Safety of N-acetylcysteine in Maternal Chorioamnionitis

描述（由申请人提供）：宫内感染与新生儿明显的白色和灰质脑损伤相关，在脑室周围白质软化和脑瘫的发病机制中尤其重要。细胞因子的释放会导致影响深远的炎性胎儿脑损伤，这也会降低对缺氧缺血性损伤的耐受性。在这一领域很少进行转化研究，因为通过胎盘和母体/胎儿循环保护胎儿大脑提出了独特的挑战。N-乙酰半胱氨酸（NAC）是一种有前途的治疗方法，在绒毛膜炎动物模型中显示出有效的神经保护作用，并且具有良好的安全性，已知副作用似乎是有限的和可管理的。在妊娠母亲中具有广泛的药物和安全性临床经验，并已建立了早产儿的药代动力学数据。在这项初步试验中，我们将确定2个队列中不同剂量递增的安全性，以调整清除率和血清浓度的预期差异。测量母体PK以及母体负荷剂量后的婴儿PK，并估计配对母体和脐带血的胎盘转移，包括本试验的一些主要目的。然后将分析母体和婴儿NAC浓度与安全性和短期疗效结局的关系，以回答以下问题：什么剂量或目标血清浓度的NAC在早产儿和足月儿中几乎没有毒性和短期疗效的证据？这些研究将产生成功设计后续III期临床试验所必需的数据。有效和安全的神经保护疗法可能对这一人群的神经系统发病率产生巨大影响。由于可用于该人群的神经保护化合物非常罕见，因此在该初步试验中对NAC的评价将为进一步确定性临床试验提供重要信息。NAC在这一患者人群中的治疗干预对于胎儿神经保护的下一个具体目标将是开创性的。

DESCRIPTION (provided by applicant): Intrauterine infection is associated with significant white and grey matter brain injury in newborns and is particularly important in the pathogenesis of periventricular leukomalacia and cerebral palsy. Cytokine release causes far-reaching inflammatory fetal brain injury, which reduces tolerance for hypoxic ischemic injury as well. Very little translational research has been attempted in this area, because protecting the fetal brain through the placenta and the maternal/fetal circulations presents unique challenges. N-acetylcysteine (NAC) is a promising therapy that has shown effective neuroprotection in the animal model of chorioamnionitis, and has a favorable safety profile with known side effects, which appear to be limited and manageable. There is extensive clinical experience with the drug and safety in pregnant mothers and pharmacokinetic data in preterm infants have been established. In this pilot trial we will determine the safety of eifferent dose escalations in the 2 cohorts to adjust for expected differences in clearance and serum concentrations. Measuring maternal PK, as well as infant PK after a maternal loading dose, and estimating placental transfer with paired maternal and cord blood comprise some of the main aims of this trial. Maternal and infant NAC concentrations will then be analyzed for relationship to safety and short term efficacy outcomes to answer the question, what doses or target serum concentrations of NAC have little toxicity and evidence of short term efficacy in preterm and term infants? These studies will generate data which are essential for successful design of a subsequent phase III clinical trial. Neuroprotective therapies which are effective and safe could have a huge impact on neurologic morbidity in this population. As neuroprotective compounds which can be used in this population are quite rare, the evaluation of NAC in this pilot trial will contribute important information for further definitive clinical trials. Therapeutic intervention with NAC in this patient population will be groundbreaking for the next specific aim of fetal neuroprotection.