Biomedical subjects
Publications and source records attributed to J P Raynaud.
A single injection of LHRH to the adult male rat, as of its analog [D-Ala6, des-Gly-NH102] LHRH ethylamide, resulted in a marked decrease in LH receptors in the tests. Plasma testosterone level and the weight of the seminal vesicles and prostate were also decreased after treatment. These data demonstrate that LHRH can decrease the sensitivity of LH receptors and testicular function in the rat.
The administration of LHRH or of its analog [D-Ala6, des-Gly-NH10(2)] LHRH ethylamide to the female rat on day 10 of gestation resulted in termination of pregnancy and in a marked decrease in ovarian LH receptors and plasma progesterone level. Asingle injection of either compound during diestrus I also led to a decrease in LH receptors. These data demonstrate the high sensitivity of the control of ovarian LH receptors by circulating gonadotrophins and suggest that the contraceptive action of pre- and postcoitally administered LHRH is mediated by negative control of LH receptors.
Several subcutaneous administrations of 250 microgram of LHRH (4 or 5 adminstrations at 4-hourly intervals per day) between the 2nd and 7th day post-ovulation in 4 normal women led to early luteolysis as demonstrated by a fall in serum progesterone concentration and early onset (2 to 3 days earlier) of menstruation.
The potency of 5 migrogram moxestrol (R 2858). 11beta-methoxy-17alpha-ethinyl-estra-1,3,5-[10]-triene-3,17-diol, administered orally, was compared to that of 25 microgram ethinyl estradiol in a double-blind crossover clinical pharmacology study of six postmenopausal women. At these doses, both compounds increased the eosinophilic index and decreased serum LH and FSH levels. A marked effect on circulating prolactin was observed only during ethinyl estradiol treatment.
Explore the source record for details and available documents.
To check the possible toxicity risks of the meat from swine fed with a residue producing feed additive: Carbadox, a new methodology was used. It is the "Relay Toxicity". Swine were fed with a high dose of the additive and sacrificed without any withdrawal. In such conditions meat contains a high level of residues. The frozen meat was given daily--after thawing--at 100 g or 200 g/dog to 12 beagle dogs, 6 females and 6 males, sacrificed when 87.5 months old (85 months on experiment). On these animals, no anomaly was found: on weight gain and health; on fertility and reproductive performances; on hematology and biochemical values of blood and urine; and after careful macroscopic or microscopic examinations of the animals at safrice. We were able to obtain a safety factor above 9000 when Carbadox is used at the maximum level approved 50 ppm, and the withdrawal 4 weeks before slaughtering. To conclude, the absence of anomaly allows us to confirm the safety for the human consumer when Carbadox is used as a feed additive for swine.
Explore the source record for details and available documents.
Oestrogen stimulation of plasma renin substrate (PRS) was studied in men with alcoholic cirrhosis. PRS values, before and 1, 2, 4 and 6 days after a single oral administration of 100 microgram of an oestrogen derivative, 11beta-methoxy-17-ethynyl-1,3,5(10)-estratriene-3,17beta-diol (Moxestrol), were measured by radioimmunoassay of generated angiotensin I in five men with normal liver function and five men with alcoholic cirrhosis. Basal PRS was 0.93 +/- 0.22 nmol/ml (mean +/- 1 SD) in the normal men and significantly lower (P less than 0.01) in the men with cirrhosis (0.33 +/- 0.14 nmol/ml). Two days after administration of Moxestrol, PRS rose significantly but transiently (P less than 0.05) to 1.41 +/- 0.42 nmol/ml in the normal men and to 0.47 +/- 0.15 in the cirrhotic men, the relative increase (approximately 50%) being similar in both groups. A study of the plasma kinetics and urinary excretion of Moxestrol was also performed to evaluate its metabolic clearance rate and absorption. Since the intestinal absorption of [14C] Moxestrol was not depressed in cirrhotic men, the low PRS values recorded are probably the consequence of hepatocyte dysfunction.
Explore the source record for details and available documents.
1. 4-(2-Methyl-3-(4-chlorobenzoyl)phenyl)butanoic acid (RU 16029) is a potent anti-inflammatory and analgesic agent. In humans, its ketone group is rapidly reduced to an alcohol, whereas in rats, mice and dogs, its butanoic side-chain is rapidly oxidized to the corresponding acetic acid. 2. The extent of this oxidation was studied in eleven species. Cats, dogs, rabbits, hens and rodents readily oxidized the side-chain; humans, baboons and pigs showed only weak oxidizing capacity. 3. Species differences were also recorded in the secondary biotransformations. The acetic metabolite is excreted as an acylglucuronide in humans and rats, but as an amide-like conjugate in mice. 4. Comparison with biotransformations undergone by structurally related compounds confirms that the metabolism of a new compound in different species is unpredictable.
