Paracetamol dosing in hospital and on discharge for older people who are frail or have low body weight.

AIMS: To describe paracetamol dosing and liver function test (LFT) monitoring in older hospital inpatients who are frail or have low body weight. METHODS: Retrospective observational study, at a 790-bed metropolitan public health service in Australia. Patients aged ≥70 years, with body weight <50 kg or frailty index based on laboratory data (FI-Lab) score ≥0.3, who were administered paracetamol during an admission with length-of-stay >72 hours, were included. Data were extracted from electronic medical records. Paracetamol doses administered in hospital, and doses prescribed on discharge, were compared against consensus guidelines that recommended ≤60 mg/kg/d for older people weighing <50 kg, and ≤3000 mg/d for frail older people. RESULTS: In total, 240 admissions (n = 229 patients, mean age 84.7 years) were analysed. During 150 (62.5%) admissions, higher than recommended paracetamol doses were prescribed. On 138 (57.5%) occasions, patients were prescribed paracetamol on discharge, and 112/138 (81.2%) doses were higher than recommended. Most discharge prescriptions (97/138, 70.3%) were for regular administration. The median daily dose on discharge for patients <50 kg was 83.7 mg/kg (interquartile range 73.6-90.9 mg/kg). For frail patients ≥50 kg, the median daily discharge dose was 3990 mg (interquartile range 3000-4000 mg). LFTs were measured in hospital for 151/200 (75.5%) and 93/166 (56.0%) patients who received paracetamol for >48 hours and >5 days, respectively. CONCLUSION: Majority of paracetamol doses prescribed for frail or low-weight older patients in hospital and on discharge were higher than recommended in consensus guidelines. LFTs were not measured for 44% patients who received paracetamol regularly for >5 days. Further studies are needed to explore long-term outcomes of this practice.

Drug-Polymer Interactions in Acetaminophen/Hydroxypropylmethylcellulose Acetyl Succinate Amorphous Solid Dispersions Revealed by Multidimensional Multinuclear Solid-State NMR Spectroscopy.

The bioavailability of insoluble crystalline active pharmaceutical ingredients (APIs) can be enhanced by formulation as amorphous solid dispersions (ASDs). One of the key factors of ASD stabilization is the formation of drug-polymer interactions at the molecular level. Here, we used a range of multidimensional and multinuclear nuclear magnetic resonance (NMR) experiments to identify these interactions in amorphous acetaminophen (paracetamol)/hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) ASDs at various drug loadings. At low drug loading (<20 wt %), we showed that 1H-13C through-space heteronuclear correlation experiments identify proximity between aromatic protons in acetaminophen with cellulose backbone protons in HPMC-AS. We also show that 14N-1H heteronuclear multiple quantum coherence (HMQC) experiments are a powerful approach in probing spatial interactions in amorphous materials and establish the presence of hydrogen bonds (H-bond) between the amide nitrogen of acetaminophen with the cellulose ring methyl protons in these ASDs. In contrast, at higher drug loading (40 wt %), no acetaminophen/HPMC-AS spatial proximity was identified and domains of recrystallization of amorphous acetaminophen into its crystalline form I, the most thermodynamically stable polymorph, and form II are identified. These results provide atomic scale understanding of the interactions in the acetaminophen/HPMC-AS ASD occurring via H-bond interactions.

Is intrauterine exposure to acetaminophen associated with emotional and hyperactivity problems during childhood? Findings from the 2004 Pelotas birth cohort.

BACKGROUND: Longitudinal studies have consistently reported that prenatal exposure to acetaminophen can to lead to an increased risk of attention deficit-hyperactivity disorder during childhood. This study aimed to investigate the association between intrauterine exposure to acetaminophen and the presence of emotional and behavioral problems at the ages of 6 and 11 years in a low-middle income country. METHODS: We performed a prospective longitudinal population-based study using data from the 2004 Pelotas birth cohort. From the 4231 initial cohort participants, 3722 and 3566 children were assessed at 6 and 11 years of age, respectively. The outcomes were assessed using the parent version of Strengths and Difficulties Questionnaire (SDQ). The cut-off points established for the Brazilian population were used to categorize the outcomes. Crude and adjusted odds ratio were obtained through logistic regression. RESULTS: Acetaminophen was used by 27.5% (95% confidence interval [CI]: 26.1-28.9) of the mothers at least once during pregnancy. The prevalence of emotional problems at 6 and 11 years was 13.6 and 19.9%, respectively. For hyperactivity problems, prevalence was 13.9 and 16.1%, respectively. Intrauterine exposure to acetaminophen increased the odds of having emotional (odds ratio [OR] = 1.47; 95% CI: 1.07-2.02) and hyperactivity/inattention (OR = 1.42; 95% CI: 1.06-1.92) problems in 6-year-old boys. At the age of 11, a small decrease in the effect was observed for both outcomes after adjustment: OR = 1.31 (95% CI: 0.99-1.73) for emotional problems and OR = 1.25 (95% CI: 0.95-1.65) for hyperactivity/inattention in boys. No association for any phenotypes at both ages was observed for girls. CONCLUSION: The effect of intrauterine exposure to acetaminophen in emotional and hyperactivity symptoms was dependent on sex in a Brazilian cohort. While it seemed to be important for boys, mainly at 6 years of age, for girls, no association was observed.

