NEVIRAPINE METABONOMIC AND HEPATOTOXICITY IN PREGNANCY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 最近，奈韦拉平(NVP)和抗HIV药物在感染HIV-1的孕妇中出现了严重的肝毒性和皮疹。血液中NVP及其代谢物水平与肝脏毒性风险之间的关系尚未得到研究。在这项以狒狒为模型的研究中，我们将确定在怀孕期间，血液中高水平的NVP及其代谢物是否会增加母亲和胎儿的肝脏毒性风险。共18只怀孕狒狒将被平均分成3个处理组：1组不接受NVP(对照组)，2组每天2次接受5 mg/kg的NVP，3组每天2次接受10 mg/kg的NVP。奈韦拉平将从胎龄70天开始服用。母亲的四个血液样本和一小块肝脏将在第二个和第三个三个月以及分娩后四周采集。在怀孕2、3个月时，将从胎儿身上采集少量脐带血。分娩时将分别采集一份母血、脐带血和羊水样本。所有新生的狒狒都将在分娩后被宰杀，新生儿的肝脏将被收集并在显微镜下进行检查，以寻找肝脏受损的证据。 目前，NVP是治疗孕妇HVI感染的常用药物。这项拟议研究的结果将确定血液中高水平的NVP或其代谢物是否会增加母亲和胎儿在宫内暴露后肝脏损伤的风险。产生的数据将提供所需的信息，以建立怀孕期间使用NVP的更安全剂量，并改善孕产妇和新生儿的结局。

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.