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

项目总结 早产率继续上升，全世界每年有1500多万早产，约占10%。 全球活产儿的数量。所有已知的肺结核病因的共同点是子宫的早期激活 宫缩。目前用于抑制子宫收缩的宫缩药物受到其不良脱靶作用的限制。 效果和受益期限较短。因此，发现新奇的宫缩存在着无可争辩的必要性。 具有更高安全性和有效性的药物。 几乎完全缺乏针对早产和其他产科疾病的药物开发。 有迹象表明。在传统的药物开发过程中，大约三分之二的研究药物未能通过 由于意外毒性或缺乏疗效而进行的临床试验。因此，当前应用程序以 改变现有FDA批准的药物的用途，用于治疗宫缩的新用途。我们已经筛选了FDA 在表型子宫肌层细胞收缩试验中收集药物，并确定影响 最终共同的钙(Ca~(2+))动员途径参与启动分娩。我们随后有了 通过省略拮抗多种血管内钙动员的药物来筛选子宫选择性 肌肉细胞，这是目前产后酵母菌的非靶标组织。我们的初步研究确定了20种热门药物 它们在抑制催产素诱导的细胞内钙信号的能力上具有选择性，因此， 伸缩性。由于这些热门药物已经获得了FDA的批准，大多数体外和体内药物 新陈代谢、药代动力学和毒性研究已经完成，因此这些药物可以在 临床研究。 这项应用的目标是检查FDA批准的药物的体外和体内疗效，以 调节子宫收缩能力，不会对母体和胎儿产生不良影响。在目标1中，我们将测试体外实验 人子宫肌层铅药物的宫缩效果，以及胎盘的转移和代谢 分别为胎盘。在目标2中，我们将确定体内含铅药物对宫内收缩的影响。 压力、分娩时间和小鼠的母婴健康状况。最后，在目标3中，我们将确定协同 体外调节人子宫肌层收缩能力的药物组合。我们的学业圆满完成 将为宫缩解药的进一步临床前开发或I期临床试验提供有价值的信息 对于患有PTL的女性来说。

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.