Emergency medicine

Paracetamol (acetaminophen) poisoning

Hepatic in vitro models that accurately replicate phenotypes and functionality of the human liver are needed for applications in toxicology, pharmacology and biomedicine. Notably, it has become clear that liver function can only be sustained in 3D culture systems at physiologically relevant cell densities. Additionally, drug metabolism and drug-induced cellular toxicity often follow distinct spatial micropatterns of the metabolic zones in the liver acinus, calling for models that capture this zonation. We demonstrate the manufacture of accurate liver microphysiological systems (MPS) via engineering of 3D stereolithography printed hydrogel chips with arrays of diffusion open synthetic vasculature channels at spacings approaching in vivo capillary distances. Chip designs are compatible with seeding of cell suspensions or preformed liver cell spheroids. Importantly, primary human hepatocytes (PHH) and hiPSC-derived hepatocyte-like cells remain viable, exhibit improved molecular phenotypes compared to isogenic monolayer and static spheroid cultures and form interconnected tissue structures over the course of multiple weeks in perfused culture. 3D optical oxygen mapping of embedded sensor beads shows that the liver MPS recapitulates oxygen gradients found in the acini, which translates into zone-specific acet-ami-no-phen toxicity patterns. Zonation, here naturally generated by high cell densities and associated oxygen and nutrient utilization along the flow path, is also documented by spatial proteomics showing increased concentration of periportal- versus perivenous-associated proteins at the inlet region and vice versa at the outlet region. The presented microperfused liver MPS provides a promising platform for the mesoscale culture of human liver cells at phenotypically relevant densities and oxygen exposures.

A full 3D tissue culture platform is presented, enabled by massively parallel arrays of high-resolution 3D printed microperfusion hydrogel channels that functionally mimics tissue vasculature. The platform supports long-term culture of liver models with dimensions of several millimeters at physiologically relevant cell densities, which is difficult to achieve with other methods. Human liver models are generated from seeded primary human hepatocytes (PHHs) cultured for two weeks, and from seeded spheroids of hiPSC-derived human liver-like cells cultured for two months. Both model types show improved functionality over state-of-the-art 3D spheroid suspensions cultured in parallel. The platform can generate physiologically relevant oxygen gradients driven by consumption rather than supply, which was validated by visualization of embedded oxygen-sensitive microbeads, which is exploited to demonstrate zonation-specific toxicity in PHH liver models.

The liver may sustain injury from a variety of environmental, dietary and therapeutic agents. Injury from drugs and toxins may mimic patterns of injury found in other liver diseases, but different agents affect the liver in different ways. Liver biopsy of cases of suspected toxic injury may be used to exclude alternate causes of injury and assess the severity of the injury as well as to compare the injury to literature reports of toxic injury. This chapter reviews the patterns of injury observed in toxic injury as well as what is known about injury due to particular substances.

The combination of chemometrics and electrochemical sensors modified with molecularly imprinted polymers (MIPs) towards the development of MIP-based electronic tongues (ETs) was explored herein. To demonstrate the potential of such an approach, the simultaneous determination of paracetamol, ascorbic acid and uric acid mixtures in pharmaceutical samples was evaluated. To this aim, MIP-based sensors for the different compounds were prepared by in situ electropolymerization of pyrrole in the presence of p-toluenesulfonate anion (pTS⁻), which acted as functional doping ion of the polypyrrole (PPy) MIP backbone. Morphological characterization of the MIPs was done by scanning electron microscopy (SEM), while functionalization of the electrodes was monitored electrochemically. Under the optimized measuring conditions, the developed sensors showed a good performance, with good linearity at the μM level (R² > 0.992, limits of detection between 1 and 24 μM) as well as good repeatability (intra- and inter-day RSD values between 3 and 6% over 30 consecutive measurements). Finally, the quantification of the individual substances in different pharmaceutical samples was achieved by an artificial neural networks (ANNs) model, showing satisfactory agreement between expected and obtained values (R² > 0.987).

Paracetamol, also known as acetaminophen (N-acetyl-para-aminophenol, APAP) is the world’s most used over-the-counter analgesic-antipyretic drug. Despite its good safety profile, acetaminophen can cause severe hepatotoxicity in overdose, and poisoning from paracetamol has become a major public health concern. Paracetamol is now the major cause of acute liver failure in the United States and Europe. This systematic review aims at examining the likelihood of paracetamol use in Nigeria causing more liver toxicity vis-à-vis the reduced maximum recommended daily adult dose of 3 g for the 500 mg tablet. Online searches were conducted in the databases of PubMed, Google Scholar and MEDLINE for publications using terms like “paracetamol toxicity,” “acetaminophen and liver toxicity,” “paracetamol and liver diseases in Nigeria,” and other variants. Further search of related references in PubMed was carried out, and synthesis of all studies included in this review finalized. There were 94 studies that met the inclusion criteria. Evaluation of hepatic disorder was predicated mostly on a constellation of clinical features and limited clinical laboratory investigations. Determination of blood paracetamol concentration was rarely reported, thus excluding paracetamol poisoning as one of the likely causes of liver disorders in Nigeria. In Nigeria and elsewhere, several factors are known to increase paracetamol’s predisposition to liver injury. They include: the over-the-counter status of paracetamol, use of fixed-dose combinations of paracetamol with other drugs, malnutrition, dose miscalculations, and chronic alcohol consumption. The tendency to exceed the new paracetamol maximum daily dose of 3 g in Nigeria may increase its risk for hepatotoxicity than observed in the United States of America known for emphasizing lower dose of the drug. In addition to recommending the new maximal daily paracetamol dose allowance, the historical maximum daily adult dose of 4 g should be de-emphasized in Nigeria.

Cardiometabolic syndrome has been linked with dietary modification. Therefore, we investigated the effects of D-ribose-L-cysteine (DRLC) in rats fed with high fructose high fat (HFHF) diet. Twenty rats (n = 5), divided into 4 groups were concurrently exposed to HFHF and/or DRLC (250 mg/kg, p.o) during the 8 weeks study. The result showed that compared to control group, HFHF group had significant impairment in lipid and glucose homeostasis, increased cardiac xanthine oxidase, systolic blood pressure, heart rate, %body weight change and fluid intake. Also, there were significant reductions in HDL-C, cardiac (GPX, NO&GGT), feed intake and relative heart weight in the latter, relative to the former. However, there were no significant differences in most of the observed physical and biochemical changes in HFHF + DRLC group compared to control. DRLC alone did not disrupt the level of biomarkers. Conclusively, DRLC prevented the manifestation of oxidative stress and cardiometabolic syndrome in HFHF-diet fed rats.

In the present work, a glassy carbon electrode was electrochemically modified with acetaminophen. The mechanism of this modification along with the electrochemical features of the film derived from acetaminophen were investigated. In addition to cyclic voltammetry, the modified surface was subjected to analysis by XPS and ellipsometry. As anticipated for quinone/hydroquinone like structures, both the electrochemical modification process and the electrochemical behavior of the acetaminophen derivatized electrode are strongly potential and pH dependent. It was demonstrated that the voltammetric release of N-acetyl-p-benzoquinone-imine (NAPQI) and/or acetamide can be controlled through the applied potential and pH. The release of acetamide occurs after electrochemical oxidation of the acetaminophen derivatized electrode at a relatively low over-potentials followed by a hydrolysis reaction in acidic solutions. In comparison, NAPQI is released upon applying higher potentials, independent of pH.