Phosphodiesterase Inhibition in the Treatment of Preeclampsia: What Is New?
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Purpose of Review
The present study intends to review the possibility of using phosphodiesterase inhibitors as a treatment option for preeclampsia, addressing potential risks and benefits.
Preeclampsia is the most common hypertensive disorder of pregnancy, often responsible for severe maternal and fetal complications, which can lead to early pregnancy termination and death. Despite the numerous studies, its pathophysiology is still unclear, although it seems to involve a multiplicity of complex factors related to angiogenesis, ineffective vasodilation, oxidative stress, inflammatory cytokines, and endothelial dysfunction. It has been hypothetically suggested that the use of phosphodiesterase inhibitors is capable of improving placental and fetal perfusion, contributing to gestational scenario, by decreasing the symptomatology and severity of this syndrome. In this literature review, it has been found that most of the studies were conducted in animal models, and there is still lack of evidence supporting its use in clinical practice. Research in human indicates conflicting findings; randomized controlled trials were scarce and did not demonstrate any benefit in morbidity or mortality. Data regarding to pathophysiological and interventional research are described and commented in this review.
The use of phosphodiesterase inhibitors in the treatment of preeclampsia is controversial and should not be encouraged taking into account recent data.
KeywordsSildenafil Phosphodiesterase Hypertension, pregnancy-induced Models, animal
Regarding authorship: Anne Brandolt Larré, Bartira Ercília Pinheiro da Costa, Fernando Sontag, and Carlos Eduardo Poli-de-Figueiredo worked at conception, planning, writing the paper, and final version revising. Débora Montenegro Pasin, Nathália Paludo, and Rayssa Ruszkowski do Amaral worked at planning, writing the paper, and final version revising.
Financial Support and Sponsorship
Source of Support
Laboratory of Nephrology receives support from the National Council for Scientific and Technological Development (CNPq), Research Support Foundation of the State of Rio Grande do Sul (FAPERGS), Coordination for the Improvement of Higher Education Personnel (CAPES), and the Pontifical Catholic University of Rio Grande do Sul (PUCRS). Poli-de-Figueiredo is a CNPq researcher.
Compliance with Ethical Standards
Conflict of Interest
None of the authors report any conflict of interest.
Human and Animal Rights
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.•• American College of Obstetricians and Gynecologists, Task Force on Hypertension in Pregnancy, Hypertension in pregnancy, Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy Obstet Gynecol. 2013;122:1122–31. This comprehensive guideline from The American College of Obstetricians and Gynecologists consists in an important tool to the definition, diagnosis, classification, prediction, and prevention of hypertensive disorders of pregnancy. It approaches clinical considerations and recommendations in different scenarios, regarding evaluation, managment, and treatment. Google Scholar
- 3.•• Tranquilli AL, Dekker G, Magee L, Roberts J, Sibai BM, Steyn W, et al. The classification, diagnosis and management of the hypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 2014;4:97–104. This statement from the International Society for the Study of Hypertension in Pregnancy comprises an updated view over definition, classification, diagnostic criteria, and management of hypertensive disorders of pregnancy. Considering previous key guidelines, it intends to give a new perspective over the disease in face of recent data, focusing mainly in the importance of proteinuria, antihypertensive treatment, and blood pressure target. CrossRefPubMedGoogle Scholar
- 4.ACOG practice bulletin no. 33: diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002;99:159–67.Google Scholar
- 9.Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signaling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol. 2012;165:1288–305.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Conrad KP, Kerchner LJ, Mosher MD. Plasma and 24-h NOx and cGMP during normal pregnancy and preeclampsia in women on a reduced NOx diet. Am J Phys. 1999;277:48–57.Google Scholar
- 15.• Chaiworapongsa T, Chaemsaithong P, Yeo L, Romero R. Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol. 2014;10:466–80. This review describes, mostly, the pathophysiology of preeclampsia disease, providing a very complete view over mechanisms and pathways involved in placental ischaemia, vascular remodeling, hypoxia, oxidative stress, inflammation, and immune and platelet activation. CrossRefPubMedPubMedCentralGoogle Scholar
- 18.•• Sasser JM, Murphy SR, Granger JP. Emerging drugs for preeclampsia--the endothelium as a target. Expert Opin Emerg Drugs. 2015;20:527–30. This review focus especially on the importance of endothelial dysfunction to the development of preeclampsia, addressing emerging therapies such as the inhibition of endothelin type A and phosphodiesterase-5. CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Anumba DO, Robson SC, Boys RJ, Ford GA. Nitric oxide activity in the peripheral vasculature during normotensive and preeclamptic pregnancy. Am J Phys. 1999; https://doi.org/10.1152/ajpheart.1999;277:848-54.
- 30.• Sibley CP. Treating the dysfunctional placenta. Endocr J. 2017;234(2):R81–97. This review describes preeclampsia and fetal growth restriction’ pathophysiology, while highlights therapeutic targets and potential drug therapies, proposing experimental pathways for treatment design. CrossRefGoogle Scholar
- 31.Tanaka H, Kubo M, Nii M, Maki S, Umekawa T, Ikeda T. Treatment using tadalafil for severe pre-eclampsia with fetal growth restiction. Obstet Gynecol. 2017;43:1205–8.Google Scholar
- 33.George EM, Palei AC, Dent EA, Granger JP. Sildenafil attenuates placental ischemia-induced hypertension. Am J Phys Regul Integr Comp Phys. 2013;305:397–403.Google Scholar
- 57.Reyna-Villasmil E, Torres-Cepeda D, Peña-Paredes E, Mejía-Montilla J, Reyna-Villasmil N, González-Rodríguez P. Efecto de citrato de sildenafil sobre el flujo sanguíneo de las arterias uterina, umbilical y cerebral media fetal en preeclámpticas / effect of sildenafil cytrate on blood flow of uterine, umbilical artery and cerebral media fetal artery in preeclamptic patients. Rev Obstet Ginecol Venez. 2008;68:187–94.Google Scholar
- 59.Kakigano A, Tomimatsu T, Mimura K, Kanayama T, Fujita S, Minato K, et al. Drug repositioning for preeclampsia therapeutics by in vitro screening: phosphodiesterase-5 inhibitor vardenafil restores endothelial dysfunction via induction of placental growth factor. Reprod Sci. 2015;22:1272–80.CrossRefPubMedGoogle Scholar
- 60.• Trapani A Jr, Gonçalves LF, Trapani TF, Vieira S, Pires M, Pires MM. Perinatal and hemodynamic evaluation of sildenafil citrate for preeclampsia treatment: a randomized controlled trial. Obstet Gynecol. 2016;128:253–9. One of the most recent clinical trials regarding the use of sildenafil citrate in the treatment of preeclampsia. Benefits were observed in blood pressure control during the first day after administration; and in pregnancy prolongation of approximately 4 days. CrossRefPubMedGoogle Scholar