Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Application of a generic PBK model for beef cattle: Tissue/fluid correlations of paracetamol and NSAIDs.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and paracetamol can be administered off-label to cattle. Since the use of these veterinary medicines in cattle may pose a public health risk after meat consumption, it is important to translate measured concentrations in urine and tissues into concentrations in meat for human consumption. A generic physiologically-based kinetic (PBK) model for cattle can enable this translation. In this work, a beef cattle PBK model was applied to calculate the relationships between concentrations in different bovine tissues and those were compared to measured concentrations in different matrices. Sixty-seven kidney samples, the corresponding urine and meat samples, and available 19 serum samples were analysed. Overall, 70% of the PBK model predictions are within a 2-fold factor and relationships for kidney/meat, urine/meat, and plasma/meat ratios were established. The conversions of measured kidney concentrations into meat concentrations were mostly within a factor two, while those based on plasma and urine were underpredicted. Based on these ratios, plasma and urine could be used as an appropriate surrogate matrix for a fast, simple in vivo sample screening test under field conditions, such as in local farms and slaughterhouses, to predict a maximum residue level exceedance in meat, reducing the number of test samples.

Multi-microdialysis analytical system to monitor acetaminophen and its pharmacokinetic interaction with A. bidentata in rat blood, forelimb extensor muscle, brain striatum, and the knee joint cavity.

Acetaminophen (APAP), or paracetamol, is one of the most widespread and commonly used non-prescription pain medication in the world, and is effective at managing wide range of pain, including headache, muscle ache, and minor arthritic pain. While the pharmacokinetics of APAP is generally understood, there is a lack of data for its transfer ratio especially into the knee. A novel multi-microdialysis model was developed to simultaneously sample from blood, forelimb extensor muscle, brain striatum, and the knee joint cavity in the same experimental subject to investigate the potential interaction between APAP and Achyranthes bidentata Blume (A. bidentata), another widely used traditional Chinese medicininal herb especially for pain in the lower extremity. Rats were pre-treated with A. bidentata extract (ABex), APAP was then administered (60 mg/kg, i.v.), dialysates then subsequently analyzed using HPLC-PDA. Our analysis demonstrated that APAP concentrations, achieved after its administration either alone or in combination with ABex (1 and 3 g/kg, q.d. gavage), could be modelled effectively with a one-compartment model. The distribution ratio (AUCorgan/AUCblood) of blood-to-muscle, blood-to-brain and blood-to-knee was 0.372 ± 0.053, 0.277 ± 0.095 and 0.191 ± 0.042, respectively after administration of APAP (60 mg/kg, i.v.). No significant difference was observed between the pharmacokinetics of APAP administered alone and in combination with ABex; and APAP concentration exceed the half maximal effective concentration (EC50) in all sampled organs for close to 3 hours with one single dose of drug administration, providing evidence for its broad-range analgesic effect.

Recovery of DNA from acetaminophen exploring physical state and sampling methods.

Research into the recovery of DNA from illicit drug samples has shown it is possible to get forensically useful profiles from such substrates. However, it is not yet known if the different physical states that drugs can be found in influences the quantity and quality of DNA that can be recovered or what is the best sampling method to adopt for powdered samples. This research used acetaminophen in four different states - large crystalline, powder, in solution, or residue - to determine the efficacy of current DNA technology in recovery and analysis of the resulting sample. Five replicates of each were prepared. Human blood was deposited on or mixed with the drug and left for 1 hour. The surface of the drug was sampled by wet/dry swabbing (where appropriate), or the entire sample was deposited in a tube, and the DNA then extracted using DNA-IQ™. The amount of DNA recovered (ng), degradation index, number of PCR cycles (Ct) required for the IPC to reach threshold, number of alleles in the DNA profile and average peak height (APH) were assessed. All samples, irrespective of the physical state they were collected from, returned full DNA profiles that corresponded to the DNA profile of the blood donor, with no degradation or inhibition detected. It was also found the wet/dry swabbing method returned higher levels of DNA than inclusion of the entire sample into the tube for powdered acetaminophen and the appropriate method to use will be dependent on casework circumstances. The findings of this research further develops our understanding of the recovery of DNA from drugs, and supports the need for further investigation to understand under what conditions DNA can be recovered from illicit substances.

