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Biomedical subjects

G O Potts

Publications and source records attributed to G O Potts.

At least 19 recordsLinked to original sources
PubMed1989

Effect of epostane, ZK 98299, and ZK 98734 on the interruption of pregnancy in the rat.

The objective of these studies was to determine whether treatment of 10-day pregnant rats with a combination of epostane (a progesterone biosynthesis inhibitor) and either ZK 98299 or ZK 98734 (progesterone receptor antagonists) would result in additive or synergistic effects on the interruption of pregnancy. When these compounds were tested individually, the order of potency in interrupting pregnancy was ZK 98734 greater than ZK 98299 greater than epostane (50% effective doses 1.3, 4.0, and 35 mg/kg, respectively). Epostane and ZK 98299 were then tested in combination. When epostane was given either 4 h prior to or concurrently with ZK 98299, the combined drug treatment resulted in a significant additive increase in interceptive activity compared to when ZK 98299 was administered alone. In vitro binding studies showed that ZK 98299 and ZK 98734 bound to the rat uterine progesterone receptor in vitro with approximately equal affinity. ZK 98734 bound to the rat thymus glucocorticoid receptor and to the rat ventral prostate androgen receptor with a greater affinity than ZK 98299. The affinity of ZK 98299 for the rat uterine estrogen receptor was weak while the binding of ZK 98734 was not detectable. Thus, the in vitro receptor binding profiles observed were consistent with the known progesterone and glucocorticoid antagonist activities of ZK 98299 and ZK 98734. Overall these findings show that the interceptive activity of epostane and ZK 98299, agents that exert their interceptive activity via different molecular mechanisms, is additive in the 10-day pregnant rat.

Abortion, Veterinary↗
PubMed1988

The effect of danazol in the MRL/lpr mouse model of autoimmune disease.

The purpose of the study was to determine if danazol was efficacious in the treatment of lupus MRL/MpJ (lpr) mice, as measured by longevity, proteinuria and serum amyloid protein (SAP) levels. Danazol, administered at an oral dose of 100 mg/kg, significantly prolonged survival of female MRL/MpJ (lpr) mice but had no effect on the mortality of their male counterparts. Medication with danazol began 40 days after birth of the mice and resulted in a significant decrease in proteinuria in female but not male lupus mice. The concentration of SAP, an acute phase reactant, was significantly decreased in danazol-treated female lupus mice at 80, 100, 120, 140 and 160 days of age when compared to vehicle-treated control mice. SAP levels in male lupus mice treated with danazol were significantly lower than normal control levels only at the 120 and 160 day time points. Measurements of mortality, proteinuria and SAP concentration indicate that danazol at 100 mg/kg is orally active in the treatment of MRL/MpJ (lpr) female, but not male mice.

Amyloid↗
PubMed1984

Inhibition of furosemide-induced kaliuresis in the rat by trilostane, an inhibitor of adrenal steroidogenesis.

In rats treated with furosemide, urinary losses of water, sodium and potassium were accompanied by increased circulating levels of aldosterone. Trilostane, an inhibitor of adrenal 3 beta-hydroxysteroid dehydrogenase activity, prevented furosemide-induced hyperaldosteronism which resulted in a partial inhibition of diuretic-induced kaliuresis without a change in sodium and water excretion. Spironolactone, an antagonist of mineralocorticoid action with inherent diuretic activity, produced qualitatively similar effects to those of trilostane on urinary electrolyte excretion in furosemide-treated intact rats. However, mineralocorticoid-induced potassium loss in adrenalectomized rats was not altered by trilostane but was prevented by spironolactone reflecting the direct effect of spironolactone on the kidney. In addition, furosemide-induced kaliuresis in adrenalectomized rats was not prevented by trilostane. Therefore, although both trilostane and spironolactone reduce diuretic-induced potassium loss, spironolactone acts by competing with aldosterone for the mineralocorticoid receptor while trilostane appears to act exclusively by preventing secondary hyperaldosteronism.

3-Hydroxysteroid Dehydrogenases↗
PubMed1983

Inhibition of human placental progesterone synthesis and aromatase activity by synthetic steroidogenic inhibitors in vitro.

