Prolonged inhibition of luteinizing hormone and testosterone levels in male rats with the luteinizing hormone-releasing hormone antagonist SB-75.

Abstract

Inhibitory effects of the potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine',4-chloro-D-phenylalanine2,3-(3-pyridyl)-D-alanine3, D-citrulline6,D-alaninelq]ute'iniing hormone-releasing hormone (SB-75) free of edematogenic effects were investigated in male rats. In a study to determine the effect on luteinizing hormone levels in castrated male rats, SB-75 was injected s.c. in doses of 0.625, 1.25,2.5, 5.0, and 10 pg. Blood samples were taken at different intervals for 48 hr. AU doses of SB-75 significantly decreased luteInzing hormone levels for >6 hr (P < 0.01); this inhibition lasted for >24 hr (P < 0.01) with a dose of5.0 pg and >48 hr with 10 pg (P < 0.05). Serum testosterone levels were also measured in intact male rats u 'ected with SB-75 in doses of 25, 50, and 100 pug. AU doses produced a dramatic fall in testosterone to castration levels 6 hr after injection (P < 0.01); this inhibition of serum testosterone was maintained for >72 hr, but only the 100-pg dose could keep testosterone in the castration range for >24 hr (P < 0.01). In another study using a specific RIA, we obtained the pharmacokinetic release pattern of SB-75 from two sustained delivery formulations of SB-75 pamoate microgranules and examined their effect on serum testosterone. After a single i.m. injection of 20 mg of one batch of microgranules, a large peak corresponding to SB-75 at 45.8 ng/ml was observed, corresponding to the "burst" effect. Levels of the analog decreased to 19.6 ng/ml on day 2, gradually reached a concentration of 4.7 ng/ml on day 7, and kept declining thereafter. Testosterone levels were reduced on day 1 (P < 0.01) and were maintained at low values for >7 days (P < 0.05). In rats injected with 10 mg of SB-75 pamoate microgranules ofthe second batch, SB-75 serum levels rose to 33 ng/ml 3 hr after administration and then fell gradually to =3.4 ng/ml on day 16, but a second small peak was seen on day 28. Subsequently, the analog levels decreased slowly to 2.9 ng/ml on day 42 7100The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

“…Bulk amounts of SB-75 were prepared according to the same methods by Asta Pharma (Frankfurt/Main) for microencapsulation. This product was identical with our preparation, physicochemically (HPLC, IR spectrum) and biologically in vitro and in vivo (9,12). SB-75 microcapsules were prepared by P. Orsolini, Cytotech, using a phase separation process and sterilized by y-irradiation.…”

“…Prototypes of microcapsules of somatostatin analog RC-160 and, more recently, of LH-RH antagonist SB-75 were also used in the treatment of experimental breast cancer and pancreatic cancer (20,21). More modern forms of sustained-delivery systems, which consist of microparticles (microgranules) containing pamoate or LH-RH, also have been prepared (9,12,15). Microcapsules are more uniform spherical particles with…”

“…However, progress in development and clinichl application of LH-RH antagonists has been slow (1). High-dose requirements, due to low potency of earlier compounds and side effects related to histamine release of analogs with D-arginine in position 6, delayed clinical use of LH-RH antagonists (1,4,9).…”

“…However, progress in development and clinichl application of LH-RH antagonists has been slow (1). High-dose requirements, due to low potency of earlier compounds and side effects related to histamine release of analogs with D-arginine in position 6, delayed clinical use of LH-RH antagonists (1,4,9).Modem LH-RH antagonists, free of edematogenic and anaphylactoid reactions, containing neutral hydrophilic D-ureidoalkyl amino acids such as D-citrulline and D-homocitrulline at position 6, were recently synthesized in our laboratory and tested in vitro and in vivo (10-12). Among these analogs,…”

“…RH; SB-75} was shown to be one of the most powerful antagonists in blocking ovulation and inhibiting LH levels in rats (9,11,12). The use of antagonists in tumor therapy would avoid the transient stimulation that occurs initially in response to LH-RH agonists and prevent the temporary clinical "flareup" of the disease.…”