Intestinal injury in paracetamol overdose (ATOM-8).

BACKGROUND AND AIM: Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. METHODS: Serial samples of 30 patients with acute paracetamol overdose (> 10 g or 200 mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2 mmol/L within 12 h post ingestion. RESULTS: In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720 µg/L [interquartile range, IQR, 533-1644] vs 270 µg/L [IQR 153-558], P < 0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028 µg/L [IQR 1399-3556] vs 574 µg/L [IQR 526-943], P = 0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P = 0.019 and P = 0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r = 0.55) and lactate (r = 0.60). CONCLUSIONS: Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.

Short-Term Safety of Repeated Acetaminophen Use in Patients With Compensated Cirrhosis.

Current guidelines recommend restricting acetaminophen (APAP) use in patients with cirrhosis, but evidence to support that recommendation is lacking. Prior studies focused on pharmacokinetics (PK) of APAP in cirrhosis but did not rigorously examine clinical outcomes, sensitive biomarkers of liver damage, or serum APAP-protein adducts, which are a specific marker of toxic bioactivation. Hence, the goal of this pilot study was to test the effects of regularly scheduled APAP dosing in a well-defined compensated cirrhosis group compared to control subjects without cirrhosis, using the abovementioned outcomes. After a 2-week washout, 12 subjects with and 12 subjects without cirrhosis received 650 mg APAP twice per day (1.3 g/day) for 4 days, followed by 650 mg on the morning of day 5. Patients were assessed in-person at study initiation (day 1) and on days 3 and 5. APAP-protein adducts and both conventional (alanine aminotransferase) and sensitive (glutamate dehydrogenase [GLDH], full-length keratin 18 [K18], and total high-mobility group box 1 protein) biomarkers of liver injury were measured in serum on the mornings of days 1, 3, and 5, with detailed PK analysis of APAP, metabolites, and APAP-protein adducts throughout day 5. No subject experienced adverse clinical outcomes. GLDH and K18 were significantly different at baseline but did not change in either group during APAP administration. In contrast, clearance of APAP-protein adducts was dramatically delayed in the cirrhosis group. Minor differences for other APAP metabolites were also detected. Conclusion: Short-term administration of low-dose APAP (650 mg twice per day, <1 week) is likely safe in patients with compensated cirrhosis. These data provide a foundation for future studies to test higher doses, longer treatment, and subjects who are decompensated, especially in light of the remarkably delayed adduct clearance in subjects with cirrhosis.

Bifunctionalized isotopologs as calibrants for standard-free quantitation of drug metabolites in plasma by liquid chromatography coupled with radiometry and mass spectrometry.

The reported method involves a novel workflow that eliminates the need for authentic reference standards for the quantitation of drug metabolites in biological samples using a single multi-isotopically labeled compound bearing both radio and stable isotopes. The resulting radio and stable bifunctionalized isotopolog (RADSTIL) of the parent drug is employed as a substrate for in vitro biotransformation to targeted RADSTILs of metabolites as calibrants. Inclusion of a radio label enables both radiometric and mass spectrometric detection. The addition of stable labels ensures the subsequent isotopic interference-free quantitation of unlabeled metabolites in preclinical and clinical samples. This affords a more accurate quantitation workflow compared with the current semi-quantitation method, which utilizes isotopic interfering radio isotopologs of metabolites alone as calibrants. The proof-of-concept is illustrated with (14 C,13 C2 )-acetaminophen where in vitro biotransformation produced (14 C,13 C2 )-sulfate and (14 C,13 C2 )-glucuronide calibrants. Absolute quantitation of the acetaminophen metabolites was then achieved by liquid chromatography coupled with radiometry and mass spectrometry. Quantitative data obtained by this method fell within 82-86% of the values from conventional LC-MS/MS method.

Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product.

Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.

Simultaneous determination of dantrolene and paracetamol in human plasma by liquid chromatography tandem mass spectrometry.

A simple, sensitive, rapid and specific method based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for the simultaneous quantification of dantrolene (DAN) and paracetamol (PAR) in real human plasma was developed and validated. The preparation of sample was achieved by liquid-liquid extraction with tertiary butyl methyl ether. The analysis was performed on a reversed-phase C18column (1.7 µm, 2.1 × 30 mm) using acetonitrile: 0.1% formic acid (80:20, v/v) as the mobile phase and pumped in an isocratic mode at a flow rate of 0.3 mL/min using citalopram (CIT) as an internal standard. Tandem mass spectrometric detection was carried out by both positive and negative electrospray ionization (ESI) in the multiple-reaction monitoring mode (MRM). The analysis was carried out within 1 min for each sample which made it possible to analyze more than 350 human samples per day. Validation of the method was performed according to FDA guidelines for bio-analytical method. The method was found to be linear in the range of 25-2500 ng/mL and 100-10,000 ng/mL for DAN and PAR, respectively. The method was applied successfully for the determination of the two analytes in the plasma after oral administration of Dantrelax® compound capsules to healthy volunteers. The study was accomplished after approval of the ethics committee.

Evaluation of Physiologically Based Pharmacokinetic Models to Predict the Absorption of BCS Class I Drugs in Different Pediatric Age Groups.

Age-related changes in many parameters affecting drug absorption remain poorly characterized. The objective of this study was to apply physiologically based pharmacokinetic (PBPK) models in pediatric patients to investigate the absorption and pharmacokinetics of 4 drugs belonging to the Biopharmaceutics Classification System (BCS) class I administered as oral liquid formulations. Pediatric PBPK models built with PK-Sim/MoBi were used to predict the pharmacokinetics of acetaminophen, emtricitabine, theophylline, and zolpidem in different pediatric populations. The model performance for predicting drug absorption and pharmacokinetics was assessed by comparing the predicted absorption profile with the deconvoluted dose fraction absorbed over time and predicted with observed plasma concentration-time profiles. Sensitivity analyses were performed to analyze the effects of changes in relevant input parameters on the model output. Overall, most pharmacokinetic parameters were predicted within a 2-fold error range. The absorption profiles were generally reasonably predicted, but relatively large differences were observed for acetaminophen. Sensitivity analyses showed that the predicted absorption profile was most sensitive to changes in the gastric emptying time (GET) and the specific intestinal permeability. The drug's solubility played only a minor role. These findings confirm that gastric emptying time, more than intestinal permeability or solubility, is a key factor affecting BCS class I drug absorption in children. As gastric emptying time is prolonged in the fed state, a better understanding of the interplay between food intake and gastric emptying time in children is needed, especially in the very young in whom the (semi)fed condition is the prevailing prandial state, and hence prolonged gastric emptying time seems more plausible than the fasting state.

A simple method to measure sulfonation in man using paracetamol as probe drug.

