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

描述（由申请人提供）：孕期物质相关疾病构成了一个公共卫生问题，增加了孕产妇和新生儿发病率和死亡率的风险。药物滥用的强化与起效率和给药途径有关。我们提出了一项探索性项目，旨在测试一种新的策略，即通过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蛋白的活性，从而降低吗啡到达母体大脑和发育中的胎儿的速度和数量。该研究将使用怀孕的Sprague-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，我们已经在初步数据中表明SJW可以诱导p -糖蛋白。将进行药代动力学研究，以比较口服或静脉注射吗啡的速率和数量，与用载药剂治疗的动物相比，SJW预处理的动物在14天内到达各种组织。胎儿脑、全胎、母体脑等组织中药物暴露的变化将与相应组织中mRNA和蛋白表达的变化相关联，以确认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，利用药物转运蛋白活性的上调来同时减少母体和胎儿对阿片类药物的暴露是一种治疗怀孕成瘾者的新方法，以前没有研究过。这一探索性项目的成功完成可以为临床前数据提供基础，从而推出一种全新的治疗怀孕期间成瘾的方法。

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.