A-75998 - A 4TH GENERATION GNRH ANTAGONIST .1. PRECLINICAL STUDIES INMALE PRIMATES

A-75998 is a fourth generation GnRHant. Here, we report the results of pre-clinical investigations in intact adult male cynomolgus monkeys. In study I, daily s.c. administration of 0.1 mg/kg/day A-75998 in sali ne for 10 days suppressed serum levels of T to less than 0.5 ng/ml wit hin 4 days and maintained suppression until 3 to 4 days after cessatio n of treatment when a marked rebound effect was seen, In study II, dai ly s.c. administration of 0.03 mg/kg/day for 30 days was ineffective i n producing suppression of serum T levels. Rather, an apparent pseudos timulatory effect on serum T levels was seen with this dose regimen. B oth 0.1 and 0.3 mg/kg/day were fully effective in producing, and maint aining full suppression of serum T levels for the 30 day duration of t reatment, In study III, A-75998 was administered as a slow i.v. (jugul ar) infusion via Alzet osmotic minipumps. Levels of T in the three mon keys receiving 0.03 mg/kg/day were not fully suppressed whereas T leve ls of all monkeys receiving either 0.1 and 0.2 mg/kg/day were fully su ppressed for the 7 days the pumps were present, In study IV, we re-exa mined the apparent stimulatory effects of daily s.c. administration of 0.03 mg/kg/day A-75998, We found that administration of 0.03 mg/kg sc resulted in an initial decline in serum T levels, reaching a nadir by 12 h followed by a return to pretreatment values (or above) by 24 h. We conclude that A-75998 is capable of producing full suppression of s erum T levels in adult male monkeys when administered either as daily s.c. injections or as a slow i.v. infusion via Alzet osmotic minipumps .