Novel approaches to combat preeclampsia: from new drugs to innovative delivery

Alwis, Natasha de; Binder, Natalie; Beard, Sally; Kaitu’u-Lino, Tu’uhevaha J; Tong, Stephen; Brownfoot, Fiona; Hannan, Natalie J.

doi:10.1016/j.placenta.2020.08.022

Cited by 33 publications

(29 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, a randomized-placebo controlled trial has already been initiated where the consequences of daily esomeprazole administration to women at high risk of preeclampsia will be assessed. 5 We reported a substantially higher neonatal intubation rate in the nonomeprazole group compared with the omeprazole group. The nonsignificant higher baseline sFlt-1/PlGF ratio in the nonomeprazole group might partially explain higher disease severity and therefore more iatrogenic preterm birth in the latter group.…”

Section: Discussionmentioning

confidence: 70%

See 1 more Smart Citation

Omeprazole Administration in Preterm Preeclampsia: a Randomized Controlled Trial to Study Its Effect on sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1), PlGF (Placental Growth Factor), and ET-1 (Endothelin-1)

et al. 2022

View full text Add to dashboard Cite

BACKGROUND: Low sFlt-1 (soluble Fms-like tyrosine kinase-1) and ET-1 (endothelin-1) levels have been reported in preeclamptic women using proton pump inhibitors. METHODS: Here, we examined whether the proton pump inhibitor omeprazole could acutely reduce sFlt-1 and ET-1 (measured as CT-proET-1 [C-terminal pro-endothelin-1]), or increase free PlGF (placental growth factor) in 20 women with confirmed preeclampsia. Primary outcome was specified as the difference in sFlt-1, PlGF, or CT-proET-1 after 4 days of omeprazole versus 20 preeclamptic women not receiving omeprazole. RESULTS: Mean maternal age was 30 years, and median gestational age was 30 +3 weeks. Baseline sFlt-1 levels were identical in both groups, and the same was true for PlGF or CT-proET-1. After 4 days, sFlt-1 levels remained similar in women not receiving omeprazole compared with women receiving omeprazole, while the levels of PlGF and CT-proET-1 also did not differ between groups. Women receiving omeprazole had a similar prolongation of pregnancy after inclusion compared with those in the nonomeprazole group (median 15 versus 14 days). Except for a higher neonatal intubation rate in the nonomeprazole group (31% versus 4%, P =0.02), there were no differences in maternal/perinatal complications. Finally, making use of the placenta perfusion model, we established that both omeprazole and its S-isomer, esomeprazole, when maternally applied, reached the fetal compartment (fetal-to-maternal ratio’s 0.43–0.59), while only esomeprazole inhibited placental sFlt-1 release. CONCLUSIONS: Administration of omeprazole to women with confirmed preeclampsia does not alter their circulating levels of sFlt-1, PlGF, or ET-1, arguing against a role of this drug as a treatment for this syndrome.

show abstract

Section: Discussionmentioning

confidence: 70%

“…As such, current studies focus on novel therapies that could target these (anti-)angiogenic factors. 5 Recently, proton pump inhibitors (PPIs) were shown to dose-dependently reduce sFlt-1 release in placental explants or trophoblast cells. 6 PPIs are commonly prescribed for the treatment of gastric acid reflux and are considered safe for use in pregnancy.…”

mentioning

confidence: 99%

Omeprazole Administration in Preterm Preeclampsia: a Randomized Controlled Trial to Study Its Effect on sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1), PlGF (Placental Growth Factor), and ET-1 (Endothelin-1)

et al. 2022

View full text Add to dashboard Cite

show abstract

“…PE is characterized by a dysfunctional placenta, where impaired maternal spiral artery remodelling can cause intermittent placental hypoxia and ischaemic injury [ 56 ]. Identifying the important pathological stages in the progression of PE allows us to evaluate candidate therapeutic options [ 57 ]. Three important stages in the pathophysiology are: (1) placental hypoxia and oxidative stress, (2) excess release of anti-angiogenic and pro-inflammatory factors, and (3) widespread systemic endothelial dysfunction and vasoconstriction [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

“…Identifying the important pathological stages in the progression of PE allows us to evaluate candidate therapeutic options [ 57 ]. Three important stages in the pathophysiology are: (1) placental hypoxia and oxidative stress, (2) excess release of anti-angiogenic and pro-inflammatory factors, and (3) widespread systemic endothelial dysfunction and vasoconstriction [ 57 ]. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and thrombotic events with placental infarcts [ 14 , 58–60 ].…”

Section: Discussionmentioning

confidence: 99%

Augmentation index and pulse wave velocity in normotensive versus preeclamptic pregnancies: a prospective case–control study using a new oscillometric method

