Fomepizole is a promising new treatment for preventing liver injury following paracetamol (acetaminophen) overdose. However, we need robust clinical trials to be performed to demonstrate its effect ...on clinical outcomes that are important to our patients and important to healthcare providers. Until such trials are performed, the toxicology community should learn the lessons from the COVID pandemic—potential novel therapeutic options may be theoretically appealing, but their effectiveness needs to be assessed in robust clinical trials before they are used in clinical practice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
Post‐transcriptional gene silencing targets and degrades mRNA transcripts, silencing the expression of specific genes. RNA interference technology, using synthetic structurally well‐defined ...short double‐stranded RNA (small interfering RNA siRNA), has advanced rapidly in recent years. This introductory review describes the utility of siRNA, by exploring the underpinning biology, pharmacology, recent advances and clinical developments, alongside potential limitations and ongoing challenges. Mediated by the RNA‐induced silencing complex, siRNAs bind to specific complementary mRNAs, which are subsequently degraded. siRNA therapy offers advantages over other therapeutic approaches, including ability of specifically designed siRNAs to potentially target any mRNA and improved patient adherence through infrequent administration associated with a very long duration of action. Key pharmacokinetic and pharmacodynamic challenges include targeted administration, poor tissue penetration, nuclease inactivation, rapid renal elimination, immune activation and off‐target effects. These have been overcome by chemical modification of siRNA and/or by utilising a range of delivery systems, increasing bioavailability and stability to allow successful clinical translation. Patisiran (hereditary transthyretin‐mediated amyloidosis) was the first licensed siRNA, followed by givosiran (acute hepatic porphyria), lumasiran (primary hyperoxaluria type 1) and inclisiran (familial hypercholesterolaemia), which all use
N
‐acetylgalactosamine (GalNAc) linkage for effective liver‐directed delivery. Others are currently under development for indications varying from rare genetic diseases to common chronic non‐communicable diseases (hypertension, cancer). Technological advances are paving the way for broader clinical use. Ongoing challenges remain in targeting organs beyond the liver and reaching special sites (e.g., brain). By overcoming these barriers, siRNA therapy has the potential to substantially widen its therapeutic impact.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Exosomes are released from multiple cell types, contain protein and RNA species, and have been exploited as a novel reservoir for disease biomarker discovery. They can transfer information between ...cells and may cause pathology, for example, a role for exosomes has been proposed in the pathophysiology of Alzheimer's disease. Although studied in several biofluids, exosomes have not been extensively studied in the cerebrospinal fluid (CSF) from humans. The objective of this study was to determine: 1) whether human CSF contains exosomes and 2) the variability in exosomal protein content across individuals.
CSF was collected from 5 study participants undergoing thoraco-abdominal aortic aneurysm repair (around 200 - 500 ml per participant) and low-density membrane vesicles were concentrated by ultracentrifugation. The presence of exosomes was determined by western blot for marker proteins, isopycnic centrifugation on a sucrose step gradient and transmission electron microscopy with immuno-labelling. Whole protein profiling was performed using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR).
Flotillin 1 and tumor susceptibility gene 101 (TSG101), two exosomal marker proteins, were identified in the ultracentrifugation pellet using western blot. These markers localized to a density consistent with exosomes following isopycnic centrifugation. Transmission electron microscopy visualized structures consistent with exosomes in size and appearance that labelled positive for flotillin 1. Therefore, the pellet that resulted from ultracentrifugation of human CSF contained exosomes. FT-ICR profiling of this pellet was performed and 84-161 ions were detected per study participant. Around one third of these ions were only present in a single study participant and one third were detected in all five. With regard to ion quantity, the median coefficient of variation was 81% for ions detected in two or more samples.
