PRECLINICAL TOXICOLOGY STUDIES WITH THE NEW DOPAMINE AGONIST PERGOLIDE - ACUTE, SUBCHRONIC, AND CHRONIC EVALUATIONS

Pergolide (LY127809, CAS 66104-23-2), a dopamine agonist for the treat ment of Parkinson's disease, was evaluated for toxicity in acute, subc hronic, and chronic studies. Acute toxicity tests using oral, intraven ous and intraperitoneal routes were conducted in rats, mice, rabbits, and dogs. The acute oral median lethal doses (MLD) ranged from 8.4 to 33.6 mg/kg in Wistar and Fischer 344 rats, and from 54.0 to 87.2 mg/kg in ICR mice. Oral doses of 20 and 25 mg/kg produced no mortality in r abbits or dogs, respectively. The MLD by the iv route ranged from 0.59 to 0.87 mg/kg for Fischer 344 rats and from 11.6 to 37.1 mg/kg for IC R mice. The predominant signs of toxicity in the acute studies include d hyperactivity, poor grooming, ptosis, aggressive behavior, increased gnawing activity, tremors, convulsions, and emesis. In the subchronic and chronic studies, Fischer 344 rats, B6C3F1 mice, and beagle dogs w ere administered pergolide either by gavage or in the diet for up to 1 year Daily doses in these studies ranged up to 20 mg/kg for rats, 45 mg/kg for mice, and 5 mg/kg for dogs. The predominant treatment-relate d effects seen in these studies were attributable to the pharmacologic activity of pergolide. These consisted primarily of CNS-mediated clin ical signs in rats and dogs, weight loss or decreased weight gain, eme sis in dogs, and inhibition of lysis of corpora lutea with a correspon ding increase in the weight of the uterus and ovaries. Pergolide treat ment was not associated with any specific target organ toxicity. Decre ased erythrocytic parameters and increased serum enzyme values seen in the repeated-dose studies were considered to be secondary responses t o the effects on body weight. In the 1-year studies with rats and dogs , the no-observed-adverse-effect levels (NOAEL) were 0.06 and 0.1 mg/k g, respectively.