< Back to previous page

Project

Optimalization of a biomodulation protocol to attenuate ichemia/reperfusion injury in view of expanding the amount of organs for transplantation.

Liver transplantation is the preferred treatment for patients with irreversible liver failure. The results of liver transplantation are excellent (European Liver Transplant Registry). The application of liver transplantation is however limited by the shortage in donor organs. On equal pace the mortality of the patients on the liver waiting list increases. To compensate for this shortage, more marginal donors such as non-heart-beating donors (NHBD) are transplanted. These organs develop in situ however warm ischemic damage and upon transplantation have a higher probability for morbidity and mortality. The experimental large animal liver transplantation model developed in our research group reflexes exactly the clinical practice. In this model we studied the maximal tolerance for warm ischemia, data that were clinically unknown. To attenuate the risk for PNF, a study was conducted to modulate warm ischemia damage in the graft as well as in the receptor. We developed a multi-factorial drug cocktail, based on the action mechanisms that were unraveled during the tolerance study. Application of this cocktail resulted in a spectacular improvement of the function of NHBD-livers after transplantation (control group: 5/9 transplant failure, vs. 0/6 for the cocktail protocol) and short term survival of the receptor (control group: 2/9 vs. 5/6 in the cocktail protocol, p=0.038). Despite these positive results, several pertinent questions still exist regarding the mechanisms and interactions. To address these question we want to investigate other drugs (working on other molecular mechanisms) in a rat model to determine the optimal protocol for each separately. We want to combine these drug with the first formulation into a new protocol that then can be evaluated in the pig model as next step to clinical application. 3. Objectives: a) The role of apotransferrine administration in ischemia reperfusion injury: short and long term effects in rat b) The role of alpha-1-acido-glycoproteïne administration in ischemia reperfusion injury: short and long term effects in rat c) The role of C1-esterase administration in ischemia reperfusion injury: short and long term effects in rat d) Combination of the optimal drug dose in rat: short and long term effects e) To test the optimized cocktail in a large animal model
Date:1 Jan 2009 →  31 Dec 2012
Keywords:Transplantation
Disciplines:Immunology, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences