Pharmacokinetics of RU 486

“…In contrast, a significantly reduced binding of [ 3 H]dexamethasone to brain and pituitary GR of animals chronically treated with ORG 34116 was observed. Different pharmacokinetics of the compounds might account for these different findings, as rats chronically treated with ORG 34116 still had considerably high circulating levels of the compound even 48 h after administration of the drug had (Deraedt et al, 1985;Lähteenmaäki et al, 1987): The substance displays extensive binding to a1-acid glycoprotein in humans and to albumin (for a review see Bamberger and Chrousos, 1995;Cadepond et al, 1997), accounting for its long plasma halflife of 20 h. The pharmacokinetics of ORG 34850 and ORG 34116 have not been investigated by the manufacturer. Moreover, no reports describing the pharmacokinetic properties of the selective GR antagonists have been published so far.…”

Section: Discussionmentioning

confidence: 99%

Effect of Chronic Administration of Selective Glucocorticoid Receptor Antagonists on the Rat Hypothalamic–Pituitary–Adrenocortical Axis

Bachmann

Linthorst

Holsboer

et al. 2002

Neuropsychopharmacol

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The effects of the selective glucocorticoid receptor (GR) antagonists ORG 34850, ORG 34116, and ORG 34517 on the rat hypothalamic-pituitary-adrenocortical (HPA) system were investigated. To assess the potency of the compounds to occupy GR in the brain and pituitary, we applied a single acute subcutaneous (s.c.) injection (10 mg/kg). ORG 34517 was most potent to occupy GR in the anterior pituitary and distinct brain areas, whereas all compounds were unable to occupy mineralocorticoid receptor (MR). Chronic administration of ORG 34850, ORG 34116, and ORG 34517 (20 mg/kg/day) for 1, 3, and 5 weeks resulted only in minor changes in brain GR levels. However, profound increases of hippocampal MR were observed virtually at all time points. Treatment with ORG 34850 and ORG 34116 elicited episodic increases in HPA axis activity, whereas ORG 34517 did not cause any changes in HPA activity. Thus, the GR antagonists exert distinct effects on the HPA axis, which may be pertinent for the proposed antidepressant activity of these compounds.

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“…These drugs have a poor bioavailability and scarcely reach the brain (49, 50). Furthermore, the available type II antagonist RU 38486 is poorly specific, since this drug has been designed and is used as an antagonist of progesterone receptors (50). Inhibitors of glucocorticoid synthesis, such as metyrapone, might be an alternative to glucocorticoid antagonists.…”

Section: Discussionmentioning

confidence: 99%

Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission

Piazza

Barrot

Rougé‐Pont

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

112

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Specific antagonists of central dopaminergic receptors constitute the major class of antipsychotic drugs (APD). Two principal effects of APD are used as criteria for the pre-clinical screening of their antipsychotic action: (i) inhibition of basal and depolarization-induced activity of mesolimbic dopaminergic neurons; (ii) antagonism of the locomotor effects of dopaminergic agonists. Given that glucocorticoid hormones in animals increase dopamine release and dopamine-mediated behaviors and that high levels of glucocorticoids can induce psychotic symptoms in humans, these experiments examined whether inhibition of endogenous glucocorticoids might have APD-like effects on mesolimbic dopaminergic transmission in rats. It is shown that suppression of glucocorticoid secretion by adrenalectomy profoundly decreased (by greater than 50%): (i) basal dopaminergic release and the release of dopamine induced by a depolarizing stimulus such as morphine (2 mg͞kg, s.c.), as measured in the nucleus accumbens of freely moving animals by microdialysis; (ii) the locomotor activity induced by the direct dopaminergic agonist apomorphine. The effects of adrenalectomy were glucocorticoid specific given that they were reversed by the administration of glucocorticoids at doses within the physiological range. Despite its profound diminution of dopaminergic neurotransmission, adrenalectomy neither modified the number of mesencephalic dopaminergic neurons nor induced gliosis in the mesencephalon or in the nucleus accumbens, as shown by tyrosine hydroxylase and glial fibrillary acidic protein immunostaining. In conclusion, these findings suggest that blockade of central effects of glucocorticoids might open new therapeutic strategies of behavioral disturbances.The discovery of treatments reducing the activity of the central dopaminergic (DA) transmission is one of the main goals of neuroscience and pharmacological researches. Interest in dopamine has been sustained by the discovery that antipsychotic drugs (APD) were potent antagonists of the DA receptors (1). Decades of intensive research has considerably enlarged our knowledge about the functional role of DA neurons (2), suggesting that their hyperactivity may be involved in various behavioral pathologies, such as psychosis and addiction (3, 4). Nevertheless, antagonists of DA receptors are still the only class of drugs used in clinical practice to antagonize DA activity.There is evidence indicating that glucocorticoid hormones may be one of the factors determining a pathological hyperactivity of DA neurons. First, an increase in glucocorticoids can induce behavioral changes that are among those attributed to the enhancement of DA activity. For example, high levels of glucocorticoids can generate mood changes ranging from euphoria to psychosis in humans (5, 6), and increase the propensity to develop self-administration of drugs of abuse in animals (7). Second, administration of glucocorticoids increases extracellular concentrations of dopamine in vivo (8) and in vitro (9) and faci...

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Pharmacokinetics of RU 486

Cited by 37 publications

References 6 publications

A regulatory system for use in gene transfer.

A regulatory system for use in gene transfer.

Effect of Chronic Administration of Selective Glucocorticoid Receptor Antagonists on the Rat Hypothalamic–Pituitary–Adrenocortical Axis

Suppression of glucocorticoid secretion and antipsychotic drugs have similar effects on the mesolimbic dopaminergic transmission

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