Plasma Paracetamol Concentration Research Articles

Post-prandial acyl ghrelin infusion in heart failure patients increases gastric emptying rate

Abstract Background Acyl ghrelin (ghrelin) increases cardiac output (CO) and contractility in patients with heart failure with reduced ejection fraction (HFrEF). In healthy humans, ghrelin increases gastric emptying rate (GER) and hunger, a potential add-on benefit for HFrEF patients suffering from cachexia with symptoms of delayed gastric emptying and loss of appetite. Aim Determine if post-prandial ghrelin infusion increases GER and hunger in HFrEF patients; compare to CO. Methods This study was a component of a double-blind placebo-controlled trial of acyl ghrelin vs. placebo in HFrEF. Patients (n=29) arrived fasted and received a 500 kcal breakfast and 1.5 g paracetamol. They next received placebo (vehicle, n=15) or ghrelin infusion (0.1 µg/kg/min, n=14) for 120 min. Blood was tapped for plasma at 0, 30, 60, 120 and 150 min into the meal. Plasma concentration of paracetamol was measured to assess GER of a liquid bolus. Hunger scores and CO were recorded. Mann-Whitney rank sum test was used for statistics. Results Paracetamol peaked at 30 min in 8 of 14 (57%) in the ghrelin treatment group versus 1 of 15 (7%) in the placebo group (P=0.004, Fig 1). Remaining patients peaked at later time points. There were no anomalous peaks at 0 min baseline or 2880 min (2 days). The ghrelin treatment group data was segregated into rapid (peak at 30 min, n=8) and slow (peak >30 min, n=6) GER subgroups. The rapid subgroup had a ghrelin treatment effect on CO (one-way repeat measures) (P<0.001, Fig 2). Baseline (t=0) CO for the rapid GER subgroup was 4.06 ±1.41 L/min (median ±SD) and 3.95 ±0.62 L/min for the slow GER subgroup (P=0.31). Data points shown are median ± SEM, each patient normalized to own baseline (100%); * P<0.05, ** P<0.01, *** P<0.001, pairwise comparison to baseline. Hunger gradually increased. The greatest increase in hunger was at 150 min, at which time median fold increase in hunger relative baseline was 1.6 (placebo), 1.7 (ghrelin, slow GER) and 2.3 (ghrelin, rapid GER). These hunger differences between groups did not reach significance. However, this trend was consistent with ghrelin induction of hunger, especially in those with potent GER and CO responses. Conclusions Ghrelin increases GER, and potentially hunger, in HFrEF patients in addition to increasing CO. Some HFrEF patients may benefit from this add-on effect.Fig 1.Time of paracetamol peak.Fig 2.Cardiac output.

A Pharmacokinetic Study of the Interaction Between Regorafenib and Paracetamol in Male Rats

Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (IIREG, regorafenib 20 mg/kg, n = 8), PA group (IIIPA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (IREG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC–UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the Cmax and AUC0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (Cmax and AUC0–∞, respectively). A difference in the ratio of M-2/REG for AUC0–∞ and Cmax between the groups was observed, but not for M-5/REG. The AUC0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC0–∞ for SPA increased by 91.35% in the IREG+PA group. A difference in the ratio of GPA/PA for Cmax and for SPA/PA for AUC0–t and AUC0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment.

Agreement Between a Colorimetric Assay and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry for Quantifying Paracetamol Plasma Concentrations.

Special populations, like geriatric patients, experience altered paracetamol pharmacokinetics (PK), complicating pain management. More PK research is essential to optimize paracetamol (acetaminophen) dosing. Yet, the reference method ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) is not readily available. Therefore, we aimed to evaluate the agreement between UPLC-MS/MS and the more accessible colorimetric Roche acetaminophen (ACETA) assay in quantifying paracetamol plasma concentrations, to facilitate PK studies and therapeutic drug monitoring for pain management. Patient data and plasma samples were obtained from a prospective study including geriatric patients admitted to the geriatric wards. ACETA and UPLC-MS/MS assays were performed in two separate laboratories. Bland-Altman plot and Passing-Bablok regression were used to assess agreement. Accuracy was evaluated using the McNemar test for a threshold value of 10mg/L. Population PK modeling was employed to bridge PK data obtained from both methods (NONMEM 7.5). A total of 242 plasma sample pairs were available from 40 geriatric patients (age range, 80-95years). Paracetamol plasma concentrations from ACETA (median 9.8 [interquartile range 6.1-14.4] mg/L) and UPLC-MS/MS (9.5 [6.2-14.8] mg/L) did not differ significantly (P > 0.05). No significant proportional nor additive bias was observed between both assay methods. The classification accuracy (at threshold 10mg/L) was 85% (P = 0.414). The conversion factor between ACETA and UPLC-MS/MS was estimated at 1.06 (relative standard error 5%), yet with a 13.4% (relative standard error 23%) interindividual variability. ACETA assay showed no systematic bias in comparison with the UPLC-MS/MS assay in determining paracetamol exposure in geriatric blood samples despite the imprecision.

