General Obstetrics and Gynecology: ObstetricsDelay of preterm birth in sheep by THG113.31, a prostaglandin F2α receptor antagonist
Section snippets
Material and methods
All experiments and procedures were approved by the Monash University Animal Ethics Committee.
In vitro inhibitory activity of THG113.31
Incubation of strips of longitudinal or circular myometrium with THG113.31 had no effect on spontaneous contractile activity. PGF2α evoked concentration-dependent increases in tension in strips of both longitudinal and circular myometrium. Although co-incubation with THG113.31 had no effect on the sensitivity to PGF2α per se (pD2 in Table I), analysis of variance (ANOVA) revealed a significant (P = .002 and <.0001, for longitudinal and circular myometrium, respectively) inhibitory effect of
Comment
Here we show that the novel FP inhibitor THG113.31 specifically decreases PGF2α-induced contractions in sheep myometrial strips in vitro and that it suppresses myometrial electromyographic activity and prolongs pregnancy in RU486-induced preterm labor in vivo. These actions suggest that THG113.31 presents 3 distinct advances in tocolytic therapy. First, they identify a new target for tocolysis, the FP receptor. Second, they demonstrate the usefulness of a new platform technology, antagonizing G
Acknowledgments
We thank Mrs Eileen Marco for assistance with the manuscript and Theratechnologies (Montreal, Canada) for the gift of THG113.31.
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2022, Peptide and Peptidomimetic Therapeutics: From Bench to BedsideThe intrauterine to intra-arterial pressure ratio: A new parameter for the study of uterine contractility physiology
2010, Reproductive BioMedicine OnlineCitation Excerpt :In addition, the endometrium itself is able to generate various prostaglandins, and this may play an important role in placentation and in regulating the lifespan of the corpus luteum (Waclawik et al., 2006). Endogenous or exogenous prostaglandins are important uterine stimulators (Hirst et al., 2005). Interactions between prostaglandins and oxytocin are described; each is able to influence the receptor status of the other and the corresponding myometrial contractile response, as they act by different mechanisms (Carnahan et al., 1996; Franczak et al., 2005).
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2009, Fertility and SterilityCitation Excerpt :The investigation of uterine contractility and its regulation by prostaglandins or oxytocin is of clinical interest not only in obstetrics—e.g., to induce labor or to delay birth and prolong pregnancy—but also in gynecology and reproductive medicine, especially in connection with embryo implantation (3) and sperm transport (40). Endogenous or exogenous prostaglandins are important uterine stimulators (14). Prostaglandins play an important role in the onset and maintenance of labor (16).
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2008, Journal of Reproductive ImmunologyCitation Excerpt :Myometrial PTGFR mRNA is elevated at term and preterm birth in humans and rodents (Brodt-Eppley and Myatt, 1999; Cook et al., 2003). Also, infusion of a specific inhibitor, THG113.31, in sheep and mice delays preterm birth and prolongs gestation (Hirst et al., 2005; Peri et al., 2002). In rats, myometrial PTGFR mRNA expression rate is decreased during pregnancy, and its expression increases significantly again at term (Matsumoto et al., 1997).
Arrest of preterm labor in rat and mouse by an oral and selective nonprostanoid antagonist of the prostaglandin F2α receptor (FP)
2007, American Journal of Obstetrics and GynecologyCitation Excerpt :Likewise, prostanoid FP receptor is expressed in term human myometrium14,27 Although we should be cautionary in extrapolating rodent data to humans, our findings suggest that pharmacological intervention in women at the level of prostanoid FP receptor might represent a new modality for the management of preterm labor. Our data obtained with the highly selective antagonist AS604872 support a recent report that an injectable noncompetitive peptide antagonist of prostanoid FP receptor functions was delaying preterm labor in mouse and sheep.18,19 In the mouse parturition model, the endotoxin LPS triggers an inflammatory response through up-regulation of cytokines followed by the release of prostaglandins that may represent the response seen in cases of ascending bacterial infection of the genital tract, a common cause of human preterm labor.
Supported by the Canadian Institutes of Health Research, the Alberta Heritage Foundation for Medical Research, and the National Health and Medical Research Council of Australia.