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G Germain

Publications and source records attributed to G Germain.

At least 19 recordsLinked to original sources
PubMed1990

Heterogeneity of oxytocin receptors in the pregnant rat myometrium near parturition.

The contractile response of longitudinal and circular strips of rat myometrium to oxytocin (OT), [Arg8]vasotocin (AVT) and [Arg8]vasopressin (AVP) was examined in vitro in late pregnancy (controls at day 20, day 21, day 22) and 24 h after treatment with the antiprogestin, RU 486 (or mifepristone, given on day 20 or day 21 of gestation). In controls, the maximal effect (Emax) of OT in longitudinal strips increased with gestation, but there was no change in OT sensitivity in either myometrial layer. The pA2 values for the OT/AVP V1 antagonist, d(CH2)5[Tyr(Me)2]OVT, against OT, AVT and AVP on longitudinal strips and against AVT and AVP on circular strips were not different. However, the antagonist did not inhibit the effect of OT in circular strips, indicating that the receptor activated by OT is different from that in longitudinal strips. RU 486 treatment did not modify the characteristics of responses to AVT and AVP. RU 486 improved the response to OT in circular strips from rats treated at day 20, however the sensitivity to OT in longitudinal strips was decreased compared to that in the controls.

Animals↗
PubMed1990

Cellular pharmacology of 5-fluorouracil in a human colon adenocarcinoma cell line selected for thymidine kinase deficiency.

A human colon adenocarcinoma cell line (GC3TK-) was selected for thymidine kinase (TK) deficiency from cloned parental cells (GC3C1) by exposure to 5-bromodeoxyuridine (BrdUrd). The cellular pharmacology of 5-fluorouracil (FUra) and the influence of physiological concentrations of thymidine (dThd; 0.1 to 1 microM) on FUra cytotoxicity during brief exposure in both cell lines were examined. The uptake of FUra during a 1-hr drug exposure, its metabolism to ribo- and deoxyribonucleotides, incorporation into RNA, and inhibition of thymidylate synthase were similar in GC3C1 and GC3TK- cells as were the IC50 values for FUra (26 and 23 microM respectively). TK deficiency did not reduce the intracellular concentrations of FdUMP generated from FUra. In GC3C1, at FUra concentrations up to 100 microM, cytotoxicity was prevented by co-administration of dThd (0.1 to 20 microM). The relationship between cell survival and thymidylate synthase inhibition was close under these conditions. At higher drug concentrations, less dThd protection was observed, and none was detected in GC3TK- cells. Thus, the metabolism of FUra did not appear to be altered substantially in GC3C1 cells selected for TK deficiency. Also in these cells, at concentrations of FUra less than 100 microM, FUra cytotoxicity appeared to be mediated via the inhibition of thymidylate synthase.

Adenocarcinoma↗
PubMed1990

Changes in electrical impedance of the vaginal medium during the menstrual cycle of female rhesus monkeys (Macaca mulatta).

Changes in electrical impedance of the vaginal medium during the menstrual cycle were recorded in female Rhesus monkeys using electrical probe and were correlated with estradiol-17 beta and progesterone plasma concentrations. A gradual decrease in impedance was observed during the follicular phase, the lowest values being observed between days 12-17 of the cycle. Impedance increased again during the first third of the luteal phase until day 21. The reversal of the impedance gradient's sign was nearly concomitant with the appearance of a detectable plasma progesterone concentration. These results support the use of vaginal impedance measurements as a help for the diagnosis of the periovulatory time in the female Rhesus monkey.

Animals↗
PubMed1990

[Primates in the study of mechanisms of pregnancy].

In the field of reproductive physiology, laboratory primates share large homology with the human species, namely the regulation of the steroid production during gestation, the functional anatomy of the uterus and the lack of any recognized endocrine signal preceding the parturition. Primates are largely used in studies on uterine contractility and on the related controling factors (e.g. steroids, catecholamines, isosanoids...). Other studies attempt to identify the origin of impaired fetal vitality in utero. Primates are also good surrogates to establish safe procedures for antenatal surgery. Constraints in connection with the use of primates are primarely the cost of the animals, their low fertility rate and the fact that only very few species (i.e. macaque and baboon) are available for sophisticated studies.

