PubMed Health⌕ Search

Biomedical subjects

C Tournemine

Publications and source records attributed to C Tournemine.

11 recordsLinked to original sources
PubMed1989

New analogues of mifepristone with more dissociated antiprogesterone activities.

Mifepristone (RU 486 or RU 38486) possesses strong antiprogesterone and antiglucocorticoid along with moderate antiandrogen properties, which would limit its use in some therapeutic applications. In a search for more dissociated derivatives, the hydroxy substituent and the propynyl group in position 17 of the RU 486 series was replaced by a spiroether group, which is known to induce specific affinity for the progestin receptor in steroid series. The substituents in the para position of the 11 beta-phenyl group, leading to the most potent derivatives in the RU 486 series, were retained. The new derivatives have been studied in vitro for their relative binding affinities (RBAs) for the steroid receptor and in vivo for their hormonal and antihormonal activities. The selected compounds, RU 46556 and RU 49295 display the following properties: in vitro, like RU 486, they show a strong RBA for the rabbit progestin receptor, but a much lower one for the rat thymus glucocorticoid receptor; in vivo they are about three times more active than RU 486 for inducing abortion in rats, but unlike the latter they are devoid of any antiglucocorticoid activity on the thymus weight in rats. These antiprogesterone effects have been confirmed on the deciduoma formation in rats and on the endometrial proliferation in rabbits. However, in contrast to RU 486 in the latter test, some progestomimetic activity has been observed. RU 46556 and RU 49295 are now under extensive pharmacological study.

Abortifacient Agents↗
PubMed1988

The antiandrogen anandron potentiates the castrating effect of the LH-RH agonist buserelin in the rat.

When buserelin (0.04-25 micrograms/kg/day), a potent LH-RH agonist, was administered s.c. daily for 15 days to male rats, prostate weight decreased after a transient increase in the first days of treatment but never as much as after orchidectomy, since testosterone secretion was never totally suppressed. The combination of the pure nonsteroid antiandrogen Anandron (20 mg/kg/day) with even low doses of buserelin led to an immediate decrease in prostate weight that was complete at 15 days. This could be explained (a) by an additivity of effects: inhibition by Anandron of the action of residual testosterone unsuppressed by buserelin on the prostate and prevention by buserelin of the rebound testosterone increase induced by Anandron: (b) by a potentiation by Anadron of the direct castrating effect of buserelin on the testis since testis weight and testosterone secretion were lowered to a greater extent by the combination than by buserelin alone. Anandron might increase the sensitivity of LH-RH receptors to LH-RH agonist in the testes, as has been shown in the pituitary. In contrast, the combination of the antiandrogenic steroid progestin, cyproterone acetate, with buserelin never potentiated the castrating effect of buserelin on testis weight and testosterone and only partially potentiated prostate atrophy. If such actions also exist in the human, the addition of Anandron to LH-RH agonist treatment would not only counter flare-up and adrenal androgen effects on the prostate but would also lower the doses of peptide or the time required for chemical castration.

Administration, Oral↗
PubMed1987

Early glycogenesis in the uterine glandular cells of the rabbit induced by progestins: a quantitative investigation.

A single administration of progesterone (P) to primed immature rabbits induces the appearance of glycogen in uterine glandular cells. This phenomenon, which is rapid and transitory, precedes a mitotic surge in the glandular epithelium. Ultrastructural studies allowed us to observe the beginning of glycogenesis as early as 1 h after the injection of P. Quantitative image analysis in the course of a kinetic study showed that glycogen levels reached a maximum at the sixth h and after 24 h had fallen dramatically. Promegestone, a potent progestomimetic compound, gave similar results, but estradiol, testosterone and dexamethasone failed to induce the appearance of glycogen in the uterine glands. Mifepristone (RU 486) had an antagonistic effect on the action of P. These results suggest that early P-dependent glycogenesis in the endometrial glandular cells of the rabbit may play an important role in the increased rate of mitosis and cellular proliferation that are necessary events in preparing the endometrium for implantation.

Animals↗
PubMed1986

Pharmacology of an antiandrogen, anandron, used as an adjuvant therapy in the treatment of prostate cancer.

