Measurements of blood pressure and electrocardiogram in conscious freely moving guineapigs: a model for screening QT interval prolongation effects.
The pro-arrhythmic risk inherent to a new drug must be assessed at an early preclinical stage. Telemetry system implantation is a method widely used in vivo in various species. The present study was designed to assess whether conscious freely moving guineapigs can be used to predict QT prolongation in vivo. The guineapig has three advantages over the dog and the primate. First, it has specific ion channels similar to man; second, a smaller amount of test article is required for the investigation and third, its housing is less expensive. Under sterile conditions and isoflurane anaesthesia, telemetry transmitters were implanted intraperitoneally in male Dunkin Hartley guineapigs. Blood pressure, heart rate and electrocardiographic intervals were measured from two days up to eight months. Chronic implantation of the telemetry device did not lead to anatomic or macroscopic alterations in the abdominal cavity and no inflammation of the peritoneum or infection was observed. Four reference compounds were used: three positive (sotalol, terfenadine and dofetilide) and one negative reference (enalapril). Single oral administration of all three positive references dose-dependently induced bradycardia and QT corrected (QTc) prolongation. In contrast, neither enalapril nor its vehicle prolonged the QTc. These results demonstrate that the guineapig is both a suitable model and a good alternative to dogs or primates to assess the potential of compounds for QT interval prolongation in the early stages of drug development.
Hess
P
P
Pharmacology and Preclinical Development, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland. patrick.hess@actelion.com
Rey
M
M
Wanner
D
D
Steiner
B
B
Clozel
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001795:Blood Pressure Determination; D004562:Electrocardiography; D004656:Enalapril / Q000494:pharmacology; D006168:Guinea Pigs / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D010627:Phenethylamines / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013686:Telemetry; D016593:Terfenadine / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D010627:Phenethylamines; D013449:Sulfonamides; D004656:Enalapril; D016593:Terfenadine; D013015:Sotalol; C063533:dofetilide