loreclezole and Epilepsy

Topics: Animals; Anticonvulsants; Dose-Response Relationship, Drug; Drugs, Investigational; Electroencephalography; Epilepsy; Evoked Potentials; Humans; Triazoles

Loreclezole is an experimental anticonvulsant drug. We found previously that several established anticonvulsants increase extracellular serotonin as measured by microdialysis. We have concluded that the increase in extracellular serotonin and the anticonvulsant effect produced by these anticonvulsant drugs are related in a cause and effect manner. To determine if anticonvulsant doses of loreclezole increase extracellular serotonin, we determined anticonvulsant dose-response relationships in genetically epilepsy-prone rats (GEPRs). Then, we administered ED99 doses of loreclezole to GEPRs and determined the effect on extracellular serotonin as measured by microdialysis in the striatum. We conclude that loreclezole produces a dose-related anticonvulsant effect in GEPRs and that anticonvulsant doses of loreclezole increase extracellular serotonin in these animals.

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Epilepsy; Genetic Predisposition to Disease; Hydroxyindoleacetic Acid; Microdialysis; Rats; Rats, Sprague-Dawley; Serotonin; Triazoles

Effects of loreclezole (R72063), a triazole derivative with anticonvulsant properties, were studied on field potentials in rat hippocampal slices and on different patterns of low Mg(2+)-induced epileptiform activity in combined entorhinal cortex-hippocampal slices. Lowering extracellular Mg2+ induced recurrent (10-60/min), short (40-80 ms) discharges in hippocampal areas CA1 and CA3. In the entorhinal cortex (EC) up to 90 s long ictaform events associated with large negative field potential and changes in the neuronal microenvironment were generated. These seizure like events changed their characteristics after one to two hours to recurrent discharges of 0.8 to 10 s. 20 microM loreclezole blocked the seizure like events in the entorhinal cortex completely 30-80 min after onset of application. The recurrent short discharges in the hippocampus were reliably blocked by 40 muM loreclezole 60-90 min after bath application with incomplete recovery after washout of several hours. The recurrent discharges in the entorhinal cortex were reliably blocked by 80 microM loreclezole applied for 80-100 min. Decreases in [Ca2+]o and associated slow field potentials evoked by repetitive stimulation of the stratum radiatum were depressed in a dose dependent manner, while similar changes induced by alvear stimulation remained almost unaffected. A paired pulse stimulus paradigm used to test for effect of loreclezole on synaptically evoked transient field potentials in normal medium revealed interference with mechanisms involved in frequency potentiation. While responses to alvear stimulation were largely unaffected, the response to a paired pulse stimulus to stratum radiatum was depressed over the whole range of tested stimulus intervals (15 to 150 ms). The findings suggest that loreclezole has effects on different patterns of epileptiform activity induced by extracellular low Mg2+ possibly by interfering with processes leading to frequency potentiation.

Topics: Animals; Anticonvulsants; Calcium; Cerebral Cortex; Epilepsy; Evoked Potentials; Female; Hippocampus; In Vitro Techniques; Magnesium; Rats; Rats, Wistar; Triazoles

In hippocampal slices from guinea-pig a paired-pulse stimulation protocol was used to examine the effects of loreclezole, R-(+)-etomidate, phenobarbital and pentobarbital on orthodromic and antidromic GABAergic neuronal inhibition in the CA1 region. All four compounds increased orthodromic GABAergic inhibition, with R-(+)-etomidate and pentobarbital inducing a quantitatively larger effect than loreclezole and phenobarbital. Only R-(+)-etomidate and pentobarbital increased antidromic GABAergic inhibition. We propose that all four compounds are anticonvulsant by increasing feed-forward dendritic GABAergic inhibition, whilst only the sedative/hypnotic compounds (R-(+)-etomidate, pentobarbital) increase feedback recurrent GABAergic inhibition. Loreclezole was also shown to inhibit 'low Ca2+' and 'low Mg2+' epileptogenesis at similar concentrations to those active on inhibition. Thus loreclezole may possess other pharmacodynamic properties, beyond its ability to increase feed-forward GABAergic neuronal inhibition, which contribute to its antiepileptic action.

Topics: Animals; Anticonvulsants; Calcium; Electric Stimulation; Epilepsy; Etomidate; gamma-Aminobutyric Acid; Guinea Pigs; Hippocampus; In Vitro Techniques; Magnesium Deficiency; Pentobarbital; Phenobarbital; Triazoles

Thirteen drug-resistant epilepsy patients received loreclezole as add-on therapy. The trial lasted 6 months. Loreclezole was dosed to reach a target plasma concentration between 1 and 3 mg/l. The seizure frequency in the total group decreased by 23%. A reduction of 50% or more was observed in four patients. These effects are most likely related to loreclezole, as doses and plasma levels of the associated anti-epileptic drugs remained unchanged during the study. Loreclezole was tolerated well and no changes in haematological or biochemical parameters were observed.

Topics: Adult; Anticonvulsants; Drug Resistance; Drug Therapy, Combination; Epilepsy; Female; Humans; Male; Middle Aged; Triazoles

Photosensitivity can be used as a model in short-term studies for assessing the efficacy of new antiepileptic drugs in man. As a quantitative measure of photosensitivity, the photosensitivity range is employed. This is the range between the highest and the lowest flash rate producing a photoparoxysmal response (generalized paroxysmal activity on the EEG). An efficacious new antiepileptic drug should, like all currently available antiepileptic drugs, reduce the photosensitivity range. Single-dose administration of 100-150 mg of loreclezole resulted in a decreased photosensitivity in all patients tested. This effect was attributable to loreclezole as no acute interactions with valproic acid could be demonstrated. The rapid onset of activity indicates that loreclezole readily passes the blood-brain barrier. The doses applied were very well tolerated.

Topics: Adult; Anticonvulsants; Drug Administration Schedule; Epilepsy; Female; Humans; Male; Molecular Structure; Photic Stimulation; Triazoles