NEVIRAPINE METABONOMIC AND HEPATOTOXICITY IN PREGNANCY

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。最近，在HIV-1感染的孕妇中，奈韦拉平（NVP）和抗HIV药物报告了严重的肝毒性和皮疹。尚未研究NVP及其代谢产物的血液水平与肝毒性风险之间的关系。在本研究中，我们将以狒狒为模型，确定高血NVP及其代谢产物水平是否会增加妊娠期间母亲和胎儿的肝毒性风险。将总共18只妊娠狒狒平均分为三个处理组：第1组不接受NVP（对照），第2组接受5 mg/kg NVP，每日两次，第3组接受10 mg/kg NVP，每日两次。从孕龄70天开始给予奈韦拉平。将在第二和第三孕期以及分娩后四周收集母亲的四份血液样本和一小块肝脏。将在妊娠中期和妊娠晚期采集少量脐带血。分娩时采集母血、脐带血和羊水各一份样本。分娩后处死所有新生狒狒，采集一块新生肝脏，并在显微镜下检查肝损伤证据。 目前，NVP通常用于治疗孕妇的HVI感染。拟议研究的结果将确定高血液水平的NVP或其代谢产物是否会增加母体和胎儿在子宫内暴露后肝损伤的风险。生成的数据将提供必要的信息，以确定妊娠期间使用NVP的更安全剂量，并改善孕产妇和新生儿结局。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recently, serious liver toxicity and rash have been reported with nevirapine (NVP), and anti-HIV drug, in HIV-1 infected pregnant women. The relationship between the blood levels of NVP and its metabolites and the risk of liver toxicity has not been investigated. In this study using baboons as a model, we will determine if high blood levels of NVP and its metabolites may increase the risk of liver toxicity in the mother and the fetus during pregnancy. A total of 18 pregnant baboons will be equally divided into three treatment groups: group 1 will not receive NVP (control) group 2 will receive NVP at 5 mg/kg twice a day, and group 3 will receive NVP at 10 mg/kg twice a day. Nevirapine will be administered starting at day 70 gestational age. Four blood samples and a small piece of liver from the mother will be collected at 2nd and 3rd trimesters, and four weeks following delivery. A small amount of cord blood will be collected from the fetus at 2nd and 3rd trimesters. One sample each of maternal blood, cord blood, and amniotic fluid will be collected at delivery. All newborn baboons will be sacrificed following delivery and a piece of the newborn liver will be collected and reviewed under the microscope for evidence of liver damage. Currently, NVP is commonly used in the treatment o HVI infection in pregnant women. The results from the proposed study will determine if high blood levels of NVP or its metabolites may increase the risks of liver injuries in the mother and fetus following in utero exposure. The data generated will provide the needed information to establish safer dosages for NVP use during pregnancy and to improve maternal and neonatal outcomes.