Sulfotransferase enzymes (SULT) catalyse sulfoconjugation of drugs, as well as endogenous mediators, gut microbiota metabolites and environmental xenobiotics. To address the limited evidence on sulfonation activity from clinical research, we developed a clinical metabolic phenotyping method using paracetamol as a probe substrate. Our aim was to estimate sulfonation capability of phenolic compounds and study its intraindividual variability in man. A total of 36 healthy adult volunteers (12 men, 12 women and 12 women on oral contraceptives) received paracetamol in a 1 g-tablet formulation on three separate occasions. Paracetamol and its metabolites were measured in plasma and spot urine samples using liquid chromatography-high resolution mass spectrometry. A metabolic ratio (Paracetamol Sulfonation Index-PSI) was used to estimate phenol SULT activity. PSI showed low intraindividual variability, with a good correlation between values in plasma and spot urine samples. Urinary PSI was independent of factors not related to SULT activity, such as urine pH or eGFR. Gender and oral contraceptive intake had no impact on PSI. Our SULT phenotyping method is a simple non-invasive procedure requiring urine spot samples, using the safe and convenient drug paracetamol as a probe substrate, and with low intraindividual coefficient of variation. Although it will not give us mechanistic information, it will provide us an empirical measure of an individual's sulfonator status. To the best of our knowledge, our method provides the first standardised in vivo empirical measure of an individual's phenol sulfonation capability and of its intraindividual variability. EUDRA-CT 2016-001395-29, NCT03182595 June 9, 2017.

Quantification of serum levels in mice of seven drugs (and six metabolites) commonly taken by older people with polypharmacy.

Polypharmacy (use of ≥ 5 drugs) is common in older people but has minimal preclinical or clinical evidence of safety or efficacy and is associated with adverse outcomes in older people. Drug-drug interactions are poorly understood beyond drug pairs. An efficient and sensitive method to measure multiple serum drugs and metabolites could inform drug dosing in polypharmacy. Development of a sensitive liquid chromatography - tandem mass spectrometry method to simultaneously measure seven drugs and their respective metabolites in serum in a preclinical model of polypharmacy. This method was validated for optimal recovery, matrix effect, limit of quantification (LOQ), inter- and intra-day variability, and carry over. Serum samples from mice (n = 5-6/group) treated with chronic oral doses of three polypharmacy regimens and five monotherapies were screened for drug and metabolite levels (metoprolol, α-hydroxymetoprolol, O-desmethylmetoprolol, omeprazole, 5-hydroxyomeprazole, omeprazole sulphone, acetaminophen, irbesartan, citalopram, oxybutynin, oxycodone, noroxycodone, oxymorphone and tenivastatin). The LOQ for the compounds ranged from 0.05 to 0.1 ng/mL in serum. Recovery, matrix effect, and inter- and intra-day variability peak response were acceptable. No carry over was observed at the concentrations tested. Analytes were detectable in mice treated with these drugs, and differences in drug levels were observed with different polypharmacy and monotherapy regimens. The method is sensitive and robust to measure parent drugs and metabolites simultaneously in the context of polypharmacy. Polypharmacy appeared to affect drug levels in a preclinical model. This model can be used to understand pharmacokinetics of chronic polypharmacy, which could inform prescribing and improve outcomes for older people.

Pharmacokinetics of acetaminophen after intravenous and oral administration in fasted and fed Labrador Retriever dogs.

Acetaminophen (paracetamol) is used in dogs to manage fever and mild pain. The aim of this study was to assess the pharmacokinetics of acetaminophen in both fed and fasted Labrador Retrievers after a single intravenous and oral administration (20 mg/kg). Six healthy dogs underwent three treatments in a randomized block study (a, n = 2; b, n = 2; c, n = 2). In phase one, group a received acetaminophen intravenously, group b and c orally after being fasted and fed, respectively. In phase two and three, groups were swapped, and the experiment was repeated. At the end of the trial, each dog received the same treatment. Acetaminophen plasma concentrations were detected using a validated HPLC-UV method. The pharmacokinetic analysis was performed using a noncompartmental model. Clearance, volume at steady state and half-life of acetaminophen in Labrador Retrievers were 0.42 L/kg hr, 0.87 L/kg and 1.35 hr, respectively. No significant statistical differences were found between fasted and fed dogs regarding maximum plasma concentration, time at maximum concentration and bioavailability as measured by the AUC. Feeding does not significantly affect the acetaminophen oral pharmacokinetics.

In vitro testing of the hemaPEN microsampling device for the quantification of acetaminophen in human blood.

