Fourteen-Day, Repeat-Dose Toxicity Evaluation of Aconiazide Administered Orally to Male and Female Fischer 344 Rats

Abstract

Aconiazide, a hydrazone derivative of isoniazid, has been proposed for the treatment of tuberculosis. As a first step toward assessing the safety of this drug, the effects of a daily oral 14-day treatment on weight gain, pathology, and several hematologic and clinical chemistry parameters were determined in Fischer 344 (F344) rats. Dosage-related changes in body weight were observed and these became significant at dosages of 500 mg aconiazide/kg body weight. Pathologic lesions involved the sciatic nerve, liver, and bone marrow, with the incidence typically becoming significantly elevated at dosages of 500 mg aconiazide/kg body weight. Aconiazide treatment caused statistically significant changes in certain clinical chemistry and hematologic parameters; however, the values of these were still within the normal range reported for rats of a comparable age. The plasma concentrations of aconiazide were dosage-related, tended to be higher in females, and did not increase with repeated dosing.