotransferase (ALT) was normal (18 IU/L) and total bilirubin was 262 µmol/L (N < 300). Acetylcysteine infusion was commenced and ceased 27 h later, when serum paracetamol was undetectable and alanine aminotransferase remained normal.Initial paracetamol elimination half-life was 14.5 h. Analysis of serum paracetamol metabolites showed paracetamol-glucuronide was the major metabolite on presentation (64%). After acetylcysteine was commenced, paracetamol concentration fell, serum bilirubin increased, and paracetamol-sulfate represented a larger proportion of total metabolites (72%). Notably, paracetamol cytochrome (CYP450), cysteine- and mercapturate-conjugates, represented 21% of total measured metabolites on presentation.Conclusion: Repeated supratherapeutic ingestion of paracetamol in the neonate was associated with prolonged elimination half-life. Of note, this was in the presence of unconjugated hyperbilirubinaemia. CYP450 metabolism of paracetamol did not appear to be reduced in this neonate when compared to paracetamol metabolite ratios in older age groups.

Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass.

Children undergoing cardiac surgery often receive acetaminophen (paracetamol) as part of their postoperative pain treatment. To date, there is no information on the pharmacokinetics (PK) of acetaminophen in this special population, even though differences, as a result of altered hemodynamics and/or use of cardiopulmonary bypass, may be anticipated. Therefore, the aim of this study was to investigate the PK of intravenous acetaminophen in children after cardiac surgery with cardiopulmonary bypass. In the study, both children with and without Down syndrome were included. A population PK analysis, using NONMEM 7.2, was performed based on 161 concentrations of acetaminophen, acetaminophen sulfate, acetaminophen glucuronide, and oxidative metabolites from 17 children with Down syndrome and 13 children without Down syndrome of a previously published study (median age, 177 days [range, 92-944], body weight, 6.1 kg [4.0-12.9]). All children received 3 intravenous acetaminophen doses of 7.5 mg/kg (<10 kg) or 15 mg/kg (≥10 kg) at 8-hour intervals after cardiac surgery. For acetaminophen and its metabolites, 1-compartment models were identified. Clearance of acetaminophen and metabolites increased linearly with body weight. Acetaminophen clearance in a typical child of 6.1 kg is 0.96 L/h and volume of distribution 7.96 L. Down syndrome did not statistically significantly impact any of the PK parameters for acetaminophen, nor did any other remaining covariate. When comparing the PK parameters of acetaminophen in children after cardiac surgery with cardiopulmonary bypass with those from children of the same age following noncardiac surgery reported in the literature, clearance of acetaminophen was lower and volume of distribution higher.

An improved ultra-high-performance liquid chromatography-tandem mass spectrometric method for the quantitation of dexmedetomidine in small volume of pediatric plasma.

Dexmedetomidine (Dex), a highly selective α2 -adrenergic agonist, is used primarily for the sedation and anxiolysis of adults and children in the intensive care setting. A sensitive and selective assay for Dex in pediatric plasma was developed by employing ultra-high-performance liquid chromatography-tandem mass spectrometry with d4-Dex as an internal standard. Dex was extracted from 0.1 mL of plasma by micro-elution solid-phase extraction. Separation was achieved with a Waters XBridge C18 column with a flow rate of 0.3 mL/min using a mobile phase comprising 5 mm ammonium acetate buffer with 0.03% formic acid in water and methanol-acetonitrile (50:50, v/v). The intra-day precision (coefficient of variation) and accuracy for quality control samples ranged from 1.32 to 8.91% and from 92.8 to 108%, respectively. The inter-day precision and accuracy ranged from 2.13 to 8.45% and from 97.0 to 104%, respectively. The analytical method showed excellent sensitivity using a small sample volume (0.1 mL) with a lower limit of quantitation of 5 pg/mL. This method is robust and has been successfully employed in a pharmacokinetic study of Dex in neonates and infants postoperative from cardiac surgery.

Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion.

CONTEXT: To compare degree of liver injury and paracetamol metabolite concentrations after treatment with standard of care (20-h) vs. abbreviated (12-h) acetylcysteine regimens used in paracetamol overdose (NACSTOP trial). METHODS: Timed blood samples from a cohort of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-h acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) were assayed for paracetamol metabolites as a pilot study, using liquid chromatography/mass spectrometry. Control group subjects received a 20-h course of acetylcysteine (200 mg/kg over 4 h, 100 mg/kg over 16 h). The intervention group received a 12-h acetylcysteine regimen (stopped after at least 12 h of treatment). Positive control groups not in the trial with acute liver injury (ALI) or hepatotoxicity were also studied. RESULTS: One hundred and forty-one blood samples were collected from 40 patients receiving acetylcysteine after paracetamol overdose. Median ALT after 20 h of acetylcysteine was 12 U/L (IQR 8.14) in the abbreviated regimen group, compared to the control group 16 U/L (IQR 11.21) (p = .46). There was no significant difference in median metabolite concentrations on presentation and after 20 h of acetylcysteine between these two groups (p > .05). Presentation median sum CYP-metabolite/total metabolite percentages were 2.5 and 3.0 in the abbreviated and control NACSTOP groups, respectively. CONCLUSIONS: An abbreviated 12-h acetylcysteine regimen for paracetamol overdose used in the NACSTOP trial had similar circulating metabolite concentrations compared to a 20-h regimen in selected subjects with low risk of hepatotoxicity. This suggests that further acetylcysteine may not be needed in the abbreviated group at time of cessation.

Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability.

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.

Analgesic effectiveness, pharmacokinetics, and safety of a paracetamol/ibuprofen fixed-dose combination in children undergoing adenotonsillectomy: A randomized, single-blind, parallel group trial.

