07 Nov Evaluating preclinical emesis induced by PDE4 inhibitors via a noradrenergic pathway
Emesis and/or Nausea are commonly reported side effects associated with several drugs such as 4 phosphodiesterase (PDE4) inhibitors and is a major drawback for the therapeutic use of these drugs. The mechanism responsible for this side effect has been investigated in an attempt to discover non-emetic PDE4 inhibitors.
As rodents do not possess an emetic reflex, it is not possible to directly investigate the role of different isoforms of PDE4 in preclinical emesis, however, a surrogate biological response can be observed as a measure of an emetic response: the reversal of anaesthesia induced by α2-adrenoceptor agonists. The role of this alternative biological response was assessed in ferrets, the usual model to study emesis because it has an emetic reflex. Pre-treatment with different α2-adrenoceptor antagonists caused sudden and unexpected vomiting in ferrets whereas α2-adrenoceptor agonist did not induce emesis at doses ranging from 62.5–250 μg/kg s.c.
At higher doses (250 μg/kg), it was also shown that α2-adrenoceptor agonist could also have a protective role in ferrets against emesis induced by the PDE4 inhibitors. It was postulated that PDE4 inhibitors trigger emesis by mimicking the pharmacological actions of α2-adrenoceptor antagonists by raising cyclic AMP within central noradrenergic terminals. Indeed, PDE4 inhibitors and different different α2-adrenoceptor antagonists can also reverse the hypnotic effect of α2-adrenoceptor induced anaesthesia.
These studies suggest that the ferret is an appropriate model to study emesis induced by PDE4 inhibitors and that these compounds trigger the emetic reflex via a noradrenergic pathway, mimicking the pharmacological actions of a pre-synaptic α2-adrenoceptor inhibition. In other animal models, the emetic reflex of PDE4 inhibitors could be studied by looking at a surrogate biological response, a reversal of anaesthesia induced by α2-adrenoceptor agonists
Syncrosome is an Efficacy Characterization CRO that offers relevant disease models, cutting-edge techniques and a comprehensive background of physiopathology to assist drug discovery companies. Syncrosome uses ferret models and porcine models for emesis testing of drugs.
Key words: preclinical CRO, preclinical study, animal model, disease model, animal research, efficacy testing, drug screening, nausea, emesis, emetic, noradrenergic, PDE4, PDE5, ferret, porcine, pig.