Introduction of an electrochemical point-of-care assay for quantitative determination of paracetamol in finger-prick capillary whole blood samples.

Measuring venous plasma paracetamol concentrations is time- and resource-consuming. We aimed to validate a novel electrochemical point-of-care (POC) assay for rapid paracetamol concentration determinations. Twelve healthy volunteers received 1 g oral paracetamol, and its concentrations were analysed 10 times over 12 h for capillary whole blood (POC), venous plasma (high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS)), and dried capillary blood (HPLC-MS/MS). At concentrations >30 μM, POC showed upward biases of 20% (95% limits of agreement [LOA] -22 to 62) and 7% (95% LOA -23 to 38) compared with venous plasma and capillary blood HPLC-MS/MS, respectively. There were no significant differences between mean concentrations for the paracetamol elimination phase. Upward biases in POC compared with venous plasma HPLC-MS/MS were likely due to higher paracetamol concentrations in capillary blood than in venous plasma and to faulty individual sensors. The novel POC method is a promising tool for paracetamol concentration analysis.

Securing a diagnosis in patients presenting with suspected paracetamol (acetaminophen) poisoning: Aretrospective cohort study.

Paracetamol (acetaminophen) is the most commonly ingested drug in self-poisoning. The correlation between an ingested self-reported dose of paracetamol and plasma paracetamol concentration is moderate. The usefulness of this correlation to rule out paracetamol ingestion has to be investigated. The objective of this study is to evaluate the performance of medical history in diagnosis of paracetamol ingestion in patients admitted to the Emergency Department (ED) for deliberate self-poisoning. This retrospective cohort study was carried out in two EDs at an urban university hospital in Toulouse, France, from January 1 to June 30, 2018. All patients older than 15 years of age attending the ED for suspected deliberate self-poisonings who underwent blood testing were included. Medical history was considered positive for paracetamol intoxication if patients directly reported the use of paracetamol for deliberate self-poisoning during their ED admission or if paramedics reported the presence of paracetamol packages at the patient's home. We defined paracetamol ingestion as any concentration of paracetamol > 5 mg/L measured on presentation. We included 709 patients. 151 (21%) patients had a positive plasma paracetamol concentration. 165 (23%) patients revealed a positive medical history in terms of paracetamol ingestion. 29 (4%) patients had a false-negative medical history, and 45 (6%) patients had a false-positive history. The sensitivity of the medical history (95% confidence interval) was 79% (72-87), and its specificity was 92% (89-94). Diagnosis of self-poisoning involving paracetamol cannot be made using patient's medical history alone. Screening for paracetamol intoxication is proposed.

Impact of oral gavage technique of drug-containing microcontainers on the gastrointestinal transit and absorption in rats

Oral gavage is the most common way to administer drug formulations orally to rats. Yet, the technique applied and its influence on gastrointestinal (GI) transit receive little attention. This study aims to investigate the impact of three oral gavage techniques on GI transit and drug absorption utilizing microcontainers (MCs). The MCs were filled with paracetamol and BaSO4 (1:1 w/w ratio), coated with Eudragit S100, and filled into size-9 gelatin capsules. An in vitro study confirmed the intactness of the coating, and the capsules were administered to rats with air, water, or a piston. X-ray imaging determined the locations of the MCs, and the corresponding plasma concentration of paracetamol established a correlation with the location. The fastest GI transit occurred with air-dosing, while water-dosing caused delayed gastric emptying for 3 h with non-quantifiable paracetamol absorption. Piston-dosed MCs were retained in the stomach for up to 1 h, though for 3 h in one rat. Air-dosing caused discomfort and stress in rats, thus limiting its ethical and physiological relevance. Water-dosing confined its use due to delayed gastric emptying. In conclusion, the oral gavage technique affected the GI transit of MCs and, consequently, drug absorption. Piston-dosing appeared to be the superior dosing technique.

