Kratom alkaloid exposure during pregnancy

项目摘要/摘要 本项目由美国国立卫生研究院探索/发展研究资助项目提交，项目编号：PA- 20-195。大花木是一种原产东南亚的树种，俗称KrATOM。树叶 KrATOM及其商用产品的处方是治疗疼痛、改善情绪和缓解疼痛。 阿片类药物戒断症状。据介绍，全球有1500多万KrATOM消费者 美国，包括育龄女性。有阿片吸食史的女性使用KrATOM 治疗他们怀孕期间的疼痛和阿片类药物戒断症状，相信草药替代 对他们的孩子来说，传统的阿片类药物会更安全。根据已发表的病例报告和与新生儿的讨论 医学专家称，暴露于Krtom可能会影响胎儿发育和阿片类药物戒断症状 已在新生儿中观察到。然而，大多数在怀孕期间服用KrATOM的母亲都有 非法物质摄入，没有明确的科学证据表明KrATOM是否与戒断直接相关 新生儿的症状。迫切需要了解Krtom生物碱是否能通过胎盘屏障 并导致新生儿出现严重的戒断症状。我们认为评估宫内影响是很重要的。 不仅是三叶草和7-羟基三叶草，而且是传统的KrATOM制剂(作为冻干的 茶叶)和一种商用产品(OPMS Gold)。在大鼠身上，我们将建立胎儿暴露和代谢 三尖杉碱和代谢物以及其他主要的Krtom生物碱。我们可以同时量化11个 生物基质中的Krtom生物碱和/或三尖杉碱及其三种主要代谢物。在一个 基于药代动力学的特定目标1，我们将建立口服剂量后胎儿对Krtom生物碱的暴露 三氯硝胺、冻干茶和商业用产品(OPMS Gold)。我们会检查系统 胎儿尿液中三氢呋喃、7-羟基三氢呋喃等生物碱排泄的研究 羊水。我们将建立一个多室药动学模型来描述药物的浓度。 母亲和胎儿的时间数据。在基于药效学的特定目标2中，我们将测试子宫内暴露 Krtom生物碱的使用会导致新生儿出现戒断症状。我们将评估纳曲酮沉淀的阿片类药物 幼崽出生后立即出现戒断症状。我们还将进行免疫组织化学研究 戒断特异性生物标志物(NR2B、Arc、GFAP和C-FOS)。两年后，我们将建立直接关系 怀孕期间Krtom的摄入量与其对新生儿的影响之间的关系。如果被认为是合理的，一条毯子 在妊娠期可发出停止使用KrATOM的警告，并将进行进一步的研究 目的：探讨宫内暴露对子代长期记忆和学习能力的影响。

PROJECT SUMMARY/ABSTRACT This project is submitted under NIH Exploratory/Developmental Research Grant Program Number: PA- 20-195. Mitragyna speciosa Korth., commonly known as kratom, is a tree native to Southeast Asia. The leaves of kratom and its commercially available products are self-prescribed to treat pain, enhance mood, and mitigate opioid withdrawal symptoms. According to reports, there are more than 15 million kratom consumers in the United States, including childbearing age females. Women with a history of opioid intake consume kratom to treat their pain and opioid withdrawal symptoms during pregnancy with a belief that herbal replacement of traditional opioids will be safer for their child. According to published case reports and discussions with neonatal medicine specialists, exposure to kratom may affect fetal development and opioid withdrawal symptoms have been observed in neonates. However, most mothers that consume kratom during pregnancy have a history of illicit substance intake and there is no clear scientific evidence if kratom can be directly connected to withdrawal symptoms in newborns. There is an urgent need to understand if kratom alkaloids can cross the placental barrier and lead to serious withdrawal symptoms in newborns. We believe it is important to assess the in utero effects of not only mitragynine and 7-hydroxymitragynine, but also the traditional kratom preparation (as a lyophilized tea) and a commercially used product (OPMS Gold). In rats, we will establish the fetal exposure and metabolism of mitragynine and metabolites along with other major kratom alkaloids. We can simultaneously quantify eleven kratom alkaloids and/or mitragynine along with its three major metabolites in biological matrices. In a pharmacokinetic-based Specific Aim 1, we will establish the fetal exposure of kratom alkaloids after oral doses of mitragynine, lyophilized tea and commercially used product (OPMS Gold). We will check the systemic excretion of mitragynine, 7-hydroxymitragynine and other kratom alkaloids through fetal urine by analyzing the amniotic fluid. We will establish a multi-compartmental pharmacokinetic model to describe the concentration- time data for mothers and fetuses. In a pharmacodynamic-based Specific Aim 2, we will test if in utero exposure of kratom alkaloids leads to withdrawal symptoms in newborns. We will evaluate naltrexone precipitated opioid withdrawal symptoms in pups immediately after birth. We will also perform immunohistochemistry studies for withdrawal-specific biomarkers (NR2B, Arc, GFAP and C-fos). After 2 years, we will establish a direct relationship between kratom intake during pregnancy and its consequences on newborns. If deemed reasonable, a blanket warning can be issued to stop the use of kratom during the gestation period and further studies will be performed to evaluate the effect of in utero exposure of kratom on long-term memory and learning capacity of progeny.