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

项目摘要 早产（PTB）率继续增加，全世界每年超过1500万例PTB，占总人口的约10%。 全球范围内的活产。所有已知的PTB病因的共同点是子宫内膜异位症的早期激活。 宫缩目前用于抑制子宫收缩的宫缩抑制剂受到其不期望的脱靶限制 效果好，受益时间短。因此，发现新的保胎药存在着无可争议的必要性 具有改进的安全性和有效性的药剂。 几乎完全缺乏用于早产（PTL）和其他产科疾病的药物开发。 迹象。在传统的药物开发过程中，大约三分之二的研究药物失败， 临床试验由于意外的毒性或缺乏疗效。因此，当前的应用集中在 将现有FDA批准的药物重新用于新的治疗性保胎用途。我们筛选了食品药品管理局 在表型子宫肌层细胞收缩性测定中收集药物，并鉴定影响子宫肌层细胞收缩性的药物。 最后共同钙（Ca 2+）动员途径参与劳动的开始。我们随后 筛选子宫的选择性，通过省略药物，拮抗钙动员在各种血管平滑肌 肌肉细胞，其是当前宫缩抑制剂的脱靶组织。我们的初步研究确定了20种热门药物 其在抑制催产素诱导的细胞内Ca 2+信号传导的能力方面是子宫选择性的，因此， 收缩性由于这些热门药物已经获得FDA批准，因此大多数体外和体内药物 已经进行了代谢、药代动力学和毒性研究，因此药物已准备好进行预处理。 临床研究。 本申请的目的是检查FDA批准的药物的体外和体内功效， 调节子宫收缩力，对母体和胎儿无不良影响。在目标1中，我们将测试离体 使用人子宫肌层的铅药物的宫缩抑制功效以及胎盘转移和代谢， 胎盘，分别。在目的2中，我们将确定体内铅药物对子宫内收缩的影响， 压力、分娩时间和小鼠的母体/胎儿健康状况。最后，在目标3中，我们将确定 调节体外人子宫肌层收缩性的药物组合。顺利完成学业 将为保胎药物的进一步临床前开发或I期临床试验提供有价值的信息 对于PTL的女性。

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.