Silicon-Based Piezo Micropumps Enable Fully Flexible Drug Delivery Patterns.

Drug release plays a crucial role in drug delivery. While current formulation approaches are capable of coarse-tuning the release profile, their precision and reproducibility are limited by the physicochemical properties of the excipients and active pharmaceutical ingredient (API). Innovative and advanced approaches are urgently needed, especially for site-specific targeting of drugs and to address their pharmacological requirements for optimal therapy. The 5 × 5 × 0.6 mm3 piezoelectric micropump developed by Fraunhofer EMFT was designed to enable precise drug delivery in a low volume format. In this study, we investigated the ability of the micropump to deliver solutions of highly soluble APIs using a wide range of customized pump profiles. Additionally, we examined the ability of the micropump to deliver suspensions containing various defined particle sizes. While results for suspensions indicate that pumping performance is highly dependent on the size and concentration of the suspended particles, results with API solutions demonstrate high precision and reproducibility of release, coupled with maximum flexibility in the release profile of the API. The piezoelectric micropump thus lays the cornerstone in the development of a wide range of innovative drug delivery profiles, enabling customized release profiles to be programmed and thus paving the way to fully personalized medicine.

High-resolution mass spectrometry identifies delayed biomarkers for improved precision in acetaminophen/paracetamol human biomonitoring.

Paracetamol/acetaminophen (N-acetyl-p-aminophenol, APAP) is a top selling analgesic used in more than 600 prescription and non-prescription pharmaceuticals. To study efficiently some of the potential undesirable effects associated with increasing APAP consumption (e.g., developmental disorders, drug-induced liver injury), there is a need to improve current APAP biomonitoring methods that are limited by APAP short half-life. Here, we demonstrate using high-resolution mass spectrometry (HRMS) in several human studies that APAP thiomethyl metabolite conjugates (S-methyl-3-thioacetaminophen sulfate and S-methyl-3-thioacetaminophen sulphoxide sulfate) are stable biomarkers with delayed excretion rates compared to conventional APAP metabolites, that could provide a more reliable history of APAP ingestion in epidemiological studies. We also show that these biomarkers could serve as relevant clinical markers to diagnose APAP acute intoxication in overdosed patients, when free APAP have nearly disappeared from blood. Using in vitro liver models (HepaRG cells and primary human hepatocytes), we then confirm that these thiomethyl metabolites are directly linked to the toxic N-acetyl-p-benzoquinone imine (NAPQI) elimination, and produced via an overlooked pathway called the thiomethyl shunt pathway. Further studies will be needed to determine whether the production of the reactive hepatotoxic NAPQI metabolites is currently underestimated in human. Nevertheless, these biomarkers could already serve to improve APAP human biomonitoring, and investigate, for instance, inter-individual variability in NAPQI production to study underlying causes involved in APAP-induced hepatotoxicity. Overall, our findings demonstrate the potential of exposomics-based HRMS approach to advance towards a better precision for human biomonitoring.

Evaluating the hepatoprotective, ameliorative and antioxidant potentials of the crude aqueous leafy extracts of Mangifera indica plant against acute paracetamol-induced hepatotoxicity in a mouse model.

