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16
Language Development
- In
, 1968
"... Vasopressin and oxytocin in normal reproduction and in the patophysiology of preterm labour and primary dysmenorrhoea. ..."
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Vasopressin and oxytocin in normal reproduction and in the patophysiology of preterm labour and primary dysmenorrhoea.
Nuclear Factor Kappa B Activation Occurs in the Amnion Prior to Labour Onset and Modulates the Expression of Numerous Labour Associated Genes
"... Background: Prior to the onset of human labour there is an increase in the synthesis of prostaglandins, cytokines and chemokines in the fetal membranes, particular the amnion. This is associated with activation of the transcription factor nuclear factor kappa B (NFkB). In this study we characterised ..."
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Background: Prior to the onset of human labour there is an increase in the synthesis of prostaglandins, cytokines and chemokines in the fetal membranes, particular the amnion. This is associated with activation of the transcription factor nuclear factor kappa B (NFkB). In this study we characterised the level of NFkB activity in amnion epithelial cells as a measure of amnion activation in samples collected from women undergoing caesarean section at 39 weeks gestation prior to the onset of labour. Methodology/Principal Findings: We found that a proportion of women exhibit low or moderate NFkB activity while other women exhibit high levels of NFkB activity (n = 12). This activation process does not appear to involve classical pathways of NFkB activation but rather is correlated with an increase in nuclear p65-Rel-B dimers. To identify the full range of genes upregulated in association with amnion activation, microarray analysis was performed on carefully characterised nonactivated amnion (n = 3) samples and compared to activated samples (n = 3). A total of 919 genes were upregulated in response to amnion activation including numerous inflammatory genes such cyclooxygenase-2 (COX-2, 44-fold), interleukin 8 (IL-8, 6-fold), IL-1 receptor accessory protein (IL-1RAP, 4.5-fold), thrombospondin 1 (TSP-1, 3-fold) and, unexpectedly, oxytocin receptor (OTR, 24-fold). Ingenuity Pathway Analysis of the microarray data reveal the two main gene networks activated concurrently with amnion activation are i) cell death, cancer and morphology and ii) cell cycle, embryonic
The effect of oxytocin receptor blockade on parturition in guinea pigs
- Journal of Clinical Investigation
, 1995
"... The mechanism of the onset of labor is unknown in humans and guinea pigs. Contrary to most other species, progester-one withdrawal appears not to precede the onset of labor. To elucidate the role of oxytocin in the onset and mainte-nance of labor, guinea pigs were fitted with vascular cathe-ters, an ..."
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The mechanism of the onset of labor is unknown in humans and guinea pigs. Contrary to most other species, progester-one withdrawal appears not to precede the onset of labor. To elucidate the role of oxytocin in the onset and mainte-nance of labor, guinea pigs were fitted with vascular cathe-ters, an intraabdominal pressure catheter and an array of uterine electromyogram electrodes. An oxytocin antagonist (des-Gly9-[D-Trp2,Thr',Orn8]dC'-oxytocin, 20,ug/kg per h, n = 11) or saline solution (n = 12) was infused starting on day 66 of gestation (term is 69 d). Oxytocin receptor blockade resulted in decreased uterine activity and a pro-longed expulsive phase (second stage) of labor. Fetal deliv-ery was delayed and fetal mortality was increased. The onset of the expulsive phase of labor was delayed but maximum uterine activity occurred in time together with a timely change in uterine electromyogram activity from a prepar-tumr to a postpartum pattern following an unaltered pro-gressive increase in baseline uterine activity. This indicates that oxytocin is requisite for the normal progress of the first and second stage of labor, but has no involvement in the mechanism of the onset and the timing of labor. (J. Clin.
Pharmacology of (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2 -methyl[1,1 -biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a new potent and selective nonpeptide antagonist of the oxytocin receptor.
- J Pharmacol Exp Ther
, 2003
"... ABSTRACT We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2Ј-methyl[1,1Ј-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1). We report the biochemical, pharmacological, and pharmaco ..."
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ABSTRACT We have discovered a new, potent, selective, and orally active oxytocin receptor antagonist, (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-1-[(2Ј-methyl[1,1Ј-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide (compound 1). We report the biochemical, pharmacological, and pharmacokinetic characterization in vitro and in vivo of this compound. Premature birth is a major problem in obstetrics affecting about 10% of all births and being the largest cause of perinatal morbidity and mortality. The impact on society is significant in terms of costs of neonatal intensive care and for the emotional and social stress to the family. The physiopathology of human preterm labor is complex and multifactorial. Preterm increase of uterine activity is a common complication of pregnancy and accounts for many cases of preterm labor. Pharmacological interventions aimed at maintaining uterine quiescence (tocolysis) have been, and are likely to remain, the cornerstone of pharmaceutical management of preterm labor. However, current tocolytic agents (-mimetics, magnesium sulfate, calcium channel blockers, or prostaglandin synthesis inhibitors) suffer from a minimal effectiveness and show important fetal and maternal side effects. Therefore, it is obvious that a safe and effective oral treatment delaying spontaneous preterm birth would have tremendous clinical benefits. The peptide hormone oxytocin (OT) is a potent contractor of the human uterus. OT mediates its effect through activation of the G protein-coupled oxytocin receptor (OT-R) that is expressed in myometrial cells. OT-R is coupled to phospholipase C activation, leading to intracellular synthesis of inositol phosphates and mobilization of calcium. In turn, the rise in intracellular calcium concentration promotes a cascade of events, including phosphorylation of myosin, that then acts on actin and induces uterine muscle cell contraction. Before onset of labor and in the term myometrium, the OT-R density Article, publication date, and citation information can be found at
Inflammatory Aetiology of Human Myometrial Activation Tested Using Directed Graphs
"... There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the ..."
