Progress report on new antiepileptic drugs: a summary of the Third Eilat Conference.

The Third Eilat Conference on New Antiepileptic Drugs was held at the Royal Beach Hotel from May 27 to May 30, 1996. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss critical issues in drug development, new antiepileptic drugs (AEDs) in development, progress reports and recent findings of newly marketed AEDs, the use of AEDs in special populations and their utilization in non-epileptic disorders. Over the last seven years, six new AEDs have been introduced worldwide and new information on their safety and efficacy has become available. These include felbamate, gabapentin, lamotrigine, oxcarbazepine, topiramate and vigabatrin. Drugs in development include those at an advanced stage, such as remacemide and tiagabine, as well as those just entering clinical trials, such as rufinamide (CGP 331010) and levetiracetam (ucb LO59). The following is a summary of the presentations for drugs in development and recent findings on newly marketed drugs.

Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo correlation.

Six patients stabilized with carbamazepine (CBZ) therapy received an 8-day "add-on" supplement of valnoctamide (VCD), a tranquilizer available over the counter (OTC) in several European countries that exhibits promising anticonvulsant activity in animal models. During VCD intake, serum levels of the active CBZ metabolite, carbamazepine-10,11-epoxide (CBZ-E), increased fivefold from 1.5 +/- 0.7 micrograms/ml at baseline to 7.4 +/- 4.4 micrograms/ml after 4 days of VCD therapy and 7.7 +/- 3.1 micrograms/ml after 7 days of VCD therapy (means +/- SD, p < 0.01). In 4 patients, the increase in serum CBZ-E levels was associated with clinical signs of CBZ intoxication. CBZ-E levels returned to baseline after VCD therapy was discontinued. Serum CBZ levels remained stable throughout the study. The interaction observed in this study is similar to that described in patients treated with CBZ and valpromide (VPD, an isomer of VCD). In a mechanistic study, therapeutic concentrations of VCD inhibited hydrolysis of styrene oxide in human liver microsome preparations. Thus, VCD is a potent inhibitor of microsomal epoxide hydrolase (IC50 15 microM). There was a striking similarity between in vitro and in vivo inhibition potencies. In this study, VCD clearance was higher in epileptic patients (treated with CBZ) than in healthy subjects.

Experimental anticonvulsant cinromide in monkey model: preliminary efficacy.

Cinromide (3 brono-N-ethylcinnamide), an experimental anticonvulsant (Burroughs-Wellcome Pharmaceutical Co.), was given a preliminary evaluation in our alumina-gel monkey model. The parent drug has a biological half-life in monkey of 1-2 hr and its active metabolite, 3-bromocinnamide, a half-life of 4-6 hr. In phase 1, 6 chronically epileptic monkeys, with focal motor and secondarily generalized tonic-clonic seizures, received the drug in a vehicle of 65% polyethylene glycol 400 (PEG) by constant-rate intravenous infusion followed by baseline days of saline only and PEG only. Three different concentrations of Cinromide (12, 24, and 36 mg/ml/hr) were administered, respectively, to achieve mean steady state plasma levels of approximately 5, 10 and 20 micrograms/ml of the metabolite (0.5 to 5.0 micrograms/ml of the parent drug). In phase 2, Cinromide was administered for 7 days at the middle concentration to all monkeys. Baseline periods similar to those of phase 1 were used as controls. The data tentatively suggest that Cinromide is efficacious in the monkey model at a plasma concentration range of 7-14 micrograms/ml of the metabolite. With the exception of one animal, no secondarily generalized seizures were exhibited during drug administration (but were evident in the baseline periods), and EEG bursting decreased significantly in several monkeys. Minimal side effects were manifested at these plasma levels but withdrawal seizures were evinced with cessation of the drug. Further evaluation of Cinromide by gastric administration in our animal model is planned.