The use of the dog electroencephalogram (EEG) in safety pharmacology to evaluate proconvulsant risk.
BACKGROUND
The dog is frequently used for cardiovascular safety pharmacology and for toxicology studies, but is not often used for central nervous system (CNS) safety pharmacology purposes. We have therefore examined the electroencephalogram (EEG) in conscious dogs by means of radio-telemetry methods using the proconvulsant agent pentylenetetrazole (PTZ) as reference substance. Assessment of proconvulsant risk is an important aspect of CNS safety evaluation and the EEG is a sensitive technique for identifying pathologic brain activity, most importantly paroxysmal activity.


METHODS
Dogs were implanted with epidural electrodes wired to subcutaneously placed radiotransmitters. Following baseline recording, the test substance was administered and the EEG and electromyogram (EMG) activities were recorded from dogs placed in slings. The EEG was assessed visually for abnormal activity and dogs were also continuously observed for the appearance of overt convulsive activity. The PTZ infusion was stopped and diazepam was administered as soon as clear and sustained EEG effects and/or behavioural symptoms occurred.


RESULTS
Slow i.v. infusion of PTZ (1.5 mg/kg/min) induced clear paroxysmal effects on the EEG trace in the form of spike and wave trains of 4-5 Hz. Paroxysmal activity associated with clonic convulsions occurred between 17 and 36 min after the start of infusion (a mean of 24 min) but in most cases paroxysmal activity was observed approximately 60 s prior to any overt convulsive activity.


CONCLUSIONS
These data show the usefulness of the telemetered dog EEG in safety pharmacology. The dog EEG is appropriate in situations where results from cardiovascular and CNS safety tests in the same species are required, or where the use of other species is contraindicated because of metabolic or pharmacokinetic particularities.
Dürmüller
Niklaus
N
Porsolt and Partners Pharmacology, 9bis rue Henri Martin, 92100 Boulogne-Billancourt, France. ndurmuller@porsolt.com
Guillaume
Philippe
P
Lacroix
Pierre
P
Porsolt
Roger D
RD
Moser
Paul
P
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003292:Convulsants / Q000008:administration & dosage / Q000633:toxicity*; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004569:Electroencephalography / Q000379:methods*; D007262:Infusions, Intravenous; D008297:Male; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000633:toxicity; D018570:Risk Assessment / Q000379:methods; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology* / Q000517:prevention & control; D013686:Telemetry / Q000295:instrumentation / Q000379:methods
D000927:Anticonvulsants; D003292:Convulsants; D003975:Diazepam; D010433:Pentylenetetrazole