Not all partial dopamine D2 receptor agonists are the same in treating schizophrenia. Exploring the effects of bifeprunox and aripiprazole using a computer model of a primate striatal dopaminergic synapse

Species differences in physiology and unique active human metabolites contribute to the limited predictive value of preclinical rodent models for many central nervous system (CNS) drugs. In order to explore possible drivers for this translational disconnect, we developed a computer model of a dopaminergic synapse that simulates the competition among three agents and their binding to pre- and postsynaptic receptors, based on the affinities for their targets and their actual concentrations. The model includes presynaptic autoreceptor effects on neurotransmitter release and modulation by presynaptic firing frequency and is calibrated with actual experimental data on free dopamine levels in the striatum of the rodent and the primate. Using this model, we simulated the postsynaptic dopamine D2 receptor activation levels of bifeprunox and aripiprazole, two relatively similar dopamine D2 receptor agonists. The results indicate a substantial difference in dose–response for the two compounds when applying primate calibration parameters as opposed to rodent calibration parameters. In addition, when introducing the major human and rodent metabolites of aripiprazole with their specific pharmacological activities, the model predicts that while bifeprunox would result in a higher postsynaptic D2 receptor antagonism in the rodent, aripiprazole would result in a higher D2 receptor antagonism in the primate model. Furthermore, only the highest dose of aripiprazole, but not bifeprunox, reaches postsynaptic functional D2 receptor antagonism similar to 4 mg haloperidol in the primate model. The model further identifies a limited optimal window of functionality for dopamine D2 receptor partial agonists. These results suggest that computer modeling of key CNS processes, using well-validated calibration paradigms, can increase the predictive value in the clinical setting of preclinical animal model outcomes

Forty years of neuromuscular monitoring and postoperative residual curarisation : a meta-analysis and evaluation of confidence in network meta-analysis

Funding: Willy Gepts (Univeristair Ziekenhuis Brussel, Brussels, Belgium).Peer reviewedPostprin

La synapse virtuelle : quel apport pour la compréhension de la neurotransmission ?

Le traitement cholinomimétique dans la maladie d'Alzheimer a permis d'étudier la relation entre la modulation de la neurotransmission cholinergique et les aspects cliniques dans de larges essais. Deux de ces thérapies ont des activités pharmacologiques additionnelles, telles que la modulation du récepteur nicotinique pour la galantamine et l'inhibition additionnelle de la butyrylcholinestérase pour la rivastigmine. Comprendre le lien entre cette pharmacologie et les effets cliniques devient alors difficile. La simulation par modèle mathématique de cette pharmacologie complexe peut permettre d'identifier des relations spécifiques entre le mode d'action pharmacologique et les effets sur la neurotransmission cholinergique. Le modèle de synapse virtuelle est basé sur l'intégration de multiples données publiées. Le modèle est validé par la prédiction d'un résultat spécifique concernant la modulation du niveau de la dopamine et la vérification expérimentale dans des tissus striataux. Quelques exemples de cette approche dans la réalité clinique seront présentés