Has the time come to stop routine N-acetylcysteine treatment in young children in Denmark? A review of 300 suspected paracetamol overdoses in children aged 0-6 years.

To evaluate the prevalence of potentially hepatoxic paracetamol ingestion and associated N-acetylcysteine treatment in young children suspected of paracetamol poisoning. A retrospective cohort study of children aged 0-6years suspected of paracetamol poisoning with a related plasma-paracetamol measurement in the Capital Region of Denmark in the period 2010-2017. Data from the clinical laboratory system were linked to data from electronic patient records via the unique identification number given to all Danish residents. Of 297 children included, suspected single paracetamol overdoses were present in 281 (95%). Sixty-nine per cent were treated with N-acetylcysteine, and the mean treatment period was 20.3h (SD 20.8). A maximum of 6 (2%) of the children suspected of single overdose had plasma-paracetamol concentrations that exceeded the recommended treatment thresholds. No cases of severe hepatotoxicity were registered. Adverse events to N-acetylcysteine-treatment were registered in 3 (2%) children including one anaphylactoid reaction (0.5%). This study shows that initiating N-acetylcysteine as a 'one size fit all' treatment regimen in all children aged 0-6years with a suspected single paracetamol overdose leads to substantial overtreatment. The data support that it is feasible to initiate N-acetylcysteine within 10h based on an early plasma-paracetamol test.

Paracetamol toxicity in mild overdose in combination with opioids: A retrospective observational study.

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

Pharmacokinetics of 2 oral paracetamol formulations in hospitalized octogenarians.

It is currently unclear how paracetamol should be dosed in order to increase its efficacy while warranting safety in very old adults. The objective was to evaluate the pharmacokinetics of 2 oral paracetamol formulations and its metabolites in hospitalized octogenarians. Geriatric inpatients aged 80 years and older received a 1000-mg paracetamol tablet or granulate at 08.00, 14.00 and 20.00. After at least 4 consecutive gifts, plasma samples were collected around the 08.00 dose (trough, +0.5, +1, +2, +4, +5 and +6h). Plasma concentrations of paracetamol and its metabolites were determined and individual pharmacokinetic parameters were derived. The Edmonton Frail Scale was used to assess frailty. An analgesic plasma target was defined as an average plasma concentration (Cavg ) of 10mg/L. The mean (±standard deviation) age was 86.78 (±4.20) years. The majority (n =26/36, 72%) received the tablet, 10 (28%) the granulate. Thirty patients (85%) were classified with moderate to severe frailty. Seven (21%) patients had a Cavg above 10mg/L. The median [interquartile range] time to reach the peak concentration was 50.5 [31.50-92.50] and 42.50 [33.75-106.75] min for the tablet and granulate, respectively. The coefficient of variation was 95% for time to reach the peak concentration and 30% for Cavg of paracetamol. A correlation of Cavg of paracetamol was observed with female sex and total serum bilirubin. Large interindividual differences were found for pharmacokinetic parameters of oral paracetamol in frail inpatients after multiple dosing. Female sex and higher total serum bilirubin concentrations were associated with paracetamol exposure. No significant differences were observed between the tablet and granulate.

Clinical and pharmacological approaches to the choice of a drug for a tension-type headache relief

The purpose of this study is a comparative analysis of the pharmacodynamic and pharmacokinetic parameters of ibuprofen and paracetamol as a part of fixed dose combination and as monotherapy in tension type headaches. Comparative dissolution kinetics test; Comparative analysis of pharmacokinetic parameters using the PubMed/MEDLINE database. The median Tmax of ibuprofen as a part of a fixed-dose combination and as a monotherapy is 75 minutes. The median Tmax of paracetamol is 30 min when taken in a fixed dose combination and 40 min as a monotherapy. In patients who received the fixed dose combination, the concentration of ibuprofen in the blood plasma after 10 minutes 6.64 g/ml-1; after 20 minutes 16.81 g/ml-1, while when taken in the same dose in as a monotherapy, respectively, 0.58 and 9.00 g/ml-1. The mean plasma concentrations of paracetamol after 10 and 20 minutes in patients receiving the fixed combination were 5.43 and 14.54 g/ml-1, respectively, compared with 0.33 and 9.19 g/ml-1 for paracetamol as monotherapy. dissolution kinetics test of the Paracytolgin: after 5 minutes, 20% of paracetamol passed into the solution in a system with a pH of 1.2; in a system with a pH of 4.5 36.4%; in a system with a pH of 6.8 33.5%; after 10 minutes, respectively 68.5, 98.0 and 89.6%. After 15 minutes, almost complete dissolution was noted in all systems: 98.5, 98.8 and 100.5%, respectively. The combination of ibuprofen and paracetamol makes it possible to enhance the analgesic effect as a result of additive action by the help of central mechanisms. The fixed dose combination of ibuprofen and paracetamol significantly increases the rate of absorption of paracetamol, which has potential therapeutic benefits in terms of a faster analgesias onset. The fixed dose combination of ibuprofen and paracetamol provides faster and long-term anaesthesia with a comparatively lower dosage of each analgesic.

