© 1993 Oxford University Press
research-article |
Toxicity of CI-949, a Novel Anti-allergy Agent1
*Parke-Davis Research Institute 2270 Speakman Drive, Mississauga, Ontario, L5K 1B4, Canada
Parke-Davis Pharmaceutical Research, Warner-Lambert company Ann Arbor, Michigan 48104
Received October 27, 1993; accepted May 19, 1993
The toxicity of CI-949, an effective inhibitor of allergic mediator release in pharmacology models, was evaluated in rodents and dogs. Median lethal doses at 24-hr postdose ranged from 343 to 453 mg/kg in mice and 806 to 2058 mg/kg in rats. Delayed toxicity was observed at 300 mg/kg and greater in mice and at 500 mg/kg and greater in rats. Mortality and clinical intolerance occurred in rats at 200 and 400 mg/kg in the subacute studies, and at 100 and 150 mg/kg in the 13-week study. In rats, dose-dependent lymphoid tissue atrophy and depletion or necrosis of lymphocytes in lymphoid tissues were seen in deaths and moribund terminations. Although doses up to 60 mg/kg administered for 2 weeks to dogs were well tolerated, 60 and 120 mg/kg in the 13-week dog study were poorly tolerated. Cutaneous sores, mucocutaneous purulent discharge, emesis, diarrhea, and weight loss were identified at these lethal doses. Histopathologic changes in dogs included myocardial, vascular and soft tissue inflammation, and gastric ulceration at 60 and 120 mg/kg, and thymic atrophy at 20 mg/kg and greater. Doses of 10 and 50 mg/kg were no-effect doses in 13-week repeated dose studies in dogs and rats, respectively. These results were used to support initial human clinical trials of CI-949.