Abstracts

RATIONALE: Valrocemide (N-Valproyl glycinamide, TV1901) is a new antiepileptic drug, currently undergoing phase II clinical trials. The purpose of this study was to investigate the spectrum of anticonvulsant activity of TV1901 and to evaluate its teratogenic potential in well-defined animal models.
METHODS: The anticonvulsant activity of TV1901 was examined in mice and rats following intraperitoneal (ip) or oral administration. The ability of TV1901 to block electrically, chemically, or sensory induced seizures was evaluated in mice in the maximal electroshock (MES), subcutaneous metrazole (ScMet), subcutaneous bicuculline and subcutaneous picrotoxin models, 6Hz [dsquote]psychomotor[dsquote] seizure model and in audiogenic seizure susceptible mice. TV1901 was also tested in rats for its ability to prevent seizures induced by MES and ScMet and in the kindled rat model of epilepsy.
The teratogenic potential of TV1901 and its primary metabolite, N-Valproyl Glycine (TV1900), was evaluated in an inbred murine strain (SWV), that is highly susceptible to Valproic acid-induced neural tube defects.
RESULTS: In mice, TV1901 afforded complete protection against MES, ScMet, picrotoxin- and bicuculline-induced seizures, and 6Hz [dsquote]psychomotor[dsquote] seizures with median effective doses (ED[sub]50[/sub]s) of 151, 132, 275, 248 and 237 mg/kg ip, respectively. TV1901 was also effective in preventing sound-induced seizures in the Frings audiogenic-seizure susceptible mice (ED[sub]50[/sub] 52 mg/kg). The median neurotoxic dose (TD[sub]50[/sub]) in mice was 332 mg/kg. Following oral administration to rats, TV1901 was active in the MES test with an ED[sub]50[/sub] of 73 mg/kg, where the TD[sub]50[/sub] was [gt]1000 mg/kg. In the hippocampal kindled rat TV1901(300 mg/kg ip) blocked the generalized seizures induced by threshold stimulation and shortened the afterdischarge duration significantly (P[lt]0.05). TV1901 also provided complete protection from focal seizures in the corneally kindled rats (ED[sub]50[/sub] = 161 mg/kg).
TV1901 and its primary metabolite TV1900 were free from any detectable teratogenic potential in the SWV mice. No exencephaly was observed in any of the litters whose dams were treated with 600 mg/kg (ip) of TV1901 and only a single fetus presenting a neural tube defect (not significantly different from control) was observed following administration of 600 mg/kg of TV1900 (ip). In contrast, 73% of the SWV embryos, that were exposed in utero to valproic acid were exencephalic. Additionally, TV1901 did not appear to be embryotoxic, since exposure to this drug did not significantly increase the resorption rate.
CONCLUSIONS: These results show that Valrocemide has a broad spectrum of anticonvulsant activity and low teratogenic potential. This study also suggests that TV1901 has a potential to become a new, nonteratogenic antiepileptic drug.
Support: Supported by NINDS Contract NO1-NS-4-2311. Travel of N.I. was supported by The David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem, Israel.