Spectrum of effects detected in the rat functional observational battery following oral administration of non-CNS targeted compounds.
BACKGROUND
The Functional Observational Battery (FOB) is a systematic evaluation of nervous system function in the rat, comprising more than 30 parameters across autonomic, neuromuscular, sensorimotor and behavioural domains. We have collated FOB outcomes from 50 compounds that were not targeted at CNS disorders, and would therefore be anticipated to have relatively few CNS side-effects, for evaluation of the FOB as part of the safety pharmacology 'core battery'.


METHODS
Male Han Wistar rats (200-300 g) were used, with n=6 per treatment group. Each compound was tested acutely at 3 dose levels (oral route), from the therapeutic dose up to either 100 times this dose or to the maximal tolerated dose (MTD). A vehicle control group was included in each study.


RESULTS
Effects were detected in the FOB for 94% of compounds tested. The commonest effects were weight loss/decreased body weight gain overnight post-dose (46% of compounds), and changes in core temperature (36%). Dose-related effects were observed with 62% of compounds; the commonest was decreased body weight gain (32%), followed by effects on tail flick latency (14%), landing foot splay (12%), decreased rectal temperature (10%), time to exit the centre circle in the open field (10%), diarrhoea/loose faeces (8%), respiratory effects (4%), grasping reflex (4%) and supported rears in the open field (4%). Remaining parameters were affected by < or =2% of compounds.


CONCLUSIONS
The value of doing the FOB as part of the safety pharmacology 'core battery' is emphasised by the fact that, even for non-CNS targeted compounds, the majority affected at least one of the parameters in the FOB. These data may also help to anticipate the most frequently required 'follow-up' studies.
Redfern
William S
WS
Safety Assessment UK, AstraZeneca R&D Alderley Park, Cheshire SK10 4TG, UK. will.redfern@astrazeneca.com
Strang
Isobel
I
Storey
Sharon
S
Heys
Clive
C
Barnard
Claire
C
Lawton
Katherine
K
Hammond
Tim G
TG
Valentin
Jean-Pierre
JP
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008297:Male; D020714:Maximum Tolerated Dose; D009420:Nervous System / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015262:Xenobiotics / Q000633:toxicity*
D002491:Central Nervous System Agents; D015262:Xenobiotics