Background: Drug-induced hepatotoxicity is a major public health issue of concern. It significantly affects the development of new pharmaceutical drugs and has led to the withdrawal of many promising pharmaceutical drugs from the pharmaceutical market. Aim: The aim of this study was to evaluate the hepatoprotective, ameliorative and antioxidant effects of the crude aqueous leafy extract of Mangifera indica plant and its different separating medium fractions against acute acetaminophen (paracetamol)-induced hepatotoxicity in a mouse model. Methods & materials: Twelve different groups of six mice (three males and three females) were used for this study. Acetaminophen at a single lethal hepatotoxic dose of 3 g/kg was orally administered on the seventh day to the mice in groups 2 to 12 after their 6-day pretreatment duration for the induction of hepatotoxicity; and were then left for 24 hours before the collection of specimen samples were completed, while group 1 served as control. Results: The crude aqueous leafy extract of M. indica (125-250 mg/kg) produced a dose-dependent reversal of the lethal hepatotoxic effect of oral 3 g/kg dose of paracetamol. At the dose of 250 mg/kg, it significantly (p < 0.0001) reduced the levels of hepatic enzymes markers (alanine transaminase [ALT], aspartate transaminase [AST] and alkaline phosphatase [ALP]) in the serum of treated animals. Also, the effects of the crude aqueous leafy extract were found to be statistically significant (p < 0.0001) more than that of its different separating medium fractional components. Conclusion: The findings from this study demonstrated that the crude aqueous leafy extract of M. indica possesses hepatoprotective effect, possibly mediated through the induction of antioxidant enzymes to prevent the occurrence of oxidative stress damage or most likely through the inhibition of pro-inflammatory mediators which are being induced by the lethal hepatotoxic dose of paracetamol.

Mechanism of dasabuvir inhibition of acetaminophen glucuronidation.

OBJECTIVES: Acetaminophen (APAP) (paracetamol) is a widely used non-prescription drug for pain relief and antipyretic effects. The clearance of APAP is mainly through phase-2 biotransformation catalysed by UDP-glucuronosyl transferases (UGT). Dasabuvir is an anti-hepatitis C drug reported to inhibit several UGT isoforms. The study evaluated the in-vitro inhibitory capacity of dasabuvir versus APAP glucuronidation. METHODS: Procedures included human liver microsomal incubations with APAP and isoform-selective probe substrates. KEY FINDINGS: Dasabuvir inhibited APAP metabolism by a reversible, mixed-type (competitive and non-competitive) partial inhibition, with an inhibition constant Ki = 3.4 µM. The index constant 'a' was 6.7, indicating the relative contribution of competitive and non-competitive inhibition. The enzyme-inhibitor complex was still able to catalyse the reaction by 12% of the control capacity. Dasabuvir produced strong partial inhibition effect of UGT1A1 and UGT1A9 and relatively complete inhibition of UGT1A6. CONCLUSIONS: Consistent with previous reports, dasabuvir inhibits the activity of 3 UGT isoforms associated with APAP metabolism. In-vitro to in-vivo scaling by 2 different approaches showed identical results, predicting an increased AUC of APAP by a factor of 1.3-fold with coadministration of dasabuvir. Until the findings are confirmed in clinical drug interaction studies, APAP dosage should not exceed 3 g per day in dasabuvir-treated patients to avoid potentially hepatotoxic APAP exposures.

Selenium Status in Diet Affects Acetaminophen-Induced Hepatotoxicity via Interruption of Redox Environment.

Aims: Drug-induced liver injury, especially acetaminophen (APAP)-induced liver injury, is a leading cause of liver failure worldwide. Mouse models were used to evaluate the effect of microelement selenium levels on the cellular redox environment and consequent hepatotoxicity of APAP. Results: APAP treatment affected mouse liver selenoprotein thioredoxin reductase (TrxR) activity and glutathione (GSH) level in a dose- and time-dependent manner. Decrease of mouse liver TrxR activity and glutathione level was an early event, and occurred concurrently with liver damage. The decreases in the GSH/glutathione disulfide form (GSSG) ratio and TrxR activity, and the increase of protein S-glutathionylation were correlated with the APAP-induced hepatotoxicity. Moreover, in APAP-treated mice both mild deprivation and excess supplementation with selenium increased the severity of liver injury compared with those observed in mice with normal dietary selenium levels. An increase in the oxidation state of the TrxR-mediated system, including cytosolic thioredoxin1 (Trx1) and peroxiredoxin1/2 (Prx1/2), and mitochondrial Trx2 and Prx3, was found in the livers from mice reared on selenium-deficient and excess selenium-supplemented diets upon APAP treatment. Innovation: This work demonstrates that both Trx and GSH systems are susceptible to APAP toxicity in vivo, and that the thiol-dependent redox environment is a key factor in determining the extent of APAP-induced hepatotoxicity. Dietary selenium and selenoproteins play critical roles in protecting mice against APAP overdose. Conclusion: APAP treatment in mice interrupts the function of the Trx and GSH systems, which are the main enzymatic antioxidant systems, in both the cytosol and mitochondria. Dietary selenium deficiency and excess supplementation both increase the risk of APAP-induced hepatotoxicity.

