Four Week Oral (Gavage) Dose Range-Finding Study of Halofantrine Hydrochloride in Mice
Abstract
This study evaluated the toxicity of halofantrine hydrochloride in B6C3F1 mice following four weeks of daily oral (gavage) administration. Dose levels studied were 0 (vehicle control), 4, 20 and 100 mg/kg/day. Clinical signs of toxicity (rough coat, hunched posture, decreased activity and lethargy) and decreased body weight gains were limited to high dose animals. During week 3, one high dose male was found dead and the other four high dose male animals were sacrificed moribund. Splenic lymphocytic necrosis, observed in all high dose males and three of five high dose females, and moderate splenic lymphocytic depletion, were considered possible contributing factors to their deaths. Splenic granulopoiesis secondary to the splenic lymphocytic necrosis, supported by neutrophilia and splenomegaly, was observed in high dose females. Marginal leukopenia, consisting of decreased numbers of mature neutrophils and lymphocytes, was seen in mid dose males but not females and may be indicative of the initial insult producing splenic lymphocytic depletion in the high dose animals. Dose-related, mild, microcytic, apparent iron-deficiency anemia was seen in high dose females and to a lesser extent in mid dose animals and low dose females. Thrombocytosis in high dose females may have been secondary to the anemia. Increased serum ALT and cholesterol levels in high dose females and increased serum ALT in mid dose males, not accompanied by corresponding histologic changes, suggests that halofantrine may be marginally hepatotoxic. Decreases in serum alkaline phosphatase levels were also observed in high dose females, and may have been related to reductions in food intake. The purpose of the study was to select dose levels for a three month toxicity study in mice. Because marginal halofantrine-induced toxicity was seen in low dose females, the following dose level ranges are suggested: 1 - 2, 4 - 8 and 15-30 mg/kg/day.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 26, 1994
- Accession Number
- ADA640653
Entities
Organizations
- University of Illinois at Chicago