Paracetamol Serum Concentration Research Articles

Exposure to Paracetamol in Early Pregnancy and the Risk of Developing Cerebral Palsy: A Case-Control Study Using Serum Samples

To investigate whether maternal paracetamol use in early pregnancy is associated with cerebral palsy (CP) in offspring. We conducted a registry and biobank-based case-control study with mother-child pairs. We identified CP cases (n=322) born between 1995 and 2014 from a nationwide CP-registry. Randomly selected controls (n=343) and extra preterm controls (n=258) were obtained from a birth registry. For each mother, a single serum sample from early pregnancy (gestation weeks 10-14) was retrieved from a biobank and analyzed for serum concentrations of paracetamol, categorized into unexposed (<1ng/ml), mildly exposed (1-100ng/ml), and highly exposed (>100ng/ml), and in quartiles. Analyses were performed using logistic regression and adjusted for potential confounders. Separate analyses were conducted including only those children born preterm and only those born term. Of the 923 participants, 36.8% were unexposed, 53.2% mildly exposed, and 10% highly exposed to paracetamol. Overall, prenatal exposure to paracetamol was not associated with CP. Sensitivity and subgroup analyses showed no clear associations between paracetamol and CP across strata of term/preterm birth as well as subtypes of CP. The present study does not support an association between intrauterine exposure to paracetamol in early pregnancy and the risk of CP. However, it is important to stress that the exposure estimate is based on a single serum sample.

Evaluation of Supervised Machine Learning Algorithms and Computational Structural Validation of Single Nucleotide Polymorphisms Related to Acute Liver Injury with Paracetamol.

To identify single nucleotide polymorphisms (SNPs) of paracetamol-metabolizing enzymes that can predict acute liver injury. Paracetamol is a commonly administered analgesic/antipyretic in critically ill and chronic renal failure patients and several SNPs influence the therapeutic and toxic effects. To evaluate the role of machine learning algorithms (MLAs) and bioinformatics tools to delineate the predictor SNPs as well as to understand their molecular dynamics. A cross-sectional study was undertaken by recruiting critically ill patients with chronic renal failure and administering intravenous paracetamol as a standard of care. Serum concentrations of paracetamol and the principal metabolites were estimated. Following SNPs were evaluated: CYP2E1*2, CYP2E1_-1295G>C, CYP2D6*10, CYP3A4*1B, CYP3A4*2, CYP1A2*1K, CYP1A2*6, CYP3A4*3, and CYP3A5*7. MLAs were used to identify the predictor genetic variable for acute liver failure. Bioinformatics tools such as Predict SNP2 and molecular docking (MD) were undertaken to evaluate the impact of the above SNPs with binding affinity to paracetamol. CYP2E1*2 and CYP1A2*1C genotypes were identified by MLAs to significantly predict hepatotoxicity. The predictSNP2 revealed that CYP1A2*3 was highly deleterious in all the tools. MD revealed binding energy of -5.5 Kcal/mol, -6.9 Kcal/mol, and -6.8 Kcal/mol for CYP1A2, CYP1A2*3, and CYP1A2*6 against paracetamol. MD simulations revealed that CYP1A2*3 and CYP1A2*6 missense variants in CYP1A2 affect the binding ability with paracetamol. In-silico techniques found that CYP1A2*2 and CYP1A2*6 are highly harmful. MD simulations revealed CYP3A4*2 (A>G) had decreased binding energy with paracetamol than CYP3A4, and CYP3A4*2(A>T) and CYP3A4*3 both have greater binding energy with paracetamol. Polymorphisms in CYP2E1, CYP1A2, CYP3A4, and CYP3A5 significantly influence paracetamol's clinical outcomes or binding affinity. Robust clinical studies are needed to identify these polymorphisms' clinical impact on the pharmacokinetics or pharmacodynamics of paracetamol.

The pharmacokinetics of intravenous paracetamol in neonates: size matters most

BackgroundThe aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates.MethodsA population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27–45...

Paracetamol for intravenous use in medium- and intensive care patients: pharmacokinetics and tolerance

We studied the pharmacokinetics of paracetamol and determine the incidence of hypotension after intravenous administration in medium- (MCU) and intensive care (ICU) patients. All patients on the ICU/MCU starting with paracetamol i.v. were included, yielding 38 patients. Blood samples were collected at predetermined time points to determine paracetamol serum concentration. The number of patients with a clinically relevant reduction in systolic blood pressure (SBP) and the number of patients that needed intervention to regain an acceptable blood pressure level were assessed. Overall, pharmacokinetic data were roughly comparable with earlier publications, but differences were noted in the subgroup ICU patients. Also, there was a trend to a larger peak serum concentration (p = 0.052) and a significantly smaller volume of distribution (p = 0.033) in MCU patients compared with ICU patients. Twenty-two percent (22%) and 33% of patients had a clinically relevant reduction in systolic blood pressure (SBP) 15 and 30 min after start of paracetamol infusion, respectively. In six patients (16%), an intervention was needed to correct blood pressure. Overall, SBP was significantly reduced at T = 15 min and 30 min postinfusion (p < 0.003 at both time points) when compared with SBP at the start of paracetamol infusion. Further research on differences in paracetamol pharmacokinetics between ICU and MCU patients is warranted, as these differences might result in differences in efficacy. Furthermore, administration of paracetamol i.v. as potential cause of hypotension in the critically ill patient must not be overlooked.