Animals↗
PubMed1989

Plasma levels of SP1-like immunoreactive material (SP1) and progesterone throughout pregnancy and following RU 486-induced early abortion in the cynomolgus monkey (Macaca fascicularis).

A human-SP1 immunoassay was used to detect SP1-like material (SP1) in the plasma of cynomolgus monkeys. In 27 females remaining non-pregnant during a mating period of 4 months, SP1 was occasionally detected at a mean concentration of 2.5 ng/ml. In 14 non-pregnant females of subsequent proven fertility, SP1 was detected 20 days following unfertile mating at a mean concentration of 4.8 ng/ml in 86% of cycles. At day 20 of proven pregnancies, SP1 was at 12 ng/ml in 93% of these animals. SP1 levels during pregnancy increased in two steps, a slow rise between days 20 and 50, followed by an abrupt rise between days 50 and 60 and afterwards a plateau at 600 ng/ml. Seven other pregnant monkeys received 10 mg/kg of the antiprogestin RU 486 at 28 days. Four aborted and the others continued their gestation. SP1 was always dramatically depressed by this treatment; in animals with abortion failure, it remained at a low concentration for 3 months, then the normal concentration range was recovered. The assay of SP1-like material does not allow early diagnosis of pregnancy, however, it remains interesting as a follow-up parameter after 60 days. Also, antiprogestins appear to be useful tools to analyse the metabolism of SP1.

Abortion, Induced↗
PubMed1989

Pregnancy-associated plasma protein-A in pregnant cynomolgus monkeys (Macaca fascicularis): radioimmunoassay, normal levels, effect of RU 486, and preliminary characterization.

Pregnancy-associated plasma protein-A (PAPP-A) is a human macromolecular glycoprotein produced by the trophoblast and possibly by the decidua. Its biological function is unknown, but in vitro, PAPP-A has been reported to be an inhibitor of granulocyte elastase. The present study was undertaken to see if pregnant cynomolgus monkeys could be an animal model sufficiently close to the human situation to study the physiology of PAPP-A. An antiserum to pregnant cynomolgus plasma was raised in rabbits. After adsorption with normal monkey plasma, this antiserum was used together with radioiodinated human PAPP-A to develop an heterologous radioimmunoassay for measurements of monkey PAPP-A. On polyacrylamide gel electrophoresis, it was shown that this polyspecific-antiserum bound the same molecular species of radioiodinated human PAPP-A as the available anti-human PAPP-A antiserum. The concentrations of cynomolgus PAPP-A (cPAPP-A) throughout pregnancy follow the same pattern as human PAPP-A (hPAPP-A) with an almost exponential increase up to term. The doubling time of cPAPP-A was similar to that of hPAPP-A. After RU 486-induced abortion or after spontaneous abortion, the levels of cPAPP-A decreased, with an apparent half-life of 2-3 days. Preliminary characterization of cPAPP-A revealed that although cPAPP-A was only immunologically related to hPAPP-A, it was biochemically very similar: they had the same PI and the same molecular weight, and both PAPP-As bound heparin. It is concluded that pregnant cynomolgus monkeys are a good model to study the physiology of PAPP-A.

Abortifacient Agents↗
PubMed1989

Beta 2-adrenoceptor response in the rat uterus at the end of gestation and after induction of labor with RU 486.

