Sildenafil for the treatment of preeclampsia, an update: should we still be enthusiastic?

Simon-Tillaux, Noémie; Lecarpentier, Édouard; Tsatsaris, Vassilis; Hertig, Alexandre

doi:10.1093/ndt/gfy328

Cited by 18 publications

(11 citation statements)

References 68 publications

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“…Others have also reported beneficial blood pressure and/or fetal effects of sildenafil in pregnant hypertensive animals (21,(36)(37)(38)(39)(40)(41)(42). However, these promising pre-clinical data have not translated smoothly into clinical trials (19,43). Earlier studies reported no beneficial effects of sildenafil treatment on pregnancy duration, isolated vessels, or fetal outcomes (22,44,45).…”

Section: Discussionmentioning

confidence: 99%

High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

et al. 2021

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The maternal innate immune system plays a central role in preeclampsia (PE). Toll-like receptors (TLRs) are innate immune system receptors that recognize characteristics of extracellular endogenous ligands or pathogens, and their activation leads to a pro-inflammatory immune response. We and others have reported that excessive activation of TLRs causes pregnancy-dependent hypertension in animals and is associated with PE in women. Activation of TLR3 by poly I:C mimics the innate immune system activation by viruses that women who develop PE encounter during pregnancy. Vardenafil was approved by the FDA for erectile dysfunction but has recently been examined as a potential PE medication due to studies done with a similar drug, sildenafil. Preclinical as well as recent clinical studies demonstrate the potential effectiveness of sildenafil for PE. However, vardenafil is more potent than sildenafil and acts by increasing expression of placental growth factor in addition to increasing cGMP levels. We hypothesized that vardenafil will be more potent and effective in reducing the negative health effects in a mouse model of virus-induced PE. Pregnant mice were injected with the TLR3 agonist poly I:C (PPIC) on gestational days 13, 15, and 17. We treated PPIC mice with a high dose of vardenafil (50 mg human equivalent), a lower dose of vardenafil (20 mg human equivalent), or sildenafil (50 mg human equivalent) on gestational days 15–17 after hypertension was established. Daily i.p. injections of either high dose or low dose vardenafil significantly decreased systolic blood pressure in PPIC mice whereas sildenafil had no effect. There were no differences in body weight between the groups. The splenomegaly induced in PPIC mice was ameliorated in high dose vardenafil-treated PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still exhibited splenomegaly. High dose vardenafil-treated PPIC mice also did not exhibit any fetal demise characteristic of PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still had significantly increased incidences of fetal demise. These data support the notion that high dose vardenafil may be safe and effective at reducing blood pressure during a virus-associated hypertensive pregnancy.

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Section: Discussionmentioning

confidence: 99%

High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

et al. 2021

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“…inhibitor use for these off-label uses is currently sparse, although there are some in vitro and in vivo studies suggesting that PDE5 inhibitor administration may have potential benefits for pre-eclampsia, 23,24 when administered during pregnancy, and wound healing. 25,26 To our knowledge, this was the first study evaluating PDE5 inhibitor use in pregnant and reproductive-age women in the United States using large population-based databases.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase type 5 inhibitor use among pregnant and reproductive‐age women in the United States

Liu

Menzin

Woods

et al. 2020

Pharmacoepidemiology and Drug

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PurposeTo assess the prevalence and potential indications of PDE5 inhibitor use among pregnant and reproductive‐age women in the United States.MethodsWe identified women 15 to 50 years with a livebirth from January 2001 through March 2018 in Sentinel Database. We assessed the prevalence of PDE5 inhibitor use prior to and during pregnancy by trimester, identified potential on‐ and off‐label indications using predefined diagnosis codes recorded within 90 days before the estimated last menstrual period through delivery. Separately, we used data from IQVIA's National Prescription Audit and Total Patient Tracker to estimate the dispensed prescriptions for PDE5 inhibitors and the number of patients with PDE5 inhibitor prescriptions.ResultsWe identified approximately 3.3 million pregnancies during 2001 to 2018, 96 of which had PDE5 inhibitor use during pregnancy. Prevalence of PDE5 inhibitor use was 2.61, 0.62, and 0.62 per 100, 000 live‐born pregnancies during the first, second, or third trimesters, respectively. Among women exposed to a PDE5 inhibitor from 90 days before conception to the end of pregnancy, 25.0%, 31.1%, and 15.5% had a diagnosis code for fetal growth restriction, preeclampsia, and pulmonary arterial hypertension. In IQVIA data, an estimated 223, 000 prescriptions from July 2015 through June 2018 and 58, 000 women received prescriptions for PDE5 inhibitors in 2017, of whom approximately 15, 000 (26%) were aged 15 to 50 years.ConclusionWe found a low prevalence of PDE5 inhibitor use in pregnant and reproductive‐age women. Given the very low prevalence of use and the inconsistency of neonatal mortality data across STRIDER centers, the risk to public health is low at present.

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“…These effects could be particularly interesting for maternal or fetal pathology during pregnancy. Sildenafil only modestly reduces blood pressure, granting it a particularly desirable profile for pregnancy where systemic hypotension is deleterious for the fetus [ 7 , 9 ]. Moreover, the hepatic CYP3A4 and CYP2C19 isoenzymes involved in sildenafil’s metabolization were present and active prenatally [ 10 , 11 ].…”

Section: Sildenafilmentioning

confidence: 99%

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

Bie

Basurto

Kumar

et al. 2022

IJERPH

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Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.

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Sildenafil for the treatment of preeclampsia, an update: should we still be enthusiastic?

Cited by 18 publications

References 68 publications

High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

Phosphodiesterase type 5 inhibitor use among pregnant and reproductive‐age women in the United States

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

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