In vitro and in vivo comparison of microcontainers and microspheres for oral drug delivery

Microcontainers, which are microfabricated cylindrical devices with a reservoir function, have shown promise as an oral drug delivery system for small molecular drug compounds. However, they have never been evaluated against a relevant control formulation. In the current study, we prepared microcrystalline cellulose (MCC) microspheres as a control for in vitro and in vivo testing of SU-8 microcontainers as an oral drug delivery system. Both dosage forms were loaded with paracetamol and coated with chitosan or polyethylene glycol (PEG) (12 kDa). These coatings were followed by an additional enteric coating of Eudragit® S100. In addition, a control dosage form was coated with Eudragit® alone. The dosage forms were evaluated in vitro, in a physiologically relevant two-step model simulating rat gastrointestinal fluids, and in vivo by oral administration to rats. In vitro, the microcontainers coated with PEG/Eudragit® resulted in a prolonged release of paracetamol compared to the respective microspheres, which was consistent with in vivo observations of a later time (Tmax) for maximum plasma concentration (Cmax) for the microcontainers. For microspheres and microcontainers coated with chitosan/Eudragit®, the time for complete in vitro release of paracetamol was very similar, due to an earlier release from the microcontainers. This trend was supported by very similar Tmax values in vivo. The in vitro in vivo relation was confirmed by a linear regression with R2 = 0.9, when Tmax for each dosage form was plotted as a function of time for 90% paracetamol release in vitro. From the in vivo study, the average plasma concentration of paracetamol 120 min after dosing was significantly higher for microcontainers than for microspheres (0.3 ± 0.1 µg/mL and 0.1 ± <0.1 µg/mL, respectively) – regardless of the coating applied.

Investigation of plasma concentrations of paracetamol, metacetamol, and orthocetamol in Japanese racehorses using liquid chromatography–electrospray ionisation–tandem mass spectrometry

Paracetamol is used widely as an over-the-counter analgesic and antipyretic medication for humans, but not for Japanese racehorses. Paracetamol can be an environmental substance, and is found together with its two isomers, metacetamol and orthocetamol, in equine urine. However, the sources and routes of paracetamol exposure remain unclear. To control the misuse of paracetamol, it is appropriate to establish residue limits for paracetamol to differentiate the administration of paracetamol from its environmental levels. In this study, we developed and validated a quantitative method for paracetamol, metacetamol, and orthocetamol in equine plasma using liquid chromatography-electrospray ionization-tandem mass spectrometry and applied it to postrace samples from 320 Japanese racehorses for approximately 1 year. In addition, we conducted feed analysis and related pharmacokinetics simulations to evaluate the contributions from exposure via feed. The hydrolyzed plasma concentrations of paracetamol, metacetamol, and orthocetamol ranged from 0.787 to 39.8 ng/mL (median 5.87 ng/mL), 0 to 2.13 ng/mL (0.347 ng/mL), and 1.98 to 82.8 ng/mL (16.6 ng/mL), respectively. Such low concentrations of paracetamol were deemed irrelevant to therapeutic effect. Based on statistical analysis, the preliminary Japanese residue limits of unhydrolyzed and hydrolyzed paracetamol were determined to be 70.5 ng/mL and 112 ng/mL, respectively, in plasma, at a risk factor of 1 in 10,000. Furthermore, we detected paracetamol and orthocetamol in feed samples. A pharmacokinetics simulation showed that the presence of orthocetamol is most probably related to daily feed rations. As for paracetamol, feed can be one of the sources and other possible sources require further investigation.