To study the relationship between the progesterone environment and beta-adrenoceptors in the myometrium, rats were treated with the antiprogestin RU 486 (10 mg per rat) at 08:30 h on day 21 of gestation. Under these conditions, more than 60% of animals delivered within 24 h after this treatment, while none of the control animals delivered within the same time period. beta-Adrenoceptors were identified using the radiolabeled antagonist (-)-[125I] iodocyanopindolol. The density (Bmax approximately 33-45 fmol/mg protein) and the affinity (KD approximately 0.105-0.106 nM) were not changed (during the late stages of gestation) in RU 486 treated rats compared with control rats. These results were correlated with the relaxation of longitudinal and circular strips of myometrium placed in high KC1 medium and exposed to beta-adrenoceptor agonists. The adrenoceptors implicated in the relaxation of myometrial strips were mainly of the beta 2-subtype. There was no difference in their affinity between control and RU 486 treated rats. Mean pA2 values were 8.46 for propranolol and 8.27 for ICI 118-551 against salbutamol. Altogether these results indicate in the rat that the blockade of the action of progesterone at its receptor site by RU 486 did not modify either the affinity or the sensitivity of beta 2-adrenoceptors in the myometrium, although it induced parturition.

Albuterol↗
PubMed1988

The efficacy and safety of sulindac (400 mg vs 600 mg daily) in rheumatoid arthritis. A Canadian Multicentre Study.

Sulindac, an indene derivative of indomethacin, was compared at 2 dosages (400 mg and 600 mg daily) in patients with rheumatoid arthritis. One hundred sixty-two patients from 19 centers completed the study--85 in the low dose group and 77 in the high dose. No difference in efficacy was found between these 2 regimens. Overall adverse reactions were more frequent with the high dose group especially with respect to blood chemistry and gastrointestinal reactions.

Adolescent↗
PubMed1988

Evolution of tissue levels of steroids: oestradiol-17 beta, oestrone and progesterone in the macaque myometrium during gestation.

In 15 cynomolgus monkeys between days 30-160 of gestation, tissue levels of oestrone (E1), oestradiol 17 beta (E2) and progesterone (P4) were assayed by RIA in the myometrium and the placenta. Myometrial samples were subdivided as follows: inner and outer layers adjacent to the placental area (IMP and OMP) and inner and outer layers from antiplacental areas (IMAP and OMAP). Steroid levels (ng/g wet wt) were in the range of known plasma values (ng/ml) and there was no asymmetric distribution of steroids between the various locations. When the results obtained in all the layers were pooled the gestational profiles indicated a decrease of E1 between days 80-130, whereas at the same time E2 and P4 increased. The ratio P4/E2 was 8 on day 40, 17 on day 80 and 9 on day 160. In the placenta, levels of E2 and P4 were 4 times higher, levels of E1 10 times higher than in the myometrium. Gestational profiles of the three steroids in the placenta increased from day 30 to day 160. Myometrium steroid content therefore does not appear to be a simple reflection of steroid diffusion from the site of production.

Animals↗
PubMed1987

Development and characterization of a human colon adenocarcinoma xenograft deficient in thymidine salvage.

In order to determine the contribution of thymidine (dThd) salvage to intrinsic resistance to antimetabolites (5-fluoropyrimidines, antifolates) in the human colon adenocarcinoma xenograft, H X GC3, a subline deficient in thymidine kinase has been developed. A cell line (GC3/M) was established in continuous culture that demonstrated a karyotype identical to that of the stem line of H X GC3 (46,X, - Y + 12). After inoculation of GC3/M cells into immune-deprived CBA/CaJ mice, the H X GC3/M xenografts retained histological, histochemical, and growth characteristics of the H X GC3 xenograft. To develop a line deficient in dThd salvage, GC3/M cells were selected with BrdUrd (100 micrograms/ml). Three clones characterized were unable to proliferate in HAT medium, and were deficient (less than 10% control) in the cytosolic form of thymidine kinase. Activities of dThd phosphorylase and dTMP synthase were unchanged from parental GC3/M cells. Of the three clones inoculated into mice, GC3/M TK- 100 C3 was tumorigenic, the xenografts demonstrating histological and growth characteristics similar to H X GC3. The in vivo activity of the cytosolic form of dThd kinase was 3.5% of that in H X GC3 xenografts. Incorporation in vivo of [methyl-3H]dThd into acid insoluble material was 14% of that in H X GC3 tumors. Autoradiographs prepared from these tumors demonstrated that incorporation of radiolabel into nuclei occurred only in stromal cells derived from the host. It is anticipated that H X GC3/M TK- 100 C3 will be a line valuable for determining the role of dThd salvage in intrinsic resistance to 5-fluoropyrimidines or antifolates in human colon adenocarcinomas growing as xenografts and also the relevance of dTMp synthase as a target for antimetabolites in this histiotype.

