Cortricotropin‐releasing factor (CRF) injected into the brain or the periphery induces protection against indomethacin‐caused gastric injury through glucocorticoids and the CRF receptors types 1 and 2 (840.10)
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In the present study we investigated whether CRF injected into the brain or the periphery induces protection against indomethacin‐caused gastric injury and the role of glucocorticoids, the CRF receptor types 1 and 2 (CRF1 and CRF2 receptors) in the protection. Gastric injury was caused by indomethacin (35 mg/kg, subcutaneously) in preliminary fasted rats and CRF was injected 30 min before indomethacin administration. The participation of glucocorticoids was studied by inhibitor of glucocorticoids’ synthesis metyrapone, and glucocorticoid receptor antagonist RU‐38486. The role of the CRF1 and CRF2 receptors was investigated by the nonselective CRF1/CRF2 receptor antagonist astressin, the selective CRF1 receptor antagonist NBI 27914, and the selective CRF2 receptor antagonist astressin2‐B. Intracerebroventricular or intraperitoneal injection of CRF at the doses, which markedly increased plasma corticosterone levels, significantly suppressed the occurrence of gastric erosion induced by indomethacin. The protective effect of CRF on the gastric mucosa against indomethacin‐produced injury was significatly attenuated by metyrapone and RU‐38486 as well as by astressin, NBI 27914 and also astressin2‐B. The results suggest that CRF injected into the brain or the periphery may induce protection against indomethacin‐caused gastric injury through glucocorticoids, CRF1 and CRF2 receptors. Grant Funding Source : Supported by grants from RFBR N13‐04‐01680‐a and Programs of Presidium RAS 7PKeywords:
Metyrapone
Corticosterone
Antiglucocorticoid
Abstract: 11–Deoxycortisol (cortexolone) has previously been used as a glucocorticoid antagonist in vitro and in adrenalectomized rats. Antiglucocorticoid properties of 11–deoxycortisol in intact rats were examined by studying the effect of 11–deoxycortisol on the induction of hepatic tryptophan oxygenase (TO) by corticosterone. No antiglucocorticoid effect was observed. When 11–deoxycortisol was injected into rats, the TO activity increased. This was probably mainly caused by an elevation of the serum corticosterone level. The induction of TO by 11–deoxycortisol was inhibited by metyrapone. However, 11–deoxycortisol (100 mg/ kg) was still not a glucocorticoid antagonist even in presence of metyrapone
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Metyrapone
Corticosterone
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Antiglucocorticoid
Refractory (planetary science)
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An analysis of receptor mechanisms of glucocorticoid and antiglucocorticoid effect was made. The limiting link in glucocorticoid and antiglucocorticoid realization are specific cytoplasmic glucocorticoid receptors (GR) which function is controlled by heat shock protein (HSP) of 90 kD molecular weight. Under the influence of glucocorticoids (G), GR are released from GR-HSP complex, forming GR-G complexes. The latter are translocated into cell nucleus activate the function of genetic apparatus, change biosynthesis of specific enzymes realizing intracellular glucocorticoid effect Receptor mechanism of antiglucocorticoid effect is realized via competition of steroid and non-steroid drugs with glucocorticoids for binding sites on GR or pharmacological stabilization of GR-HSP complex, decreasing 4SGR release, 4S GR-G forming, and 4SGR-G translocation into cell nucleus. New data about GR chemical structure according to which GR contain 3 functional domains, characterized by regulatory DNA-binding and ligand-binding activity promote researches of antiglucocorticoids. It promoted synthesis of a new most active receptor antiglucocorticoid RU-486 (19-norsteroid), that inhibits ovalbumin and conalbumin synthesis induced by glucocorticoids.
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Mifepristone is an antiprogestin which adds to progesterone receptor.It also acts as an antiglucocorticoid through its binding to the glucocorticoid receptor.Mifepristone is a specific cell cycle inhibitor through its restraining DNA synthesis.Also it can inhibit the growth by inducing apoptosis of tumor cell.
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Aim To search for novel progesterone receptor antagonist with higher efficiency and less antiglucocorticoid effects.Methods The structure of progesterone receptor antagonist mifepristone at C_ 11,C_ 13,C_ 17-substitute were modified.Seven mifepristone derivatives were synthesized from 3-ketal-5(10),9(11)-estradiene-17-one through epoxidation,the addition of aromatic Grignard agent,addition,reduction and hydrolysis.All of them have not been reported in literature previously.Their structures were confirmed by IR, 1H-NMR and MS spectra.Result All the compound showed similar or lower antagonistic effect on progesterone receptor.The antiprogesterone effect of compound 9d was similar to mifepristone with less antiglucocorticoid effects.Conclusion Introduction of bigger group at C_ 11 will not alter the antiprogesterone effect,while introduction of polar group at C_ 17 may induce less antiglucocorticoid effects.
