gsk221149a and Premature-Birth

To assess the efficacy, safety, and tolerability of retosiban-a novel tocolytic unavailable in the US-in the management of preterm labor.. We searched ClinicalTrials.Gov, MEDLINE, PubMed, SCOPUS, Web of Science, and the Cochrane Library for relevant clinical trials using the terms "retosiban" and "preterm labor" through 09/2020. We included all published randomized clinical trials (three) that compared retosiban to placebo for preterm labor, excluding conferences, books, reviews, posters, case reports, and animal studies. We analyzed homogeneous data under the fixed-effects model and heterogeneous data under the random-effects model.. With the limited high quality evidence available, retosiban demonstrates no clear benefit over placebo in the management of preterm labor. Nevertheless, its favorable safety profile, oral bioavailability, and novel mechanism of action and the limited number of studies available for review warrant further analysis.

Topics: Female; Humans; Piperazines; Pregnancy; Premature Birth; Receptors, Oxytocin; Tocolysis; Tocolytic Agents

The aims of the present study were to investigate the maternal, fetal and neonatal safety and tolerability, pharmacodynamics and pharmacokinetics of intravenous (IV) retosiban in pregnant women with spontaneous preterm labour (PTL) between 34. In parts A and B of a three-part, double-blind, placebo-controlled, multicentre study, women were randomized 3:1 (Part A) or 2:1 (Part B) to either 12-h IV retosiban followed by a single dose of oral placebo (R-P) or 12-h IV placebo followed by single-dose oral retosiban (P-R).. A total of 29 women were randomized; 20 to R-P and nine to P-R. An integrated analysis found that adverse events were infrequent in mothers/newborns and consistent with events expected in the population under study or associated with confounding factors. Retosiban was rapidly absorbed after oral administration, with an observed half-life of 1.45 h. Efficacy analyses included 19 women. While not statistically significant, those receiving R-P more frequently achieved uterine quiescence in 6 h (R-P, 63%; 95% credible interval [CrI]: 38, 84; P-R, 43%; 95% CrI: 12, 78) and more achieved a reduction of ≥50% in uterine contractions in 6 h (R-P, 63%; 95% CrI: 38, 84; P-R, 29%; 95% CrI: 4, 64). The number of days to delivery was increased in women receiving R-P (median 26 days for R-P vs. 13 days for P-R).. Intravenous retosiban has a favourable safety and tolerability profile and might prolong pregnancies in women with PTL. The study provides the rationale and dosing strategy for further evaluation of the efficacy of retosiban in the treatment of PTL.

Topics: Administration, Intravenous; Administration, Oral; Adult; Double-Blind Method; Female; Half-Life; Humans; Infant, Newborn; Obstetric Labor, Premature; Pilot Projects; Piperazines; Pregnancy; Premature Birth; Receptors, Oxytocin; Tocolytic Agents; Uterine Contraction; Young Adult

The aim was to investigate the efficacy and safety of intravenous retosiban in women with spontaneous preterm labour.. This was a randomized, double-blind, placebo-controlled, phase 2 trial. Retosiban was administered intravenously for 48 h to women in spontaneous preterm labour between 30(0/7) and 35(6/7)  weeks' gestation with an uncomplicated singleton pregnancy in an in-patient obstetric unit. Outcome measures were uterine quiescence (primary endpoint), days to delivery, preterm delivery and safety.. Uterine quiescence was achieved in 62% of women who received retosiban (n = 30) compared with 41% who received placebo (n = 34). The relative risk (RR) was 1.53 (95% credible interval [CrI] 0.98, 2.48; NS). Retosiban resulted in a significant increase in time to delivery compared with placebo (mean difference 8.2 days, 95% CrI 2.7, 13.74). This difference was consistent across all gestational ages. The proportion of preterm births in the retosiban and placebo groups was 18.7% (95% CrI 7.4%, 33.7%) and 47.2% (95% CrI 31.4%, 63.4%), respectively. The RR of preterm birth in women treated with retosiban was 0.38 (95% CrI 0.15, 0.81). There were no deliveries within 7 days in the retosiban group, but there were six (17.6%) births in the placebo group. The maternal, fetal and neonatal adverse events were comparable in the retosiban and placebo groups.. Intravenous administration of retosiban in women with spontaneous preterm labour was associated with a greater than 1 week increase in time to delivery compared with placebo, a significant reduction in preterm deliveries, a non-significant increase in uterine quiescence and a favourable safety profile.

Topics: Administration, Intravenous; Adult; Double-Blind Method; Female; Humans; Middle Aged; Obstetric Labor, Premature; Piperazines; Pregnancy; Premature Birth; Receptors, Oxytocin; Time Factors; Uterine Contraction; Young Adult

Novel small molecule inhibitors of the oxytocin receptor (OTR) may have distinct pharmacology and mode of action when compared with first-generation oxytocin antagonists when used for the prevention of preterm birth. The aim was to determine the mechanism of action of small molecule OTR antagonists retosiban and epelsiban compared with the currently used peptide-based compound atosiban. Human myometrial samples were obtained at cesarean section and subjected to pharmacological manipulations to establish the effect of antagonist binding to OTR on downstream signaling. Retosiban antagonism of oxytocin action in human myometrium was potent, rapid, and reversible. Inhibition of inositol 1,4,5-trisphosphate (IP3) production followed single-site competitive binding kinetics for epelsiban, retosiban, and atosiban. Retosiban inhibited basal production of IP3 in the absence of oxytocin. Oxytocin and atosiban but not retosiban inhibited forskolin, and calcitonin stimulated 3',5'-cyclic adenosine 5'-mono-phosphate (cAMP) production. Inhibition of cAMP was reversed by pertussis toxin. Oxytocin and atosiban, but not retosiban and epelsiban, stimulated extracellular regulated kinase (ERK)1/2 activity in a time- and concentration-dependent manner. Oxytocin and atosiban stimulated cyclo-oxygenase 2 activity and subsequent production of prostaglandin E2 and F2α. Prostaglandin production was inhibited by rofecoxib, pertussin toxin, and ERK inhibitor U0126. Oxytocin but not retosiban or atosiban stimulated coupling of the OTR to Gα q G-proteins. Oxytocin and atosiban but not retosiban stimulated coupling of the OTR to Gα i G-proteins. Retosiban and epelsiban demonstrate distinct pharmacology when compared with atosiban in human myometrial smooth muscle. Atosiban displays agonist activity at micromolar concentrations leading to stimulation of prostaglandin production.

Topics: Diketopiperazines; Drug Evaluation, Preclinical; Female; Humans; Morpholines; Myometrium; Piperazines; Premature Birth; Primary Cell Culture; Receptors, Oxytocin

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.. 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.. 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.. 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).. 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.

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