Development and validation of the maximal electro-shock seizure model in dogs.
The development and validation of the maximal electro-shock (MES) model using phenobarbital (Pb) as the positive control is described. This approach builds on previous work in rodent model systems, and has been adapted to dogs as a tool for pharmaceutical dose selection. Dogs, like rodents, exhibit generalized convulsions which manifest as progressive clinical signs in a dose (electrical current) dependent fashion. At the limit (300 mA, 200 msec) animals underwent clonic-tonic convulsions consistent with complete generalized (Grand Mal) seizures with a grade 3 clinical score (CS) and a menace response time of 98.5 +/- 24.4 sec (n = 8). Pretreatment of animals with Pb at 3, 10, and 30 mg/kg, in a 4-by-4 complete block crossover design (Latin-Square), resulted in a dose-dependant reduction in CS and menace response time. Estimates of plasma Pb concentration taken prior to MES induction showed a similar dose-dependent reduction in CS and menace response time with concentration. Using a cumulative logistic regression model, a predicted 50% probability of a CS = 1 was approximately 11.4 mg/kg. In addition, plasma Pb concentrations predicted a 50% probability of a CS = 1 occurs at plasma Pb concentration of approximately 16.0 mug/mL. Combined these data suggest that MES is a useful model for evaluating generalized convulsions in canines and may provide a tool for dose selection of novel pharmaceutical compounds.
Territo
P R
PR
Lilly Center for Molecular and Anatomical Imaging, Lilly Research Laboratories, A Division(s) of Eli Lilly and Company, Greenfield, IN 46140, USA. territop@lilly.com <territop@lilly.com>
Freise
K J
KJ
Newhall
K
K
Barnhart
S D
SD
Peters
S C
SC
Engleking
D R
DR
Burnett
T J
TJ
Abdul-Karim
B
B
Shannon
H E
HE
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000503:physiopathology*; D004285:Dogs / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000662:veterinary; D004830:Epilepsy, Tonic-Clonic / Q000188:drug therapy / Q000503:physiopathology / Q000662:veterinary*; D008297:Male; D010634:Phenobarbital / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015203:Reproducibility of Results
D000927:Anticonvulsants; D010634:Phenobarbital