Halting the Canadian STRIDER randomised controlled trial of sildenafil for severe, early-onset fetal growth restriction: ethical, methodological, and pragmatic considerations

Dadelszen, Peter von; Audibert, François; Bujold, Emmanuel; Bone, Jeffrey; Sandhu, Ash; Li, Jing; Kariya, Chirag; Chung, Youkee; Lee, Tang; Au, Kelvin; Skoll, Michael; Vidler, Marianne; Magee, Laura A.; Baker, Philip N.; Lalji, Sayrin; Lim, Kenneth

doi:10.1186/s13104-022-06107-y

Cited by 5 publications

(1 citation statement)

References 14 publications

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“…However, what is known is that the administration of sildenafil in the context of severe early-onset FGR may be harmful to the neonate. The STRIDER Canada trial, a national multisite double-blind, placebo-controlled randomized controlled trial aimed at determining the efficacy and safety of sildenafil, was discontinued due to an increased risk of neonatal pulmonary hypertension and a non-significant trend toward increased neonatal mortality [230,231]. Safety remains the foremost consideration in the development of any therapeutic method aimed at targeting protein misfolding mechanisms.…”

Section: Treatmentmentioning

confidence: 99%

Protein Misfolding in Pregnancy: Current Insights, Potential Mechanisms, and Implications for the Pathogenesis of Preeclampsia

Medegan Fagla,

Buhimschi

2024

Molecules

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Protein misfolding disorders are a group of diseases characterized by supra-physiologic accumulation and aggregation of pathogenic proteoforms resulting from improper protein folding and/or insufficiency in clearance mechanisms. Although these processes have been historically linked to neurodegenerative disorders, such as Alzheimer’s disease, evidence linking protein misfolding to other pathologies continues to emerge. Indeed, the deposition of toxic protein aggregates in the form of oligomers or large amyloid fibrils has been linked to type 2 diabetes, various types of cancer, and, in more recent years, to preeclampsia, a life-threatening pregnancy-specific disorder. While extensive physiological mechanisms are in place to maintain proteostasis, processes, such as aging, genetic factors, or environmental stress in the form of hypoxia, nutrient deprivation or xenobiotic exposures can induce failure in these systems. As such, pregnancy, a natural physical state that already places the maternal body under significant physiological stress, creates an environment with a lower threshold for aberrant aggregation. In this review, we set out to discuss current evidence of protein misfolding in pregnancy and potential mechanisms supporting a key role for this process in preeclampsia pathogenesis. Improving our understanding of this emerging pathophysiological process in preeclampsia can lead to vital discoveries that can be harnessed to create better diagnoses and treatment modalities for the disorder.

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Section: Treatmentmentioning

confidence: 99%