TY - JOUR
T1 - Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea
T2 - A potential for a second generation drug to valproic acid
AU - Shimshoni, Jakob Avi
AU - Yagen, Boris
AU - Pessah, Neta
AU - Wlodarczyk, Bogdan
AU - Finnell, Richard H.
AU - Bialer, Meir
PY - 2008/7
Y1 - 2008/7
N2 - Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential second-generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES-ED50 of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED50 of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED50 = 35 mg/kg), the psychomotor 6 Hz mouse model (ED50 = 80 mg/kg at 32 mA and ED50 = 133 mg/kg at 44 mA), the bicuculline- and picrotoxin-induced seizure mouse model (ED50 = 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half-life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.
AB - Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential second-generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES-ED50 of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED50 of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED50 = 35 mg/kg), the psychomotor 6 Hz mouse model (ED50 = 80 mg/kg at 32 mA and ED50 = 133 mg/kg at 44 mA), the bicuculline- and picrotoxin-induced seizure mouse model (ED50 = 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half-life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.
KW - Anticonvulsants
KW - Maximal electroshock seizure test
KW - Pharmacokinetics
KW - Subcutaneous pentylentetrazole seizure test
KW - Teratogenicity
UR - http://www.scopus.com/inward/record.url?scp=47249142849&partnerID=8YFLogxK
U2 - 10.1111/j.1528-1167.2008.01624.x
DO - 10.1111/j.1528-1167.2008.01624.x
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C2 - 18435754
AN - SCOPUS:47249142849
SN - 0013-9580
VL - 49
SP - 1202
EP - 1212
JO - Epilepsia
JF - Epilepsia
IS - 7
ER -