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• W2951904972 abstract "Preeclampsia is one of the most serious complications of pregnancy, diagnosed when a pregnant woman presents in the second half of pregnancy with hypertension, proteinuria and oedema. Sadly, it is responsible for significant maternal and perinatal morbidity and mortality, with the greatest burden experienced in the developing world. Preeclampsia causes widespread injury to many of the mother's organ systems including her blood vessels (hypertension), kidneys, liver, haematological system and brain. It can also cause fetal growth restriction [[1]Young B.C. Levine R.J. Karumanchi S.A. Pathogenesis of preeclampsia.Annu Rev Pathol. 2010; 5: 173-192Crossref PubMed Scopus (525) Google Scholar]. Preeclampsia is believed to stem from poor placental invasion early in pregnancy [[1]Young B.C. Levine R.J. Karumanchi S.A. Pathogenesis of preeclampsia.Annu Rev Pathol. 2010; 5: 173-192Crossref PubMed Scopus (525) Google Scholar]. The preeclamptic placenta releases elevated levels of injurious factors into the maternal circulation. These include anti-angiogenic factors and pro-inflammatory cytokines that cause maternal blood vessel injury [[2]Maynard S.E. Karumanchi S.A. Angiogenic factors and preeclampsia.Semin Nephrol. 2011; 31: 33-46Summary Full Text Full Text PDF PubMed Scopus (324) Google Scholar]. The net result of this is systemic vascular dysfunction and end organ damage. A feature of endothelial dysfunction in preeclampsia is reduced bioavailability of nitric oxide (NO) activity. NO is a key factor contributing to vasorelaxation and lowering of blood pressure [[3]Johal T. Lees C.C. Everett T.R. Wilkinson I.B. The nitric oxide pathway and possible therapeutic options in pre-eclampsia.Br J Clin Pharmacol. 2014; 78: 244-257Crossref PubMed Scopus (72) Google Scholar]. Thus, reduced vasorelaxation activity and enhanced vasoconstrictor influences impact upon the vascular smooth muscle and contribute to the hypertension that is characteristic of preeclampsia. Given the only effective treatment for preeclampsia is delivery of the baby and placenta, there has been much interest in re-purposing therapies as a means to treat this disease. One such medication is sildenafil, a treatment widely used to treat erectile dysfunction. Sildenafil's main mechanism of action is as a phosphodiesterase-5 inhibitor that induces vasorelaxation. Indeed, in animal models, sildenafil has shown potential to improve both fetal and maternal pregnancy outcomes in preeclampsia models [[4]Gillis E.E. Mooney J.N. Garrett M.R. Granger J.P. Sasser J.M. Sildenafil treatment ameliorates the maternal syndrome of preeclampsia and rescues fetal growth in the Dahl salt-sensitive rat.Hypertension. 2016; 67: 647-653Crossref PubMed Scopus (54) Google Scholar,[5]Ramesar S.V. Mackraj I. Gathiram P. Moodley J. Sildenafil citrate decreases sFlt-1 and sEng in pregnant l-NAME treated Sprague-Dawley rats.Eur J Obstet Gynecol Reprod Biol. 2011; 149: 22-26Summary Full Text Full Text PDF Scopus (50) Google Scholar]. In humans, a randomised controlled trial suggested sildenafil reduces blood pressure, improves blood flow to the uterus and prolongs pregnancy in preeclamptic patients by 4 days, relative to placebo treated controls [[6]Trapani Jr., A. Goncalves L.F. Trapani T.F. Vieira S. Pires M. Pires M.M. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial.Obstet Gynecol. 2016; 128: 253-259Crossref PubMed Scopus (64) Google Scholar]. In an article in EBioMedicine, Hitzerd and others [[7]Hitzerd E. Broekhuizen M. Mirabito Colafella K. et al.Placental effects and transfer of sildenafil in healthy and preeclamptic conditions.EBioMedicine. 2019; https://doi.org/10.1016/j.ebiom.2019.06.007Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar] have tested the effects of sildenafil in placentas and vessels obtained from human preeclamptic pregnancies. The team initially dissected the effects of sildenafil on vasorelaxation in arteries obtained from the fetal side of the placenta. The rationale for these studies was that if sildenafil was to be a beneficial treatment for preeclampsia, it should enhance vasorelaxation. In vessels obtained from healthy term pregnancies, Hitzerd and colleagues showed that sildenafil enhanced nitric oxide dependent vasorelaxation, whilst this effect was not observed in preterm preeclamptic vessels; suggesting differential effects of the drug on vasorelaxation in healthy versus diseased samples. The team also attempted to assess sildenafil transfer across the placenta in healthy and preeclamptic placentas using perfusion studies. They were limited in their study of preeclamptic placentas due to difficulties in perfusing preterm placentas, and thus did not attempt to perfuse gestation matched samples due to these same difficulties. In their small sample size of just two preterm preeclamptic placentas, they suggest that sildenafil transfer may be higher in preeclamptic placentas relative to term healthy controls. Although interpretation of the placental transfer findings warrants caution due to very small sample numbers and varied gestation at placental collection, the findings from Hitzerd and colleagues raises important considerations for those working in the field of therapeutic discovery. In particular these findings highlight the need for testing therapeutics in both healthy and preeclamptic samples given the pathophysiology of the disease is likely to produce perturbations in signalling pathways important for therapeutic action. Moreover, consideration of placental transfer rates appears essential given the potential unknown effects of novel therapies on fetal wellbeing. Indeed, recently sildenafil was tested as a potential therapeutic for severe early onset fetal growth restriction in an international consortium of large multi-centre randomised controlled trials (the STRIDER study). The major reason for trialling sildenafil was its potential to enhance vasodilation and blood flow to the compromised feto-placental unit. Whilst no net-benefit of sildenafil was observed in the first two cohorts [[8]Groom K.M. McCowan L.M. Mackay L.K. et al.STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.BJOG. 2019; 126: 997-1006PubMed Google Scholar,[9]Sharp A. Cornforth C. Jackson R. et al.Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial.Lancet Child Adolesc Health. 2018; 2: 93-102Summary Full Text Full Text PDF PubMed Scopus (116) Google Scholar], the Dutch STRIDER trial was closed prematurely due to an increase in cases of pulmonary hypertension in the newborns [[10]Groom K.M. Ganzevoort W. Alfirevic Z. Lim K. Papageorghiou A.T. Consortium S. Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR): comment from the STRIDER Consortium.Ultrasound Obstet Gynecol. 2018; 52: 295-296Crossref PubMed Scopus (60) Google Scholar]. Whilst the statistical analyses from the Dutch STRIDER trial following its cessation remain a work in progress, the effects of sildenafil on vascular reactivity and placental transfer rates in human fetal growth restriction have not been investigated. Thus, it appears essential that pre-clinical studies for novel therapies not currently used in pregnancy must carefully tease out the effects of drugs in both healthy and diseased samples, as well as considering placental transfer studies to determine the potential level of fetal exposure. Moreover, for those drug therapies that are known to be safe to administer during pregnancy, clarification of the amount of drug that reaches the placenta, and/or placental transfer that occurs, may be important considerations for future work and to inform dosage for clinical trials. None. Placental effects and transfer of sildenafil in healthy and preeclamptic conditionsThe absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. Full-Text PDF Open Access" @default.
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• W2951904972 title "Therapeutic interventions: The importance of including diseased and healthy samples in preclinical studies" @default.
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