scholarly journals Acute Liver Failure Induced by Thioacetamide: Selection of Optimal Dosage in Wistar and Lewis Rats

2014 ◽  
pp. 491-503 ◽  
Author(s):  
E. KOBLIHOVÁ ◽  
I. MRÁZOVÁ ◽  
Z. VERNEROVÁ ◽  
M. RYSKA
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Experimental Studies ◽  
Optimal Dose ◽  
Therapeutic Window ◽  
Optimal Dosage ◽  
Lewis Rats ◽  
Human Disorder ◽  
Time Gap ◽  
Animal Size

Acute liver failure (ALF) is a clinical condition with very high mortality rate. Its pathophysiological background is still poorly understood, which necessitates a search for optimal experimental ALF models with features resembling those of the human disorder. Taking into consideration reproducibility of induction of ALF, adequate animal size, cost of animals, the required time gap between insult and death of animals (“therapeutic window”), potential risk to investigator and other aspects, administration of thioacetamide (TAA) in rats is currently most recommended. However, the fundamental details of this ALF model have not yet been evaluated. This prompted us to investigate, first, the course of ALF as induced by intraperitoneal TAA at doses increasing from 175 to 700 mg/kg BW per day. The animals’ survival rate, plasma alanine and aspartate aminotransferase activities, and bilirubin and ammonia levels were determined over the follow-up period. Second, we examined whether Wistar and Lewis rats exhibit any differences in the course of ALF induced by different TAA doses. We found that the optimal dose for ALF induction in rats is 350 mg.kg-1 i.p., given as a single injection. Wistar rats proved more susceptible to the development of TAA-induced ALF compared with Lewis rats. Collectively, our present findings provide a sound methodological background for experimental studies aimed at evaluation of pathophysiology and development of new approaches in the therapy of ALF.

Acute Liver Failure Following Minocycline Treatment – A Case Report and Review of the Literature

2012 ◽  
Vol 50 (08) ◽  
pp. 771-775 ◽  
Author(s):  
A. Kuhn ◽  
C. Weiler-Normann ◽  
C. Schramm ◽  
S. Kluge ◽  
M. Behne ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Experimental Studies ◽  
Type I ◽  
Type Ii ◽  
Minocycline Treatment ◽  
Tnf Α ◽  
Ige Mediated ◽  
Ifn Γ

AbstractWe present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

scholarly journals Hepatocyte Transplantation Attenuates the Course of Acute Liver Failure Induced by Thioacetamide in Lewis Rats

2015 ◽  
pp. 689-700 ◽  
Author(s):  
E. KOBLIHOVÁ ◽  
O. LUKŠAN ◽  
I. MRÁZOVÁ ◽  
M. RYSKA ◽  
L. ČERVENKA
Keyword(s):  
Survival Rate ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Firefly Luciferase ◽  
Clinical Syndrome ◽  
Hepatocyte Transplantation ◽  
Plasma Albumin ◽  
Lewis Rats ◽  
New Therapeutic Approaches ◽  
Recipient Liver

Acute liver failure (ALF) is a clinical syndrome resulting from widespread damage of hepatocytes, with extremely high mortality rate. Urgent orthotopic liver transplantation was shown to be the most effective therapy for ALF but this treatment option is limited by scarcity of donor organs. Therefore, hepatocyte transplantation (Tx) has emerged as a new therapeutical measure for ALF, however, the first clinical applications proved unsatisfactory. Apparently, extensive preclinical studies are needed. Our aim was to examine if hepatocytes isolated from transgenic “firefly luciferase” Lewis rats into the recipient liver would attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Untreated Lewis rats after TAA administration showed a profound decrease in survival rate; no animal survived 54 h. The rats showed marked increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, in plasma level of bilirubin and ammonia (NH3), and in a significant decrease in plasma albumin. Hepatocyte Tx attenuated the course of TAA-induced ALF Lewis rats which was reflected by improved survival rate and reduced degree of liver injury showing as lowering of elevated plasma ALT, AST, NH3 and bilirubin levels and increasing plasma albumin. In addition, bioluminescence imaging analyses have shown that in the TAA damaged livers the transplanted hepatocyte were fully viable throughout the experiment. In conclusion, the results show that hepatocyte Tx into the liver can attenuate the course of TAA induced ALF in Lewis rats. This information should be considered in attempts to develop new therapeutic approaches to the treatment of ALF.

scholarly journals Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure

2020 ◽  
Vol 174 (2) ◽  
pp. 159-167 ◽  
Author(s):  
Hartmut Jaeschke ◽  
Jephte Y Akakpo ◽  
David S Umbaugh ◽  
Anup Ramachandran
Keyword(s):  
Liver Injury ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Kinase Inhibitor ◽  
Antioxidant Activities ◽  
Clinical Problem ◽  
Therapeutic Window ◽  
Cytochrome P450 Enzymes ◽  
Protective Strategies ◽  
High Doses