Evaluation of the dentate gyrus in adult mice exposed to acetaminophen (paracetamol) on postnatal day 10.

Acetaminophen (AAP; or paracetamol) is a widely used nonprescription drug with antipyretic and analgesic properties. Alarmingly, there is an increasing body of evidence showing that developmental exposure to AAP is associated with adverse behavioural outcomes later in life. We have previously shown that relevant doses of AAP in 10-day-old mice affected memory, learning and locomotor activity in the adult animals. Interestingly, the neurons of the dentate gyrus (DG) have a relatively late time of origin as they are generated during the first two weeks of postnatal life in rodents. Since the generation of these cells, which are important for memory processing, coincides with our AAP exposure, we aim to investigate if the cytoarchitecture of the DG is affected by postnatal day 10 AAP treatment. In addition, we investigate if markers for differentiation and migration in the hippocampus were affected by the same treatment. We did not observe any visual effects in adult DG cytoarchitecture, nor any changes of markers for differentiation/migration in the hippocampus in 24 hr after exposure. Even though a large effect size was estimated on adult DG thickness following AAP exposure, the estimated 95% CIs around the differences of the means reveal no significant effect. Hence, larger sample sizes are warranted to clarify if neonatal AAP exposure affects adult DG thickness in mice.

Effects of naloxone and flumazenil on antinociceptive action of acetaminophen in rats.

BACKGROUND: Studies of acetaminophen suggest that multiple nociceptive pathways are involved in the drug's analgesic action. OBJECTIVE: The purpose of this study was to determine whether naloxone and flumazenil were able to modify or antagonize the antinociceptive effect of acetaminophen in rats. METHODS: Adult albino Wistar rats were used in the study and randomly allocated to 1 of 4 groups. The acetaminophen group (A group) was administered IP saline and then 300 mg/kg IP acetaminophen 5 minutes thereafter. The acetaminophen + naloxone group (AN group) was pretreated with 1 mg/kg IP naloxone, followed by 300 mg/kg IP acetaminophen 5 minutes later. The acetaminophen + flumazenil group (AF group) was pretreated with 1 mg/kg IP flumazenil, followed by 300 mg/kg IP acetaminophen 5 minutes later. The control group received 2.5 mL IP saline, followed by an additional 2.5 mL IP injection of saline 5 minutes later. The paw-withdrawal latency period of the rats was assessed by an investigator blinded to treatment using the hot-plate test at 30, 45, 60, and 90 minutes after administration of acetaminophen. RESULTS: Thirty-two rats were evenly randomized by envelope method into 4 groups of 8 rats each. Baseline values for the A, AN, AF, and control groups were not significantly different (9.1 [2.3], 10.5 [2.7], 9.8 [3.0], and 8.9 [1.4] sec, respectively). In the AF group, flumazenil appeared to antagonize the analgesic effect exerted by the acetaminophen in the hot-plate test (30 min, 10.3 [3.7] sec; 45 min, 11.7 [5.1] sec; 60 min, 12.1 [5.1] sec; and 90 min, 12.2 [4.9] sec) and values were not significantly different from those obtained in the control group (30 min, 9.8 [2.2] sec; 45 min, 9.0 [1.6] sec; 60 min, 9.2 [1.6] sec; and 90 min, 8.5 [2.0] sec). In the AN group, naloxone did not significantly affect the values observed in the hot-plate test (30 min, 18.0 [4.5] sec; 45 min, 21.5 [7.8] sec; 60 min, 20.5 [5.9] sec; and 90 min, 22.3 [7.4] sec) and values at all time points were not significantly different from those obtained in the A group (30 min, 17.8 [7.6] sec; 45 min, 20.9 [6.9] sec; 60 min, 21.5 [7.3] sec; and 90 min, 23.8 [8.6] sec). All postbaseline values in the A and AN groups were significantly increased versus baseline and versus the control group values (all, P < 0.05). All postbaseline values in the A group were significantly greater than those in the AF group (all, P < 0.05). CONCLUSION: Flumazenil antagonized the analgesic effect exerted by acetaminophen, while naloxone had no significant effect on acetaminophen's antinociceptive action in this pain model in rats.

A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis.

Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline.

