CHRONIC TOXICITY STUDY ON DIFLUPREDNATE IN DOGS

Abstract

The chronic toxicity of a new topical glucocorticoid, difluprednate (DFBA) was studied in Beagle dogs. DFBA ointment (0.05%) was percutaneously treated to the back of dogs at daily doses of 125, 12.5 and l.25 μg/kg for 6 months. 1. The local effects of DFBA; In the treated area, thinning of the skin and inhibition of the fur-growth were observed with scale and erythema. The skin showed histological atrophy of the epidermis, a decrease of the adipose tissue and atrophy of the adnexa. These changes returned to normal after the 2-month withdrawal period. 2. The systemic effects of DFBA; (1) In the 125μg/kg group, the following changes were observed, although neither death nor severe symptoms occurred: a) General observations were seen an increase of water intake and urinary volume. b) A decrease of lymphocytes and eosinophils, and an increase of neutrophils were observed in the hematological examination. c) There were high sodium and low potassium levels, and an increase of alkaline phosphatase and γ-glutamyltranspeptidase activities in the biochemical examination. d) The organ weights showed a decrease of the thymus, adrenals, prostate and ovaries, and an increase of the liver and kidney. e) An atrophy of the lymphatic tissues and adrenal cortex, retardation of the sexual maturation, glycogen deposit in the hepatic cells, slight degeneration of the renal tubuli, and slight thinning of the sternum and non-treated skin were noted in the pathological examination. These changes returned to normal after the 2-month withdrawal period. (2) In the 12.5μg/kg group, the atrophic changes in the thymus, adrenal and non-treated skin appeared slight. (3) In the 1.25μg/kg group, no changes were found. 3. Conclusively, all the local and systemic changes observed by DFBA in this study were due to the already known pharmacological effects of glucocorticoids. It is considered that a 12.5μg/kg dosage is similar to a non-effect dose.