To improve the inhibition of prostate cancer growth obtained by surgical or chemical castration (estrogens or LHRH analogs), blockade of the action of residual androgens of adrenal origin has been proposed. Among antiandrogens acting through the androgen receptor (AR), the nonsteroid anandron (RU 23908) has several advantages over available compounds: megestrol acetate and cyproterone acetate, both steroids, bind substantially to other hormone receptors (progestin, gluco- and mineralocorticoid); and anandron binds only to AR. The nonsteroid flutamide is a prodrug converted to the active metabolite, hydroxyflutamide; anandron is well absorbed on oral administration of an active dose and intact compound disappears slowly from plasma. This may explain why, although in vitro anandron interacts very transiently with AR, in vivo a high level of untransformed anandron is present at the receptor site to induce its antiandrogenic activity. Animal experiments confirm that anandron can counteract the effect of adrenal androgens and inhibit the LHRH analog-induced initial increase in androgen ("flare-up"). Thus, in rats castrated either surgically or by buserelin or DES and supplemented with adrenal androgens (since endogenous adrenal secretion is very low in this species compared to man), anandron decreased prostate weight to control levels. The administration of buserelin to intact rats over 15 days resulted in a significant increase in prostate weight between Days 1 and 5. The addition of anandron to the buserelin inhibited this increase and, furthermore, led to a far greater decrease in prostate weight than that due to buserelin alone at 15 days, indicating a synergy of action.

Androgen Antagonists↗
PubMed1986

Effect of a new topically active antiandrogen (RU 38882) on the rat sebaceous gland: comparison with cyproterone acetate.

RU 38882 is a new antiandrogen. When given by subcutaneous or oral route, RU 38882 is about 25 times less potent than cyproterone acetate. However, when applied topically to the intact rat skin, RU 38882 (0.25-25 mg/rat/day for 5 days or 3 weeks) decreases, in a dose-related manner, the volume density of the smooth endoplasmic reticulum vesicles of the differentiating cells of the sebaceous gland, a structure directly involved in sebum lipid synthesis. Under these conditions RU 38882 is about 100 times more potent than cyproterone acetate and unlike cyproterone acetate, does not modify the prostate weight. The lack of efficacy of cyproterone acetate on the sebaceous gland could be due to its partial androgenic activity while RU 38882, under these conditions, acts as a pure antiandrogen which inhibits the nuclear androgen-receptor translocation.

Administration, Topical↗
PubMed1985

Antiandrogenic activity of a series of des-A-steroid derivatives.

In the search for new antiandrogens, a number of des-A-steroids were prepared by condensation of Grignard reagents with lactone 3. From the resulting key intermediates 5, various structural modifications were performed such as the introduction of an additional unsaturation to afford dienones 8 and aromatic derivatives 10 or the introduction of an alkyl substituent mostly in position 10 (11-13) but also in some cases in position 16 (22). In addition, 13-ethyl analogues were also prepared from lactone 4. The relative binding affinities (RBAs) for the androgen receptor of these compounds were determined under various conditions. Some compounds exhibit a capacity to interact with the receptor comparable to that of testosterone. One of the most potent compounds is 17beta-hydroxy-des-A-androsta-9,11-dien-5-one (8b), RBA value 73% of that of testosterone. More interestingly, several compounds were found to have an antiandrogenic profile in vitro and in vivo. One of the most effective compounds is 10-ethyl-17beta-hydroxy-des-A-estra-9-en-5-one (5c), which exhibits a strong local antiandrogenic activity in hamsters, without any significant systemic antiandrogenic effects. The corresponding 17beta-acetyl derivative (RU 38882) has been selected for extended pharmacological studies.

Androgen Antagonists↗
PubMed1983

Substituted derivatives of A-nor-5 alpha-androstane and A-nor-5 alpha-estrane--structure and affinity for hormonal receptors.

The interactions of A-nor-5 alpha-androstane and A-nor-5 alpha-estrane derivatives with the estrogen and androgen receptors, have been evaluated by measuring their relative binding affinities (RBAs), under two sets of incubation conditions in order to discriminate between potent agonists from weak agonists with potential antagonist activities. Surprisingly some of these compounds which do not possess a phenolic hydroxyl group interact somewhat markedly with the estrogen receptor. This interaction is characteristic of weak estrogens, with potential anti-estrogenic activity (RBA values decreasing when increasing time and temperature of incubation). Results are in good agreement with data obtained in vivo. Moreover, some of these compounds interact also to some extent with the androgen receptor. Results will be discussed in order to outline some structure-activity relationships in these series.

Animals↗