Pre-clinical studies to repurpose FDA-approved drugs for tocolytic use

将 FDA 批准的药物重新用于宫缩抑制剂的临床前研究

基本信息

批准号：
10414897
负责人：
Jennifer L. Herington
金额：
$ 44.47万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-05 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10414897
关键词：
Adult Adverse effects Affect Agonist Amniotic Fluid Aorta Biological Assay Birth Rate Blood Chemical Analysis Brain Calcium Cells Cesarean section Clinical Trials Collection Detection Discipline of obstetrics Dose Drug Antagonism Drug Combinations Drug Kinetics Drug usage Ductus Arteriosus Effectiveness FDA approved Fetal Tissues Fetal health Goals Grant Health Status Heart Human In Vitro Investigation Investigational Drugs Kidney Laboratories Lead Libraries Lipopolysaccharides Live Birth Liver Lung Metabolic Metabolism Microsomes Molecular Monitor Mus Myometrial Nature Organ Outcome Outcome Study Oxytocin Pathway interactions Pb clearance Perfusion Pharmaceutical Preparations Phase I Clinical Trials Phenotype Placenta Preclinical Testing Pregnancy Pregnant Women Premature Birth Premature Labor Process Safety Series Signal Pathway Signal Transduction Smooth Muscle Myocytes Testing Time Tissues Tocolytic Agents Toxic effect Toxicology Uterine Contraction Uterus Vascular Smooth Muscle Woman Work antagonist drug development drug efficacy drug metabolism drug repurposing effectiveness evaluation fetal fetal blood hemodynamics improved in utero in vivo infant morbidity/mortality inhibitor inhibitor therapy mouse model myometrium neonate novel novel therapeutics placental transfer preclinical development preclinical study pressure public health relevance response screening uterine contractility

项目摘要

PROJECT SUMMARY Preterm birth (PTB) rates continue to increase, with over 15 million PTB/year worldwide, constituting ~10% of live births globally. The common denominator for all known causes of PTB is the early activation of uterine contractions. Current tocolytics used to inhibit uterine contractions are limited by their undesirable off-target effects and short duration of benefit. Thus, an undisputed necessity exists for discovering novel tocolytic agents with improved safety and efficacy. There is almost a complete lack of drug development for preterm labor (PTL) and other obstetric indications. In the traditional drug development process, approximately two-thirds of investigational drugs fail in clinical trials due to unexpected toxicity or lack of efficacy. Thus, the current application is centered on the repurposing of existing FDA-approved drugs for novel therapeutic tocolytic use. We have screened the FDA collection of drugs in a phenotypic uterine myometrial cell contractility assay, and identified drugs that affect a final common calcium (Ca2+)-mobilization pathway involved in the initiation of labor. We have subsequently screened for uterine selectivity by omitting drugs that antagonized Ca2+-mobilization in various vascular smooth muscle cells, which are off-target tissues of current tocolytics. Our preliminary studies identified 20 hit-drugs that are uterine selective in their ability to inhibit oxytocin-induced intracellular Ca2+-signaling, and thus, contractility. Since these hit-drugs are already FDA-approved, the majority of in vitro and in vivo drug metabolism, pharmacokinetics and toxicity studies have been performed, therefore the drugs are ready for pre- clinical studies. The goal of this application is to examine the in vitro and in vivo efficacy of FDA-approved drugs to regulate uterine contractility without adverse maternal and fetal effects. In Aim 1 we will test the ex vivo tocolytic efficacy, as well as placental transfer and metabolism, of lead-drugs using human myometrium and placenta, respectively. In Aim 2 we will determine in vivo effect of lead-drugs on intrauterine contractile pressure, timing of delivery and maternal/fetal health status in mice. Finally in Aim 3, we will identify synergistic drug combinations to regulate in vitro human myometrial contractility. The successful completion of our studies will provide valuable information for further pre-clinical development of tocolytic drugs or phase-I clinical trials for women with PTL.

项目摘要早产（PTB）的率继续增加，全球范围超过1500万PTB，构成约10％全球活产。 PTB所有已知原因的共同点是子宫的早期激活收缩。用于抑制子宫收缩的当前尿液溶剂受其不良脱靶的限制效果和福利持续时间。因此，发现新型的溶溶性存在无可争议的必要性具有提高安全性和有效性的代理商。早产（PTL）几乎完全缺乏药物开发和其他产科适应症。在传统的药物开发过程中，大约三分之二的研究药物失败了由于意外毒性或缺乏功效而进行的临床试验。因此，当前的应用程序以重新利用现有的FDA批准药物，用于新型治疗性溶性使用。我们已经筛选了FDA 在表型子宫肌层细胞收缩力测定中收集药物，并确定了影响A的药物最终常见钙（CA2+） - 涉及劳动的动员途径。我们随后通过省略在各种血管平滑中拮抗Ca2+ - 动物的药物来筛选子宫选择性肌肉细胞，是当前淋巴结剂的靶向组织。我们的初步研究确定子宫选择性具有抑制催产素诱导的细胞内Ca2+标志性的能力，因此收缩力。由于这些杀手已经批准了FDA，因此大部分体外药物和体内药物已经进行了代谢，药代动力学和毒性研究，因此这些药物已准备好临床研究。该应用的目的是检查FDA批准的药物对体外和体内功效调节子宫收缩性，而没有不良母体和胎儿影响。在AIM 1中，我们将测试离体使用人子宫和胎盘分别。在AIM 2中，我们将确定铅药物对宫内收缩的体内影响小鼠的压力，分娩时间和孕产妇/胎儿健康状况。最终在AIM 3中，我们将确定协同作用药物组合以调节体外人体肌层收缩力。我们的学习成功完成将提供有价值的信息，以进一步临时开发溶溶性药物或I期临床试验适用于PTL的女性。