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Retosiban Prevents Stretch-Induced Human Myometrial Contractility and Delays Labor in Cynomolgus Monkeys.

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Aye, Irving LMH 
Moraitis, Alexandros A 
Stanislaus, Dinesh 
Charnock-Jones, D Stephen 
Smith, Gordon CS 


CONTEXT: Stretch of the myometrium promotes its contractility and is believed to contribute to the control of parturition at term and to the increased risk of preterm birth in multiple pregnancies. OBJECTIVE: To determine the effects of the putative oxytocin receptor (OTR) inverse agonist retosiban on (1) the contractility of human myometrial explants and (2) labor in nonhuman primates. DESIGN: Human myometrial biopsies were obtained at planned term cesarean, and explants were exposed to stretch in the presence and absence of a range of drugs, including retosiban. The in vivo effects of retosiban were determined in cynomolgus monkeys. RESULTS: Prolonged mechanical stretch promoted myometrial extracellular signal-regulated kinase (ERK)1/2 phosphorylation. Moreover, stretch-induced stimulation of myometrial contractility was prevented by ERK1/2 inhibitors. Retosiban (10 nM) prevented stretch-induced stimulation of myometrial contractility and phosphorylation of ERK1/2. Moreover, the inhibitory effect of retosiban on stretch-induced ERK1/2 phosphorylation was prevented by coincubation with a 100-fold excess of a peptide OTR antagonist, atosiban. Compared with vehicle-treated cynomolgus monkeys, treatment with oral retosiban (100 to 150 days of gestational age) reduced the risk of spontaneous delivery (hazard ratio = 0.07, 95% confidence interval 0.01 to 0.60, P = 0.015). CONCLUSIONS: The OTR acts as a uterine mechanosensor, whereby stretch increases myometrial contractility through agonist-free activation of the OTR. Retosiban prevents this through inverse agonism of the OTR and, in vivo, reduced the likelihood of spontaneous labor in nonhuman primates. We hypothesize that retosiban may be an effective preventative treatment of preterm birth in high-risk multiple pregnancies, an area of unmet clinical need.



Animals, Female, Humans, Labor, Obstetric, Macaca fascicularis, Myometrium, Parturition, Piperazines, Pregnancy, Premature Birth, Receptors, Oxytocin, Reflex, Stretch, Uterine Contraction

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J Clin Endocrinol Metab

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The Endocrine Society
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Disclosure Summary. This work was funded by a research grant from GSK to GCSS and DSCJ. IA has received salary support and a travel grant from the above grant. AM has received a travel grant from GSK. GCSS is a named inventor in a patent submitted by GSK (UK), for the use of retosiban to prevent preterm birth in multiple pregnancy Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation (PCT/EP2014/062601). GCSS receives/has received research support from GE and Roche, has been paid to attend advisory boards by GSK and Roche, and has acted as a paid consultant to GSK. DS is an employee of GSK.