Anthoulakis

Mamopoulos

2021

Annals of Medicine

View full text Add to dashboard Cite

Objectives The objective of this study was to investigate whether oscillometric AS measurements are different in pregnant women with and without preeclampsia (PE). Study design This was a prospective case–control study in singleton pregnancies that had been diagnosed with PE ( n = 46) versus normotensive controls ( n = 46) between 2014 and 2019. In the case group, pregnancies complicated by PE were classified as either early-onset (<34 weeks of gestation) or late-onset (≥34 weeks of gestation) PE and subgroup analysis was performed. Main outcome measures Pulse wave velocity (PWV), augmentation index (Alx), and Alx at a heart rate of 75 beats per minute (Alx-75) were measured using a brachial cuff-based automatic oscillometric device (Mobil-O-Graph 24 h PWA). Results In pregnancies complicated by PE, in comparison with normotensive pregnancies, there were significant differences in PWV ( p ˂ .001), and Alx-75 ( p ˂ .001). In pregnancies complicated by early-onset PE, in comparison with pregnancies complicated by late-onset PE, there were significant differences in PWV ( p = .006), and Alx-75 ( p = .009). There was no significant difference in Alx in either of the analyses. Conclusions PWV and Alx-75 are higher in pregnancies complicated by PE, in comparison with normotensive pregnancies, as well as in early-onset PE, in comparison with late-onset PE. Key messages Pulse wave velocity is higher in pregnancies complicated by preeclampsia. Augmentation index at a heart rate of 75 beats per minute is higher in pregnancies complicated by preeclampsia. Arterial stiffness assessment is a promising risk-stratification tool for future cardiovascular complications but further studies are required.

show abstract

“…Inflammation, oxidative stress, and vascular dysfunction in PE have become important targets for innovative therapeutics 7 . Nowadays, numerous candidate therapies, including melatonin, have shown potential to prevent PE in both preclinical studies and human trials 8,9 . Melatonin is a lipid hormone that modulates circadian rhythms, induces expression of antioxidants, and has direct free radical scavenging properties 10 .…”

Section: Introductionmentioning

confidence: 99%

Melatonin regulates trophoblast pyroptosis, invasion and migration in preeclampsia by inhibiting HtrA1 transcription through the microRNA‐520c‐3p/SETD7 axis

Liu

Chen

Chang

et al. 2022

American J Rep Immunol

View full text Add to dashboard Cite

Objective Melatonin has an inhibitory effect on preeclampsia (PE). This study was launched to explore the way that melatonin regulated trophoblast migration, invasion, and pyroptosis in PE and to provide new ideas for the diagnosis and treatment of PE. Methods Expression levels of melatonin receptors (MT1 and MT2), microRNA (miR)‐520c‐3p, SETD7, and HtrA1 in placental tissues and HTR8/SVneo cells were measured by RT‐qPCR and Western blot. Scratch, Transwell, and Western blot assays were performed to detect migration, invasion, and pyroptosis of hypoxia/reoxygenation (H/R)‐treated HTR8/SVneo cells. Dual‐luciferase reporter assay was utilized to verify the targeting relationship between miR‐520c‐3p and SETD7. ChIP experiment was conducted to detect the enrichment of H3K4me3 and SETD7 in HtrA1 promoter. Results Low expression of MT1, MT2, and miR‐520c‐3p and high expression of SETD7 and HtrA1 were observed in the placental tissues of PE patients and H/R‐treated HTR8/Svneo cells. A high concentration of melatonin promoted migration and invasion and inhibited pyroptosis of PE cell models. Knockdown of miR‐520c‐3p, overexpression of SETD7, or overexpression of HtrA1 impaired migration and invasion and accelerated pyroptosis of H/R‐treated HTR8/SVneo cells, but these outcomes could be reversed by treatment with 1000 μM melatonin. miR‐520c‐3p targeted SETD7 which promoted histone methylation in the promoter region of HtrA1. Conclusion Melatonin may inhibit HtrA1 transcription through the miR‐520c‐3p/SETD7 axis to promote trophoblast invasion and migration and reduce trophoblast pyroptosis in PE.

show abstract

Novel approaches to combat preeclampsia: from new drugs to innovative delivery

Cited by 33 publications

References 91 publications

Omeprazole Administration in Preterm Preeclampsia: a Randomized Controlled Trial to Study Its Effect on sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1), PlGF (Placental Growth Factor), and ET-1 (Endothelin-1)

Omeprazole Administration in Preterm Preeclampsia: a Randomized Controlled Trial to Study Its Effect on sFlt-1 (Soluble Fms-Like Tyrosine Kinase-1), PlGF (Placental Growth Factor), and ET-1 (Endothelin-1)

Augmentation index and pulse wave velocity in normotensive versus preeclamptic pregnancies: a prospective case–control study using a new oscillometric method

Melatonin regulates trophoblast pyroptosis, invasion and migration in preeclampsia by inhibiting HtrA1 transcription through the microRNA‐520c‐3p/SETD7 axis

Contact Info

Product

Resources

About