Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases

Abstract

If successfully translated to patients the GDH-based therapy might provide a less aggressive therapeutic alternative for patients with severe hyperammonemia.

Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage

“…For pharmacokinetic analysis a cocktail of caffeine (5 mg/kg), midazolam (2 mg/kg), torsemide (2 mg/kg), codeine (2 mg/kg), talinolol (1 mg/kg) and pravastatin (20 mg/kg) was injected as intravenous bolus in the tail vein of untreated mice as well as on day one after CCl 4 administration. Blood samples were collected in a time-resolved manner (2, 15, 30, 60 and 120 min) after administration of the cocktail from the portal vein, the hepatic vein and the right heart chamber as described before 29 . Three mice were used for each time point.…”

“…Hematoxylin and eosin (H&E) staining was performed in 5 µm thick formalin-fixed paraffin-embedded liver tissue sections as described before 29 . The dead cell area was quantified using Cell M software (Olympus, Hamburg, Germany) in ten representative images from each mouse.…”

Possibilities and limitations of intravital imaging

“…Two-photon imaging can be used to study compound transport in vitro and in vivo by precisely the same method. Third, spatio-temporal modelling has become a well-established technique in systems biology (Drasdo et al, 2014[3][4]; Ghallab et al, 2016[7]; Hammad et al, 2014[11]). A basic principle of spatio-temporal modelling is that tissues are reconstructed in a way that the position of each cell in a three-dimensional space is known; next further processes of interest, e.g.…”

Characterization of hepatocyte-based in vitro systems for reliable toxicity testing

“…These systems allow, at least in part, to tackle challenges like dedifferentiation or poor toxicological responses to chemicals. Such interdisciplinary endeavours should be strongly encouraged, as they will expedite the establishment of reliable in vitro systems that accurately predict chemical-induced hepatotoxicity (Ghallab et al 2016). A wide spectrum of parameters is currently used to demonstrate the acquisition of in vivo-like hepatocellular physiology and toxicity in such novel hepatic in vitro systems.…”