NEVIRAPINE METABONOMIC AND HEPATOTOXICITY IN PREGNANCY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。最近，有报道称奈韦拉平（NVP）和抗hiv药物在感染HIV-1的孕妇中出现严重的肝毒性和皮疹。血液中NVP及其代谢物水平与肝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，我们将确定高血液水平的NVP及其代谢物是否会增加怀孕期间母亲和胎儿肝脏毒性的风险。将18只怀孕狒狒平均分为三个治疗组：第一组不接受NVP（对照），第二组每天接受5 mg/kg的NVP，第三组每天两次接受10 mg/kg的NVP。奈韦拉平将在妊娠70天开始使用。在妊娠二、晚期和分娩后四周采集母亲的四份血样和一小块肝脏。少量脐带血将被收集从胎儿在第二和第三个月。分娩时采集产妇血、脐带血和羊水各一份。所有新生狒狒将在分娩后被处死，并收集一块新生的肝脏，在显微镜下检查肝脏损伤的证据。目前，NVP通常用于治疗孕妇的hiv感染。拟议研究的结果将确定高血液水平的NVP或其代谢物是否会增加母体和胎儿在子宫内接触后肝脏损伤的风险。所产生的数据将提供必要的信息，以确定怀孕期间使用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.