Trem-2 Promotes Emergence of Restorative Macrophages and Endothelial Cells During Recovery From Hepatic Tissue Damage.

Macrophages are pivotal in mounting liver inflammatory and tissue repair responses upon hepatic injury, showing remarkable functional plasticity. The molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) and chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts of liver macrophages and impacts endothelial cell differentiation during tissue recovery. Trem-2 gene ablation led to a delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. During tissue recovery, we found that macrophages transitioning to Kupffer cells expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with a unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2. During tissue recovery, lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs), whose transcriptional program was compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and by striking in vitro morphological changes towards typical endothelial cells. In conclusion, we found that the dynamics of liver macrophages in response to liver injury are critically controlled by Trem-2 and this regulation is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from pro-inflammatory to tissue repair phase by driving the acquisition of restorative properties in phagocytic macrophages.

Pharmacotherapy for patent ductus arteriosus closure.

Even though up to 60% of premature infants less than 28 weeks gestation develop persistent patent ductus arteriosus (PDA), there remains controversy regarding if, when, and how to close the PDA. Failure to close the PDA has been associated with significant morbidity but no cause-and-effect has been proven for short-term or long-term outcomes in modern times. Surgical closure has the advantage of eliminating the PDA, but short-term complications and long-term adverse outcomes are worrisome. Intravenous indomethacin has been the "gold standard" for pharmacologic treatment over the past 40 years with high closure rates and decreased incidence of severe intraventricular hemorrhage (IVH) and pulmonary hemorrhage with early treatment but without improvement in long-term outcomes and with risk of renal toxicity. Intravenous ibuprofen has less vasoconstrictive toxicity than indomethacin with comparable closure rates but without improvement in IVH and with hyperbilirubinemia risks. Earlier this decade, acetaminophen (paracetamol) was discovered to effectively close the PDA with good short-term safety profile. Although promising, acetaminophen treatment requires further studies regarding long-term safety as well as ideal dosing and route of administration.

A Single δ9-Tetrahydrocannabinol (THC) Dose During Brain Development Affects Markers of Neurotrophy, Oxidative Stress, and Apoptosis.

δ9-tetrahydrocannabinol (THC) is one of the most used drugs during pregnancy and lactation and efficiently crosses the placental and blood-brain barriers. Despite the recent legalization initiatives worldwide, the adverse outcome pathway (AOP) of THC following exposure during brain development is incompletely understood. We have previously reported that a single injection of THC on postnatal day (PND) 10 altered adult spontaneous behavior and habituation rates in adult mice. Similar behavioral alterations have been reported following PND 10 exposure to the commonly used over-the-counter analgesic acetaminophen (AAP; also known as paracetamol); as both THC and AAP interact with the endocannabinoid system, we hypothesize that this system might be involved in the AOP of both these pharmaceuticals/drugs. Here, we report that a single THC dose on PND 10 decreased transcript levels of tropomyosin receptor kinase b (Trkb) 24 h after exposure in both the frontal and parietal cortex, and in the hippocampus in mice. An increase in the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) ratio were also found in both the parietal cortex and hippocampus following neonatal exposure to THC. In addition, THC exposure increased transcript levels of cannabinoid receptor type 1 (Cb1r) in the parietal cortex and increased the apoptosis regulator BAX in the frontal cortex. This study is important for mainly 3 reasons: 1) we are starting to get information on the developmental neurotoxic AOP of PND 10 exposure to THC, where we suggest that transcriptional changes of the neurotrophic receptor Trkb are central, 2) our PND 10 exposure model provides information relevant to human exposure and 3) since PND 10 exposure to AAP also decreased Trkb transcript levels, we suggest THC and AAP may share key events in their respective AOP through endocannabinoid-mediated alterations of the brain-derived neurotrophic factor (BDNF)-TRKB signaling pathway.

EDC IMPACT: Is exposure during pregnancy to acetaminophen/paracetamol disrupting female reproductive development?

Concern has been raised over chemical-induced disruption of ovary development during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggests that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario. Therefore, in this review, we discuss three recent reports that collectively indicate that prenatal exposure in a period of 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in the reduction of primordial follicles, irregular menstrual cycle, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause. This could especially affect the Western parts of the world, where the age for childbirth is continuously being increased and acetaminophen is recommended during pregnancy for pain and fever. We therefore highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches.

Fetal programming of mental health by acetaminophen? Response to the SMFM statement: prenatal acetaminophen use and ADHD.

