In this context, non-clinical seizure liability studies may reduce overall drug development costs and ensure that drugs are advanced in the clinic at doses demonstrated to be safe in relevant models. From a clinical perspective, confirmation that drug-induced seizures are self-limiting

and that conventional anti-convulsive drugs (e.g. diazepam, phenytoin or propofol) can SRT1720 chemical structure successfully treat drug-induced seizure can be of importance. Low safety margins between the anticipated efficacious plasma concentration and plasma levels that have induced seizure in some animals further increase the relevance of emergency seizure treatment confirmation. Interpretation of video-EEG data will typically be

undertaken using automated detection of seizure activity (Authier et al., 2009 and White et al., 2006) combined with manual and qualitative review of EEG by an expert. When using automated tools, a preference is given for high sensitivity over specificity to minimize the incidence of false negative events. False positive activity can be classified during manual qualitative review of EEG. Interrater agreement is recognized to be high for cases with frank seizures as observed with epilepsy (Benbadis et al., 2009). Several features of EEG traces facilitate identification of generalized seizure events including postictal depression characterized by an increase find protocol in slow low voltage activities (Kaufman, 2006). It remains that inter-observer discrepancies

in EEG interpretation are reported (Walczak, Radtke, & Lewis, 1992) especially for more subtle changes suggestive of altered seizure threshold. This highlights the importance of using baseline/pre-drug and time-matched EEG data as a reference for each individual during interpretation of post-dosing EEG traces. Abnormal EEG traces are often associated with behavioral manifestations. Consequently, qualitative EEG review at times when selected behavioral changes (e.g. tremors, myoclonus, ataxia, asymmetric posture, facial twitches, stupor, etc.) were noted is common as part of data interpretation. In some cases, telemetry implantation for EEG monitoring may interfere Thymidine kinase with the primary scientific endpoints as would be the case in general toxicology studies where histopathology is performed on an exhaustive list of organs. Surgical implantation of a telemetry transmitter may induce histopathological changes and is typically avoided in general toxicology. Surface EEG monitoring at selected timepoints for 10–30 min at each occasion based on available pharmacology data represents an alternative strategy to investigate seizure liabilities in toxicology studies. When using surface EEG electrodes, the addition of EEG monitoring immediately upon identification of selected abnormal clinical signs may increase sensitivity of the safety assessments.