Safety evaluation studies on oxisuran, a differential inhibitor of cell-mediated hypersensitivity

Abstract

Preclinical toxicity studies were conducted on oxisuran, 2-[(methylsulfinyl) acetyl]-pyridine, an immunosuppressant with selective inhibition of cell-mediated hypersensitivity. Oral LD50 values were 5280 and 6610 mg/kg in female mice and rabbits, respectively, and 6550 mg/kg in female and male rats. An LD50 could not be established in dogs because of emesis at a dose of 5000 mg/kg. Intravenous LD50 values were 2510 mg/kg for mice and 1800 mg/kg for female and male rats. Feeding the drug in the diet to rats at dosages of 20, 100, 300, and 1000 mg/kg for 13 weeks caused a slight reduction in food consumption and body weight gain at the higher dosages. At doses of 100, 300, and 1000 mg/kg, cloudy swelling and fatty infiltration of the liver and hyperplasia of the thyroid occurred in dose-related patterns (mild to moderate) in many animals. No significant changes were found in thyroid function studies which included thyroid uptake ( 125I) and T 3 and T 4 determinations. The thyroid hyperplasia seen at 13 weeks disappeared within a few days of drug withdrawal. Oral daily administration of 20, 125, 500, and 2000 mg/kg of oxisuran to dogs for 13 weeks produced a decrease in food consumption and body weight in the latter phase of the study in the males treated with the high dose. Serum glutamic-pyruvic transaminase was mildly elevated in dogs given 2000 mg/kg. At this dose, some animals showed slightly increased thyroid and liver weights. Histologically, thyroid hyperplasia was moderate in females (2000 mg/kg) and mild to moderate in males (125, 500, and 2000 mg/kg). The liver, in the animals of the high-dose group showed a slight degree of vacuolar changes and bile retention. Thyroidal radioiodine uptake ( 125I), PBI, TI, and serum cholesterol were slightly below normal values. The histology and function tests of the thyroid were within normal ranges at 4 weeks post-treatment.