Hours Of Overdose Research Articles

Diploid hepatocytes promote compensatory liver regeneration following acetaminophen induced acute liver injury

Background Acetaminophen (APAP) is a commonly used analgesic that can be safely used at doses under 4 g/day. When taken in excess, APAP causes acute liver injury, which leads to acute liver failure and death. APAP overdose leads to 56,000 emergency room visits and 26,000 hospitalizations annually and is the leading cause of acute liver failure in the United States. The only available pharmacological treatment, N-acetyl cysteine, is effective within hours of overdose. The only other treatment option is orthotopic liver transplantation, and this is limited by the availability of donor organs. Considering the paucity of therapeutic options, there is an urgent need to understand mechanisms of liver regeneration and repair. Most mammalian somatic cells are diploid and contain pairs of each chromosome, but there are also polyploid cells, such as hepatocytes that contain additional sets of chromosomes. Polyploid hepatocytes are among the best described, and in adult humans and mice comprise more than 25% and 90%, respectively, of the hepatocyte population. The cellular and molecular mechanisms that regulate polyploidy have been well-characterized; however, it is poorly understood if diploid and polyploid hepatocytes play specialized roles in liver injury and repair. Methods Our lab recently found that diploid hepatocytes are inherently more proliferative than polyploid hepatocytes. Additionally, we can specifically study diploid hepatocytes using mice lacking E2f7 and E2f8 in the liver (referred to as “LKO” mice), which are functionally normal, but livers are depleted of polyploid hepatocytes. Considering that liver regeneration affects the outcome of APAP-medicated injury, we asked if LKO mice enriched with highly proliferative diploid hepatocytes would respond differently than control livers. We fasted LKO and control mice for 16 hours, injected intraperitoneally with 300 mg/kg (the LD50 dose) APAP and harvested livers after 0.5, 3, 6, 12, 24, 48, 72 and 96 hours. We used these tissues to investigate differences in liver injury, necrosis, and proliferation. Results Liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were higher in control mice compared to LKO mice beginning at 3 hours. Necrotic liver tissue was abundant in control mice and was markedly reduced in LKO mice. We also measured more apoptotic, TUNEL positive hepatocytes in control mice. We next assessed the proliferation response after APAP-induced liver injury by staining tissues for PCNA which was induced by 6 hours in LKO mice compared to 24 hours in control mice. We treated wild-type 19-day old hepatocytes with 5 mM APAP for 12, 24, and 36 hours in vitro and found that diploid hepatocytes proliferate more readily compared to polyploids as marked by BrdU incorporation. Finally, we found higher doses of APAP eliminate the advantages seen in LKO mice. Conclusion Based on these data, diploid hepatocytes appear to be the main contributors of early-stage compensatory regeneration following APAP-mediated liver injury. These data suggest that, compared to polyploid hepatocytes, diploids initiate and drive liver healing/regeneration after acute injury.

Diploid Hepatocytes Resist Acetaminophen Induced Acute Liver Injury and Drive Compensatory Liver Regeneration

BackgroundAcetaminophen (APAP) is a commonly used analgesic that can be safely used at doses under 4 g/day. When taken in excess, APAP causes acute liver injury, which leads to acute liver failure and death. APAP overdose leads to 56,000 emergency room visits and 26,000 hospitalizations annually and is the leading cause of acute liver failure in the United States. The only available pharmacological treatment, N‐acetyl cysteine, is effective within hours of overdose. The only other treatment option is orthotopic liver transplantation, and this is limited by the availability of donor organs. Considering the paucity of therapeutic options, there is an urgent need to understand mechanisms of liver regeneration and repair.Most mammalian somatic cells are diploid and contain pairs of each chromosome, but there are also polyploid cells, such as hepatocytes that contain additional sets of chromosomes. Polyploid hepatocytes are among the best described, and in adult humans and mice comprise more than 25% and 90%, respectively, of the hepatocyte population. The cellular and molecular mechanisms that regulate polyploidy have been well‐characterized; however, it is poorly understood if diploid and polyploid hepatocytes play specialized roles in liver injury and repair.MethodsOur lab recently found that diploid hepatocytes are inherently more proliferative than polyploid hepatocytes. Additionally, we can specifically study diploid hepatocytes using mice lacking E2f7 and E2f8 in the liver (referred to as “LKO” mice), which are functionally normal, but livers are depleted of polyploid hepatocytes. Considering that liver regeneration affects the outcome of APAP‐medicated injury, we asked if LKO mice enriched with highly proliferative diploid hepatocytes would respond differently than control livers. We fasted LKO and control mice for 16 hours, injected intraperitoneally 300 mg/kg (the LD50 dose) APAP and harvested livers after 0.5, 3, 6, 12, 24, and 48 hours. We used these tissues to investigate differences in liver injury, necrosis, and proliferation.ResultsLiver injury enzymes, alanine aminotransferase and aspartate aminotransferase, were higher in control mice compared to LKO mice beginning at 3 hours. Necrotic liver tissue was abundant in control mice and was markedly reduced in LKO mice. We also measured more apoptotic, TUNEL positive hepatocytes in control mice. We next assessed the proliferation response after APAP‐induced liver injury by staining for PCNA which was induced by 6 hours in LKO mice compared to 24 hours in control mice. Finally, we treated wild‐type 19‐day old hepatocytes with 5 mM APAP for 12, 24, and 36 hours in vitro and found that diploid hepatocytes proliferate more readily compared to polyploids as marked by BrdU incorporation.ConclusionBased on these data, diploid hepatocytes appear to be the main contributors of early‐stage compensatory regeneration following APAP‐mediated liver injury. These data suggest that, compared to polyploid hepatocytes, diploids initiate and drive liver healing/regeneration after acute injury.Support or Funding InformationThis work supported by the NIH to AWD (R01DK103645).

Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen

Introduction: Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol–aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen.Methods: We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L).Results: Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase.Conclusions: The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

Persistent Choreoathetosis in a Fatal Olanzapine Overdose: Drug Kinetics, Neuroimaging, and Neuropathology

Atypical antipsychotics are a relatively new group of medications for the management of psychosis. Currently approved medications of this category include clozapine, risperidone, quetiapine, and olanzapine. Olanzapine was first marketed in 1996 in the United States as an atypical antipsychotic medication similar to clozapine for schizophrenia. By 2002, olanzapine was widely used and in the top 20 drugs by sales (1). Olanzapine belongs to the thienobenzodiazepine drug class and is known to have a high affinity for dopamine D2, D3, and D4 receptors, all five serotonin HT2 receptor subtypes, the 5-HT6 receptor, acetylcholine muscarinic receptors, and α1-adrenergic and histamine H1 receptors (2). The drug is well absorbed from the gut and reaches maximum plasma concentration about 6 hours after an oral dose (3). In plasma, 93% of the drug is bound to serum proteins, especially albumin (3). The drug is extensively eliminated by first-pass metabolism in the liver and has a mean elimination half-life of 30 hours, with a range of 21–54 hours (3). Olanzapine is considered to have a good overall safety profile at therapeutic doses (4). Adverse effects of olanzapine that affect the nervous system include mental status deterioration and extrapyramidal signs and, rarely, delirium, mutism, confusion, aggression, and lethargy that can progress to coma. Seizures, status epilepticus, and hypersalivation occasionally develop (5, 6). Extrapyramidal signs may include dystonia, parkinsonism, akathisia, choreoathetosis, and neuroleptic malignant syndrome (7– 9). Serious systemic complications include diabetes mellitus, tachycardia and supraventricular tachycardia, arrhythmias, and cardiopulmonary arrest (10, 11). Overdoses can lead to deaths. The American Association of Poison Control Centers Toxic Exposure Surveillance System reported the number of deaths associated with olanzapine to be six in 2000 (12), 10 in 2001 (13), and 10 in 2002 (14). Before some of these deaths, concomitant agents were ingested. The majority of deaths occurred within 12 hours of overdose, and the results of autopsies, when available, were often unremarkable (15–17). We report here a patient who survived the early phase of an overdose. He then developed coma with persistent choreoathetosis and hypersalivation, and neuroimaging and autopsy findings suggested damage to the basal ganglia.

Tricyclic antidepressant poisoning

To review poisoning with tricyclic antidepressants. English language literature search using Australian Medlars Service (1977-1989), manual search of journals and review of bibliographies in identified articles. Approximately 250 articles, abstracts and book chapters were selected for analysis. The literature was reviewed and 93 articles were selected as representative of important advances. The major features of overdose are neurological, cardiac, respiratory and anticholinergic. Life-threatening complications develop within six hours of overdose or not at all. All patients seen within six hours of overdose should have their stomachs emptied. All patients should receive activated charcoal. Coma, convulsions, respiratory depression and hypotension are treated with standard resuscitation techniques and drugs. Treat patients with significant cardiotoxicity or cardiac arrest with alkalinisation by sodium bicarbonate or hyperventilation, aiming for an arterial pH of 7.45-7.55. Lignocaine is used for ventricular arrhythmias. Other antiarrhythmic drugs are contraindicated (Class 1A, Class 1C), potentially lethal (Class II), of no benefit (phenytoin) or of unproven efficacy (Class III and Class IV). Physostigmine has no role at all. Haemodialysis and haemoperfusion are of no benefit. The death rate of those who reach hospital is 2%-3%. Most of these deaths are cardiac in origin, and are caused by direct depression of myocardial function rather than cardiac arrhythmias.

168 QRS vs. LEVEL IN PREDICTING CLINICAL SEVERITY IN ACUTE TCA OVERDOSE

From 1/6/84-6/6/84, 49 acute overdoses involving tricyclic antidepressants (TCA's) were followed for seizures and ventricular arrhythmias. Arrhythmias were defined as: idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, prolonged bigeminy or trigeminy, and asystole. Patients were divided into two groups. Group 1 (N=13): QRS < 0.1 seconds. Group 2 (N=36): QRS ≥ 0.1 seconds. Results in Group 1: 100% survival, 0% seizures or arrhythmias. Mean TCA concentration was 792 ± 621 ng/ml (range 351-2677 ng/ml). Average age: 34.4 ± 19.7 yrs. Results in Group 2: 100% survival, 33% seizures, 13.97, ventricular arrhythmias. Mean TCA concentration 1473 ± 967 ng/ml. Average age: 33.8 ± 12.4 yrs. All seizures or arrhythmias occurred within 6 hours of the overdose and resolved by 24 hours. TCA concentration did not correlate with QRS duration, symptoms, or prognosis. A QRS duration ≥ 0.1 seconds did correlate with seizures (p < 0.05), while a QRS ≥ 0.16 seconds correlated with ventricular arrhythmias (p < 0.0005). We conclude, in contrast to earlier reports, that: a) a QRS ≥ 0.1 seconds (and not peak TCA levels) identifies patients at high risk for seizures, b) similarly, a QRS ≥ 0.16 seconds identifies patients at high risk for ventricular arrhythmias, c) a QRS < 0.1 seconds effectively excludes patients from risk of seizures and/or ventricular arrhythmias, and d) seizures and/or ventricular arrhythmias occur within 6 hours and abate by 24 hours of an acute TCA overdose.