The inhibitory effect in vitro of four synthetic steroids on enzyme systems of placental progesterone synthesis at term was analyzed. Cholesterol side chain cleavage enzyme (CSCC) was not influenced by azastene, trilostane, and WIN 32,729. A 50% inhibition of CSCC was found by 10 microM cyanoketone. The 3 beta-hydroxysteroid dehydrogenase was dose-dependently inhibited by azastene (I50 = 1 microM, trilostane (I50 = 4 nM), cyanoketone (I50 = 3 nM), and WIN 32,729 (I50 = 5 nM). A competitive inhibition of the 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSDH) by azastene (I50 = 0.6 microM), trilostane (I50 = 4.1 microM), cyanoketone (I50 = 0.6 microM), and WIN 32,729 (I50 = 1.5 microM) was observed. No difference in the effect of steroids on the 20 alpha-HSDH of early gestational and term placenta was found. The four steroidogenic inhibitors did not affect the activity of placental aromatase in vitro. Our results allow a comparison of inhibitory potencies of four steroidogenic inhibitors on different steroidogenic enzymes in vitro.

20-Hydroxysteroid Dehydrogenases↗
PubMed1981

Win 32,729, a new, potent interceptive agent in rats and rhesus monkeys.

Win 32,729 [(2 alpha, 4 alpha, 5 alpha, 17 beta)-4,5-epoxy-17-hydroxy-4,17-dimethyl-3-oxoandrostane-2-carbonitrile] is an orally active interceptive agent in rats and rhesus monkeys (M mulatta). A single oral dose of 48 mg/kg terminated gestation when given on Day 10 of pregnancy. When given orally for up to 5 days to pregnant monkeys, it terminated pregnancy in 26 of 34 animals at a dose of 50 mg/monkey (ca 7 mg/kg), in 18 of 24 at a dose of 100 mg/monkey (ca 14 mg/kg) and in all 6 at 250 mg/monkey (ca 35 mg/kg). It did not inhibit ACTH-stimulated glucocorticoid production at 50 mg/monkey but did at a dose of 250 mg/monkey. This preferential gonadal inhibition was not evident in rodents. While in most cases five oral medications of 50-100 mg were required to terminate gestation in 50-day pregnant monkeys, a single subcutaneous medication with 250 mg was also effective, terminating pregnancy in 7 of 7 monkeys.

Abortifacient Agents↗
PubMed1979

Inhibition of ovarian, placental, and adrenal steroidogenesis in the rhesus monkey by trilostane.

Trilostane inhibits adrenal, ovarian, and placental steroidogenesis when administered orally to rhesus monkeys. By inhibiting 3 beta-hydroxysteroid dehydrogenase activity, it causes an increase in circulating levels of pregnenolone. Trilostane reverses the stimulation of luteal progesterone production and the delay in onset on menstruation induced by human chorionic gonadotropin. In pregnant monkeys it reduces circulating progesterone levels and is an effective interceptive agent if given for 5 days beginning on day 16, 25, or 50 of gestation. Concurrent administration of progesterone prevents this interceptive effect. Trilostane reduces plasma cortisol levels at doses lower than those necessary to terminate pregnancy.

3-Hydroxysteroid Dehydrogenases↗
PubMed1978

Trilostane, an orally active inhibitor of steroid biosynthesis.

Trilostane is a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase. In vitro, the drug inhibits conversion of pregnenolone to progesterone but does not alter conversion of cholesterol to pregnenolone nor progesterone to corticoid hormones. When given orally to rats, trilostane inhibits corticosterone and aldosterone production and elevates circulating levels of pregnenolone at doses lower than those that produce adrenal hypertrophy or inhibit gonadal steroidogenesis.

3-Hydroxysteroid Dehydrogenases↗
PubMed1978

Fertility in the rhesus monkey following long-term inhibition of ovarian function with danazol.

Danazol was previously reported to be an oral contraceptive in the rhesus monkey at doses of 200 and 400 mg/monkey/day for 90 days. The drug is now shown to be an effective long-term inhibitor of ovarian function in the monkey. In the final 3 months of a 27-month period of treatment at a dose of 400 mg/monkey/day, the drug continued to be an effective oral contraceptive. During the 27-month treatment period, three of seven monkeys were amenorrheic and the remaining had only 16 of the 109 expected menstrual cycles. Following the discontinuation of medication, all seven monkeys conceived within 2 to 6 weeks. One monkey aborted early in pregnancy and the remaining six delivered normal, healthy infants at term. Therefore, following the discontinuation of long-term treatment with danazol in the monkey, there was rapid and complete return of normal ovarian function.

