A validation safety pharmacology study of the central nervous system,employing a functional observational battery in female cynomolgus monkey

The objective of this study was to establish and validate a functional observational battery(FOB) at the Center for Drug Safety Evaluation & Research(CDSER) that provides a basic neurological and behavioral assessment in cynomolgus monkey.Four female cynomolgus monkeys were assigned to this study and were administered the vehicle and substances〔chlorpromazine,(+)-MK-801 or caffeine〕in 4 separated days(a 7-d wash-out period between each drug treatment).On each dosing day,4 animals were staggered for dosing.A FOB was performed and recorded by two independent observers for each animal at designated time points.Discordances between two observers were evaluated and actions were taken to minimize the subjective biases.The administration of 5 mg·kg-1 chlorpromazine resulted in sedative effect between 0.5 and 3 h post dose and decreased body temperature at 1 h post dose.The administration of(+) MK-801(0.1,0.5,1.25 and 2.5 mg·kg-1) resulted in suppressed behavior(low arousal,infrequent vocalization,hypoactive,etc),autonomic responses(salivation,decreased respiration and rectal temperature,etc) and sensorimotor / neuromuscular alternations(unsteady,un-coordinated,lack of auditory response,tremor and convulsion,etc) at all doses,and monkeys becoming unconscious and /or pupil dilation at high dose levels(1.25 and 2.5 mg·kg-1).The observations were mainly recorded between 0.5 and 3 h post dose.Caffeine resulted in stimulant behavioral changes(high arousal,hyperactivity and /or intermittent circling behavior) in one monkey at a dose of 30 mg·kg-1(between 0.5 and 4.5 h post dose) or one of two monkeys at a dose of 45 mg·kg-1(between 0.5 and 1 h post dose).At higher doses(one monkey dosed at 45 mg·kg-1 and one at 60 mg·kg-1),caffeine resulted in decreased arousal and hypoactive between 0.5 and 3 h post dose.Autonomic alteration caused by caffeine was evidenced by vomiting /retching seen in the 45 mg·kg-1 monkey at 0.5 h post dose and in the 60 mg·kg-1 monkey between 0.5 and 3 h post dose.In conclusion,the observations recorded in this study were consistent with expected pharmacological effects of the neurosedative or neurostimulant reference substances under the conditions of the study.A FOB in cynomolgus monkeys has been successfully established at CDSER.This standard FOB can now be conducted in safety pharmacology and /or toxicology studies to support regulatory submission.