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

说明(申请人提供)：妊娠期间与物质有关的疾病构成一个公共卫生问题，增加了孕产妇和新生儿发病率和死亡率的风险。药物滥用的强化与行动的起始率和给药途径有关。有人提出了一个探索性项目，以测试一种新的策略，即使用天然产物圣约翰草(SJW)来增加位于血脑屏障和胎盘的外排药物转运体的活性，从而降低吗啡到达母体大脑和发育中胎儿的速度和数量。这项研究将使用怀孕的Spraogue-Dawley大鼠作为怀孕模型。吗啡是ABCB1基因产物P-糖蛋白(P-gp)的底物，我们在初步数据中表明，SJW可以诱导。将进行药代动力学研究，以比较口服或静脉注射吗啡14天的动物与使用赋形剂的动物到达不同组织的速率和数量。药物暴露在胎脑、全胎儿、母体脑和其他组织中的变化将与相应组织中mRNA和蛋白质表达的变化相关联，以确定基因转录或翻译的变化是否与药物暴露的变化相对应。据我们所知，通过上调药物转运体的活性来同时将母亲和胎儿对阿片类药物的暴露降至最低，是治疗怀孕吸毒者的一种新方法，此前尚未对其进行调查。这一探索性项目的成功完成可能为临床前数据提供基础，从而启动一种全新的方法来治疗妊娠期成瘾。 公共卫生相关性：这项临床前研究将确定是否可以通过使用一种天然产品来增加位于血脑屏障和胎盘中的外排药物转运体的活性，从而最大限度地减少吗啡到达怀孕大鼠的母体大脑和发育中的胎儿的量。这一结果将是对治疗患有阿片类药物依赖/成瘾的孕妇的一种新的药理策略的测试。

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.