Pharmacologic Contributors to Patent Ductus Arteriosus

动脉导管未闭的药理学贡献者

• 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
• 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; 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

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.

项目摘要 出生后的血管适应取决于胎儿血管shutt的闭合（DA） 连接肺动脉和主动脉。 DA关闭失败导致DA（PDA）的持续通畅， 与最脆弱的婴儿的发病率和死亡率增加有关的常见疾病。当前的 PDA的药理学治疗有限，仅关注单一治疗途径 - 环氧合酶介导的前列腺素（PG）合成。但是，最近的数据揭示了复杂的网络 血管舒张到毒气收缩的转移涉及的基因和可吸毒的途径驱动产后DA 关闭。识别新的DA选择性血管收缩剂的努力忽略了正在进行的血管舒张的可能性 刺激会永久放松并抑制其闭合。因为重病的早产新生儿暴露于 在闭合发生的时间，多种药物，我们假设使用的药理学剂 在新生儿ICU中，防止DA关闭并促进PDA。 开发了过早出生的婴儿DA以应对血管舒张信号。我们的先验 使用小鼠模型和人类数据的研究表明，早产儿经常使用的药物具有 对DA的意外血管舒张作用，包括特定的抗生素，抗酸和利尿剂。这些数据 表明药物诱导的DA放松是PDA的可修改贡献者，但这并非系统性地造成 评估。因此，我们假设NICU中常用的药物对 过早DA的关闭和该特定药物组合协同作用以损害产后 DA关闭。小鼠和人体组织将以三个目的来检验这一假设：1）确定是否是否 新生儿药物中的药物阻止了DA闭合的初始阶段 - 平滑肌收缩 - 导致DA Lumen的生理封闭； 2）确定新生儿药物中的药物是否损害 DA闭合的第二阶段 - 纤维肌肉重塑 - 导致狭窄的永久密封 da; 3）确定与DA闭合相互作用相互作用的药物组合。药物作用会 使用早产小鼠DA平滑肌的主要（体外）高吞吐量筛选（HTS）检查 细胞。一系列辅助筛选测定将优先考虑基于命中的单一和协同组合 关于效力/有效性，DA选择性和毒性，以进一步研究其离体和体内血管活性对 DA。一种新型的离体小鼠DA-Reopesensess将用于筛查感兴趣的药物。命中的效果 DA缩减化合物将在体内的新生儿DA段和一个大的国家中进行检查 早产儿的数据库。这些研究具有很高的转化潜力，并将确定确定哪个 药物或药物组合构成早产儿的PDA风险增加，提供了一种创新的方法 增强NICU的保守PDA管理工作。