Chronic Effects of the Novel Glucocorticosteroid RPR 106541 Administered to Beagle Dogs by Inhalation

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Abstract
The preclinical safety of RPR 106541, a novel 17-thiosteroid, was evaluated in young adult and mature dogs by inhalation exposure for 26 weeks and 52 weeks, respectively. A dry powder formulation of RPR 106541 in lactose was administered to young adult dogs (approximately 6 months of age at initiation) at doses of 0 (air and placebo controls), 10, 100, or 1,000 μg/kg/d for 26 weeks. A solution-based aerosol formulation was administered to mature dogs (approximately 10 months at initiation) from a pressurized metered dose inhaler at 0 (air and placebo controls), 10, 50, and 150 μg/kg/d for 52 weeks. Clinical evidence of glucocorticosteroid-induced immunosuppression was observed by weeks 20-26 following relatively high, dose exposures (100 μg/kg/d and 1,000 μg/kg/d) in young dogs receiving the dry powder formulation for 26 weeks. Classic glucocorticosteroid effects were observed, including adrenocortical atrophy, reduced bone mass with retention of epiphyseal growth plates in long bones, prominence of stromal adipose tissue in bone marrow, and atrophy of lymphoid tissues. Inhalation administration of RPR 106541 to sexually mature dogs facilitated more definitive characterization of endocrine affects of RPR 106541 as compared with administration in younger, sexually immature animals. Significant effects in female reproductive organs included absence of corpora lutea in association with atresia of vesicular follicles within the ovaries, endometrial hyperplasia, and lobular development of mammary tissue. Discordant development of mammary tissue, accumulation of secretory material within hyperplastic endometrial glands, and hypertrophy of uterine lining epithelium in absence of ovulation were consistent with a secondary progestin effect by a potent glucocorticosteroid.