Delay of preterm birth in sheep by THG113.31, a prostaglandin F 2a receptor antagonist Jonathan J. Hirst, PhD, a Helena C. Parkington, PhD, a I. Ross Young, PhD, a Hannah K. Palliser, BSc(Hons), a Krishna G. Peri, PhD, b David M. Olson, PhD c, * Department of Physiology, Monash University, Clayton, Victoria, Australia a ; Theratechnologies Inc, Montreal, Canada b ; The Perinatal Research Centre, Canadian Institutes of Health Research Group in Perinatal Health and Disease, Departments of Obstetrics and Gynecology, Pediatrics, and Physiology, University of Alberta, Edmonton, Alberta, Canada c Received for publication August 19, 2004; revised October 13, 2004; accepted November 3, 2004 KEY WORDS Prostaglandin F 2a Receptor (FP) Antagonist Preterm birth Sheep Electromyographic activity Objective: A novel prostaglandin F 2a receptor antagonist, THG113.31, was tested for the suppression of uterine contractility and delay of preterm labor in sheep. Study design: We determined the tocolytic effectiveness of THG113.31 on contractions that were stimulated in vitro by prostaglandin F 2a and E 2 in longitudinal and circular myometrial strips. We also tested the ability of THG113.31 in vivo to lower uterine electromyographic activity that was induced by the progesterone receptor blocker, RU486, and to delay preterm birth. Results: THG113.31 suppressed the amplitude of prostaglandin F 2a , but not prostaglandin E 2 – induced contractions of both circular and longitudinal myometrium (P ! .01). The times to delivery after RU486 were 34.8 G 1.1 hours (saline solution) and 41.9 G 0.5 hours (THG113.31; P ! .001) or an average delay of 7.1 hours. There were no changes in fetal blood gases (PaO 2 , PaCO 2 , pH, or SaO 2 ) because of THG113.31. Fetal cortisol levels rose in each group, and fetal and maternal prostaglandin E 2 and F 2a metabolite concentrations rose similarly in both groups. Conclusion: THG113.31 specifically suppresses prostaglandin F 2a –induced myometrial contrac- tility and delays delivery. Ó 2005 Elsevier Inc. All rights reserved. The prevention of preterm birth is considered to be the most important perinatal challenge facing industri- alized countries. 1,2 Despite O40 years of directed efforts at understanding the physiologic process of birth and the testing and use of tocolytics, there has been no abate- ment in the incidence of preterm birth. Preterm birth accounts for 60% to 80% of all perinatal deaths 3 and is an important determinant of neonatal and infant morbidity, which includes neurodevelopmental handi- cap, chronic respiratory problems, infections, and oph- thalmologic problems. 1-3 In the United States, the rate was 12% in 2002. 4 Most strategies for delaying preterm birth rely on the reduction of uterine contractions. It is well accepted that 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. * Reprint requests: David M. Olson, PhD, Perinatal Research Centre, 220 HMRC, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail: david.olson@ualberta.ca 0002-9378/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.11.009 American Journal of Obstetrics and Gynecology (2005) 193, 256–66 www.ajog.org