Paracetamol serum concentration in preterm infants treated with paracetamol intravenously: A case series of nine

Paracetamol serum concentration in preterm infants treated with paracetamol intravenously: A case series of nine

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Therapeutic doses of paracetamol (acetaminophen) are normally considered safe. But in a recent experiment, healthy young volunteers taking therapeutic doses of the drug developed abnormal liver function after only a...

Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis1

The aim of this study was to describe propacetamol pharmacokinetics in children in order to predict concentrations after a standard dosing regimen of propacetamol 30 mg x kg(-1) (15 mg x kg(-1) paracetamol) 6 h. A population pharmacokinetic analysis of paracetamol time-concentration profiles (846 observations) from 144 children [postconception age (PCA) 27 weeks-14 years] was undertaken using nonlinear mixed effects models (NONMEM). These data were taken from seven separate studies involving children given intravenous propacetamol. Time-concentration profiles (503 observations) from a further 86 children (PCA: 37 weeks-14 years) given paracetamol elixir orally were included in the analysis to assess relative bioavailability of intravenous propacetamol. A three-compartment (depot, central and peripheral) linear disposition model fitted data better than a two-compartment (depot and central) model. Population parameter estimates (between subject variability, %) were central volume (V2/F(oral)) 24 (55%) l x 70 kg(-1), peripheral volume of distribution (V3/F(oral)) 30 (32%) l x 70 kg(-1), clearance (CL/F(oral)) 16 (40%) l x h(-1) x 70 kg(-1) and intercompartment clearance (Q/F(oral)) 55 (116%) l x h(-1) x 70 kg(-1). Clearance increased from 27 weeks PCA (1.87 l x h(-1) 70 kg(-1)) to reach 84% of the mature value by 1 year of age (standardized to a 70 kg person using allometric '1/4 power' models). Peripheral volume of distribution decreased from 27 weeks PCA (45.0 l x 70 kg(-1)) to reach 110% of its mature value by 6 months of age. Central volume of distribution and intercompartment clearance did not change with age. Between occasions variability for the peripheral volume of distribution (V3/F(oral)) and clearance (CL/F(oral)) were 18.5 and 19.3%, respectively. A rate constant representing hydrolysis of propacetamol to paracetamol (K(a) 96 h(-1)) was size related, but not age related. The relative bioavailability of intravenous propacetamol compared with an oral elixir was 0.5. A mean paracetamol serum concentration of 10 mg x l(-1) is achieved in children 2-15 years given a standard dose of propacetamol 30 mg x kg(-1) 6 h. This concentration in the effect compartment is associated with a pain reduction of 2.6/10 after tonsillectomy and provides satisfactory analgesia for mild to moderate pain. Clearance is reduced in children less than 1 year of age and the target concentration of 10 mg x l(-1) may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group.

Randomized, double‐blind, placebo‐controlled study of the effect of rectal paracetamol on morphine consumption after abdominal hysterectomy

Paracetamol is widely used for postoperative analgesia. The effect is well documented in minor and moderate extensive surgery, but the effect of paracetamol as an adjunct to opioids in major abdominal surgery is less examined. Seventy-eight patients scheduled for elective, benign, and abdominal hysterectomy were included in a prospective, randomized, double-blind, parallel group, placebo-controlled study to evaluate the effect of rectal paracetamol in conjunction with intravenous patient-controlled analgesia (PCA) morphine. Paracetamol 1000 mg or placebo suppositories were given four times daily during the 60-h study period. I.V. morphine was administered via a PCA pump, limited to maximum of 12 mg h-1. Morphine consumption, pain and morphine-related adverse effects were recorded. A single-point analysis was comprised of serum concentrations of paracetamol and morphine. Sixty patients were evaluated: 30 in each group. A 16.6% reduction in overall-accumulated morphine consumption in the treatment group (99.6 vs. 83.3 mg) was observed (NS, P = 0.06). Mean paracetamol serum concentration was 0.03 mmol l-1 (range: 0.01-0.06 mmol l-1). None of the patients had a paracetamol concentration within the therapeutic range for antipyretic efficacy. Patients with a higher paracetamol concentration had a lower concomitant morphine (P = 0.025) and morphine-6-glucuronide (P = 0.014) concentration 2 h after paracetamol administration. A dosage of rectal paracetamol 1000 mg four times daily is too low, as all displayed a suboptimal serum paracetamol concentration. To study the effect of rectal paracetamol after major surgery we have to increase the dose, as higher serum concentrations of paracetamol may cause lower serum concentrations of morphine.