Background: The hemaPEN is a liquid microsampling device for the reproducible collection and storage of blood samples as dried blood spots, for subsequent quantitative analysis. Materials & methods: We examined the device's ability to collect accurate and precise blood volumes, at different hematocrit levels, via in vitro studies using acetaminophen in human blood. We also investigated the impact of different user training approaches on device performance. Results: The hemaPEN demonstrated acceptable volumetric accuracy and precision, regardless of the training medium used. Issues with apparent hematocrit-dependent bias were found to be associated with the extraction process, rather than the volumetric performance of the device. Conclusion: The hemaPEN is capable of readily producing high quality blood microsamples for reproducible and accurate quantitative bioanalysis.

Density Functional Theory-Assisted Electrochemical Assay Manipulated by a Donor-Acceptor Structure toward Pharmaceutical Diagnostic.

Oxidative stress is a state of stress injury, which leads to the pathogenesis of most neurodegenerative diseases. Moreover, this is also one of the main reasons for the loss of dopaminergic neurons and the abnormal content of dopamine (DA). In the past decades, a number of studies have found that acetaminophen (AP) is metabolized and distributed in the brain when it is used as a neuroprotective compound. In this context, we proposed an electrochemical sensor based on 9-(4-(10-phenylanthracen-9-yl)phenyl)-9H-carbazole with the goal of diagnosing these two drugs in the body. Carbazole groups can easily be formed into large π-conjugated systems by electropolymerization. The introduction of anthracene exactly combined the carbazole group to establish an efficient electron donor-acceptor pattern, which enhanced π-π interaction with the electrode surface and charge transporting ability. The diagnostic platform showed good sensing activity toward the oxidation of DA and AP. The detection range for DA and AP is from 0.2 to 300 µM and from 0.2 to 400 µM, respectively. The simultaneous detection range is from 0.5 to 250 µM, which is wider than most reports. After a series of electrochemical assessments were determined, the sensor was finally developed to the analysis of pharmaceutical and human serum, displaying a meaningful potential in clinical evaluation.

The Clinical Value of Routine Acetaminophen Level Screening in Pediatric Patients Presenting to the Emergency Department.

BACKGROUND: Acetaminophen is the most common drug involved in pediatric poisonings, both intentionally and accidentally, and is the leading cause of acute liver failure among all age groups. OBJECTIVES: To define the characteristics of patients admitted to a pediatric emergency department (ED) where serum acetaminophen concentrations were measured, and to determine which variables are associated with significant risk of acetaminophen toxicity. METHODS: Acetaminophen serum concentrations were measured, in a retrospective case series, of patients younger than 18 years who had been admitted to the ED at Shamir Medical Center between 1 January 2008 and 31 December 2015. RESULTS: During the study period 180,174 children were admitted to the ED. Acetaminophen serum concentrations were measured in 209 (0.12%) patients. Mean age was 12.4 ± 5.9 years. Elevated liver enzymes were found in 12 patients, 5 of whom had documented acute liver injury. All five were older than 11years.Two cases of acute liver injury were attributable to acetaminophen ingestion. In both cases the cause was intentional overdose. Univariate analysis showed a significant (P < 0.05) correlation between detectable acetaminophen blood level and a positive history of drug or acetaminophen ingestion, and suicide attempt. Not all children with non-severe acetaminophen poisoning had been diagnosed during the study period. A positive history of acetaminophen ingestion was associated with a 28-fold higher risk for detectable acetaminophen blood level. CONCLUSIONS: In the absence of a positive history of acetaminophen ingestion and in young children with accidental intoxication, the risk of hepatotoxicity is relatively low.

In-Syringe Electrokinetic Protein Removal from Biological Samples prior to Electrospray Ionization Mass Spectrometry.