Suspected paracetamol overdose in Monrovia, Liberia: a matched case\u2013control study

BackgroundA cluster of cases of unexplained multi-organ failure was reported in children at Bardnesville Junction Hospital (BJH), Monrovia, Liberia. Prior to admission, children’s caregivers reported antibiotic, antimalarial, paracetamol, and traditional treatment consumption. Since we could not exclude a toxic aetiology, and paracetamol overdose in particular, we implemented prospective syndromic surveillance to better define the clinical characteristics of these children. To investigate risk factors, we performed a case–control study.MethodsThe investigation was conducted in BJH between July 2015 and January 2016. In-hospital syndromic surveillance identified children with at least two of the following symptoms: respiratory distress with normal pulse oximetry while breathing ambient air; altered consciousness; hypoglycaemia; jaundice; and hepatomegaly. After refining the case definition to better reflect potential risk factors for hepatic dysfunction, we selected cases identified from syndromic surveillance for a matched case–control study. Cases were matched with in-hospital and community-based controls by age, sex, month of illness/admission, severity (in-hospital), and proximity of residence (community).ResultsBetween July and December 2015, 77 case-patients were captured by syndromic surveillance; 68 (88%) were under three years old and 35 (46%) died during hospitalisation. Of these 77, 30 children met our case definition and were matched with 53 hospital and 48 community controls. Paracetamol was the most frequently reported medication taken by the cases and both control groups. The odds of caregivers reporting supra-therapeutic paracetamol consumption prior to admission was higher in cases compared to controls (OR 6.6, 95% CI 2.1–21.3). Plasma paracetamol concentration on day of admission was available for 19 cases and exceeded 10 μg/mL in 10/13 samples collected on day one of admission, and 4/9 (44%) collected on day two.ConclusionsIn a context with limited diagnostic capacity, this study highlights the possibility of supratherapeutic doses of paracetamol as a factor in multi-organ failure in a cohort of children admitted to BJH. In this setting, a careful history of pre-admission paracetamol consumption may alert clinicians to the possibility of overdose, even when confirmatory laboratory analysis is unavailable. Further studies may help define additional toxicological characteristics in such contexts to improve diagnoses.

From the Editor's Desk…

From the Editor's Desk…

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.

Interventional cohort study of prolonged use (>72 hours) of paracetamol in neonates: protocol of the PARASHUTE study

IntroductionAnticipated or actual pain in neonates results in use of paracetamol for prolonged pain relief in many neonatal intensive care units. Clinical trials examining safety of paracetamol exposure in neonates...

The Influence of Diabetes Mellitus on Glucuronidation and Sulphation of Paracetamol in Patients with Febrile Neutropenia.

Background and ObjectivesNumerous studies have confirmed the influence of diabetes mellitus on the pharmacokinetics of drugs. Paracetamol (APAP) is an antipyretic that is commonly used in febrile neutropenia (FN) therapy. APAP is chiefly metabolised by glucuronidation and sulphation. This study assessed the influence of diabetes on the pharmacokinetics of paracetamol and its metabolites: glucuronide (APAP-glu) and sulfate (APAP-sulfate) in FN patients.MethodsPatients with FN received single intravenous dose 1000 mg of APAP. The FN patients were allocated to one of two groups: diabetics (DG, n = 7) or non-diabetics (NDG, n = 11). The plasma concentrations of paracetamol and its metabolites were measured with the validated high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection.ResultsPharmacokinetic parameters (mean [SD]) of APAP in the DG and NDG groups were as follows: Cmax (maximum comcentration) = 21.50 [11.23] vs. 23.42 [9.79] mg/L, AUC0–t (area under the concentration–time curve) = 44.23 [17.93] vs. 41.43 [14.57] mg·h/L, t1/2kel (elimination half-life) = 2.28 [0.80] vs. 2.11 [0.80] h. In both groups the exposure to APAP was comparable. The study did not reveal differences between the two groups in the pharmacokinetics of APAP-glu and APAP-sulfate. The Cmax and AUC0–t ratio between the metabolites and APAP were similar.ConclusionsNo differences in the pharmacokinetics of APAP, APAP-glu and APAP-sulfate in patients with FN indicates that diabetes does not influence glucuronidation and sulfatation of paracetamol.

