Chronic effects of the novel glucocorticosteroid RPR 106541 administered to beagle dogs by inhalation

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 initiati on) at doses of 0 lair and placebo controls), 10, 100, or 1,000 mu g/kg/d f or 26 weeks. A solution-based aerosol formulation was administered to matur e dogs (approximately 10 months at initiation) from a pressurized metered d ose inhaler at 0 (air and placebo controls), 10, 50, and 150 mu g/kg/d for 52 weeks. Clinical evidence of glucocorticosteroid-induced immunosuppressio n was observed by weeks 20-26 following relatively high dose exposures (100 mu g/kg/d and 1,000 mu g/kg/d) in young dogs receiving the dry powder form ulation for 26 weeks. Classic glucocorticosteroid effects were observed, in cluding adrenocortical atrophy, reduced bone mass with retention of epiphys eal growth plates in long bones, prominence of stromal adipose tissue in bo ne marrow, and atrophy of lymphoid tissues. Inhalation administration of RP R 106541 to sexually mature dogs facilitated more definitive characterizati on of endocrine affects of RPR 106541 as compared with administration in yo unger, sexually immature animals. Significant effects in female reproductiv e organs included absence of corpora lutea in association with atresia of v esicular follicles within the ovaries, endometrial hyperplasia, and lobular development of mammary tissue. Discordant development of mammary tissue, a ccumulation of secretory material within hyperplastic endometrial glands, a nd hypertrophy of uterine lining epithelium in absence of ovulation were co nsistent with a secondary progestin effect by a potent glucocorticosteroid.