Exosomes were identified in human CSF and their proteome is a potential new reservoir for biomarker discovery in neurological disorders such as Alzheimer's disease. However, techniques used to concentrate exosomes from CSF need refinement to reduce variability. In this study we used relatively large starting volumes of human CSF, future studies will focus on exosome isolation from smaller 'real life' clinical samples; a key challenge in the development of exosomes as translational tools.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Poisoning by paracetamol Dear, James W
Medicine (Abingdon. 1995, UK ed.),
June 2024, 2024-06-00, Volume:
52, Issue:
6
Journal Article
Peer reviewed
Paracetamol overdose is common. If left untreated, liver and/or renal failure can develop. Administration of the antidote, acetylcysteine, within 8–10 hours of overdose minimizes or prevents liver ...damage. After overdose, the tests used to identify that patients are at risk of liver injury are well established but have limitations. Once liver injury has occurred, important prognostic factors are the presence of hepatic encephalopathy, the international normalized ratio, acid–base status and renal function. The only treatment for acute liver failure is transplantation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Drug‐induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, ...and new markers and mediators of DILI still need to be identified. This review highlights the strengths and weaknesses of using zebrafish as a high‐throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different from that of the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways to those in humans; they possess a wide range of cytochrome P450 enzymes that enable metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de‐ethylation. Following exposure to a range of hepatotoxic drugs, the zebrafish liver develops histological patterns of injury comparable to those of mammalian liver, and biomarkers for liver injury can be quantified in the zebrafish circulation. The zebrafish immune system is similar to that of mammals, but the zebrafish inflammatory response to DILI is not yet defined. In order to quantify DILI in zebrafish, a wide variety of methods can be used, including visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring of histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
INTRODUCTIONLiver toxicity due to medicines (drug-induced liver injury) is a challenge for clinicians and drug developers. There are well-established biomarkers of drug-induced liver injury, which ...are widely used and validated by decades of clinical experience. These include alanine aminotransferase and bilirubin. Limitations of the current biomarkers are well described, and this has resulted in global efforts to identify and develop new candidates. This process has been aided by regulatory pathways being established for biomarker qualification. This article aims to provide a broad overview of the mechanisms of liver toxicity and discuss emerging novel biomarkers. There is a focus on the recent advances in the identification and validation of novel biomarkers, their potential applications in drug development and clinical practice, and the challenges and opportunities in translating these biomarkers into routine clinical use. CURRENT GOLD-STANDARD BIOMARKERSAlanine and aspartate aminotransferase activities perform well in diagnosing established drug-induced liver injury but may lack specificity and are not prognostic. THE BURDEN OF PROOF FOR NOVEL BIOMARKERSThe amount of evidence required for a new biomarker will depend on its context-of-use, specifically on the impact on patient outcome of a false negative or false positive result. LEADING POTENTIAL BIOMARKERSCytokeratin-18, glutamate dehydrogenase, microRNA-122, high-mobility group box 1 proteins, osteopontin, and macrophage colony-stimulating factor receptor 1 are examples of lead candidates. POTENTIAL APPLICATIONS OF NOVEL BIOMARKERSThe early detection of drug-induced liver injury, interpretation of an alanine aminotransferase activity increase, and decisions about dose escalation in clinical trials may all be informed by new biomarkers. CONCLUSIONSThere have been numerous exploratory studies describing differences in biomarkers and their potential value in risk-stratifying populations or identifying specific patients who may be failed by current assessment protocols. Additionally, the use of exploratory biomarkers to guide clinical trial decision-making is becoming routine. The challenge is now clinically validating leading candidate biomarkers in the assessment of patients presenting with conditions such as paracetamol overdose, which place them at risk of acute liver injury. This will require robust clinical trials. If the use of these biomarkers is to be widely adopted, they will need to unequivocally demonstrate benefit in overall cost, morbidity or mortality.
This study presents a new strategy and level of mechanistic understanding for ultrasensitive detection of short, non-coding RNAs without target amplification or chemical modification using ...electrochemical biosensors. Electrochemical impedance spectroscopy (EIS) has been used for probe target interaction detection because of its high utility for sensitive and label-free measurements of the nucleic acid targets as a result of hybridisation. EIS measurements of different probe target combinations in a range of spatial orientations and sequence overlaps showed that bringing the target overhangs closer to the nanometer proximity of the electrode surface improved the EIS signal significantly. Systematic investigations using different lengths of overhangs towards the electrode surface revealed proportionally higher EIS signals with increasing lengths of the overhangs. Our observations could be explained using the Poisson-Boltzmann and Gouy-Chapman model and followed our experimental modelling. In conclusion, the optimized arrangements of our EIS biosensor system enabled us to detect microRNA-122, a known biomarker for liver injury, as well as three common isoforms to a 1 nM (equivalent to 80 fmole) detection limit. This will enable us to develop solutions for the detection of this important blood biomarker at point of care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acetaminophen overdose is a common reason for hospital admission and the most frequent cause of hepatotoxicity in the Western world. Early identification would facilitate patient‐individualized ...treatment strategies. We investigated the potential of a panel of novel biomarkers (with enhanced liver expression or linked to the mechanisms of toxicity) to identify patients with acetaminophen‐induced acute liver injury (ALI) at first presentation to the hospital when currently used markers are within the normal range. In the first hospital presentation plasma sample from patients (n = 129), we measured microRNA‐122 (miR‐122; high liver specificity), high mobility group box‐1 (HMGB1; marker of necrosis), full‐length and caspase‐cleaved keratin‐18 (K18; markers of necrosis and apoptosis), and glutamate dehydrogenase (GLDH; marker of mitochondrial dysfunction). Receiver operator characteristic curve analysis and positive/negative predictive values were used to compare sensitivity to report liver injury versus alanine transaminase (ALT) and International Normalized Ratio (INR). In all patients, biomarkers at first presentation significantly correlated with peak ALT or INR. In patients presenting with normal ALT or INR, miR‐122, HMGB1, and necrosis K18 identified the development of liver injury (n = 15) or not (n = 84) with a high degree of accuracy and significantly outperformed ALT, INR, and plasma acetaminophen concentration for the prediction of subsequent ALI (n = 11) compared with no ALI (n = 52) in patients presenting within 8 hours of overdose. Conclusion: Elevations in plasma miR‐122, HMGB1, and necrosis K18 identified subsequent ALI development in patients on admission to the hospital, soon after acetaminophen overdose, and in patients with ALTs in the normal range. The application of such a biomarker panel could improve the speed of clinical decision‐making, both in the treatment of ALI and the design/execution of patient‐individualized treatment strategies. (Hepatology 2013;58:777–787)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular ...cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5-15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.
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