Abstracts

RATIONALE: Remacemide (RMD) and its active metabolite, desglycinyl remacemide (DGR), are primary amine compounds with potential applications in epilepsy and other neurological conditions. Although both compounds have recognised inhibitory effects on neuronal sodium channels and at the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor, DGR is reportedly more potent in both respects. The following studies were designed to compare the pre-clinical profiles of RMD and DGR. METHODS: The neuropharmacokinetics of RMD and DGR were determined following single drug administration to adult male ICR mice. The extent of in vitro conversion of RMD to DGR was determined in rat hippocampal slices. In both cases samples were analysed by a novel HPLC method. Finally, the pharmacological effects of RMD and DGR on 4-aminopyridine (4-AP)/zero-Mg2+- induced epileptiform spiking in rat hippocampal slices were studied. RESULTS: RMD and DGR were detectable in mouse brain 10 minutes after intraperitoneal injection of RMD (50 mg/kg). Brain concentrations of RMD and DGR approached maximal at around 30 and 120 minutes post-dosing, respectively. DGR was not detectable in hippocampal slices following exposure to RMD (500?M) for up to 30 minutes. DGR (0-100?M) decreased 4-AP/zero-Mg2+induced epileptiform activity in rat hippocampal slices, while RMD was without effect. CONCLUSIONS: These studies support the rapid in vivo conversion of RMD to DGR and suggest that the neuropharmacokinetics of DGR outlast those of the parent compound. In contrast, in vitro conversion of RMD to DGR would appear to be negligible. This observation is supported, at least in part, by clear differences in the effects of RMD and DGR on epileptiform bursting in the rat hippocampus. Further studies are required to investigate the pharmacokinetics and pharmacodynamics of RMD and DGR in greater detail.