Serum paracetamol concentration: an alternative to X-rays to determine feeding tube location in the critically ill.

Placement of enteral feeding tubes is an important clinical issue. Previous studies suggest that paracetamol absorption is very fast after jejunal administration. The aim was to determine whether paracetamol serum concentration measured by immunoassay can determine the tip position of the feeding tube. Thirty-three critically ill patients requiring enteral nutrition with either gastric or post-pyloric feeding tubes were enrolled prospectively in the surgical intensive care unit of a university hospital. Paracetamol was administered in the feeding tube (15 mg/kg) after a baseline blood sample (T0). Thereafter, 8 blood samples were taken between 2.5 and 240 minutes. Paracetamol was analyzed using an automated homogenous immunoassay. The patients did not differ with respect to age or severity of disease. Peak paracetamol concentrations were significantly higher after post-pyloric administration with 42.6 +/- 13.5 versus 20.5 +/- 7.5 mg/L (p < .0001). Time-to-peak paracetamol concentration was significantly shorter with post-pyloric tubes (median, 5 versus 60 minutes; p < .0001). The receiver operating characteristic (ROC) curves showed the highest sensitivity and specificity at 5 minutes with 94.1% and 100%, respectively, for discriminating between gastric and post-pyloric location. Because of paracetamol's rapid absorption after jejunal administration, the test seems to be a safe and inexpensive alternative to X-ray control for assessment of the enteral feeding tube location. Its value in clinical practice remains to be established.

Approaches toward repeated supratherapeutic doses of paracetamol in children: a survey of medical directors of poison centres in North America and Europe.

During the last few years there has been an increase in the number of reports of liver failure associated with prolonged paracetamol (acetaminophen) administration in children for therapeutic reasons. To describe the approach taken by medical directors of poison centres regarding the treatment of repeated supratherapeutic doses of paracetamol in children. Questionnaires mailed to the medical directors of 76 poison centres in North America and 48 poison centres in Europe asked respondents to comment on the management of a hypothetical case of a child who had received repeated doses of paracetamol at a daily dose of 90 mg/kg during a febrile illness and who presented to the emergency department with mildly elevated serum transaminase levels. The response rate was 62% for North American centres and 44% for European centres. There was a wide range of answers regarding the maximal safe daily dose of paracetamol. For the case described, 71% of the respondents suggested measuring paracetamol serum concentration. Fifty-four percent suggested treating the patient with acetylcysteine and 35% suggested not treating the patient. Our study showed that there is little agreement among medical directors of poison centres on the toxic threshold for chronic exposure to paracetamol in children and on how these cases should be managed.

Serum drug concentrations after oral administration of paracetamol to patients with surgical resection of the gastrointestinal tract.

Serum concentrations of paracetamol were measured at 30, 60, 120 and 180 min after oral administration of a solution of 1500 mg paracetamol in normal subjects (n = 32) (Group A) and in patients with total gastrectomy (Roux-en-Y reconstruction) (n = 5) (Group B), distal partial gastrectomy (Billroth I reconstruction) (n = 7) (Group C), pylorus preserving pancreatoduodenectomy (Billroth I type reconstruction) (n = 12) (Group D), and short bowel syndrome (n = 5) (Group E). In Group B, the dose was delivery directly into the jejunum 20 cm distal to the duodenojejunal flexure. The highest serum drug concentrations were observed in the 30 min sample in Groups B and C and in the 120 min sample in Groups A, D, and E. Mean (+/- s.d.) concentrations at these times were 18.90 +/- 1.55 micrograms ml-1 (Group B), 12.89 +/- 2.12 micrograms ml-1 (Group C), 11.12 +/- 3.16 micrograms ml-1 (Group A), 9.78 +/- 2.85 micrograms ml-1 (Group D), and 4.89 +/- 1.96 micrograms ml-1 (Group E), respectively. We conclude that in patients with normal intact gastrointestinal tract, most of a dose of oral paracetamol is absorbed from the jejunum distal to the duodenojejunal flexure.

Chronopharmacokinetics of paracetamol in normal subjects.

The chronopharmacokinetics of paracetamol was studied in six male volunteers. Serum concentrations of paracetamol were determined after a single oral dose of 1 g, on three occasions, spaced at least 1 week apart. Plasma drug concentration vs time curves were obtained after dosage at 08.00 h (Day 1), 14.00 h (Day 2) and 20.00 h (Day 3), under standardized conditions. Pharmacokinetic parameters compared were t1/2,alpha, t1/2,Z, tmax, Cmax and AUCpo. No statistically significant differences were found.