Vascular toxicity in dogs associated with overdoses of a novel benzodiazepine receptor partial agonist.

Necrotizing arteritis and periarteritis were found in Beagle and German Shepherd dogs treated for 13 or 52 weeks with the novel benzodiazepine receptor (BZR) partial agonist Ro 16-6028 (generic name bretazenil). Eight male and one female out of a total of 20 dogs treated with 40-60 mg/kg/day Ro 16-6028 developed the arteritis, predominantly in the heart or the epididymis. Two of these animals died prematurely following treatment at the initial dosing levels of 80 and 55 mg/kg/day; one of these two dogs was asymptomatic and in good general condition until death. Clinically, all but one of the dogs showed sedation, ataxia, stiff gait, body weight-loss and a deterioration of the general condition as well as changes of some laboratory parameters. No signs of arteritis and untoward clinical or laboratory findings were seen at lower doses. Possible aetiologies, as well as the mechanisms involved in arteritis in general and the genetic disposition of beagles in particular for this type of effect, are discussed. Reflections on the potential risk to man of this so far unknown finding after oral treatment with 1,4-benzodiazepines (BZs) are presented.