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Bridget M Arman Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Natalie K Binder Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Natasha de Alwis Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Tu’uhevaha J Kaitu’u-Lino Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Natalie J Hannan Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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In brief

Preterm birth is the leading cause of perinatal morbidity and mortality; however, current therapies offer limited efficacy to delay birth and improve neonatal outcomes. This review explores the potential of repurposing drugs with known safety profiles to quench uterine contractions and inflammation, identifying promising agents for clinical trials.

Abstract

Preterm birth is the leading cause of neonatal morbidity and mortality globally. Despite extensive research into the underlying pathophysiology, rates of preterm birth have not significantly reduced. Currently, preterm labour management is based on optimising neonatal outcomes. Treatment involves administering drugs (tocolytics) to suppress uterine contractions to allow sufficient time for transfer to an appropriate facility and administration of antenatal corticosteroids for fetal lung maturation. Current tocolytics are limited as they are associated with adverse maternal and fetal effects and only delay delivery for a short period. There has been a serious lack of therapeutic development for preterm birth, and new approaches to protect against or delay preterm birth are urgently needed. Repurposing drugs for the prevention of preterm birth presents as a promising approach by reducing the time and costs associated with pharmaceutical drug development. In this review, we explore the evidence for the potential of therapies, specifically proton pump inhibitors, tumour necrosis factor inhibitors, prostaglandin receptor antagonists, aspirin, and statins, to be repurposed as preventatives and/or treatments for preterm birth. Importantly, many of these innovative approaches being explored have good safety profiles in pregnancy. We also review how delivery of these drugs can be enhanced, either through targeted delivery systems or via combination therapy approaches. We aim to present innovative strategies capable of targeting multiple aspects of the complex pathophysiology that underlie preterm birth. There is an urgent unmet need for preterm birth therapeutic development, and these strategies hold great promise for improving neonatal outcomes.

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Bridget M Arman B Arman, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Natalie K Binder N Binder, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Heidelberg, Australia

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Natasha de Alwis N de Alwis, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Sally Beard S Beard, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Anjali Garg A Garg, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Tu'uhevaha J Kaitu'u-Lino T Kaitu'u-Lino, Obstetrics and Gynaecology, Translational Obstetrics Group, University of Melbourne, Heidelberg, Australia

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Natalie J Hannan N Hannan, Obstetrics and Gynaecology; Therapeutics Discovery and Vascular Function in Pregnancy Group, University of Melbourne, Melbourne, Australia

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Preterm birth remains a significant global health challenge, affecting approximately 10% of pregnancies and resulting in one million deaths globally every year. Tocolytic agents, used to manage preterm labour, have considerable limitations including lack of efficacy, and adverse side-effects, emphasising the urgent need for innovative solutions. Here, we explore repurposing an antiplatelet cardioprotective drug, ticagrelor, as a potential treatment to prevent preterm birth. Ticagrelor has demonstrated pleiotropic actions beyond platelet inhibition, including relaxant effects on smooth muscle cells and anti-inflammatory effects in models of diabetes and sepsis. As preterm birth is underscored by inflammatory processes triggering uterine contractions, these actions position ticagrelor as an attractive candidate for prevention or delay of preterm birth. Utilising primary human myometrial tissue, human myometrial cells, and a mouse model of preterm birth, we investigated ticagrelor's potential as a safe and effective therapy for preterm birth. We showed that ticagrelor did not reduce the frequency or strength of spontaneous muscle contractions of ex vivo myometrial tissue nor did it reduce in vitro inflammation-induced contractility in myometrial cells. Additionally, ticagrelor did not exhibit the anticipated anti-inflammatory effects in myometrial cell culture experiments. In our mouse model of preterm birth, ticagrelor neither improved the preterm birth rate or fetal survival outcomes. Gene expression of pro-inflammatory cytokines and contraction-associated proteins in postpartum mouse uteri were unaltered by ticagrelor. In conclusion, ticagrelor is not a strong candidate to continue investigations in clinical trial for the treatment of preterm labour and prevention of preterm birth.

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Bridget M Arman Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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Natalie K Binder Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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Natasha de Alwis Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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Sally Beard Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Anjali Garg Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Tu’uhevaha J Kaitu’u-Lino Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia
Translational Obstetrics Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia

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Natalie J Hannan Therapeutics Discovery and Vascular Function in Pregnancy Group, Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia
Mercy Perinatal, Mercy Hospital for Women, Heidelberg, Australia

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In brief

Preterm birth is the leading cause of perinatal morbidity and mortality, and new therapies that delay preterm birth and improve neonatal outcomes are urgently needed. This study investigates whether ticagrelor inhibits uterine contractility and inflammation in preclinical in vitro, ex vivo (human) and in vivo (mouse) studies, to explore the potential of repurposing ticagrelor for the prevention of preterm birth.

Abstract

Preterm birth remains a significant global health challenge, affecting approximately 10% of pregnancies and resulting in one million deaths globally every year. Tocolytic agents, used to manage preterm labour, have considerable limitations including lack of efficacy, and adverse side effects, emphasising the urgent need for innovative solutions. Here, we explore repurposing an antiplatelet cardioprotective drug, ticagrelor, as a potential treatment to prevent preterm birth. Ticagrelor has demonstrated pleiotropic actions beyond platelet inhibition, including relaxant effects on smooth muscle cells and anti-inflammatory effects in models of diabetes and sepsis. As preterm birth is underscored by inflammatory processes triggering uterine contractions, these actions position ticagrelor as an attractive candidate for prevention or delay of preterm birth. Utilising primary human myometrial tissue, human myometrial cells, and a mouse model of preterm birth, we investigated ticagrelor’s potential as a safe and effective therapy for preterm birth. We showed that ticagrelor did not reduce the frequency or strength of spontaneous muscle contractions of ex vivo myometrial tissue nor did it reduce in vitro inflammation-induced contractility in myometrial cells. Additionally, ticagrelor did not exhibit the anticipated anti-inflammatory effects in myometrial cell culture experiments. In our mouse model of preterm birth, ticagrelor neither improved the preterm birth rate or fetal survival outcomes. Gene expression of pro-inflammatory cytokines and contraction-associated proteins in postpartum mouse uteri were unaltered by ticagrelor. In conclusion, ticagrelor is not a strong candidate to continue investigations in clinical trial for the treatment of preterm labour and prevention of preterm birth.

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