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

摘要 先兆子痫影响所有孕妇的5%-8%，占孕产妇死亡率的近15%。粗略地 0.5%的先兆子痫是早发性的，发生在怀孕34周时，因此每年影响多达2万人 美国妇女和婴儿。除了接生，没有其他治疗方法。早发性疾病的期待治疗 先兆子痫(EOP)为胎儿争取宫内时间已有报道；然而，有一半的早产儿病例 患有早产儿的妇女的分娩是由于母亲的并发症，如发生严重的高血压或 其他结束器官损伤。目前认为子痫前期起源于浅层滋养细胞的侵袭。这 导致血管内皮细胞激活，随后上调可溶性FMS-酪氨酸激酶 (sflt-1)；刺激内皮素(ET)-1；激活ADPR-Cyclase，导致强大的血管收缩。 烟酰胺是一种水溶性维生素，可以抑制ADPR环化酶，从而减少下游的 SFlt-1上调的作用。采用以ET-1上调为特征的子痫前期小鼠模型 异常胎盘：烟酰胺可降低高血压和蛋白尿，增加 母婴存活率。我们对10名患有EOP的妇女口服小剂量烟酰胺的I期研究 表现出安全性和耐受性。在我们的临床前和第一阶段研究结果的基础上， 这项建议是为了测试更大剂量的烟酰胺补充对患有EOP的妇女的影响 监测母体平均动脉压(MAP)，并进一步评价其安全性。对以下项目有益效果的演示 烟酰胺饮食补充对产妇血压的影响将是迄今为止支持医学的第一个证据 对试图延迟交付的EOP的处理。成功完成这项提案将指导 这种低成本、无毒、延长妊娠的膳食补充剂的未来临床研究进展 EOP。 好了！

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. !