Repurposing of the PDE5 inhibitor sildenafil for treatment of persistent pulmonary hypertension in neonates

Author
Poitras, Erika L.
Gust, Stephen L.
Kerr, Paul
Plane, Frances
Faculty Advisor
Date
2021
Keywords
sildenafil , cyclic GMP , neonate , nitric oxide , phosphodiesterase inhibitor , pulmonary hypertension
Abstract (summary)
Nitric oxide (NO), an important endogenous signaling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5’-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil, prolong the availability of cGMP and therefore, enhance NO-mediated signaling. PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches. Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, are summarized and then current evidence for the utility of further repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.
Publication Information
Poitras, E. L., Gust, S. L., Kerr, P.M., Plane, F. (2021). Repurposing of the PDE5 inhibitor sildenafil for treatment of persistent pulmonary hypertension in neonates. Current Medicinal Chemistry, 28, (12), pp. 2418-2437. DOI: 10.2174/0929867327666200923151924
Notes
Item Type
Article
Language
English
Rights
All Rights Reserved