St. John's wort for Drug Abuse Treatment During Pregnancy

描述（由申请方提供）：妊娠期物质相关疾病构成了一个公共卫生问题，孕产妇和新生儿发病率和死亡率风险增加。滥用药物的强化与起效速度和给药途径有关。一个探索性的项目，提出了测试一种新的策略，即通过使用圣约翰草（SJW），一种天然产物，以增加位于血脑屏障和胎盘的外排药物转运蛋白的活性，可以减少到达母体大脑和发育中的胎儿的吗啡的速率和量。这项研究将使用怀孕的Sprague-Dawley大鼠作为怀孕模型。吗啡是ABCB 1基因产物P-糖蛋白（P-gp）的底物，我们已经在初步数据中显示了它可以被SJW诱导。将进行药代动力学研究，以比较与用溶剂处理的动物相比，经口或静脉内施用的吗啡到达用SJW预处理14天的动物的各种组织的速率和量。胎儿脑、全胎儿、母体脑和其他组织的药物暴露变化将与相应组织中mRNA和蛋白质表达的变化相关，以确认基因转录或翻译的变化是否对应于药物暴露的变化。使用药物转运蛋白活性的上调，同时减少母体和胎儿暴露于阿片类药物是一种新的方法来治疗怀孕的成瘾者，以前没有调查，据我们所知。成功完成这一探索性项目可以为临床前数据奠定基础，从而推出一种全新的治疗妊娠期成瘾的方法。 公共卫生相关性：这项临床前研究将确定是否可以使用天然产品来增加位于血脑屏障和胎盘中的外排药物转运蛋白的活性，从而最大限度地减少到达妊娠Sprague-Dawley大鼠中母体脑和发育中胎儿的吗啡量。结果将是一个新的药理学策略治疗孕妇阿片类药物依赖/成瘾的测试。

DESCRIPTION (provided by applicant): Substance related disorders in pregnancy constitute a public health problem with increased risk of maternal and neonatal morbidity and mortality. Reinforcement from drugs of abuse is related to the rate of onset of action and route of administration. An exploratory project is proposed to test a novel strategy that the rate and amount of morphine reaching the maternal brain and the developing fetuses can be reduced by using St Johns wort (SJW), a natural product, to increase the activity of efflux drug transporters located in the blood brain barrier and placenta. The research will use pregnant Sprague-Dawley rats as a model for pregnancy. Morphine is a substrate of the ABCB1 gene product, P-glycoprotein (P-gp), that we have shown in preliminary data can be induced by SJW. Pharmacokinetic studies will be performed to compare the rate and amount of morphine, administered either orally or intravenously, reaching various tissues in animals pre-treated with SJW for fourteen days compared to animals treated with vehicle. Changes in drug exposure to fetal brain, whole fetus, maternal brain, and other tissues will be correlated with changes in mRNA and protein expression in corresponding tissues to confirm whether changes in gene transcription, or translation, correspond to changes in drug exposure. Using up-regulation of drug transporter activity to simultaneously minimize maternal and fetal exposure to an opioid is a novel approach to treatment of the pregnant addict that has not been previously investigated, to our knowledge. Successful completion of this exploratory project could provide a foundation of pre-clinical data from which to launch an entirely new approach to treatment of addiction during pregnancy. PUBLIC HEALTH RELEVANCE: This preclinical study will determine if the amount of morphine that reaches the maternal brain and developing fetus in pregnant Sprague-Dawley rats can be minimized with the use of a natural product to increase the activity of efflux drug transporters located in the blood brain barrier and the placenta. The results will be a test of a novel pharmacological strategy for treatment of pregnant women with opioid dependence/addiction.