BACKGROUND: Pain following tonsillectomy is often poorly managed in the home setting. Multimodal analgesia with acetaminophen (paracetamol) and nonsteroidal anti-inflammatory drugs offers superior analgesia over monotherapy but may be difficult for caregivers to manage. A fixed-dose combination oral suspension product containing paracetamol and ibuprofen has been developed to facilitate pediatric dosing. AIMS: The aims of this study are to determine the analgesic effectiveness, pharmacokinetics, and safety of the fixed-dose combination at two doses in the pediatric population. METHODS: In this prospective, multicenter, randomized, single-blind, parallel group trial, 251 children aged 2-12 years undergoing day-stay (adeno)tonsillectomy were randomized to two dose groups of the fixed-dose combination. A doubled loading dose was given preoperatively, followed by treatment for up to 11 days (Higher dose: paracetamol 15 mg/kg + ibuprofen 4.5 mg/kg, Lower dose: paracetamol 12 mg/kg + ibuprofen 3.6 mg/kg). Blood samples were collected for pharmacokinetic analysis for up to 6 hours after the loading dose. The analgesic effectiveness was examined on the first day after surgery using both Parents Postoperative Pain Measurement and modified Wong-Baker Faces pain scales. Rescue medication consumption was recorded throughout the study. RESULTS: Differences in maximum plasma concentration (Cmax ) and total exposure (AUC0→t ) between the treatment groups for both analytes were consistent with a 25% increase in dose; there was no difference in time to peak concentration (Tmax ). On the first postoperative day, there was no difference in pain scores or rescue medication use between treatment groups (approximately 30% in both groups). The combination was well tolerated by both groups. The most common adverse events were vomiting and nausea. The incidence of postoperative bleeding was 4.4%. CONCLUSION: The shallow dose-response relationship and good tolerability of the fixed-dose combination over an extended study period supports the utility of both doses of the fixed-dose combination in the home setting.

Acetaminophen, ibuprofen, and tramadol analgesic interactions after adenotonsillectomy.

BACKGROUND: The impact of tramadol in children given acetaminophen-ibuprofen combination therapy is uncertain in acute pediatric pain management. A model describing the interaction between these three drugs would be useful to understand the role of supplemental analgesic therapy. METHODS: Children undergoing tonsillectomy were given oral paracetamol and ibuprofen perioperatively. Blood was taken for paracetamol and ibuprofen drug assay on up to six occasions over 6 h after the initial dose. Tramadol was administered by caregivers for unacceptable postoperative pain. Pain was measured using the Parent's Postoperative Pain Measurement rating two hourly on the first postoperative day. A first-order absorption, one-compartment linear model with first-order elimination was used to describe acetaminophen and ibuprofen disposition. Analgesia was described using an EMAX model extended for three drugs, assuming additive effects. Curve fitting was performed using nonlinear mixed effects models. RESULTS: Pharmacodynamic parameter estimates, expressed using fractional Hill equation, were maximum effect (EMAX ) 0.65 (95%CI 0.54, 0.74), the concentration of acetaminophen associated with 50% of the maximal drug effect (C50,ACET ) 7.06 (95%CI 7.03, 7.72) mg/L, and the ibuprofen C50 (C50,IBU ) 3.95 (95%CI 2.57, 7.53) mg/L. The Hill coefficient was 1.48 (95%CI 0.92, 2.62) and an interaction term was fixed at zero (additivity). The half-time (t1/2 keo) for equilibration between the plasma and effect site was 0.34 hour (95%CI 0.23, 1.98) for acetaminophen and 1.04 hour (95%CI 0.75, 1.77) for ibuprofen. Tramadol had a C50,TRAM of 0.07 (95%CI 0.048, 1.07) mg/L with a t1/2 keo,TRAM 1.78 hour (95%CI 1.06, 1.96). CONCLUSION: Ibuprofen has an EC50 for analgesia in children similar to that of adults (3.95 mg/L; 95%CI 2.57-7.53, vs 5-10 mg/L adults). The maximum effect from combination therapy (ie, 65% reduction in pain score) achieves satisfactory analgesia with commonly used doses but increased dose adds little additional benefit. The addition of tramadol to this analgesic mixture prolongs analgesia duration.

Tolerance to hypothermic and antinoceptive effects of ∆9-tetrahydrocannabinol (THC) vapor inhalation in rats.

RATIONALE: A reduced effect of a given dose of ∆9-tetrahydrocannabinol (THC) emerges with repeated exposure to the drug. This tolerance can vary depending on THC dose, exposure chronicity and the behavioral or physiological measure of interest. A novel THC inhalation system based on e-cigarette technology has been recently shown to produce the hypothermic and antinociceptive effects of THC in rats. OBJECTIVE: To determine if tolerance to these effects can be produced with repeated vapor inhalation. METHODS: Groups of male and female Wistar rats were exposed to 30 min of inhalation of the propylene glycol (PG) vehicle or THC (200 mg/mL in PG) two or three times per day for four days. Rectal temperature changes and nociception were assessed after the first exposure on the first and fourth days of repeated inhalation. RESULTS: Female, but not male, rats developed tolerance to the hypothermic and antinociceptive effects of THC after four days of twice-daily THC vapor inhalation. Thrice daily inhalation for four days resulted in tolerance in both male and female rats. The plasma THC levels reached after a 30 min inhalation session did not differ between the male and female rats. CONCLUSIONS: Repeated daily THC inhalation induces tolerance in female and male rats, providing further validation of the vapor inhalation method for preclinical studies.