To determine the hormone-dependence of a tumor, it is preferable to use highly specific radiolabeled ligands when available, since often more than one class of steroid hormone receptor is present in the tissue specimen, and interference from classes other than the one under study cannot be readily eliminated. In this study, we describe a simple in vitro system used to define the molecular requirements for a highly specific interaction between a steroid and the receptor corresponding to a single class of hormone. It is based on the use of homogenate or crude 105,000 X g supernatant prepared from the target organs considered as end points in routine biological potency tests and on the use of available radioligands not bound by plasma proteins (tags) to single out the receptors. For each receptor singled out in the target organ cytoplasm, the ability of over 700 molecules to decrease bound radioactivity was compared to that of the natural hormone (relative binding affinity) with the use of a dextran-coated charcoal technique to separate bound from unbound steroid. On the basis of the results on 81 molecules, presented in this study, the effect of various substituents on the affinity and specificity of the natural hormones was determined. Molecules interacting markedly with several receptors were submitted to X-ray crystallography in order to establish whether overlap between the various conformations of the natural hormone and of the test molecule might not partly account for lack of specificity.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Specific, estrogen-inducible, nuclear radioactivity uptake has been demonstrated in the uterus, pituitary and hypothalamus of immature female rats after injection of a highly potent labelled progestin, R 5020 (17, 21-dimethyl-19-nor-pregna-4, 9-diene-3, 20-dione). A cytoplasmic progestin "receptor" has been characterized in these target tissues by an in vitro Dextran-coated charcoal adsorption method. R 5020 binds with the same intrinsic dissociation constant to the receptor present in these tissues; it dissociates at the same rate from the uterine and pituitary receptor (k-1 = 1 multiplied by 10(-2) min (-1), but about 6 times slower than progesterone. This evidence, together with the similar hormone specificity in the uterus and pituitary, suggests that the progestin "receptor" is a similar entity in central and peripheral target tissues.
Synthetic "progestins" currently used in the contraceptive pill inhibited the luteinizing hormone (LH) responsiveness to LH-releasing hormone in cells in culture in a way undistinguishable from that of androgens. Moreover, they competed for binding of the 3H-labeled androgen R 1881 to the rat prostate androgen receptor and stimulated seminal vesicle and prostate weight in castrated rats. R 5020, a pure progestin, was without effect on the above-mentioned parameters. However, a complete inhibition of the LH surge measured in the afternoon of expected proestrus was obtained at a dose of R 5020 similar to that of D-norgestrel. The synthetic progestin was also found to inhibit ovulation and to delay vaginal cornification. The present data show that the synthetic "progestins" commonly used in the pill possess intrinsic androgenic activity which could well be responsible, to an unknown extent, for their effectiveness as contraceptive agents. R 5020, a synthetic progestin devoid of androgenic activity, is at least as potent as the most potent 19-nortestosterone derivative, D-norgestrel, in inhibiting gonadotropin secretion and other parameters of the estrous cycle in the rat. The availability of a pure progestin devoid of androgenic activity but highly effective as an inhibitor of gonadotropin secretion could be of great interest for the development of an improved contraceptive.
The anomeric aminoglycosides, RU 21886 and RU 23468, which both have a 2-deoxystreptamine residue, stabilize 70S ribosomes to similar extents at low magnesium ion concentrations. Only RU 21886, however, has marked antibacterial and bactericidal activity and gives rise to a high level of misreading in cell-free protein synthesizing systems. It would thus appear that the ability to stabilize the association of the two ribosomal subunits does not necessarily lead to errors in translation.
At the daily dose of 24 mug for a period of 4 weeks, RU 16117 (11alpha-methoxyethinyl estradiol), a new antiestrogen, led to 65% reduction of the number of already established dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats. Not only the tumor number but also the tumor size was reduced by RU 16117 in a manner similar to that seen after ovariectomy. The absence of an inhibitory effect of doses of 0.1 to 12.5 mug 17beta-estradiol (E2) per day, a dose-range which covers the low estrogenic activity of the RU 16117 doses used, suggested that the inhibitory effect of RU 16117 was not due to its estrogenic activity. Decreased levels of receptors for E2, progesterone, and prolactin were found in the tumors remaining after ovariectomy; treatment with the dose of RU 16117 sufficient to inhibit tumor growth (24 mug) had a similar inhibitory effect on the levels of E2 and prolactin receptors. These data suggested that a reduction of hormone receptor levels in the tumor tissue could be a mechanism by which RU 16117 acts as a potent inhibitor of the growth of DMBA-induced mammary carcinoma.