作者: Lotersztajn, Sophie ; Kraus, Nico ; Moeslein, Magnus ; Schierwagen, Robert ; Brol, Maximilian Joseph ; Rautou, Pierre-Emmanuel ; Fürst, Eike ; Trebicka, Jonel ; Gu, Wenyi ; Clària, Joan ; Uschner, Frank Erhard ; Flores Costa, Roger ; Klein, Sabine ; Duran-Güell, Marta ; Grünewald, Inga

Metabolic dysfunction-associated Steatohepatitis (MASH), is a prominent cause for liver cirrhosis. MASH-cirrhosis is responsible for liver complications and there is no specific treatment. To develop new therapeutic approaches, animal models are needed. The aim of this study was to develop a fast animal model of MASH-cirrhosis in rats reflecting the human disease. Carbon tetrachloride (CCl₄) injections in combination with a high-fat Western diet (WD) were used to induce MASH-cirrhosis. To accelerate liver injury, animals received phenobarbital (PB) in their drinking water using two different regimens. Rats developed advanced MASH-cirrhosis characterized by portal hypertension, blood biochemistry, hepatic ballooning, steatosis, inflammation and fibrosis. Importantly, rats receiving low-dose PB for the long term (LT) showed ascites after 6 weeks, whereas rats with high-dose short-term (ST) PB developed ascites after 8 weeks. ST- and LT-treated rats showed increased portal pressure (PP) and decreased mean arterial pressure (MAP). Of note, hepatocyte ballooning was only observed in the LT group. The LT administration of low-dose PB with CCl₄ intoxication and WD represents a fast and reproducible rat model mimicking decompensated MASH-cirrhosis in humans. Thus, CCl₄ + WD with LT low-dose phenobarbital treatment might be the preferred rat animal model for drug development in MASH-cirrhosis.

2024-10-01·Pharmacological Reports

Padsevonil suppresses seizures without inducing cell death in neonatal rats

Article

作者: Quinlan, Sean ; Forcelli, Patrick A ; Witherspoon, Eric

BACKGROUNDPadsevonil (PSL) is a rationally designed anti-seizure medication (ASM) which has overlapping mechanisms of action with the two most common ASMs used for neonatal seizures, phenobarbital (PB) and levetiracetam (LEV). Here we evaluated the anti-seizure properties of PSL across the neonatal and adolescent period in rats in the pentlyenetetrazole (PTZ) induced seizures model.METHODSPostnatal day (P)7, P14 and P21 Sprague-Dawley rat pups were pre-treated with PSL (1-30 mg/kg), and assessed for seizure latency and severity 30 min later following injection of PTZ. A separate cohort of P7 pups were treated with neonatal ASMs and euthanized 24 h later (on P8) to assess induction of cell death, a feature common to many ASMs when given to P7 rodents. This effect has been extensively reported with PB, but not with LEV. Cell death was assessed by PathoGreen staining.RESULTSPSL suppressed PTZ-evoked seizures across multiple age groups, particularly at higher doses, without producing increased cell death compared to vehicle. The effects of PSL were particularly notable at suppressing tonic-clonic seizure manifestations (82% of P7 and 100% of P14 and P21 animals were protected from tonic-clonic seizures with the 30 mg/kg dose).CONCLUSIONSPSL displayed dose-dependent anti-seizure effects in immature rodents in the PTZ model of seizures in immature rats. While many ASMs, including PB, induce cell death in neonatal rats, PSL does not. This suggests that PSL may offer therapeutic benefit and a favorable safety profile for the treatment of neonatal seizures.

2024-09-22·Veterinary clinical pathology

Thromboelastography in dogs with idiopathic epilepsy treated with phenobarbital monotherapy.

Article

作者: Añor, S ; de la Fuente, C ; García, R ; Pastor, J

BACKGROUNDThromboelastography (TEG) is an effective technique to assess the efficiency of coagulation. Phenobarbital (PB) can induce hematological and coagulation disorders in both animals and humans, but its effects on hemostasis have been little investigated and are poorly understood in dogs.OBJECTIVESThe aim of this article was to assess coagulation using TEG in a population of dogs with idiopathic epilepsy treated with PB.MATERIAL AND METHODSProspective observational study. TEG was performed in blood samples from dogs with idiopathic epilepsy that were divided in three groups: Two groups of treated dogs that were on phenobarbital treatment for less or more than 6 months, and a control group of healthy dogs. Duration of treatment, dose, phenobarbital serum concentration and selected hematological and biochemical parameters were evaluated and correlated with the TEG results.RESULTSNo statistically significant differences were found between groups. None of the animals appeared to be in a hypo- or hypercoagulable state, however 9/19 (47,4%) dogs were classified as hyper-fibrinolytic. A statistically significant negative relationship between MA and G values and increased fibrinolytic activity (LY30) were found. No statistically significant relationship was found between PB dose or PB blood levels and TEG parameters in either group. No bleeding complications were observed.DISCUSSIONThe rise in fibrinolysis might be due to hepatic damage from PB, as indicated by elevated liver enzymes in many dogs with abnormal fibrinolytic patterns. Although TEG showed hyperfibrinolysis in some dogs, the presence of primary or secondary hyperfibrinolysis could not be confirmed due to the lack of D-dimer measurements and liver biopsy. TEG's sensitivity compared to other fibrinolysis biomarkers like PAP might also affect results.CONCLUSIONSTThe cause of hyperfibrinolysis in epileptic dogs treated with phenobarbital remains unclear, with potential links to hepatic effects or handling, and further research is needed to assess its clinical significance.

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适应症	最高研发状态	国家/地区	公司	日期
疟疾	临床2期	-	Radboud University Nijmegen	-
疟疾	临床2期	-	Program for Appropriate Technology in Health	-
疟疾	临床2期	-	Instituto de Medicina Molecular	-