Emerging tocolytics: challenges in designing and testing drugs to delay preterm delivery and prolong pregnancy

Olson, David M.; Christiaens, Inge; Gracie, Sara; Yamamoto, Yuka; Mitchell, Bryan F.

doi:10.1517/14728210802568764

Cited by 28 publications

(22 citation statements)

References 76 publications

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“…Resulting inflammatory cascade leads to the induction of UAP and promotes the onset of labor. Accordingly, data from our laboratory and others show that acute inflammatory events increase UAP expression in the myometrium and other uterine tissue (12,15,45). This notion is supported by data obtained in the current study; IL-1b and TLR ligands induced various UAP, including OXTR, PTGFR, PGHS2, CCL2, and GJA1 in myometrium.…”

Section: Discussionsupporting

confidence: 91%

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

Nadeau-Vallée

Quiniou

Palacios

et al. 2015

The Journal of Immunology

101

123

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Preterm birth (PTB) is firmly linked to inflammation regardless of the presence of infection. Proinflammatory cytokines, including IL-1β, are produced in gestational tissues and can locally upregulate uterine activation proteins. Premature activation of the uterus by inflammation may lead to PTB, and IL-1 has been identified as a key inducer of this condition. However, all currently available IL-1 inhibitors are large molecules that exhibit competitive antagonism properties by inhibiting all IL-1R signaling, including transcription factor NF-κB, which conveys important physiological roles. We hereby demonstrate the efficacy of a small noncompetitive (all-d peptide) IL-1R–biased ligand, termed rytvela (labeled 101.10) in delaying IL-1β–, TLR2-, and TLR4-induced PTB in mice. The 101.10 acts without significant inhibition of NF-κB, and instead selectively inhibits IL-1R downstream stress-associated protein kinases/transcription factor c-jun and Rho GTPase/Rho-associated coiled-coil–containing protein kinase signaling pathways. The 101.10 is effective at decreasing proinflammatory and/or prolabor genes in myometrium tissue and circulating leukocytes in all PTB models independently of NF-κB, undermining NF-κB role in preterm labor. In this work, biased signaling modulation of IL-1R by 101.10 uncovers a novel strategy to prevent PTB without inhibiting NF-κB.

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Section: Discussionsupporting

confidence: 91%

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

Nadeau-Vallée

Quiniou

Palacios

et al. 2015

The Journal of Immunology

101

123

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“…The prevalence of preterm labor in Iran has been estimated to be 10-15% of deliveries (4,5). Recent strategies to avert preterm labor are used to prevent mechanisms that increase the frequency and severity of uterine contractions (6). Although, various tocolytic drugs are commonly used in this regard, there is no consensus on which is best (7).…”

Section: Introductionmentioning

confidence: 99%

The association between level of maternal serum leptin in the third trimester and the occurrence of moderate preterm labor

Fakor

Sharami

Milani

et al. 2016

J Turkish German Gynecol Assoc

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Original Investigation 182 IntroductionPreterm birth is a serious health problem associated with neonatal morbidity and mortality (1). Preterm birth is the leading cause of neonatal mortality and the second prevalent cause of mortality in children aged less than 5 years (2). Additionally, the rate of death by other causes, such as neonatal infections, in preterm neonates are higher than term neonates (3). The World Health Organization defined preterm labor as live birth before 37 weeks of gestation. Preterm birth is classified to three subgroups as defined by gestational age: extremely preterm (<28 weeks), very preterm (28-<32 weeks), and moderate preterm (32-<37 completed weeks of gestation) (4). Moderate preterm birth includes late preterm birth (34-<37 completed weeks of gestation). The occurrence of preterm birth was reported as 5-18%, worldwide. The prevalence of preterm labor in Iran has been estimated to be 10-15% of deliveries (4,5). Recent strategies to avert preterm labor are used to prevent mechanisms that increase the frequency and severity of uterine contractions (6). Although, various tocolytic drugs are commonly used in this regard, there is no consensus on which is best (7). Leptin is a peptide and a tocolytic factor hormone. It is the product of the ob gene with a 16 kda molecular weight, 167 amino acids long, and a half-life of 25 (8-10). During pregnancy, leptin is secreted from placental trophoblasts and enters from the placenta to the fetal and maternal body. Leptin can have a significant role on fetal growth and development, angiogenesis, and hematopoiesis (8,11). Leptin levels increase during pregnancy, in which the lowest level can be assessed in the first trimester, and the highest during the second trimester. A plateau is noted in the third trimester of pregnancy (8,12). Results have shown that leptin can affect physiological processes such as glucose metabolism and immune system responses (9,13,14). Dotsch et al. (15) mentioned that the mean leptin level in term neonates was 6-fold higher than preterm neonates. According to previous investigations, various factors, such as maternal body mass index (BMI), maternal age, and smoking cigarettes could influence the umbilical leptin levels (16). Additionally, there was a linear relationship between leptin Objective: We aimed to investigate the relationship between the level of maternal serum leptin and the occurrence of moderate preterm labor. Material and Methods:This was a case control study conducted on pregnant women referred to Al-Zahra Hospital in Rasht, north of Iran in 2013. Cases included 30 moderate preterm delivering women and 30 control pregnant women with the same gestational age. The maternal serum leptin was measured for each mother at the time of entering the study. Results:The mean serum leptin in the control group (56.66±34.18) was significantly higher than the preterm (33.65±16.70) group. There were no significant differences between the groups in terms of body mass index and age. Logistic regression revealed that age and...