Paracetamol clinical dosing routine leads to paracetamol underexposure in an adult severely ill sub-Saharan African hospital population: a drug concentration measurement study

BackgroundHospitals in sub-Saharan Africa (SSA) continue to receive high numbers of severely ill (HIV-infected) patients with physical pain that may suffer from hepatic and renal dysfunction. Paracetamol is widely used for pain relief in this setting but it is unknown whether therapeutic drug concentrations are attained. The aim of this study was to assess the occurrence of therapeutic, sub-therapeutic and toxic paracetamol concentrations in SSA adult hospital population.MethodsIn a cross-sectional study, plasma paracetamol concentrations were measured in patients with an oral prescription in a referral hospital in Mozambique. From August to November 2015, a maximum of four blood samples were drawn on different time points for paracetamol concentration measurement and biochemical analysis. Study endpoints were the percentage of participants with therapeutic (≥ 10 and ≤ 20 mg/L), sub-therapeutic (< 10 mg/L) and toxic (> 75 mg/L) concentrations.ResultsSeventy-six patients with a median age of 37 years, a body mass index of 18.2, a haemoglobin concentration of 10.3 g/dL and an albumin of 29 g/L yielded 225 samples. 13.4% of participants had one or more therapeutic paracetamol concentrations. 86.6% had a sub-therapeutic concentration at all time points and 70.2% had two or more concentrations below the lower limit of quantification. No potentially toxic concentrations were found.ConclusionsRoutine oral dosing practices in a SSA hospital resulted in substantial underexposure to paracetamol. Palliation is likely to be sub-standard and oral palliative drug pharmacokinetics and dispensing procedures in this setting need further investigation.

Bioequivalence and Safety of Twice-Daily Sustained-Release Paracetamol (Acetaminophen) Compared With 3- and 4-Times-Daily Paracetamol: A Repeat-Dose, Crossover Pharmacokinetic Study in Healthy Volunteers.

Twice‐daily sustained‐release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3‐day dosing period) the pharmacokinetics, bioequivalence, and safety of twice‐daily SR paracetamol compared with extended‐release (ER) and immediate‐release (IR) paracetamol. In this open‐label, randomized, multidose, 3‐way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice‐daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0–t, 0.973–1.033; AUC0–24, 0.974–1.034; AUC0–∞, 0.948–1.011; Cmax, 1.082–1.212; Cav, 1.011–1.106) and SR/IR paracetamol (AUC0–t, 0.969–1.029; AUC0–24, 0.968–1.027; AUC0–∞, 0.963–1.026; Cmax, 0.902–1.010; Cav, 1.004–1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 μg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax, a longer half‐life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated.

Randomized Controlled Trial Comparing Different Single Doses of Intravenous Paracetamol for Placement of Peripherally Inserted Central Catheters in Preterm Infants

Background: The availability of a safe and effective pharmacological therapy to reduce procedural pain in preterm infants is limited. The effective analgesic single dose of intravenous paracetamol in preterm infants is unknown. Comparative studies on efficacy of different paracetamol doses in preterm infants are lacking. Objectives: To determine the analgesic effects of different single intravenous paracetamol doses on pain from peripherally inserted central catheter (PICC) placement in preterm infants. Methods: In a blinded randomized controlled trial, the analgesic effects of 10-, 15-, and 20-mg/kg single-dose intravenous paracetamol before PICC placement were compared in neonates with a gestational age <32 weeks. Secondly, a separate age-matched nonrandomized control group receiving oral sucrose was included. Pain was assessed with the Premature Infant Pain Profile (PIPP) and the COMFORTneo score. Peak plasma concentrations of paracetamol were determined. Results: A total of 60 patients were included in the paracetamol dose groups (median gestational age = 27.8, IQR: 25.7-29.2 weeks). PIPP scores were comparable: median = 8 (IQR: 6-10.5), 7 (IQR: 6-9), and 8 (IQR: 6-10) for the 10-, 15-, and 20-mg/kg paracetamol groups, respectively (p = 0.94). COMFORTneo scores were not statistically different between the different paracetamol dose groups (p = 0.35). All randomized subjects, except for 3 who received 10 mg/kg of paracetamol, had peak paracetamol concentrations >9 mg/L. PIPP (p = 0.78) and COMFORTneo (p = 0.08) scores were also comparable between paracetamol- and sucrose-treated patients. Conclusions: We found no analgesic benefit from intravenous paracetamol studied in different single doses over sucrose for PICC placement in preterm infants. Paracetamol is not a suitable analgesic for this procedure in preterm infants.