difluprednate and Body-Weight

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 1.25 micrograms/kg for 6 months. 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. The systemic effects of DFBA In the 125 micrograms/kg group, the following changes were observed, although neither death nor severe symptoms occurred: General observations were seen an increase of water intake and urinary volume. A decrease of lymphocytes and eosinophils, and an increase of neutrophils were observed in the hematological examination. There were high sodium and low potassium levels, and an increase of alkaline phosphatase and gamma-glutamyltranspeptidase activities in the biochemical examination. The organ weights showed a decrease of the thymus, adrenals, prostate and ovaries, and an increase of the liver and kidney. 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. In the 12.5 micrograms/kg group, the atrophic changes in the thymus, adrenal and non-treated skin appeared slight. In the 1.25 micrograms/kg group, no changes were found. 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 12.5 micrograms/kg dosage is similar to a non-effect dose.

Topics: Animals; Blood Chemical Analysis; Body Weight; Digestive System; Dogs; Drinking; Eating; Endocrine Glands; Female; Fluprednisolone; Hair; Hematologic Tests; Lymphatic System; Male; Ointments; Organ Size; Skin; Time Factors

The effects of difluprednate on the deposition of liver glycogen, the inhibition of adrenocortical function, the estrogenic, progestational and androgenic activities, and the excretion of electrolytes were investigated by comparing them with those of fluocinonide. The following results were obtained: 1) the deposition of liver glycogen was remarkably increased by subcutaneous administration of these two glucocorticoids, and in the dose of 0.1 mg/kg, the effect of difluprednate (35.1-fold the control value) was larger than that of fluocinonide (19.4-fold the control value) in mice. 2) the administration of difluprednate and fluocinonide greatly induced the decrease in the corticosterone concentration in the rat serum and adrenal gland (0.1 and 1 mg/kg, s.c.). 3) the estrogenic, progestational and androgenic activities were not recognized by administration of difluprednate in rats. 4) the two glucocorticoids induced an increase in the electrolytes excretion (especially K+) and the urine volume. 5) by the repeated injection of difluprednate (1.0 mg/kg) and fluocinonide (0.1 mg/kg), decrease of the body weight was observed in all of the experimental animals. In these experiments, it was recognized that the glucocortical action of difluprednate was similar or more potent in comparison with the action of fluocinonide and that the systemic effects of fluocinonide such as body weight loss was larger than that of difluprednate.

Topics: Adrenal Cortex; Animals; Body Weight; Corticosterone; Diuresis; Female; Fluocinonide; Fluprednisolone; Liver Glycogen; Male; Mice; Ovary; Rats; Rats, Inbred Strains; Testis; Water-Electrolyte Balance