About the project
Safety Pharmacology is defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above.
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 guidelines in 2001 has generated new challenges and resulted in suggestion to consider 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.
Aims
The primary objective of the present project is to evaluate the use of the chicken embryo in ovo model and cell culture thereof, as well as larval zebrafish, as early CNS safety pharmacology tests. Secondary objectives are to test 1) glucocorticoids dexamethasone and hydrocortisone; 2) antiepileptics valproate and lamotrigine; and 3) antidepressant fluoxetine for proliferation, apoptosis rates, Hox and Pax gene expression, number and length of neurites, and neural network activity, in several neuronal populations of the following models: chicken days 3 and 16 in ovo, cerebellar neuron culture from 16-days old chicken, and zebrafish 1 and 3 days old. In addition to shedding light on deleterious effects of these drugs on fetal CNS development and concern about the use of such drugs during pregnancy, the findings may be important for our understanding of neuronal development
Use of chicken and zebrafish will contribute to 3R (replace, reduce and refine animal testing) and may lead to routine additional test implemented in existing guidelines.
Background
The project is initiated as a network across pharmaceutical institutions (at the Universities of Tromsø and Oslo) and the Medical Faculty, University of Oslo.The project is in safety pharmacology, one 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 (project number 195484 2010–2014).