Left thoracotomy surgical approach for chronic instrumentation in dogs and monkeys providing high-quality electrocardiogram signals.
BACKGROUND
Assessment of cardiovascular parameters, including the electrocardiogram (ECG) is required by the regulatory guidelines. In safety pharmacology studies, this is typically done using chronically implanted radiotelemetry devices in non-rodent species.


METHODS
We compared ECG signal quality from ten male beagle dogs and 10 male cynomolgus monkeys with telemetry transmitters implanted using two surgical approaches: i) epicardial ECG lead placement via single incision, left side thoracotomy or ii) subcutaneous ECG lead placement via laparotomy. In addition, epicardial leads and semi-automated scoring were used in combination to detect changes in ECG values caused by moxifloxacin. Telemetry-instrumented male beagle dogs (n=8) and male cynomolgus monkeys (n=8) were given moxifloxacin at 10, 30, or 100 mg/kg (dogs) and 10, 50, or 175 mg/kg (monkeys) as a single dose by oral gavage.


RESULTS
ECG signals were of excellent quality with epicardial lead placement, and human activity in the room did not significantly alter signal quality. Administration of moxifloxacin was associated with prolongation of QTc interval, in both dogs and monkeys in a dose-dependent pattern. Dogs given 30 mg/kg and 100 mg/kg, the maximum QTcf interval prolongations were 22 ms (+9%, 8 h postdose) and 60 ms (+24%, 15 h postdose). In monkeys given 50 and 175 mg/kg, the QTcb interval was significantly prolonged from 1 to 6h postdose, and QTcb interval prolongation persisted in monkeys given 175 mg/kg through 19 h postdose. In monkeys given 175 mg/kg, the maximum QTcb interval prolongation was 43 ms (+12.9%, 16 h postdose).


CONCLUSIONS
The present study demonstrated that placing leads directly on the epicardium drastically diminishes signal disruption due to room disturbances and subsequent animal excitement. This novel surgical model demonstrated adequate sensitivity to detect changes in ECG parameters, specifically QTc interval prolongation in both the dog and monkey.
Henriques
Tracy A
TA
Covance Laboratories Inc., 3301 Kinsman Boulevard, Madison, Wisconsin 53704-2523, USA. tracy.henriques@covance.com
Beck
Thomas W
TW
Douglas
Christopher L
CL
Jones
Hilton M
HM
Kremer
John J
JJ
Kruzich
Paul J
PJ
Sarazan
R Dustan
RD
D000818:Animals; D000890:Anti-Infective Agents / Q000097:blood / Q000494:pharmacology; D001372:Aza Compounds / Q000097:blood / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000662:veterinary; D024841:Fluoroquinolones; D007813:Laparotomy / Q000662:veterinary; D008133:Long QT Syndrome / Q000662:veterinary; D008252:Macaca fascicularis; D008297:Male; D000077266:Moxifloxacin; D010496:Pericardium / Q000601:surgery; D011804:Quinolines / Q000097:blood / Q000494:pharmacology; D013686:Telemetry / Q000662:veterinary; D013908:Thoracotomy / Q000662:veterinary*; D013997:Time Factors
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin