Abstracts

Rationale: Recently, the imidazolinone derivative imepitoin (Pexion , Boehringer Ingelheim Vetmedica/Germany) has been approved for treatment of canine epilepsy in Europe. Imepitoin acts as a low-affinity partial agonist at the benzodiazepine (BZD) site of the GABA_A receptor being the first compound with such mechanism that has been developed as an antiepileptic drug (AED). This mechanism offers several advantages compared to full agonists (less severe adverse effects, lack of tolerance and dependence liability) which has been demonstrated in rodents, nonhuman primates and dogs. Seizures in dogs have been proposed as a translational platform for human therapeutic trials on new epilepsy treatments. The fact that imepitoin is an effective and safe AED in epileptic dogs, indicates that low-affinity partial BZD agonists offer a new mechanistic category of useful AEDs.Methods: We compared the anticonvulsant efficacy of imepitoin, phenobarbital (PB) and the high-affinity partial BZD agonist abecarnil in dogs (beagle dogs, n=7) and mice (NMRI, n=10-12 per group) in the timed i.v. pentylenetetrazole (PTZ) seizure threshold test. PB is the only other drug that is approved for monotherapy of canine epilepsy in Europe. For each drug 3-5 different doses were tested to construct dose-response curves by plotting dose against seizure threshold increase on a semilogarithmic scale. Log-linear regression analysis was used to calculate doses increasing the threshold by 20 (TID₂₀) and 50% (TID₅₀). Adverse effects of treatments were compared in both species. In mice, minimal neurological deficit was determined in the rotarod test and the mean neurotoxic dose (TD₅₀) was calculated by log-linear regression in a probability net.Results: All drugs dose-dependently increased the PTZ threshold in both species, but anticonvulsant efficacy was higher in dogs than mice. At the doses tested here, imepitoin was slightly less potent than PB (TID₅₀ 45.6 vs. 22.9 mg/kg p.o. in mice and 18.4 vs. 12.1 mg/kg p.o. in dogs, respectively), but markedly better tolerated in both species. In the rotarod test, imepitoin was less potent than PB after i.p. and oral administration. After oral administration in mice, imepitoin exhibited a much larger therapeutic ratio (12.3) than phenobarbital (3.48). As expected, abecarnil was highly effective in dogs and mice comparable to BZD receptor ligands such as diazepam.Conclusions: In first clinical studies in epileptic dogs, imepitoin was well tolerated, but seemed to be moderately less effective than PB at the doses tested. Effective doses of imepitoin in the PTZ seizure model in dogs were in the same range as those suppressing spontaneous recurrent seizures in epileptic dogs (L scher et al. 2004; Epilepsia 45 (10):1228-39), demonstrating that the PTZ model correctly predicted antiepileptic effects in clinical studies. The data indicate that the PTZ seizure threshold test in dogs is a useful model for comparing efficacy of investigational AEDs and may constitute a valuable tool for pharmaceutical dose selection.