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Objective:To study the binding affinity(BA) to progesterone receptors and glucocorticoid receptors of the mifepristone.Method:With radioligand binding assay,the BA of mifepristone to the monkey uterus cytosol progesterone receptor and the rat liver glucocorticoid receptor was measured.Results:The BA of mifepristone and progesterone to progesterone receptor were 175.58%±19.20% and 100%,the 50% inhibitory concentration(IC_(50)) were(17.20±1.20)nmol/L and (30.20±2.31)nmol/L,P0.01.The BA of mifepristone and dexamethasone to glucocorticoid receptor were 344.41%±57.41% and 100%,the IC_(50) were (4.21±1.02)nmol/L and (14.50±1.89)nmol/L,P0.01.Conclusion:Mifepristone,as a strong agent of antiprogestin,can block progesterone and glucocorticoid activities.
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Mifepristone (RU486) is a potent antiprogestagen, and at high doses it also acts as an antiglucocorticoid drug. Mifepristone, administered as a single 600 mg dose, is commonly employed to induce medical abortion in conjunction with prostaglandins. The long‐term safety profile of mifepristone, especially at high doses, is less well‐established. Long‐term mifepristone is considered efficacious in treating uterine myomas, endometriosis (25–100 mg/day), and possibly in inoperable meningiomas (200 mg/day), as well as inoperable Cushing's syndrome. Many animal studies document an antiproliferative effect (antioestrogenic), as do some reports in humans. However, there are also data to suggest that, as an antiprogestagen, mifepristone may promote an unopposed oestrogen milieu, and thus have a proliferative effect upon the endometrium. We hereby describe the first reported case of an adolescent female with Cushingoid features and morbid osteoporosis who was treated with mifepristone for its antiglucocorticoid effect (400 mg/day) in an attempt to prevent further bone loss. The patient's striae, weight gain, and buffalo hump markedly improved, and further bone loss was halted. However, with each of the two 6‐month courses of mifepristone (9 months apart) she developed massive simple endometrial hyperplasia and a markedly enlarged uterus. This reversed to normal after cessation of mifepristone treatment. In conclusion, High doses of the antiprogestagen mifepristone over a prolonged period of time may promote an unopposed oestrogen milieu leading to endometrial hyperplasia. Therefore, interval pelvic imaging in women who receive long‐term mifepristone may be prudent.
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Abortifacient
Endometrial hyperplasia
Hormone antagonist
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The first clinically available antiprogestin, mifepristone has generated immense interest in the research community since its' discovery in 1980. Mifepristone is a synthetic orally active steroid with potent antiglucocorticoid, antiprogestogen and a weak anti-androgen activity, used primarily for termination of pregnancy. It acts as a competitive receptor antagonist at the progesterone receptor in the presence of progesterone, and acts as a partial agonist in the absence of progesterone. Extensive research has been carried out regarding its' antiprogestogen activity for use in medical abortion. Lately other medical uses of mifepristone are being explored like for induction of labour in late preg- nancy, as oestrogen free oral contraceptive and for treatment of endometriosis, uterine fibroids, ovarian cancer, prostate cancer, meningiomas, Cushing's syndrome and major psychotic depression.
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Hormone antagonist
Progesterone receptor
Medical abortion
Uterine Fibroids
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Mifepristone is a potent antiglucocorticoid, the administration of which results in a dose-dependent activation of the hypothalamic-pituitary-adrenal axis. However, the net effect of this compound on circulating glucocorticoid activity is not known. We have used a recombinant cell bioassay to study glucocorticoid bioactivity (GBA), measured directly from serum, in 18 women undergoing medical termination of an early pregnancy with 200 mg mifepristone, followed by 0.8 mg misoprostol, a prostaglandin. Increased serum mifepristone was accompanied by an increase in serum cortisol that was insufficient to maintain circulating GBA within the normal (pre-mifepristone) range (34.7–93.8 nm cortisol equivalents); after approximately 43, 46, and 68 h of mifepristone ingestion, the mean serum GBA levels were much lower than the mean pre-mifepristone level (P < 0.0001). At the corresponding times, 16, 13, and 12 women displayed subnormal serum GBA levels (ranges, <15.6–23, <15.6–25.6, and <15.6–32.5 nm cortisol equivalents, respectively). Altogether 11 subjects displayed subnormal serum GBA (range, <15.6–32.5 nm cortisol equivalents) continuously in the presence of high concentrations of mifepristone. Two weeks after mifepristone administration, circulating GBA had returned to normal levels in all subjects. We conclude that 200 mg mifepristone elicits a significant suppression of serum GBA, to one third of the pretreatment value, despite the compensatory increase in the serum cortisol concentration.
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