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ISPBIOMED-ISP - biologi og biomedisin

Safety Pharmacology: Chicken and zebrafish as models to assess changes in brain development and function

Awarded: NOK 6.0 mill.

The present research proposal is in safety pharmacology, a research area out of four recommended by the Research Council Report "Pharmaceutical Research in Norway - -An Evaluation, 2006" to be supported on the national level. It is initiated as a network across pharmaceutical institutions (at the Universities of Tromsø and Oslo) and the Medical Faculty, University of Oslo. Safety Pharmacology is defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on p hysiological functions in relation to exposure in the therapeutic range and above (ICH S7A). The main causes for drugs withdrawals from the market are adverse drug reactions, with CNS accounting for a majority of cases. The implementation of the ICH S7A g uidelines in 2001 has generated new challenges and resulted in suggestion to considering the introduction of in vitro techniques at an early stage of safety pharmacology evaluation. Recent EU/US pediatric legislation and FDA/EMEA guidelines recognize the potential differences in safety profiles of drugs in adult versus young patients. Hence safety studies are recommended to investigate key functional domains of the developing CNS. The aim of the present study is to evaluate the use of the chicken embryo i n ovo model and cell culture thereof, as well as larval zebrafish, as early CNS safety pharmacology tests. Experimental procedures will include exposure of chicken embryo or larval zebrafish and experiments in primary neuron cell culture of drugs relevant in pediatric medicine or pregnant mothers (glucocorticoids, antiepileptics, and antidepressants). Cell division, apoptosis rates, differentiation markers, neuronal morphology, and cell activity of neuronal networks will be addressed. Use of chicken and z ebrafish will contribute to 3R (replace, reduce and refine animal testing) and may lead to routine additional test implemented in existing guidelines.

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ISPBIOMED-ISP - biologi og biomedisin

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