Teratogenicity of Levetiracetam and Its Enantiomer (R)-[alpha]-ethyl-oxo-pyrrolidine Acetamide in Mice.
Abstract number :
3.106
Submission category :
Year :
2001
Submission ID :
2729
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
O. Spiegelstein, PhD, Center for Human Molecular Genetics, University of Nebraska Medical Center, Omaha, NE; N. Isoherranen, MSc, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem; R.H. Finnell, PhD, Center for Human Molecular Genetics, Univer
RATIONALE: Levetiracetam (Keppra, LEV) is a new antiepileptic drug (AED) approved for add on therapy in patients with partial seizures. It is an ethyl analog of the nootropic drug Piracetam (PIR). In animal models, LEV has a distinct and highly enantioselective spectrum of anticonvulsant activity with a novel mechanism of action.
The purpose of this study was to evaluate the teratogenic potential of LEV, its enantiomer (R)-[alpha]-ethyl-oxo-pyrrolidine acetamide (REV) and PIR in a murine strain, that is highly sensitive to AED-induced teratogenicity.
METHODS: LEV and REV were synthesized de novo, whereas PIR was commercially available. Each compound was injected ip at 600 mg/kg once daily from gestational days 8-12 to pregnant SWV/Fnn mice. Following the first dose, urine was collected for 24 hours and a blood sample was withdrawn at 20 minutes after drug administration.
At gestational day 18 dams were sacrificed and the embryos weighted and examined for the presence of external malformations. Embryos were then evicerated and stained with Alizarin Red to detect skeletal abnormalities.
The plasma and urine concentrations of LEV, REV and PIR were analyzed using GC-MS. The urine concentrations of the phase I metabolite of LEV and REV, 2-pyrrolidone-N-butyric acid, were analyzed by HPLC.
RESULTS: No gross external malformations were observed following administration of either LEV, REV or PIR compared to control embryos (Data presented in the table). Analysis of skeletal abnormalities is currently underway.
CONCLUSIONS: The results of this study indicate that there were no significant differences in the ability of LEV, REV or PIR to induce gross teratogenic effects in our highly susceptible mouse model.[table]
Support: This study was supported by grant [pound] III-3-H3-99-71/97 the Ministry of Science Baden-Wurttenberg, Germany.