INTRODUCTION: A number of studies indicate that acetaminophen taken during pregnancy may have a programming effect on the fetal brain development. The potential adverse consequences may only surface to clinical detection years later. Should we act on these findings now or do we wait for additional evidence? Areas covered: We argue for action inspired by these well analyzed studies that are based on five prospective cohorts data collected from different countries. Several analytical options have been employed especially to address confounding, and all analyses have consistently suggested that confounding alone is an unlikely explanation for this disturbing observation. Expert opinion: Acetaminophen is often used for minor symptom or discomfort where the treatment has no strong indication and carries little, if any risk for the pregnant women. The harm of doing nothing may well exceed the harm for taking precautionary actions considering the consequences at stake.

Anaphylaxis following intravenous paracetamol: the problem is the solution.

Paracetamol is a ubiquitous analgesic and antipyretic that is widely administered, including by anaesthetists. Immediate hypersensitivity reactions to intravenous paracetamol are particularly rare. We report two cases involving four separate episodes of anaphylaxis to intravenous paracetamol in different perioperative settings without a past history of intolerance to the oral form. The allergological investigations are described, during which it became evident that both patients were allergic to an excipient (mannitol) present in the formulation and that neither was allergic to the principal agent (paracetamol). The importance of referral and investigation of perioperative drug reactions is underscored by these two cases.

"But it's just paracetamol": Caregivers' ability to administer over-the-counter painkillers to children with the information provided.

OBJECTIVE: To determine whether caregivers are able to make informed decisions about their families' use of over-the-counter (OTC) painkillers through access to and use of three mechanisms of information provision. METHODS: A cross sectional, face-to-face questionnaire was administered to 60 caregivers and seven pharmacists in Cape Town, South Africa. Caregivers answered questions related to paracetamol (acetaminophen) labels, inserts and Patient Information Leaflets (PIL). RESULTS: Most study caregivers received labels with the painkillers they purchased. Many pharmacists (43%) felt that the information provided was ineffective in preventing overdosing. Study caregivers found it difficult to understand the scientific terms in all three mechanisms of information provision. Most respondents (80%) found the PIL easiest to understand, yet few had received PILs with their purchase. Ten percent of literate respondents were unable to understand the dosage requirements for children. CONCLUSION: Most caregivers are not able to make informed decisions from the information provided with OTC painkillers. This is mostly attributable to limited provision of information and low health literacy. PRACTICE IMPLICATIONS: Written information with OTC medications in simple language and verbal counselling at dispensaries would play a significant role in increasing the health literacy of especially at risk populations of over-dosing their children.

Simultaneous quantification of acetaminophen and five acetaminophen metabolites in human plasma and urine by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry: Method validation and application to a neonatal pharmacokinetic study.

Drug metabolism plays a key role in acetaminophen (paracetamol)-induced hepatotoxicity, and quantification of acetaminophen metabolites provides critical information about factors influencing susceptibility to acetaminophen-induced hepatotoxicity in clinical and experimental settings. The aims of this study were to develop, validate, and apply high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS) methods for simultaneous quantification of acetaminophen, acetaminophen-glucuronide, acetaminophen-sulfate, acetaminophen-glutathione, acetaminophen-cysteine, and acetaminophen-N-acetylcysteine in small volumes of human plasma and urine. In the reported procedures, acetaminophen-d4 and acetaminophen-d3-sulfate were utilized as internal standards (IS). Analytes and IS were recovered from human plasma (10µL) by protein precipitation with acetonitrile. Human urine (10µL) was prepared by fortification with IS followed only by sample dilution. Calibration concentration ranges were tailored to literature values for each analyte in each biological matrix. Prepared samples from plasma and urine were analyzed under the same HPLC-ESI-MS/MS conditions, and chromatographic separation was achieved through use of an Agilent Poroshell 120 EC-C18 column with a 20-min run time per injected sample. The analytes could be accurately and precisely quantified over 2.0-3.5 orders of magnitude. Across both matrices, mean intra- and inter-assay accuracies ranged from 85% to 112%, and intra- and inter-assay imprecision did not exceed 15%. Validation experiments included tests for specificity, recovery and ionization efficiency, inter-individual variability in matrix effects, stock solution stability, and sample stability under a variety of storage and handling conditions (room temperature, freezer, freeze-thaw, and post-preparative). The utility and suitability of the reported procedures were illustrated by analysis of pharmacokinetic samples collected from neonates receiving intravenous acetaminophen.

A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.

Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.