Phase II Study of Nicotinamide (vitamin B3-amide) in Early-Onset Preeclampsia

烟酰胺（维生素 B3-酰胺）治疗早发性先兆子痫的 II 期研究

• 批准号: 9362186
• 负责人: Kim A Boggess
• 金额: $ 7.6万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9362186
• 关键词: ADP-ribosyl Cyclase; Abnormal placentation; Abruptio Placentae; Admission activity; Adverse event; Affect; Age; Amides; Animals; Antihypertensive Agents; Biological Assay; Blood Coagulation Disorders; Blood Platelets; Blood Pressure; Cessation of life; Clinical Research; Clinical Trials; Data; Development; Dietary Supplementation; Disease; Dose; Early treatment; Eclampsia; Endothelin-1; Environment; Enzymes; Equilibrium; FDA approved; Feasibility Studies; Fetal safety; Fetus; Foundations; Future; Gender; Goals; Hemolysis; Hepatotoxicity; Hypertension; Incidence; Infant; Kidney Failure; Knock-out; Liver; Liver Failure; Maternal Mortality; Measures; Medical; Mental disorders; Modeling; Mothers; Niacinamide; Oral; Organ; Pathway interactions; Phase; Phase II Clinical Trials; Placental Growth Factor; Pre-Eclampsia; Pregnancy; Pregnant Women; Premature Birth; Protein Tyrosine Kinase; Proteinuria; Pulmonary Edema; Reporting; Resolution; Risk; Safety; Seizures; Supplementation; Symptoms; Testing; Therapeutic; Time; Translational Research; Umbilical Cord Blood; Up-Regulation; Vascular Endothelium; Vasospasm; Water; Water-Soluble Vitamin; Weight; Woman; base; blood pressure reduction; cost; dietary supplements; early onset; endothelial dysfunction; fetal; in utero; infant morbidity; infant outcome; innovation; insight; liver function; maternal hypertension; maternal morbidity; maternal serum; mortality; mouse model; nervous system disorder; overexpression; phase 1 study; phase 2 study; pre-clinical; prenatal; pressure; prevent; public health relevance; randomized trial; skin disorder; trophoblast

ABSTRACT Preeclampsia affects 5-8% of all pregnant women and accounts for almost 15% of maternal mortality. Roughly 0.5% of preeclampsia is early onset and occurs at < 34 weeks gestation, thus annually affecting up to 20,000 U.S. women and infants. There is no treatment other than delivery. Expectant management of early onset preeclampsia (EOP) to gain in-utero time for the fetus has been reported; however half of the cases of preterm birth in women with EOP occur due to maternal complications such as development of severe hypertension or other end organ damage. It is believed that preeclampsia originates with shallow trophoblast invasion. This results in activation of the vascular endothelium with subsequent upregulation of soluble fms-tyrosine kinase (sFlt-1); stimulation of endothelin (ET)-1; and activation of ADPR-cyclase leading to potent vasocontriction. Nicotinamide is a water-soluble vitamin that inhibits ADPR-cyclase and thus acts to reduce the downstream effects of sFlt-1 upregulation. Using mouse models of preeclampsia characterized by ET-1 upregulation or abnormal placentation we show that nicotinamide reduces hypertension and proteinuria and increases maternal and fetal survival. Our phase I study of low-dose oral nicotinamide in 10 women with EOP demonstrates safety and tolerability. Building on our preclinical and phase I study findings, the objectives of this proposal are to test the effect of higher dose nicotinamide supplementation in women with EOP on maternal mean arterial pressure (MAP) and further evaluate its safety. Demonstration of beneficial effects of nicotinamide dietary supplementation on maternal BP will be the first evidence to date to support medical treatment of EOP to attempt to delay delivery. Successful completion of this proposal will guide the development of a future clinical study of this low cost, nontoxic dietary supplement for prolonging gestation in EOP. !

抽象的 先兆子痫影响 5-8% 的孕妇，占孕产妇死亡率的近 15%。大致 0.5% 的先兆子痫是早发的，发生在妊娠 < 34 周时，因此每年影响多达 20,000 人 美国妇女和婴儿。除了分娩外没有其他治疗方法。早期发病的期待治疗 据报道，先兆子痫（EOP）可延长胎儿在宫内的时间；然而，一半的早产病例 患有 EOP 的女性的分娩是由于产妇并发症（例如严重高血压或 其他终末器官损伤。据认为，先兆子痫起源于浅层滋养细胞侵袭。这 导致血管内皮细胞活化，随后可溶性 fms-酪氨酸激酶上调 (sFlt-1);刺激内皮素（ET）-1； ADPR 环化酶的激活导致有效的血管收缩。 烟酰胺是一种水溶性维生素，可抑制 ADPR 环化酶，从而减少下游 sFlt-1 上调的影响。使用以 ET-1 上调为特征的先兆子痫小鼠模型或 我们发现烟酰胺可降低高血压和蛋白尿并增加胎盘异常 母体和胎儿的存活率。我们对 10 名 EOP 女性进行低剂量口服烟酰胺的 I 期研究 表现出安全性和耐受性。基于我们的临床前和第一阶段研究结果，目标 该提案旨在测试 EOP 女性补充较高剂量烟酰胺的效果 产妇平均动脉压（MAP）并进一步评估其安全性。展示有益效果 膳食补充剂烟酰胺对孕产妇血压的影响将是迄今为止第一个支持医学的证据 治疗 EOP 试图延迟分娩。该提案的成功完成将指导 开发这种低成本、无毒膳食补充剂用于延长妊娠的未来临床研究 结束语。 ！