An integrated cardiovascular and neurobehavioural functional assessment in the conscious telemetered cynomolgus monkey

Abstract

Introduction: Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. The purpose of this study was to validate, in the monkey, a model that incorporates the neurobehavioural assessment into the Safety Pharmacology cardiovascular study, allowing for an integrated evaluation of these two physiological systems.

Methods: Conscious male cynomolgus (Macaca fascicularis) monkeys (n=4) were given single oral doses of vehicle, D-amphetamine (0.5, 1 and 2 mg/kg) or diazepam (0.5, 1 and 2.5 mg/kg) in a dose-escalation study design. Blood pressure, heart rate, electrocardiogram (ECG), body temperature, locomotor activity and behaviour (by video) were monitored continuously for 24h post-dose. Animals underwent a standardised neurobehavioural test battery which allowed the direct examination of 31 signs, including behavioural responses and neurological examinations, conducted the day before dose, at maximal plasma concentration time (T(max)), and 24 h post-dose. The study was carried out in a first phase with telemetric cardiovascular recording only, and a second phase with telemetric cardiovascular recording and neurobehavioural observations. Results from the second phase of the study were used to evaluate the influence of the direct neurobehavioural examination on the telemetrically acquired cardiovascular parameters.

Results: The expected cardiovascular and neurobehavioural changes, based on the pharmacological properties of the compounds tested, were accurately detected. In the second phase of the study the direct neurobehavioural examination caused fluctuations of the telemetric cardiovascular parameters for no more than 20 min from the end of the procedure and this did not alter or jeopardize the analysis and interpretation of the cardiovascular parameters.

Discussion: These results confirm the validity of this combined model capable of providing in the cynomolgus monkey a reliable and reproducible neurobehavioural and cardiovascular assessment of candidate drugs during the course of safety pharmacology evaluations.