Competitive progesterone antagonists: receptor binding and biologic activity of testosterone and 19-nortestosterone derivatives.

Testosterone and 19-nortestosterone derivatives were evaluated in a developmental scheme designed to identify competitive progesterone antagonists having abortifacient activity. Compounds that displayed significant binding to the rabbit uterine progesterone receptor were followed in biologic tests for progestational, antiprogestational, and abortifacient activities. Of the seven compounds tested for both progestational and antiprogestational activity, only one, 5 alpha-dihydronorethindrone, behaved exclusively as an antagonist. Five other 19-nortestosterones (19-nortestosterone, 17 beta-hydroxyestra-4, 9(10)-dien-3-one, norethindrone, norethindrone acetate, and R 2323) proved to be mixed agonists/antagonists. 5 alpha-Dihydronorethindrone, norethindrone, and 19-nortestosterone terminated pregnancy during the postnidatory period in rats; in addition, the latter two compounds inhibited progesterone-supported pregnancy in spayed rats and curtailed pregnancy during the postnidatory period in hamsters. These results demonstrate that several 19-nortestosterone derivatives bind to the uterine progesterone receptor and behave either as antagonists or mixed agonists/antagonists.

Measurement of a new anticonvulsant, (S)-3-(aminomethyl)-5-methylhexanoic acid, in plasma and milk by high-performance liquid chromatography.

A specific and sensitive isocratic method for the measurement of a new anticonvulsant, (S)-3-(aminomethyl)-5-methylhexanoic acid, in rat plasma and milk is described. Following deproteinization, the compound and internal standard [1-(aminomethyl)cycloheptaneacetic acid] were derivatized utilizing 2,4,6-trinitrobenzene sulfonic acid and extracted with cyclohexane. Analytes were resolved on a 5 microns Spherisorb ODSII column (250 mm x 4.6 mm) using a mobile phase of 57% acetonitrile in 0.1 M ammonium acetate, pH 4.0. Absorbance was monitored at 350 nm. Limit of quantitation was 1.00 microgram/ml for a 100-microliters aliquot of plasma or milk.

The effects of luteinizing hormone releasing hormone (LH-RH) in pregnant rats. I. Postnidatory effects.

PIP: The effects of LH-RH on pregnancy in rats were investigated. A single 500 mcg injection of LH-RH on Days 9, 10, or 11 of pregnancy terminated pregnancy, whereas injection on Days 6-8 or 13-16 had little or no effect. The ED 50 on Day 10 for b.i.d. administration was 150 mcg and 550 mcg for a single injection. Administration on Day 9 was followed by a decrease in circulating progesterone levels on Days 10 and 11. The administration of large doses of progesterone reversed the effects of LH-RH administration on Days 7-12. Treatment with estradiol-17beta did not potentiate the effect of progesterone, but appeared to slightly retard fetal resorption when administered alone. The results suggest that the antifertility effect of LH-RH is mediated via functional luteolysis.^ieng

Absence of a prenidatory effect of luteinizing hormone releasing hormone (LHRH) in hamsters.

Luteinizing hormone releasing hormone at high doses will terminate gestation in rats during early and midpregancy (ED50 approximately equal to 100 microgram/day) and rabbits during early pregnancy. Early pregnancy in hamsters, in contradistinction, seems refractory to this effect. Administration of LHRH up to massive doses (10 mg/day) over the first 3 or 7 days of pregnancy failed to affect the pregnancies in meaningful fashion. Further, a single injection (100 mg) on day 5 had no effect on pregnancy; this system has been employed for the assay of prostaglandins because hamsters are remarkably sensitive to PG's (PGF2alpha, ED50 approximately equal to 17 microgram, PGE2, ED50 approximately equal to 210 microgram). The absence of response of hamsters to LHRH cannot be interpreted at present.

Measurement of CI-979 (a candidate drug for the treatment of age-related disorders of cognition) in human plasma by capillary gas chromatography with nitrogen-selective detection.

A specific and highly sensitive method for the measurement of CI-979 in human plasma is described. The compound and internal standard were extracted from alkalinized plasma with methyl tert.-butyl ether and analyzed by capillary gas chromatography with nitrogen-selective detection. The method was demonstrated to be accurate and precise. Since the limit of quantitation was 0.10 ng/ml, this method was suitable for clinical pharmacokinetic studies in which subjects received repeated administration of 0.5-2.5 mg CI-979 every 6 h.

Postnidatory effects of luteinizing hormone releasing hormone (LHRH) in hamsters.

Whereas the administration of LHRH to pregnant hamsters has no effect during the prenidatory period, the hormone is effective in terminating pregnancy when given after implantation (days 6-10). The ED50 for pregnancy termination over this period approximates a dose of 0.35-0.4 mg b.i.d. When given to pregnant females in a second study, the effects of LHRH at this dose were completely reverse by minute doses of progesterone (30 microgram and above). Finally, administration of LHRH at 1.5 mg b.i.d., from days 6-10 was followed by daily sacrifice through day 12; bloods were sampled at autopsy for progesterone evaluation. Autopsies on days 7 and 8 showed few differences between controls and LHRH-treated hamsters, although decreased weights of the uterine/conceptus units signaled the initation of resorption. Significant LHRH-induced decreases in circulating progesterone were seen by day 9. Fetal resorption continued and was essentially complete by day 11, while progesterone levels continued depressed through the end of the study.

PIP: Postnidatory effects of LH-RH were studied in hamsters. The administration of LH-RH to pregnant hamsters had no effect during the prenidatory period, however, the hormone was effective in terminating pregnancy when given after implantation (Days 6-10). The effective-dose-50 for pregnancy termination over this period approximated a dose of .35-.4 mg twice/day. When given to pregnant females in a 2nd study, the effects of LH-RH at this dose were completely reversed by minute doses of progesterone (30 mcg and above). Finally, administration of LH-RH at 1.5 mg twice/day from Days 6 to 10 was followed by daily sacrifice through Day 12. Blood was sampled at autopsy for progesterone evaluation. Autopsies on Days 7 and 8 showed few differences between controls and LH-RH-treated hamsters, although decreased weights of the uterine conceptus units signaled the initiation of resorption. Significant (p .05) LH-RH-induced decreases in circulating progesterone were seen by Day 9. Fetal resorption continued and was essentially complete by Day 11, while progesterone levels continued depressed throughout the study.