EEG in the FEAB model: measurement of electroencephalographical burst suppression and seizure liability in safety pharmacology.
BACKGROUND
The purpose of this study was to explore the integration of electroencephalographical (EEG) measurements into the fentanyl/etomidate-anaesthetised Beagle (FEAB) model in order to detect burst suppression and/or seizure development caused by compounds, prior to new molecular entity (NME) declaration. Detecting such unfavourable side effects prevents their being found in conscious animals at a later stage of safety evaluation. In addition, this has the advantage of performing safety studies on the three vital organ systems (cardiovascular system, respiratory system and central nervous system) within one and the same animal model.


METHODS
Dogs were anaesthetized and instrumented according to the FEAB model requirements, and in addition three needle electrodes were placed on the cranium and a one lead EEG signal was measured. The raw signal was analysed by the Narcotrend® (MonitorTechnik, Bad Bramstedt, Germany) for depth of anaesthesia registration, visually analysed for burst suppression ratio calculation after different anaesthetics (pentobarbital and etomidate), and spiking and seizure activity were quantified after intravenous administration of different proconvulsant agents: pentylenetetrazole (PTZ), bicuculline (BCC), bupropion (BUP) and pilocarpine (PIL).


RESULTS
High doses of pentobarbital (60 mg/kg over 10 min) and etomidate (6 mg/kg over 10 min) induced dose-dependent burst suppression of 98 ± 2% and 61 ± 16%, respectively. Infusions of PTZ (1.5mg/kg/min), BCC (0.0625 mg/kg/min), BUP (0.5mg/kg/min) and PIL (5mg/kg/min) induced dose-dependent spiking and seizures: the thresholds were 34 ± 2, 0.15 ± 0.03, 10.0 ± 1 and 144 ± 9 mg/kg, respectively. In PTZ-treated dogs, spiking and seizures could be abolished with diazepam (2mg/kg i.v.) or with propofol (4 mg/kg i.v.).


CONCLUSIONS
The present study showed that a one lead EEG can be used reliably in the FEAB model to estimate the depth of anaesthesia, and to detect burst suppression and seizure risk in safety pharmacology studies.
van der Linde
H J
HJ
Center of Excellence for Cardiovascular Safety Research & Mechanistic Pharmacology, European Discovery Capability Organization, Belgium. hvdlinde@its.jnj.com
Van Deuren
B
B
Somers
Y
Y
Teisman
A
A
Drinkenburg
W H
WH
Gallacher
D J
DJ
D000758:Anesthesia; D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology*; D004285:Dogs; D004569:Electroencephalography / Q000379:methods*; D005045:Etomidate / Q000008:administration & dosage; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage; D008297:Male; D023421:Models, Animal; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced*; D018675:Toxicity Tests
D018686:Anesthetics, Intravenous; D003292:Convulsants; D005283:Fentanyl; D010433:Pentylenetetrazole; D001640:Bicuculline; D005045:Etomidate