Preclinical assessment of proconvulsant drug activity and its relevance for predicting adverse events in humans

Safety pharmacology studies, which are performed before first studies with investigational drugs in humans, often include experiments on proconvulsant drug activity, because such drugs are thought to promote seizures by decreasing seizure threshold. A commonly used model for the assessment of proconvulsant activity of investigational or marketed drugs is the timed intravenous pentylenetetrazole (PTZ) infusion seizure test, in which the latency to myoclonic or clonic seizures is determined by PTZ infusion in mice or rats. This test provides an extremely sensitive parametric method for assessing seizure threshold and allows detecting both anticonvulsant and proconvulsant drug effects. The aim of this review is to critically review the concept of "proconvulsant" drug activity and discuss data obtained by the PTZ and other seizure threshold tests as well as the various factors that may affect seizure threshold determinations. Furthermore, preclinical and clinical data on proconvulsant drug activity are compared. It is concluded that a battery of different tests is needed to provide the most reliable conclusions about the proconvulsant profile, if any, of drugs. Furthermore, misconceptions regarding proconvulsant drug effects, which can result in the undertreatment of brain diseases, are discussed. (C) 2009 Elsevier B.V. All rights reserved.