Abstract Liver injury and acute liver failure caused by acetaminophen (APAP, N-acetyl-p-aminophenol, paracetamol) overdose is a significant clinical problem in most western countries. The only clinically approved antidote is N-acetylcysteine (NAC), which promotes the recovery of hepatic GSH. If administered during the metabolism phase, GSH scavenges the reactive metabolite N-acetyl-p-benzoquinone imine. More recently, it was shown that NAC can also reconstitute mitochondrial GSH levels and scavenge reactive oxygen/peroxynitrite and can support mitochondrial bioenergetics. However, NAC has side effects and may not be efficacious after high overdoses. Repurposing of additional drugs based on their alternate mechanisms of action could be a promising approach. 4-Methylpyrazole (4MP) was shown to be highly effective against APAP toxicity by inhibiting cytochrome P450 enzymes in mice and humans. In addition, 4MP is a potent c-Jun N-terminal kinase inhibitor expanding its therapeutic window. Calmangafodipir (CMFP) is a SOD mimetic, which is well tolerated in patients and has the potential to be effective after severe overdoses. Other drugs approved for humans such as metformin and methylene blue were shown to be protective in mice at high doses or at human therapeutic doses, respectively. Additional protective strategies such as enhancing antioxidant activities, Nrf2-dependent gene induction and autophagy activation by herbal medicine components are being evaluated. However, at this point, their mechanistic insight is limited, and the doses used are high. More rigorous mechanistic studies are needed to advance these herbal compounds. Nevertheless, based on recent studies, 4-methylpyrazole and calmangafodipir have realistic prospects to become complimentary or even alternative antidotes to NAC for APAP overdose.

scholarly journals Sex-Linked Differences in the Course of Thioacetamide-Induced Acute Liver Failure in Lewis Rats

2020 ◽  
pp. 835-845
Author(s):  
E KOBLIHOVÁ ◽  
Iveta MRÁZOVÁ ◽  
Z VAŇOURKOVÁ ◽  
H MAXOVÁ ◽  
M RYSKA ◽  
...  
Keyword(s):  
Survival Rate ◽  
Liver Injury ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Female Rats ◽  
Male Rats ◽  
Preclinical Studies ◽  
Preclinical Research ◽  
Lewis Rats ◽  
General Terms

Acute liver failure (ALF) is a clinical syndrome with high mortality rate, resulting from widespread hepatocyte damage. Its pathophysiological background is still poorly understood and preclinical studies evaluating pathophysiology and new potential therapeutic measures are needed. The model of ALF induced by administration of thioacetamide (TAA) in Lewis rats is recommended as optimal; however, the limitation of previous studies was that they were performed predominantly in male rats. In view of the growing recognition that sex as a biological variable should be taken into consideration in preclinical research, we examined its role in the development of TAA-induced ALF in Lewis rats. We found that, first, intact male Lewis rats showed lower survival rate than their female counterparts, due to augmented liver injury documented by higher plasma ammonia, and bilirubin levels and alanine aminotransferase activity. Second, in female rats castration did not alter the course of TAA-induced ALF whereas in the male gonadectomy improved the survival rate and attenuated liver injury, reducing it to levels observed in their female counterparts. In conclusion, we found that Lewis rats show a remarkable sexual dimorphism with respect to TAA-induced ALF, and male rats display dramatically poorer prognosis as compared with the females. We showed that testosterone is responsible for the deterioration of the course of TAA-induced ALF in male rats. In most general terms, our findings indicate that in the preclinical studies of the pathophysiology and treatment of ALF (at least of the TAA-induced form) the sex-linked differences should be seriously considered.

scholarly journals Pharmacological Stimulation of Wnt/ß-catenin Signaling Pathway Attenuates the Course of Thioacetamide-Induced Acute Liver Failure

2020 ◽  
pp. 113-126 ◽  
Author(s):  
E. KOBLIHOVÁ ◽  
I. MRÁZOVÁ ◽  
Z. VAŇOURKOVÁ ◽  
H. MAXOVÁ ◽  
S. KIKERLOVÁ ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Signaling Pathway ◽  
New Approach ◽  
Lewis Rats ◽  
Hepatocyte Regeneration ◽  
Pharmacological Stimulation ◽  
Late Treatment ◽  
Final Survival ◽  
Stimulation Of

Acute liver failure (ALF) is known for extremely high mortality rate, the result of widespread damage of hepatocytes. Orthotopic liver transplantation is the only effective therapy but its application is limited by the scarcity of donor organs. Given the importance in the liver biology of Wnt/β-catenin signaling pathway, we hypothesized that its stimulation could enhance hepatocyte regeneration and attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Chronic treatment with Wnt agonist was started either immediately after hepatotoxic insult (“early treatment”) or when signs of ALF had developed (“late treatment”). Only 23 % of untreated Lewis rats survived till the end of experiment. They showed marked increases in plasma alanine aminotransferase (ALT) activity and bilirubin and ammonia (NH3) levels; plasma albumin decreased significantly. “Early” and “late” Wnt agonist treatment raised the final survival rate to 69 % and 63 %, respectively, and normalized ALT, NH3, bilirubin and albumin levels. In conclusion, the results show that treatment with Wnt agonist attenuates the course of TAA-induced ALF in Lewis rats, both with treatment initiated immediately after hepatotoxic insult and in the phase when ALF has already developed. Thus, the pharmacological stimulation of Wnt/β-catenin signaling pathway can present a new approach to ALF treatment.

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