Vanderbilt University Medical Center has received a four-year, $2.8-million federal grant to study whether drugs given to premature infants in the neonatal intensive care unit (NICU) contribute to a potentially lethal condition called patent ductus arteriosus (PDA).
The ductus arteriosus is a fetal vascular shunt connecting the pulmonary artery and aorta. If the vessel remains patent — fails to close — after birth, blood flow to the lungs may increase leading to heart failure, and peripheral blood pressure may fall, causing under-perfusion of vital organs.
Current medical treatments for PDA are frequently unsuccessful. Yet, efforts to identify new, selective vasoconstrictors that can close the ductus arteriosus overlook the possibility that other medications given in the NICU may have an inadvertent vasodilatory effect and contribute to PDA, said the grant’s principal investigator, Jeff Reese, MD.
“This will be the first time that high-throughput drug screening methods will be used to identify harmful drugs that may prevent ductus closure after birth,” Reese said. “We could not perform these complex studies without the coordinated efforts of pharmacology and physiology scientists in our lab group.”
Reese is the Mildred T. Stahlman Professor of Perinatal Research, professor of Pediatrics at VUMC and professor of Biomedical Engineering and of Cell & Developmental Biology at Vanderbilt University.
His colleagues in the study include Jennifer Herington, PhD, and Elaine Shelton, PhD, assistant professors of Pediatrics and Pharmacology, and Shajila Siricilla, PhD, a postdoctoral research fellow in the Herington lab.
Prior studies in Reese’s lab using mouse models and human data show that drugs frequently given to preterm infants, including specific antibiotics, antacids, and diuretics, have unexpected vasodilatory effects on the ductus arteriosus.
Reese and his colleagues will use mouse and human tissues to test their hypothesis that specific drug combinations act synergistically to impair postnatal closure of the ductus arteriosus.
A novel assay will be used to screen for drugs with vasodilatory effects on the vessel. The effect of these “hit” compounds will be examined in human tissue and in a large national database of preterm infants.
By identifying which drugs or drug combinations pose increased risks for PDA in preterm infants, the study should aid efforts to reduce the incidence and severity of this condition, benefiting the most vulnerable preterm infants in the NICU, the researchers said.