Adenocarcinoma↗
PubMed1987

Control of birth in rats by RU 486, an antiprogesterone compound.

Rats, isolated at mating (Day 1 of pregnancy), were submitted to either 8 h (8L:16D, Exp. I) or 14 h (14L:10D, Exp. II) of light daily with lights on from 12:00 h to 20:00 h and from 06:00 to 20:00 h respectively. In Exp. I, a single dose of RU 486 (10 mg in 0.2 ml ethanol) was given cutaneously at 08:00 h (Group A1), 12:00 h (Group B1), 19:00 h (Group C1) on Day 21 and at 08:00 h (Group D1) and 12:00 h (Group E1) on Day 22. In Exp. II, the same dose of RU 486 was given at 08:00 h (Group A2), 12:00 h (Group B2) and 19:00 h (Group C2) on Day 21. The solvent was given once at each of the preceding times to the control groups (T1 and T2) in both experiments. Groups T1 and T2 gave birth at two periods, the first on Day 22, the second on Day 23; the proportion of births during each of these periods depended on the light regimen (66.3% in 8L:16D; 50% in 14L:10D on Day 22). The distribution of births in Groups D1 and E1 treated on Day 22 were similar to their controls (T1). Rats treated on Day 21 (Groups A1, A2, B1, B2, C1, C2) gave birth over single periods on Day 22 after an interval correlated with the time of RU 486 administration. The earlier the treatment was given, the higher was the number of dead young and the lower the weight of live young 1 day after birth. These effects of prematurity did not impair further survival rates or weight at weaning.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

[Hormones and parturition in primates].

In primates, the endocrine signals which correlate with the end of gestation, i.e. account for fetal maturity, and initiate the parturition, i.e. trigger the myometrium contractility, remain unknown. Direct and indirect evidence supports the view that, as with domestic mammals, progesterone (or the estrogen/-progesterone ratio) plays a prominent role in inhibiting the contractility of the pregnant uterus. In the past few years an increasing number of endocrine factors have been identified in the placenta. They may contribute to the control of local or systemic steroid production but their effects are extraordinarily intermingled and it is impossible today to state whether any of them are relevant to the mechanism of parturition. The trophoblast and the myometrium establish close contact in the primate pregnancy. This is evidenced by histological studies and also by the influence of the proximity of the placenta on tissue steroid concentrations and the mechanisms of hormone coupling in the myometrium. Specific types or subtypes of myometrium hormone receptors are now well identified (e.g. to oxytocin, to catecholamines) and this now permits a better understanding of the role of their endogenous agonists in the course of parturition. However, such data are still lacking for other factors (e.g. prostanoids, VIP, relaxin...) involved to varying degrees in this process.

Animals↗
PubMed1987

[In utero surgery of diaphragmatic hernia in Macaca fascicularis].

The aim of this study is to be able to perform on the animal (Macacus cynomolgus) a specific in utero surgical procedure for correcting congenital diaphragmatic hernia, in order to do the same on human fetuses. The surgical technique consist in operating in utero, and to put a silastic patch on the diaphragm. A good tocolysis is very necessary to prevent early abortion. Finally the fetuses' surviving is the main problem.

Anesthesia, General↗
PubMed1986

Crystal and molecular structure of BN 52021, a PAF-acether antagonist. Comparison with the conformation of Kadsurenone and related compounds.

BN52021 (Ginkgolide B) monohydrate C20H24O10 X H2O crystallizes in the triclinic space group P1 with two independant molecules in the unit cell of which parameters are a = 7.627(2), b = 11.514(3), c = 12.941(3)A, alpha = 97.05(2), beta = 90.27(2) and gamma = 108.71(2)o, V = 1067.06A3. Calculated density Dx = 1.320g X cm-3. The crystal structure was solved by Patterson methods starting from dreiding model data. The final reliability index R = 0.099 for 3848 observed reflections collected with a four-circle diffractometer. Anti-PAF activities of Kadsurenone, Kadsurin-A, Kadsurin-B and Piperenone, molecular structure of MIRANDIN-A, related compounds and BN52021 suggest that a distance 0-0 of about 6.6A observed in Kadsurenone and in BN52021 could be favourable to anti-PAF activity.

