Pharmacologic Contributors to Patent Ductus Arteriosus

动脉导管未闭的药理学贡献者

基本信息

批准号：
10653150
负责人：
John Jeffrey Reese
金额：
$ 72.38万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653150
关键词：
Adverse effects Affect Aminoglycosides Anemia Animals Antacids Antibiotics Aorta Area Biological Assay Birth Blood Vessels Chronic Chronic lung disease Complex Critical Illness Cyclooxygenase Inhibitors Data Databases Development Disease Diuretics Drug Combinations Drug Exposure Drug Screening Drug toxicity Drug usage Ductus Arteriosus Evaluation Exposure to Failure Furosemide Gentamicins Grant Human Hypoxia Impairment In Vitro Kidney Knowledge Legal patent Life Ligation Liquid substance Mediating Molecular Morbidity - disease rate Mus Muscle Contraction Myography Neonatal Neonatal Intensive Care Units Newborn Animals Newborn Infant Operative Surgical Procedures Patent Ductus Arteriosus Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Pharmacopoeias Phase Physiological Pregnancy Premature Infant Property Prostaglandin-Endoperoxide Synthase Prostaglandins Pulmonary artery structure Relaxation Research Risk Risk Factors Sepsis Series Shunt Device Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stimulus Testing Therapeutic Time Toxic effect Transfusion Uterus Vasoconstrictor Agents Vasodilator Agents Woman clinically relevant constriction cytotoxicity drug candidate fetal fetal blood gene network high risk infant high throughput screening human data human tissue in vivo innovation interest modifiable risk mortality mouse model neonatal human neonatal mice neonate novel permissiveness pharmacologic postnatal premature prenatal exposure pressure preterm newborn prevent screening seal skills translational potential

项目摘要

Project Summary Vascular adaptation after birth is dependent on closure of the ductus arteriosus (DA), a fetal vascular shunt connecting the pulmonary artery and aorta. Failure of DA closure results in persistent patency of the DA (PDA), a common disorder associated with increased morbidity and mortality in the most vulnerable infants. Current pharmacological treatments for PDA are limited and only focus on a single therapeutic pathway – cyclooxygenase-mediated prostaglandin (PG) synthesis. However, recent data reveal complex networks of genes and druggable pathways involved in the vasodilatory-to-vasoconstrictive shift that drives postnatal DA closure. Efforts to identify new DA-selective vasoconstrictors overlook the possibility that ongoing vasodilatory stimuli perpetuate DA relaxation and inhibit its closure. Because critically ill preterm newborns are exposed to multiple medications during the time that DA closure takes place, we postulate that pharmacologic agents used in the neonatal ICU prevent DA closure and contribute to PDA. The DA of prematurely-born infants is developmentally primed to respond to vasodilatory signals. Our prior studies using mouse models and human data show that drugs frequently used in preterm infants have unexpected vasodilatory effects on the DA, including specific antibiotics, antacids, and diuretics. These data suggest that drug-induced DA relaxation is a modifiable contributor to PDA, but this has not been systematically evaluated. We therefore hypothesize that drugs commonly used in the NICU have an adverse effect on closure of the premature DA and that specific drug combinations act synergistically to impair postnatal DA closure. Mouse and human tissues will be used to test this hypothesis in three Aims: 1) Determine whether drugs in the neonatal pharmacopeia prevent the initial phase of DA closure - smooth muscle constriction - that leads to physiologic closure of the DA lumen; 2) Determine whether drugs in the neonatal pharmacopeia impair the second phase of DA closure - fibromuscular remodeling - that leads to permanent sealing of the constricted DA; 3) Identify drug combinations that interact to adversely affect either phase of DA closure. Drug effects will be examined using primary (in vitro) high throughput screening (HTS) of preterm mouse DA smooth muscle cells. A series of secondary screening assays will prioritize single- and synergistic combinations of hits based on potency/efficacy, DA-selectivity, and toxicity for further study of their ex vivo and in vivo vasoactive effects on the DA. A novel ex vivo mouse DA-reopening assay will be used to screen for drugs of interest. The effect of hit DA-vasodilatory compounds will be examined on ex vivo human neonatal DA segments and in a large national database of preterm infants. These studies have high translational potential and will definitively identify which drugs or drug combinations pose increased risks for PDA in preterm infants, providing an innovative approach to enhance conservative PDA management efforts in the NICU.

项目概要出生后的血管适应取决于胎儿血管分流动脉导管 (DA) 的闭合连接肺动脉和主动脉 DA 闭合失败导致 DA (PDA) 持续通畅，一种常见疾病，与最脆弱婴儿的发病率和死亡率增加有关。 PDA 的药物治疗是有限的，并且只集中于单一的治疗途径 – 然而，最近的数据揭示了环加氧酶介导的前列腺素（PG）合成的复杂网络。参与驱动产后 DA 的血管扩张至血管收缩转变的基因和药物途径寻找新的 DA 选择性血管收缩剂的努力忽视了持续血管舒张的可能性。因为危重早产儿会接触到刺激，从而使 DA 持续松弛并抑制其关闭。在 DA 关闭发生期间使用多种药物，我们假设使用了药物在新生儿 ICU 中，会阻止 DA 闭合并导致 PDA。早产儿的 DA 在发育上已经做好了对血管舒张信号做出反应的准备。使用小鼠模型和人类数据的研究表明，经常用于早产儿的药物对 DA 产生意想不到的血管舒张作用，包括特定的抗生素、抗酸剂和利尿剂。表明药物诱导的 DA 松弛是 PDA 的一个可改变的因素，但这尚未得到系统的研究因此，我们认为新生儿重症监护室常用的药物对患者有不良影响。过早 DA 的闭合以及特定药物组合协同作用可损害产后 DA 闭合。将使用小鼠和人体组织来检验该假设的三个目的：1) 确定是否新生儿药典中的药物可阻止 DA 闭合的初始阶段（平滑肌收缩） 2) 确定新生儿药典中的药物是否损害 DA 闭合的第二阶段 - 纤维肌肉重塑 - 导致收缩的永久封闭 DA；3) 确定对 DA 关闭的任一阶段产生不利影响的药物组合。使用早产小鼠 DA 平滑肌的初级（体外）高通量筛选 (HTS) 进行检查一系列二次筛选测定将优先考虑基于命中的单一组合和协同组合。效力/功效、DA选择性和毒性，以进一步研究它们的离体和体内血管活性作用一种新型的离体小鼠 DA 重新开放将用于筛选感兴趣的药物。 DA 血管舒张化合物将在离体人类新生儿 DA 片段上进行检查，并在大型国家实验室中进行检查。这些研究具有很高的转化潜力，将最终确定哪些早产儿。药物组合会增加早产儿 PDA 的风险，这提供了一种创新方法加强 NICU 中保守的 PDA 管理工作。