Toxicology of AMSA in beagle dogs and CDF1 mice.
The toxic effects of AMSA in single-dose (x1) or five-daily-dose (x5) regimens were studied in male and female beagle dogs and CDF1 mice. AMSA was administered orally via gelatin capsules to dogs and as a Klucel suspension to mice. Suitable placebo controls were evaluated. Doses in dogs ranged from 62.5 to 1000 mg/m2 (lethal dose [LD]) for the x1 study and from 31.25 to 500 mg/m2 (LD) for the x5 study. Dogs given the LD (x1 and x5) had degenerative lesions in the gastrointestinal mucosa, depletion of bone marrow hematopoietic tissue, and lymphoid depletion. These lesions were not seen at doses lower than the LD in the x1 study but were present in the x5 study, with severity related to dose. Toxicity appeared to be reversible at the lower doses since animals killed after a 45-day observation period had none of the above lesions. Clinical signs of emesis, diarrhea, and weight loss correlated with the above lesions as did the depressed wbc counts. The toxicity in dogs was dose- and schedule-dependent. The 14-day LD10, LD50, and LD90 values (mg/m2) for mice in the x1 study were as follows: LD10, 440 in males and 475 in females; LD50, 810 in males and 728 in females; and LD90, 1489 in males and 1117 in females. Mortality was observed initially on Day 4. Single-dose toxicity studies were conducted in mice by oral administration of doses equal to one-half of the LD10, the LD10, and the LD50. The major drug-related lesions in mice included thymic degeneration and atrophy and bone marrow depletion at the higher dose levels, while the major drug-related lesions in dogs included enteric mucosal degeneration and generalized lymphoid and bone marrow depletion. The toxicity of AMSA was reversible in mice and dogs.
D000609:Aminoacridines / Q000008:administration & dosage / Q000633:toxicity*; D000677:Amsacrine; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D007413:Intestinal Mucosa / Q000187:drug effects; D007928:Lethal Dose 50; D008208:Lymphatic System / Q000187:drug effects; D008297:Male; D051379:Mice; D010919:Placebos; D013950:Thymus Gland / Q000187:drug effects
D000609:Aminoacridines; D010919:Placebos; D000677:Amsacrine