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There are three main hypotheses for the activation of the human uterus at labour: functional progesterone withdrawal, inflammatory stimulation, and oxytocin receptor activation. To test these alternatives we have taken information and data from the literature to develop causal pathway models for the activation of human myometrium. The data provided quantitative RT-PCR results on key genes from samples taken before and during labour. Principal component analysis showed that pre-labour samples form a homogenous group compared to those during labour. We therefore modelled the alternative causal pathways in non-labouring samples using directed graphs and statistically compared the likelihood of the different models using structural equations and D-separation approaches. Using the computer program LISREL, inflammatory activation as a primary event was highly consistent with the data (p 0.925), progesterone withdrawal, as a primary event, is plausible (p 0.499), yet comparatively unlikely, oxytocin receptor mediated initiation is less compatible with the data (p 0.091). DGraph, a software program that creates directed graphs, produced similar results (p 0.684, p 0.280, and p 0.04, respectively). This outcome supports an inflammatory aetiology for human labour. Our results demonstrate the value of directed graphs in determining the likelihood of causal relationships in biology in situations where experiments are not possible.
Diverse Roles of Oxytocin
, 2015
"... The oxytocin/oxytocin receptor (OT/OTR) system has been reported to influence a variety of physiological, behavioural, and emotional processes in humans. There are a wide range of studies focusing on their role in parturition, lactation and behaviour. More recent studies have investigated the novel ..."
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The oxytocin/oxytocin receptor (OT/OTR) system has been reported to influence a variety of physiological, behavioural, and emotional processes in humans. There are a wide range of studies focusing on their role in parturition, lactation and behaviour. More recent studies have investigated the novel effects of OT/OTR system including inflammation and miRNAs, as well as the effect of their genetic polymorphisms on the onset of labour and parturition. OT also appears to have a great influence in cardiomyocyte differentiation and heart homeostasis, and an age-specific regulation of muscle maintenance and regeneration. This review will summarize the previously established role of OT/OTR system as well as the studies on their novel roles, and highlight the potential therapeutic approaches.
Timing of the Switch from Myometrial Contractures to Contractions in Late-Gestation Pregnant Rhesus Monkeys as Recorded by Myometrial Electromyogram during Spontaneous Term and Androstenedione- Induced Labor'
, 1997
"... ABSTRACT Pregnant rhesus monkeys were studied to determine the precise time in relation to photoperiod of the onset, and the nature, of the switch in myometrial activity patterns from contractures to contractions. We investigated both spontaneous term labor and androstenedione-induced preterm labor ..."
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ABSTRACT Pregnant rhesus monkeys were studied to determine the precise time in relation to photoperiod of the onset, and the nature, of the switch in myometrial activity patterns from contractures to contractions. We investigated both spontaneous term labor and androstenedione-induced preterm labor. Under general anesthesia at 127 2 days gestation (dGA) (mean ± SEM), 16 pregnant rhesus monkeys were instrumented with maternal femoral arterial and venous catheters and myometrial electromyogram electrodes. Eight animals (group I) received continuous i.v. infusion of intralipid (n = 7) or saline (n = 1) that was started at 143.3 2 dGA and maintained until the spontaneous onset of term labor. Nine animals (group II) received continuous i.v. infusion of androstenedione that was started at 139 0.4 dGA and maintained until the onset of prematurely induced labor. Myometrial activity was recorded continuously. All monkeys in both groups demonstrated nocturnal switches in myometrial activity from contractures to contractions. The mean time of onset of the switch in group I and group II monkeys was similar, occurring at 0.7 + 0.4 h or 0.8 0.5 h, respectively, after the onset of darkness. Group II monkeys demonstrated greater regularity in both the time of onset and the repetitive occurrence each night once the switch occurred, as well as greater consistency in duration in their switch patterns, than did group I monkeys.
The Role of Drug Metabolism in Drug Discovery: A Case Study in the Selection of an Oxytocin Receptor Antagonist for Development*
"... Drug discovery is a process involving multiple disciplines and interests. During the research phase of drug discovery, usually a large number of compounds are evaluated for biological activity and toxicological potential in animal species. Various types of problems with respect to pharmacodynamics, ..."
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Drug discovery is a process involving multiple disciplines and interests. During the research phase of drug discovery, usually a large number of compounds are evaluated for biological activity and toxicological potential in animal species. Various types of problems with respect to pharmacodynamics, pharmacokinetics, and toxicity are commonly encountered at this stage. Drug metabolism, as a discipline participating in a drug discovery team, can play an important role in identifying factors underlying the problems, facilitate the optimal selection of compounds for further development, provide information on metabolites for possible improvement in drug design, and contribute to the identification of the appropriate animal species for subsequent toxicity testing. During the process of evaluating oxytocin receptor antagonists for further de-velopment for treatment of preterm labor, in vivo and i vitro drug metabolism studies conducted in rats, dogs, and monkeys contributed to the selection of L-368,899 as the development candidate on the basis of pharmacokinetic and metabolism observations. The presence of active N-demethylated metabolites of two other equipotent compounds in rats and dogs was found to be the major factor responsible for the discrepancy between oral bioavailability and efficacies observed for these 2 compounds. For L-368,899, a compound that demonstrated 20-40 % oral bioavailability in rats, dogs, and chimpanzees, extensive first-pass metabolism rather than absorption was determined as the major factor responsible for the poor bioavailability (< 1%) in
unknown title
, 2006
"... doi:10.1093/humupd/dml048 Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts ..."
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doi:10.1093/humupd/dml048 Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts
Printed in U.S.A. The Oxytocin Receptor System: Structure, Function, and Regulation
"... A. Evolutionary aspects 630 B. Gene structure 631 C. Gene regulation 632 ..."
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