Anticonvulsant profile and teratogenicity of N-methyl-tetramethylcyclopropyl carboxamide: a new antiepileptic drug.

Abstract

PURPOSE:

The studies presented here represent our efforts to investigate the anticonvulsant activity of N-methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity.

METHODS:

The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague-Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acid-induced neural tube defects.

RESULTS:

In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES- and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice.

CONCLUSIONS:

The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential.

• Authors: Nina Isoherranen, H Steve White, Richard H Finnell, Boris Yagen, José H Woodhead, Gregory D Bennett, Karen S Wilcox, Matthew E Barton, Meir Bialer
• Journal: Epilepsia (Epilepsia) Vol. 43 Issue 2 Pg. 115-26 (Feb 2002) ISSN: 0013-9580 [Print] United States
• PMID: 11903457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2,2,3,3-tetramethylcyclopropane carboxamide
• Amides
• Anticonvulsants
• Convulsants
• Cyclopropanes
• N-methyl 2,2,3,3-tetramethylcyclopropane carboxamide
• Pentylenetetrazole
• Bicuculline

Topics

• Acoustic Stimulation
• Administration, Oral
• Amides (administration & dosage, adverse effects, therapeutic use)
• Animals
• Anticonvulsants (administration & dosage, adverse effects, therapeutic use)
• Behavior, Animal (drug effects)
• Bicuculline
• Convulsants
• Cyclopropanes (administration & dosage, adverse effects, therapeutic use)
• Electrophysiology
• Electroshock
• Epilepsy (drug therapy, psychology)
• Injections, Intraperitoneal
• Mice
• Mice, Inbred Strains
• Mutagenicity Tests
• Neural Tube Defects (chemically induced)
• Pentylenetetrazole
• Rats
• Rats, Sprague-Dawley
• Seizures (chemically induced, etiology, prevention & control)