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“…Because tocolytics have numerous side effects and have not been shown to improve neonatal outcome, some clinicians prefer not to use them, especially in case of late PTB. The first clinical trials of tocolytics began in the late 1960s and 1970s [11]. Since then, numerous tocolytic candidates have been used, most of them off-label (e.g.…”

Section: Pharmacological Approches In the Treatment Of Ptbmentioning

confidence: 99%

“…terbutaline, ritodrine, salbutamol), but the most used is ritodrine [11]. β-mimetics bind and activate β-adrenergic receptors on myometrial cells.…”

Section: Ritodrinementioning

confidence: 99%

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Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

Mai-Vo¹,

Nadeau-Vallée²,

Beaudry-Richard³

2017

UOJM

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Preterm birth (PTB) is the leading cause of neonatal mortality and morbidity. Although the severity of neonatal outcomes is inversely correlated with gestational age, all PTBs can lead to potentially life-threatening neonatal outcomes and major lifelong health complications. Because advances in neonatal care have substantially decreased neonatal mortality, the incidence of PTB and its complications is unabatedly rising. PTB currently affects more than 10% of births worldwide, with similar numbers in developed countries. Correspondingly, improving neonatal outcome is a key objective of the World Health Organization. The recently approved (in Europe) tocolytics drug, Atosiban, used to prolong preterm gestation, has not been shown to improve neonatal outcome, nor have other tocolytic agents used in clinic. Thus, PTB remains an unmet medical need. Recent evidence shows that most, if not all, PTBs are associated with (overt or occult) inflammatory processes in gestational tissues, independent of infection. Proinflammatory cytokines are produced from maternal and fetal cells in response to sterile or infectious stressors. These seem to orchestrate a multi-tissue response including myometrial contractility, cervical ripening, and weakening/rupture of fetal membranes, leading to the onset of preterm labor. This integrated system might have been conserved through mammalian evolution due to increased maternal and/or fetal survival when gestation is terminated in specific settings, such as infection. Hence, inflammation may be a common pathway to the numerous aetiologies of PTB. Most importantly, recent evidence suggests that inflammation is transmitted to the fetus, thereby inducing organ injuries that may underlie the development of major neonatal diseases. Targeting inflammation prenatally instead of myometrial contraction could be a more successful and safe approach for the management of PTB, as suggested by recent animal studies. ABSTRACTLa naissance prématurée est la principale cause de mortalité et de morbidité néonatale. Bien que la sévérité des issus néonataux soit inversement corrélée avec l'âge gestationnel à la naissance, toutes les naissances prématurées peuvent mener à des issus néonataux potentiellement mortels et à des complications avec répercussions s'échelonnant sur toute la vie. Étant donné que la mortalité néonatale a considérablement diminuée avec les récentes avancées en néonatalogie, l'incidence de la naissance préma-turée et de ses complications sont en hausse. La naissance prématurée affecte présentement plus de 10% des naissances à travers le monde, avec des taux similaires dans les pays développés. Conséquemment, d'améliorer l'issu néonatal est un objectif clé de l'Organisation Mondiale de la Santé. Le tocolytique Atosiban récemment approuvé (en Europe) pour prolonger les gestations pré-maturées n'a pas démontré d'efficacité pour améliorer les issus néonataux, tout comme les autres tocolytiques utilisés en clinique, et la naissance prématurée demeure un besoin médical non-atteint. Des données r...

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Emerging tocolytics: challenges in designing and testing drugs to delay preterm delivery and prolong pregnancy

Cited by 28 publications

References 76 publications

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

Novel Noncompetitive IL-1 Receptor–Biased Ligand Prevents Infection- and Inflammation-Induced Preterm Birth

The association between level of maternal serum leptin in the third trimester and the occurrence of moderate preterm labor

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

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