Safety of N-acetylcysteine in Maternal Chorioamnionitis

N-乙酰半胱氨酸在孕产妇绒毛膜羊膜炎中的安全性

• 批准号: 7575081
• 负责人: DOROTHEA DENISE JENKINS
• 金额: $ 44.16万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-27 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575081
• 关键词: Acetylcysteine; Adverse effects; Adverse event; Age-Months; Animal Model; Area; Basal Ganglia; Birth; Blood Circulation; Blood Flow Velocity; Brain; Brain Injuries; Cerebral Palsy; Cerebrovascular Circulation; Cerebrum; Choline; Clinical; Clinical Trials; Data; Diffusion Magnetic Resonance Imaging; Doppler Ultrasound; Dose; Drug Kinetics; Encephalitis; Enrollment; Evaluation; Fetus; Gestational Age; Hemorrhage; Histamine; Homeostasis; Hour; Hypotension; Hypoxia; IL8 gene; Incidence; Infant; Infection; Infection of amniotic sac and membranes; Inflammation Mediators; Inflammatory; Injury; Interleukin-6; Magnetic Resonance Imaging; Measures; Monitor; Morbidity - disease rate; Mothers; Motor Cortex; Neonatal; Neurologic; Newborn Infant; Outcome; Pathogenesis; Patients; Penetration; Perfusion; Periventricular Leukomalacia; Pharmaceutical Preparations; Phase III Clinical Trials; Placenta; Plasma; Population; Pregnancy; Pregnant Women; Premature Infant; Prothrombin time assay; Reaction; Recruitment Activity; Safety; Sample Size; Sampling; Serum; Spectrum Analysis; Therapeutic Intervention; Toxic effect; Translational Research; Umbilical Cord Blood; Umbilical cord structure; base; clinical Diagnosis; cohort; cytokine; design; experience; fetal; gray matter; middle cerebral artery; neuroprotection; patient population; pilot trial; placental transfer; postnatal; pregnant; prenatal; response; white matter; white matter injury

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.

描述（由申请人提供）：宫内感染与新生儿显着的白质和灰质脑损伤有关，并且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深远的炎症性胎儿脑损伤，从而降低对缺氧缺血性损伤的耐受性。在该领域尝试的转化研究很少，因为通过胎盘和母体/胎儿循环保护胎儿大脑提出了独特的挑战。 N-乙酰半胱氨酸（NAC）是一种有前景的疗法，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，且副作用已知，但副作用似乎有限且可控。该药物在孕妇中的安全性和安全性方面拥有丰富的临床经验，并且已建立了早产儿的药代动力学数据。在这项试点试验中，我们将确定两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。该试验的一些主要目的是测量母体 PK 以及母体负荷剂量后的婴儿 PK，并利用配对的母体和脐带血估计胎盘移植。然后将分析母体和婴儿 NAC 浓度与安全性和短期疗效结果的关系，以回答以下问题：什么剂量或目标血清浓度的 NAC 对早产儿和足月儿毒性很小，以及短期疗效的证据？这些研究将生成对于成功设计后续 III 期临床试验至关重要的数据。有效且安全的神经保护疗法可能会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相当罕见，因此本次试点试验中 NAC 的评估将为进一步的最终临床试验提供重要信息。在该患者群体中使用 NAC 进行治疗干预对于胎儿神经保护的下一个具体目标将具有开创性。