rimexolone and Body-Weight

Rimexolone is a potent anti-inflammatory corticosteroid with a lower potential for elevating intraocular pressure, relative to other ophthalmic steroids, and is indicated for postsurgical inflammation and uveitis. Fertility and peri/postnatal toxicities were evaluated at oral gavage doses of 50, 150 or 500 mg/kg, and developmental toxicity at 100, 500, or 1000 mg/kg. In the fertility study, male rats were treated daily beginning 4 weeks prior to mating and females were treated daily beginning 2 weeks prior to mating, and through gestation day 6. Females were necropsied on gestation day 15 and males were necropsied after 10 weeks of exposure. In males, dose-related reductions in mean body weights, body weight gains, and food consumption occurred in all groups. In the 500 mg/kg females, mean body weights were reduced during gestation, and there was an increase in early resorptions and concomitant decrease in viable fetuses at this level. There were no effects on copulation or fertility indices, or on the number of corpora lutea and implantation sites. The no-observed-effect level (NOEL) for fertility and reproductive effects was 150 mg/kg. In the developmental toxicity study, female rats were treated daily from gestation days 6 through 17, necropsied on gestation day 20 and fetuses were evaluated. Maternal toxicity occurred at 500 and 1000 mg/kg as indicated by reduced maternal body weights and body weight gains. However, there was no indication of a developmental effect on fetuses due to rimexolone. The NOEL was 1000 mg/kg for the developing fetuses. In the peri/postnatal toxicity study, female rats were treated daily from gestation day 6 through lactation day 20 and necropsied. F1 developmental and behavioral parameters were evaluated. Selected F1 animals were mated at 12 weeks, allowed to deliver, and necropsied on lactation day 21. At 500 mg/kg, F0 maternal body weights were reduced during gestation and lactation, and F1 pup weights were reduced during lactation and the growth phase. There were no effects on the F1 fertility or reproductive capabilities, or on F2 developmental parameters. The NOEL for the F0 females and F1 offspring was 150 mg/kg. Together, these studies indicate that, unlike some corticosteroids, rimexolone does not produce developmental or reproductive toxicity in rats.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Body Weight; Dose-Response Relationship, Drug; Eating; Female; Fertility; Growth; Male; Ophthalmic Solutions; Pregnadienes; Rats; Rats, Sprague-Dawley; Reproduction

The persistence and effects of 3H-labelled and intra-articularly administered 11 beta-hydroxy-16 alpha,17 alpha,21-trimethylpregna-1,4-diene-3,20-dione (rimexolone, [3H]-Org 6216 have been investigated in a model of fibrin-induced mono-articular arthritis in the rabbit. It appears that joint swelling is suppressed in a dose-dependent way when the drug is administered into the arthritic joint. With a dose of 15 mg the joint circumference was restored to the initial value recorded prior to antigen challenge within 14 days. Administration of rimexolone into the non-arthritic joint also suppressed contralateral arthritic joint swelling, but this effect was less pronounced and shorter lasting. Radioactivity from [3H]-rimexolone at doses of 5 or 15 mg disappears slowly from both non-arthritic and arthritic knee joints.

Topics: Animals; Arthritis; Arthritis, Experimental; Body Weight; Glucocorticoids; Kinetics; Knee Joint; Male; Pregnadienes; Rabbits