Evaluating preclinical emesis induced and nausea by PDE4 inhibitors

Evaluating preclinical emesis induced and nausea by PDE4 inhibitors

22 Mai Evaluating preclinical emesis induced and nausea by PDE4 inhibitors

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.

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