Experimental anticonvulsant cinromide in monkey model: preliminary efficacy.

Abstract

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.