Animals↗
PubMed1978

Oral progestational activity of spironolactone.

Spironolactone has progestational activity in the rabbit and rhesus monkey. It produced glandular development in the endometrium of the estrogen-primed immature female rabbit over the dosage range of 50 to 200 mg/kg and, at 400 mg/monkey, it delayed estrogen-withdrawal bleeding in ovariectomized monkeys and it inhibited menstruation in regularly cycling monkeys. These data are consistent with the menstrual irregularity and amenorrhea seen in women during treatment with spironolactone.

Animals↗
PubMed1978

Interceptive activity of azastene in rhesus monkeys.

Azastene is an orally effective "luteolytic" agent in rhesus monkeys. In nonpregnant monkeys it reverses the human chorionic gonadotropin-stimulated increase in progesterone production and delay in the onset of menstruation, and, in inseminated monkeys, it prevents pregnancy if given for 5 days beginning on day 24 of the menstrual cycle. The drug is also effective in terminating pregnancy if given for 5 days beginning on approximately day 26, day 50, or day 80 of gestation. Concurrent progesterone administration prevents the interceptive action of the drug. Although azastene inhibits gonadal and placental progesterone production, it has no effect on cortisol production in monkeys and is devoid of apparent hormonal activity.

Abortifacient Agents↗
PubMed1978

Interruption of pregnancy in rats by azastene, an inhibitor of ovarian and adrenal steroidogenesis.

Azastene (4,4,17alpha-trimethylandrost-5-eno[2,3-d]isoxazol-17-ol), when given orally to rats at a dose of 12 mg/kg once on day 10 of pregnancy, induced resorption of all fetuses and a precipitous decline of circulating progesterone levels in all test animals. The disruption of pregnancy was prevented by a single, concurrent, subcutaneous injection of progesterone (4 mg/rat). Thus, the interruption of pregnancy occurs via an acute, short-term, reversible progesterone withdrawal. The reduction of progesterone levels is brought about by competitive inhibition of ovarian 3beta-hydroxysteroid dehydrogenase activity. Despite its potency as an interceptive agent, azastene exhibited only moderate endocrine-related effects if given daily for 2 weeks to female rats at doses as high as 1000 mg/kg. Those effects were an increase in the number of vaginal estrous days and a dose-related increase in adrenal weight. The latter effect is consistent with the known adrenal inhibitory properties of this drug.

3-Hydroxysteroid Dehydrogenases↗
PubMed1977

Isolation, synthesis, and biological activity of five metabolites of danazol.

Metabolites of danazol (17 alpha-pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol), an orally effective pituitary gonadotropin inhibitory agent devoid of estrogenic and progestational activites, were isolated from urine of a female subject who had taken danzol orally at a dose of 800 mg/day for 7 days, The metabolites isolated were 17-hydroxy-17alpha-pregn-4-en-20-yn-3-one (11), 17-hydroxy-2alpha-(hydroxymethyl)-17alpha-pregn-4-3n-20-yn-3-one (5), 17-hydroxy-2-(hydroxymethyl)-17alpha-pregna-1,4-dien-20-yn-3-one(7), 6beta,17-dihydroxy-2alpha-(hydroxymethyl)-17alphapregn-4-en-20-yn-3-one(8), and 6beta, 17-dihydroxy-2(hydroxymethyl)-17alphapregna-1,4-dien-20yn-3-one(10). None of these metabolites exhibited pituitary inhibiting activity comparable to danazol.

Animals↗
PubMed1977

Pharmacology of danazol.

We have established that danazol is an orally active pituitary gonadotrophin inhibitory agent devoid of oestrogenic and progestational activity. This steroid has weak, impeded androgenic activity. Danazol is unique in possessing such a profound separation of pituitary gonadotrophin inhibitory activity from overt sex hormone activity. Separate studies have shown that danazol is antiandrogenic, anti-progestational and antioestrogenic. Extensive toxicological studies have established the safety of this steroid. Lastly, the metabolic studies provide convincing evidence that danazol is the active steroid.

Animals↗