Preclinical toxicologic study of 2,3-dihydro-1H-imidazo[1,2-b] pyrazole (IMPY) in mice, dogs, and monkeys.

Single-treatment schedules in mice and dogs and multiple-treatment schedules in dogs and monkeys were used to evaluate the toxicity of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole. The LD50 of the iv single dose in male and female mice collectively was 993 mg/kg (2980 mg/m2). The major target organs in mice, dogs, and monkeys were the bone marrow, lymphoid tissue, and gastrointestinal tract. Clinical signs at lethal and high toxic doses were weight loss, diarrhea, hematochezia, emesis, anorexia, mydriasis, dyspnea, lethargy, and stupor. The immediate toxic effect on blood cells was a depression of rbcs with suppression of lymphoid elements occurring later. In dogs, the most toxic schedule was single bolus injections. Attenuation of toxic responses occurred if rest periods were introduced between single or repeated daily dose schedules. The monkeys were more sensitive than the dogs to the high toxic dose on a milligram per meter squared basis, with similar sensitivity to the low toxic dose in the repeated daily injections.