CHRONIC TOXICITY STUDY WITH THE SEROTONIN ANTAGONIST AMESERGIDE ADMINISTERED NASOGASTRICALLY TO RHESUS-MONKEYS FOR ONE-YEAR

The chronic toxicity of amesergide, a selective (5HT(2)/5HT(1c)) serotonin antagonist, was evaluated in rhesus monkeys given daily nasogastric doses of 0, 5, 10, or 22.5 mg/kg for 1 year. An initial high dose of 25 mg/kg was reduced after approximately 1 week of dosing due to severe behavioral effects, including lethargy, a trance-like appearance, and rigidity, that interfered with the animals' ability to eat and drink. The behavioral effects, although still present at the new high dose of 22.5 mg/kg were less intense and subsided prior to subsequent daily dosing. All animals survived the treatment period. Clinical signs associated primarily with early treatment at the 25-mg/kg dose level resulted in reductions of body weights and food consumption. After the high dose was reduced from 25 mg/kg to 22.5 mg/kg, there were no significant effects on body weight gain or food consumption when compared to controls. Plasma concentrations of amesergide and its metabolites increased in a dose-dependent fashion. Areas under the plasma concentration-time curve (AUC) and peak plasma concentrations (Cmax) decreased substantially as the study progressed. Stress-related decreases occurred in leukocytic and erythrocytic parameters of high-dose males, but values returned to near pretest by study termination. Organ weights as well as gross and histological examination of tissues from animals of all treatment groups revealed no treatment-related lesions. No adverse effects occurred at daily doses of 5 or 10 mg/kg. (C) 1994 Wiley-Liss, Inc.