Male mice (CDF1) in a single-treatment schedule, male and female dogs in a single-treatment and in three multiple-treatment schedules, and male and female monkeys in one multiple-treatment schedule were used to evaluate the toxicity of 4'-(9-acridinylamino)methanesulfon-m-anisidide. Vehicle controls receiving anhydrous N,N-dimethylacetamide plus lactic acid were included in the dog and monkey studies. The liver was the major target organ of toxicity in mice. Lymphoid depletion and generalized bone marrow suppression were the most sensitive indicators of toxicity in dogs and monkeys. At high toxic doses, CNS and intestinal toxic effects were present. Hepatotoxic effects were most prominent in dogs after single iv injections. Multiple-dose regimens were more toxic than single-dose regimens in dogs, but inclusion of rest periods between multiple-treatment periods or reduction of the dose attenuated the toxic effects. The monkey was more resistant to drug toxicity than the dog. Local tissue reaction studies in guinea pigs and rabbits suggested that local irritation responses observed may have been due to the acidity of the drug and vehicle solutions.

Aminoacridines↗

PubMedDate not supplied

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.

Animals↗