Here, an electrokinetic extraction (EkE) syringe is presented allowing for on-line electrokinetic removal of serum proteins before ESI-MS. The proposed concept is demonstrated by the determination of pharmaceuticals from human serum within minutes, with sample preparation limited to a 5× dilution of the sample in the background electrolyte (BGE) and application of voltage, both of which can be performed in-syringe. Signal enhancements of 3.6-32 fold relative to direct infusion of diluted serum and up to 10.8 fold enhancement, were obtained for basic and acidic pharmaceuticals, respectively. Linear correlations for the basic drugs by EkE-ESI-MS/MS were achieved, covering the necessary clinical range with LOQs of 5.3, 7.8, 6.1, and 17.8 ng mL-1 for clomipramine, chlorphenamine, pindolol, and atenolol, respectively. For the acidic drugs, the EkE-ESI-MS LOQs were 3.1 µg mL-1 and 2.9 µg mL-1 for naproxen and paracetamol, respectively. The EkE-ESI-MS and EkE-ESI-MS/MS methods showed good accuracy (%found of 81 % to 120 %), precision (≤20 %), and linearity (r>0.997) for all the studied drugs in spiked serum samples.

Disposable Nafion-Coated Single-Walled Carbon Nanotube Test Strip for Electrochemical Quantitative Determination of Acetaminophen in a Finger-Prick Whole Blood Sample.

A disposable electrochemical test strip for the quantitative point-of-care (POC) determination of acetaminophen (paracetamol) in plasma and finger-prick whole blood was fabricated. The industrially scalable dry transfer process of single-walled carbon nanotubes (SWCNTs) and screen printing of silver were combined to produce integrated electrochemical test strips. Nafion coating stabilized the potential of the Ag reference electrode and enabled the selective detection in spiked plasma as well as in whole blood samples. The test strips were able to detect acetaminophen in small 40 µL samples with a detection limit of 0.8 µM and a wide linear range from 1 µM to 2 mM, well within the required clinical range. After a simple 1:1 dilution of plasma and whole blood, a quantitative detection with good recoveries of 79% in plasma and 74% in whole blood was achieved. These results strongly indicate that these electrodes can be used directly to determine the unbound acetaminophen fraction without the need for any additional steps. The developed test strip shows promise as a rapid and simple POC quantitative acetaminophen assay.

​False-positive paracetamol levels in a patient with hyperbilirubinaemia: clinical perspectives.

​Serum concentrations of paracetamol are measured to investigate the cause of acute hepatitis, monitor the clearance of paracetamol from the body and to determine if supratherapeutic levels warrant treatment with N-acetylcysteine (NAC). ​A 49-year-old man treated for ischaemic colitis developed worsening renal and liver function tests. As part of the investigation of hepatorenal failure, paracetamol levels were requested, which were elevated at 14 mg/L (normal <4 mg/L) resulting in treatment with NAC. Despite treatment, levels of paracetamol remained elevated and the link between hyperbilirubinemia and false-positive paracetamol levels was identified. ​Bilirubin and its by-products have intense absorbance in the ultraviolet and visible regions of the electromagnetic spectrum, causing interference in the enzymatic colorimetric assay most commonly used to measure paracetamol concentration, resulting in false-positive paracetamol levels. Laboratories correct for this interference above a predetermined bilirubin concentration, termed the Icteric Index; however, in our case this interference occurred at a lower level of hyperbilirubinaemia than previously identified as significant. This interaction was found to be more significant at lower bilirubin levels when low or no paracetamol levels were present in the serum, resulting in a change to laboratory practice and development of a 'Sliding Scale' approach to analysis. ​Concurrent bilirubin or Icteric Index measurement is recommended for all laboratories that use the enzymatic colorimetric assay for paracetamol measurement. Lower Icteric Index or bilirubin thresholds are required when low or no paracetamol levels are present in the serum to prevent false-positive paracetamol results. We describe a new 'Sliding Scale' approach to analysis, and highlight an important interaction for clinicians to be aware of.