Endocrinological studies on TAP-144-SR, a sustained-release formulation of a potent GnRH agonist (D-Leu6-[des-Gly10-NH2]-GnRH ethylamide), in male rats.
The paradoxical effects of TAP-144-SR, a biodegradable sustained-release formulation of a potent GnRH agonist (TAP-144, leuprolide acetate) were evaluated in male rats by comparing its potency with that of TAP-144 solution. A single sc injection of TAP-144-SR (equivalent to 0.1 mg/kg/day as TAP-144), prepared by encapsulating the agonist in microcapsules of copoly (DL-lactic/glycolic acid), suppressed serum levels of androgens, and the levels remained suppressed for 4 weeks. The potency of the paradoxical effects of TAP-144-SR was evaluated 4 weeks after treatment by comparing it with that of TAP-144 solution administered daily for 4 weeks. Both daily injections of TAP-144 solution and a single injection of TAP-144-SR (equivalent to 0.02, 0.2 or 2 mg/kg/day as TAP-144) decreased the weight of the testes, prostates and seminal vesicles in a dose-dependent manner in a 4-week assay in male rats. TAP-144-SR was more effective than TAP-144 solution in reducing these organ weights. Serum and pituitary concentrations of LH and FSH and serum testosterone levels were also lower in TAP-144-SR-treated than in TAP-144 solution-treated rats. These results indicate that the paradoxical effects were more extensive upon TAP-144-SR treatment, suggesting that maintaining constant serum TAP-144 levels results in more extensive desensitization of the pituitary and testes. These results also suggest advantages of TAP-144-SR over TAP-144 solution in both efficacy and convenience as an anti-prostatic tumor agent.
Sudo
K
K
Research and Development Division, Takeda Chemical Industries, Ltd. Osaka, Japan.
Masaki
T
T
Shiota
K
K
Kawase
M
M
Fujita
T
T
D000728:Androgens / Q000097:blood; D000818:Animals; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005640:Follicle Stimulating Hormone / Q000032:analysis; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D016729:Leuprolide; D007986:Luteinizing Hormone / Q000032:analysis; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010902:Pituitary Gland / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D011467:Prostate / Q000033:anatomy & histology / Q000187:drug effects; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D012669:Seminal Vesicles / Q000033:anatomy & histology / Q000187:drug effects; D013737:Testis / Q000033:anatomy & histology / Q000187:drug effects; D013739:Testosterone / Q000097:blood
D000728:Androgens; D003692:Delayed-Action Preparations; D006728:Hormones; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D016729:Leuprolide