cinromide and Epilepsy

A double-blind controlled trial of cinromide in 25 adult subjects with refractory epilepsy using the maximum tolerated dose showed that it possessed no significant antiepileptic properties.

Topics: Adolescent; Adult; Cinnamates; Clinical Trials as Topic; Epilepsy; Humans; Middle Aged

Cinromide is an experimental anticonvulsant currently in phase II testing. A single oral dose (900 mg) of cinromide was administered to 8 epileptic subjects on phenytoin therapy. Plasma samples drawn during the next 36 h were analyzed for cinromide and its amide and acid metabolites. The absorption rate of cinromide varied widely between subjects producing maximum cinromide concentrations between 0.5 and 2.5 h after the dose. The median elimination half lives of cinromide and the amide and acid metabolites were 0.73, 1.65, and 4.85 h respectively. The oral clearance of cinromide (median = 135 l/h) suggests that it is subject to first pass metabolism. In all subjects the area under the curve (AUC) of acid metabolite (632 to 1777 microM/l) was greater than the AUC of amide metabolite (77 to 185 microM/l) which was greater than the AUC of cinromide (5 to 89 microM/l). Steady-state concentration ratios of metabolite to parent drug predicted from the AUC data were 3.8 for the amide and 35.8 for the acid metabolite. The amide metabolite is known to have anticonvulsant properties and, until the relative contributions of metabolites and parent drug to the efficacy of cinromide are resolved, the monitoring of metabolites as well as parent drug is imperative.

Topics: Adult; Anticonvulsants; Biological Availability; Cinnamates; Epilepsy; Female; Humans; Intestinal Absorption; Kinetics; Male

A high-performance liquid chromatographic method is described for monitoring plasma concentrations of cinromide (3-bromo-N-ethylcinnamamide) and its de-ethylated metabolite. Carbamazepine levels can be easily measured by the same technique. The N-isopropyl analogue of cinromide is used as internal standard, and all compounds are easily separated on a reversed-phase column operated at 55 degrees with a small-diameter pre-column maintained at the same temperature. The extraction is rapid and generally applicable to plasma and urine samples that are to be analyzed by reversed-phase chromatography. Short- and long-term reproducibility studies show less than 4% relative standard deviation for replicate determinations for all drugs. Limits of quantitation are 10-20 ng/ml with an internal standard concentration of 3 micrograms/ml. Another metabolite of cinromide, 3-bromocinnamic acid, which may have some anticonvulsant effect, can be analyzed simultaneously by buffering the mobile phase and adding an ion-pairing reagent.

Topics: Anticonvulsants; Carbamazepine; Chromatography, High Pressure Liquid; Cinnamates; Epilepsy; Female; Humans