Benzofurans↗
PubMed1986

A comparison of uterine motility in the pregnant and non-pregnant cynomolgus monkey (Macaca fascicularis) and pregnant woman: a manometric and electromyographic study.

The use of a combination of manometric and electromyographic methods provided a reliable technique for evaluating variations in uterine activity in conscious macaque monkeys and women. The technique was particularly useful for obtaining data on the influence of steroid hormones. During the spontaneous menstrual cycle of the macaque, uterine motility, after being weak and poorly synchronized during the follicular phase, became still weaker with impaired synchronization during the luteal phase and then much stronger and well-synchronized at the time of menstruation. There was no evidence in vivo of any relationship between the existence of gap junctions in the myometrium of non-pregnant animals and the various patterns of uterine motility. During the last third of pregnancy in macaques, the initiation of electrical activity in various uterine areas was always synchronous with and related to mechanical contraction. The same results were obtained in preparturient women. Thus, improved uterine coordination does not appear to be the mechanism by which the uterine contractile strength increases to expulse the foetus at the end of pregnancy. Apart from the particular situation of non-pregnant animals under progestative influence, in which activity was constantly non-propagated, we could not find any evidence of a general pattern which would indicate only one site for the initiation of activity and its extension to the whole uterus.

Animals↗
PubMed1985

A longitudinal study of cyclic nucleotide phosphodiesterase activity and its relationship with nucleic acid content in the myometrium of cynomolgus monkeys (Macaca fascicularis) between days 39 and 162 of gestation.

Cyclic AMP and cGMP phosphodiesterase (PDE) activities and nucleic acid contents were assayed in crude homogenates prepared from biopsies excised between days 39 and 162 of gestation (normal full length of gestation: 165 days) in outer and inner layers of the macaque myometrium. In both layers, kinetic analysis of PDE indicated high (apparent Km 2 X 10(-6) M) and low (apparent Km 2 X 10(-5) M) affinity component for each substrate. When measured in high-affinity conditions, specific activities were elevated around day 40 and beyond day 130 of gestation. By contrast, low values were observed between days 50 and 100. They were related to the decrease of the Vmax values (expressed either per milligram protein or per microgram DNA). No significant differences were observed between outer and inner layers. Variations of tissue DNA and RNA were demonstrated throughout gestation indicating that both hyperplasia and hypertrophy were involved in uterine growth. Unlike DNA, RNA content (and consequently the RNA:DNA ratio) in the inner layer always remained above the values of the outer layer. In both layers, the RNA:DNA ratio, which presumably reflects the rate of protein synthesis and the PDE activity, reached maximum values at the same time.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Relationship between myometrial cyclic nucleotide phosphodiesterase (PDE) activity and the RNA/DNA ratio at various stages of gestation in primates.

Cyclic AMP and cGMP PDE activities were assayed in crude homogenates prepared from biopsies excised between day 39-162 of gestation (normal length of gestation, 165 days) in outer and inner layers of the macaque myometrium. In both layers, kinetic analysis of PDE indicated high (app Km approximately equal to 2 X 10(-6)M) and low (app Km approximately equal to 2 X 10(-5)M) affinity component for each substrate. Measured in high affinity conditions, specific activities were increased around day 40 and beyond day 130 of gestation. By contrast, low values were observed between days 50 and 100. No significant differences were observed between outer and inner layers. In both layers, the RNA/DNA ratio, which presumably reflects the rate of protein synthesis, culminated at the same time as the PDE activity. These variations were observed in the myometrium at specific stages of gestation. In late pregnancy, the human myometrium also displayed biphasic kinetics for cAMP and cGMP PDE activities. Non-human primates may be a partially representative model of what happens in the human myometrium.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