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

• 批准号: 10623275
• 负责人: Jennifer L. Herington
• 金额: $ 44.7万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-05 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623275
• 关键词: Adult; Adverse effects; Affect; Agonist; Amniotic Fluid; Aorta; Biological Assay; Birth Rate; Blood Chemical Analysis; Brain; Calcium; Calcium Signaling; Cell Separation; Cells; Cesarean section; Clinical Trials; Collection; Detection; Discipline of obstetrics; Dose; 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; Smooth Muscle Myocytes; Testing; Time; Tissues; Tocolytic Agents; Toxic effect; Uterine Contraction; Uterus; Vascular Smooth Muscle; Woman; Work; antagonist; delivery complications; drug development; drug efficacy; drug metabolism; drug repurposing; drug testing; effectiveness evaluation; fetal; fetal blood; hemodynamics; improved; in utero; in vivo; infant morbidity; infant morbidity/mortality; inhibitor; inhibitor therapy; mouse model; myometrium; neonate; novel; novel therapeutics; placental transfer; preclinical development; preclinical study; pressure; public health relevance; release of sequestered calcium ion into cytoplasm; response; screening; uterine contractility

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.

项目概要 早产 (PTB) 率持续上升，全球每年有超过 1500 万早产，约占 10% 全球活产率。所有已知 PTB 原因的共同点是子宫早期激活 宫缩。目前用于抑制子宫收缩的宫缩抑制剂因其不良的脱靶效应而受到限制 效果和获益持续时间短。因此，毫无争议地有必要发现新的宫缩抑制剂 具有更高安全性和有效性的药物。 几乎完全缺乏针对早产 (PTL) 和其他产科药物的开发 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了 由于意外的毒性或缺乏疗效而进行的临床试验。因此，目前的应用主要集中在 将 FDA 批准的现有药物重新用于新的宫缩治疗用途。我们已经通过FDA筛选 在表型子宫肌层细胞收缩力测定中收集药物，并鉴定出影响子宫肌层细胞收缩力的药物 最终共同钙 (Ca2+) 动员途径参与分娩开始。我们随后有 通过省略拮抗各种血管平滑肌中 Ca2+ 动员的药物来筛选子宫选择性 肌肉细胞，它们是当前宫缩抑制剂的非目标组织。我们的初步研究确定了 20 种热门药物 其抑制催产素诱导的细胞内 Ca2+ 信号传导的能力具有子宫选择性，因此， 收缩性。由于这些热门药物已获得 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试验 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，不会对母体和胎儿产生不良影响。在目标 1 中，我们将测试离体 使用人类子宫肌层和先导药物的宫缩功效以及胎盘转移和代谢 胎盘，分别。在目标 2 中，我们将确定先导药物对宫内收缩的体内影响 小鼠的压力、分娩时间和母胎健康状况。最后，在目标 3 中，我们将确定协同效应 调节体外人类子宫肌层收缩力的药物组合。我们的学业顺利完成 将为宫缩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 对于患有 PTL 的女性。