Safety of N-acetylcysteine in Maternal Chorioamnionitis

描述(申请人提供)：宫内感染与新生儿严重的脑白质和灰质损伤有关，在脑室周围白质软化和脑性瘫痪的发病机制中尤为重要。细胞因子的释放导致深远的炎症性胎儿脑损伤，这也降低了对缺氧缺血性损伤的耐受性。这方面的转化研究很少，因为通过胎盘和母体/胎儿循环保护胎儿大脑是一个独特的挑战。N-乙酰半胱氨酸(NAC)是一种很有前途的治疗方法，在绒毛膜羊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和已知的副作用，这些副作用似乎是有限的和可管理的。在孕妇的药物和安全性方面有广泛的临床经验，早产儿的药代动力学数据已经建立。在这项试点试验中，我们将确定两个队列中不同剂量增加的安全性，以调整清除量和血清浓度的预期差异。测量母亲的PK，以及母亲负荷量后婴儿的PK，以及估计配对的母亲和脐带血的胎盘转移，构成了这项试验的一些主要目标。然后将分析孕妇和婴儿的NAC浓度与安全性和短期疗效结果的关系，以回答以下问题：什么剂量或目标浓度的NAC对早产儿和足月儿的毒性和短期疗效有证据？这些研究将产生对成功设计后续第三阶段临床试验至关重要的数据。有效和安全的神经保护疗法可能会对这一人群的神经发病率产生巨大影响。由于可以在这一人群中使用的神经保护化合物非常罕见，在这项先导试验中对NAC的评估将为进一步的决定性临床试验提供重要信息。NAC在这一患者群体中的治疗干预将是下一个特定的胎儿神经保护目标的开创性进展。

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.