A canine model used to simultaneously assess potential neurobehavioural and cardiovascular effects of candidate drugs.
BACKGROUND
Unwanted effects of drugs on neurobehavioural and cardiovascular functions are normally assessed in separate studies and using different animals. A new model using dogs which allows for the integration of these assessments into a single study was established and validated, adopting the most sophisticated technologies for both monitoring behaviour by video recordings and cardiovascular parameters by telemetry.


METHODS
Conscious male beagle dogs (n=4) were given single oral doses of vehicle, and D-amphetamine (0.25, 0.75, 1.5 mg/kg) or acepromazine (0.05, 0.3, 2 mg/kg) within two different studies. Blood pressure, heart rate, electrocardiogram (EKG), body temperature, motor activity and behaviour (by video) were monitored continuously for 24 h post-dose. Animals underwent a full neurobehavioural examination the day before dosing, at the time to the maximal plasma concentration (Tmax) and 24 h post-dose.


RESULTS
D-Amphetamine: a dose-dependent increase in arterial blood pressure was noted at all doses and was generally associated with an increase in the QA interval, an index of cardiac contractility. Heart rate also increased but only at the 1.5 mg/kg dose. A dose-dependent general excitatory state of the nervous system was observed, characterised mainly by hyper-reactivity, and stereotyped activities. Acepromazine: a decrease in systolic blood pressure was detected at 0.3 and 2 mg/kg generally associated with a decrease in pulse pressure reflecting a negative inotropic effect. A dose-related increase in heart rate accompanied this effect. Dose-dependent general depression of the nervous system was noted; mainly characterised by half-closed eyes, subdued behaviour and impaired posture. In both studies, all dogs completely recovered at approximately 16 h after treatment.


CONCLUSIONS
Cardiovascular and neurobehavioural changes expected from the pharmacology of test substances were accurately detected. No significant fluctuations of the telemetric parameters recorded were noted as a consequence of the handling associated with the direct neurobehavioural examination. These results confirm the validity of this combined model capable of providing a reliable neurobehavioural and cardiovascular assessment of drugs.
Tontodonati
Marcello
M
Safety Pharmacology, Safety Assessment Department, GlaxoSmithKline R&D Centre, Via A. Fleming 4, 37135 Verona, Italy. marcello.2.tontodonati@gsk.com
Fasdelli
Nicola
N
Moscardo
Elena
E
Giarola
Alessandra
A
Dorigatti
Roberto
R
D000075:Acepromazine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D004562:Electrocardiography / Q000187:drug effects / Q000379:methods; D006339:Heart Rate / Q000187:drug effects; D006948:Hyperkinesis / Q000139:chemically induced / Q000503:physiopathology; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D012025:Reflex, Pupillary / Q000187:drug effects / Q000502:physiology; D015203:Reproducibility of Results; D012798:Sialorrhea / Q000139:chemically induced / Q000503:physiopathology; D013686:Telemetry / Q000379:methods
D015507:Drugs, Investigational; D006993:Hypnotics and Sedatives; D000075:Acepromazine; D003913:Dextroamphetamine