loreclezole and Disease-Models--Animal

The study investigated the types of interactions between loreclezole (LCZ) and a variety of newly licensed antiepileptic drugs (AEDs) with different mechanisms of actions [felbamate (FBM), lamotrigine (LTG), topiramate (TPM), and oxcarbazepine (OXC)] by isobolographic analysis.. Anticonvulsant and adverse-effect profiles of combinations of LCZ with other AEDs at fixed ratios of 1:3, 1:1, and 3:1 were investigated in the maximal electroshock (MES)-induced seizures and the chimney test (as a measure of motor impairment) in mice so as to identify optimal combinations. Protective indices (PIs) and benefit indices (BIs) were calculated so that a ranking in relation to advantageous combinations could be established.. With isobolography, it was observed that the combination of LCZ and TPM, at the fixed ratios of 1:1 and 3:1, was supraadditive (synergistic; p < 0.05), whereas LCZ with TPM at the fixed ratio of 1:3 and LCZ combined with LTG, FBM, or OXC at the fixed ratios of 1:3, 1:1, and 3:1 were associated with additive interactions. Moreover, the isobolographic analysis in the chimney test revealed that only one combination tested (LCZ and TPM at the fixed ratio of 1:1) was subadditive (antagonistic; p < 0.05), whereas the remaining combinations of LCZ with LTG, FBM, or OXC (at the fixed ratios of 1:3, 1:1, and 3:1) barely displayed additivity. However, these combinations were associated with significant pharmacokinetic interactions, in that LCZ increased brain TPM (94%), OXC (21%), FBM (46%), and LTG (8%) concentrations. In addition, brain LCZ concentrations were decreased by TPM (26%), OXC (37%), LTG (42%), and FBM (19%). None of the examined combinations between LCZ and TPM, OXC, LTG, and FBM altered long-term memory in the step-through passive-avoidance task.. LCZ plus TPM appears to be a particularly favorable combination, based on the MES test and the chimney test. LCZ and OXC also is a favorable combination. However, these conclusions are confounded by the fact that LCZ is associated with significant pharmacokinetic interactions.

Topics: Animals; Anticonvulsants; Behavior, Animal; Carbamazepine; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Electroshock; Felbamate; Fructose; Kindling, Neurologic; Lamotrigine; Male; Mice; Motor Activity; Oxcarbazepine; Phenylcarbamates; Propylene Glycols; Seizures; Topiramate; Triazines; Triazoles

Loreclezole (5 mg/kg) exerted a significant protective action against amygdala-kindled rats, reducing both seizure and afterdischarge (AD) durations. Subsequently, the effect of combinations of loreclezole (at non-effective doses) with some conventional antiepileptics (at their subtherapeutic doses) was evaluated. The co-administration of loreclezole (2.5 mg/kg) with phenobarbital (15 mg/kg) or diphenylhydantoin (2.5 mg/kg) did not influence any seizure correlates. However, the combined treatment of loreclezole (2.5 mg/kg) with valproate (50 mg/kg) significantly reduced the afterdischarge duration. Its combination with carbamazepine (15 mg/kg) reduced the seizure severity (SSv) and both seizure and afterdischarge durations. Also, the concomitant treatment of loreclezole (2.5 mg/kg) with clonazepam (0.05 mg/kg) resulted in a significant decrease of seizure and afterdischarge durations. Loreclezole did not affect the free plasma concentrations of valproate or clonazepam, so a pharmacokinetic interaction is not probable. Although, loreclezole significantly increased the free plasma concentration of carbamazepine. The results point to the potential therapeutic effects of combinations of loreclezole with valproate or clonazepam.

Topics: Amygdala; Animals; Anticonvulsants; Avoidance Learning; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Kindling, Neurologic; Male; Psychomotor Performance; Rats; Rats, Wistar; Reaction Time; Seizures; Triazoles