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

Creange, John E.; Anzalone, Anthony J.; Potts, Gordon O.; Schane, H. Philip

doi:10.1016/0010-7824(81)90042-1

Cited by 39 publications

(11 citation statements)

References 4 publications

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“…Initial studies on rats and monkeys showed that such drugs (trilostane and epostane) were orally active as interceptive agents at comparatively high dose rates although they also affected adrenocorticosteroid activity (Potts et al, 1978;Shane et al, 1979;Creange et al, 1981). Tests on pregnant sheep in late gestation showed that a single intravenous injection of trilostane caused a rapid and prolonged drop in circulating progesterone although labour was not invariably induced (Taylor et al, 1982;Jenkin & Thorburn, 1984).…”

Section: Introductionmentioning

confidence: 99%

Effects on maternal and fetal steroid concentrations of induction of parturition in the sheep by inhibition of 3 -hydroxysteroid dehydrogenase

Silver

1988

Reproduction

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Summary. Changes in circulating steroid hormones, the incidence of myometrial contractions, and the onset of labour were all monitored after administration of the 3 \ g = b \ \ x = r e q -\ hydroxysteroid dehydrogenase inhibitor, epostane, to chronically catheterized ewes and fetuses near term. In all animals the drug induced delivery 33\p=n-\36h after injection or infusion into the ewe with the birth of live healthy lambs which showed normal subsequent development.Epostane induced immediate, permanent falls in both maternal and fetal plasma progesterone concentrations, accompanied by increased PGF metabolite concentrations in the uterine vein beginning 15 min after treatment. Of the other hormonal changes observed, the most striking was the pronounced drop in both maternal and fetal plasma cortisol. In the fetus this fall was followed by increasing concentrations of circulating ACTH which eventually restored the cortisol levels. By 12\p=n-\24 h after epostane a substantial overshoot had occurred and at 27\p=n-\30h the fetal plasma cortisol concentrations were as high as those seen during normal parturition at term. No significant changes in maternal plasma oestradiol-17\g=b\ could be detected after epostane treatment or during labour. The incidence of slow myometrial contractions increased significantly during the second 3-h period after epostane, although their duration did not change. Contraction patterns typical of first stage labour were seen from 20 to 24 h. These results show that epostane may be used as a safe, predictable inducing agent in sheep if given 6\p=n-\10 days before term; the lambs showed no signs of prematurity despite their lowered plasma cortisol concentrations which persisted for some hours before labour was induced.

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Section: Introductionmentioning

confidence: 99%

Effects on maternal and fetal steroid concentrations of induction of parturition in the sheep by inhibition of 3 -hydroxysteroid dehydrogenase

Silver

1988

Reproduction

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“…A second competitive inhibitor of 3ß-HSD, epostane (4,5-epoxy-17-hydroxy-4,l 7-dimethyl-3-oxoandrostane-2-carbonitrile) has been shown to in¬ duce abortion in monkeys (Creange, Anzalone, Potts & Schane, 1981). These authors found that epostane did not inhibit adrenocorticotrophic hormonestimulated production of glucocorticoids in nonpregnant monkeys and suggested that epostane was a preferential inhibitor of the gonadal enzyme.…”

Section: Introductionmentioning

confidence: 99%

Effect of inhibition of prostaglandin synthesis on cervical softening and uterine activity during ovine parturition resulting from progesterone withdrawal induced by epostane

Ledger¹,

Webster²,

Anderson³

et al. 1985

Journal of Endocrinology

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The effects of an inhibitor of 3 beta-hydroxysteroid dehydrogenase (epostane) on uterine activity and cervical softening have been studied in eight sheep during late pregnancy. Treatment with epostane led to a rapid decline in the concentration of progesterone measured in utero-ovarian venous plasma, to less than 10% of the pretreatment value within 30 min of bolus injection. This was followed by a significant (P less than 0.02) increase in the concentrations of metabolites of prostaglandins E and F in utero-ovarian venous plasma and uterine activity similar to that seen in the final stages of normal labour. Measurements of cervical tissue extensibility made ex vivo showed the cervix to have softened considerably. These changes occurred without any significant change in the concentration of oestradiol-17 beta in utero-ovarian venous plasma. Infusion of mefenamic acid, an inhibitor of prostaglandin synthesis, prevented the changes in uterine activity and cervical softening that occurred after injection of epostane alone. Mefenamic acid also reduced the increase in concentrations of metabolites of prostaglandins E and F in plasma, although the concentration of progesterone in these animals showed the same abrupt fall which occurred in sheep after injection of epostane alone. These results suggest that progesterone withdrawal, in the absence of any subsequent rise in circulating oestrogen concentrations, is sufficient stimulus to induce cervical softening in the ewe. Cervical softening following progesterone withdrawal can be prevented by inhibition of prostaglandin synthesis.

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“…Hence, Epostane is likely to reduce the concentration of ovarian, placental and adrenal steroids. In the rat and monkey, the sensitivity of 3,f-HSD to inhibition appears to vary at the different sites as larger doses of inhibitors were needed to reduce glucocorticoid than progesterone production (Schane et al 1979;Creange et al 1981). However, in the present experiments cortisol production fell in parallel with that of progesterone in both the fetus and mother after Epostane treatment.…”

Section: General Effects Of Epostane Treatment On Sows Andfetusesmentioning

confidence: 54%

“…Compounds such as Trilostane and Epostane which competitively inhibit this enzyme reduce maternal progesterone levels during pregnancy in a variety of species (Potts, Creange, Harding & Schane, 1978;Schane, Potts & Creange, 1979;Creange, Anzalone, Potts & Schane, 1981;Taylor, Webb, Mitchell & Robinson, 1982). Recent studies in the pregnant mare have shown that Epostane can cross the placenta and hence administration of these compounds offers the possibility of investigating the effects of a simultaneous reduction in fetal and maternal progesterone (Fowden & Silver, 1987).…”

Section: Introductionmentioning

confidence: 99%

INHIBITION OF 3β‐HYDROXYSTEROID DEHYDROGENASE IN THE SOW NEAR TERM: EFFECTS ON FETAL AND MATERNAL STEROIDS AND ON DELIVERY

Silver

Fowden

1988

Exp Physiol

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SUMMARYThe effect of Epostane, a 3,8-hydroxysteroid dehydrogenase inhibitor, on maternal and fetal plasma progesterone and other steroids has been investigated in chronically catheterized pregnant sows near term. Epostane (1-2 mg/kg) was given i.v. and samples withdrawn from the uterine vein and artery and a fetal artery. In seven sows tested at 106-110 d gestation (term 115 d) Epostane induced parturition 25 + 2-1 h later with the birth of live viable young (group 1). In four sows tested with the same dose of Epostane at 106-111 d gestation parturition was not induced (group 2). A rapid drop in maternal and fetal plasma progesterone occurred after Epostane; in group 1 maternal progesterone remained below 4 ng/ml until delivery whereas in group 2 the drop was temporary, as was the decrease in fetal progesterone in all animals. Epostane also resulted in a rapid fall in maternal and fetal plasma cortisol with a gradual recovery over the following 9-12 h which was accompanied by increased ACTH (adrenocorticotrophic hormone) levels in the fetus. In group 1 fetuses a further escalation in both cortisol and ACTH occurred up to and during delivery while in group 2 basal concentrations were restored after 24 h. Epostane also reduced maternal oestrone concentrations in both groups over the 6-9 h after drug treatment. In group 2 the basal oestrone concentrations and the oestrone/progesterone ratio before and after Epostane administration were lower than in group 1 which may in part explain the failure of Epostane to induce labour in the former despite their similar gestational age. It is concluded that Epostane is not a reliable inducing agent in the sow when infused within 5-10 d of term although enhanced adrenocortical activity probably ensures the viability of the piglets if delivered.

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

Cited by 39 publications

References 4 publications

Effects on maternal and fetal steroid concentrations of induction of parturition in the sheep by inhibition of 3 -hydroxysteroid dehydrogenase

Effects on maternal and fetal steroid concentrations of induction of parturition in the sheep by inhibition of 3 -hydroxysteroid dehydrogenase

Effect of inhibition of prostaglandin synthesis on cervical softening and uterine activity during ovine parturition resulting from progesterone withdrawal induced by epostane

INHIBITION OF 3β‐HYDROXYSTEROID DEHYDROGENASE IN THE SOW NEAR TERM: EFFECTS ON FETAL AND MATERNAL STEROIDS AND ON DELIVERY

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