Kratom alkaloid exposure during pregnancy

怀孕期间卡痛生物碱暴露

• 批准号: 10592472
• 负责人: Abhisheak Sharma
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592472
• 关键词: Adrenergic Agents; Affect; Agonist; Alkaloids; Amniotic Fluid; Behavior; Behavioral; Behavioral Model; Belief; Biological; Biological Markers; Birth; Brain; Case Study; Child; Clinical; Clinical Treatment; Coffee; Consumption; Data; Development; Dose; Drug Kinetics; Excretory function; Exposure to; FOS gene; Family; Female of child bearing age; Fetal Development; Fetal Tissues; Fetus; Freeze Drying; Glial Fibrillary Acidic Protein; Guidelines; Herbal supplement; Hospitalization; Human; Immunohistochemistry; Infant; Ingestion; Intake; Learning; Measures; Medicine; Metabolism; Methods; Mitragyna; Modeling; Moods; Morphine; Mothers; Naltrexone; Natural Products; Neonatal; Neonatal Abstinence Syndrome; Newborn Infant; Opiate Addiction; Opioid; Opioid agonist; Oral; Outcome; Oxycodone; Pain; Pharmaceutical Preparations; Pharmacodynamics; Phosphorylation; Plants; Plasma; Pregnancy; Pregnant Women; Preparation; Prevalence; Protocols documentation; Publishing; Rattus; Recording of previous events; Reporting; Research Project Grants; Risk; Rubiaceae; Societies; Southeastern Asia; Specialist; Tea; Teratogenic effects; Teratogens; Testing; Time; Training; Trees; Ultrasonics; United States; United States National Institutes of Health; Urine; Withdrawal; Withdrawal Symptom; Woman; Work; behavioral study; blind; capsule; clinical diagnosis; developmental toxicity; fetal; illicit opioid; in utero; in vivo; long term memory; manufacture; mu opioid receptors; multidisciplinary; neonatal human; neonate; offspring; opioid use; opioid withdrawal; pediatrician; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pharmacologic; post pregnancy; pre-clinical; pregnant; prenatal exposure; prescription opioid; programs; pup; receptor; sex; specific biomarkers; vocalization

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.

项目总结/摘要 该项目是根据美国国立卫生研究院探索/发展研究资助计划编号：PA- 20-195.美帽菊，通常被称为kratom，是一种原产于东南亚的树木。树叶 的kratom及其市售产品是自我处方治疗疼痛，增强情绪，并减轻 阿片类药物戒断症状据报道，目前有超过1500万kratom消费者， 美国，包括育龄女性。有阿片类药物摄入史的女性消费kratom， 治疗他们的疼痛和阿片类药物戒断症状在怀孕期间，相信草药替代 传统的阿片类药物对他们的孩子更安全。根据已发表的病例报告和与新生儿的讨论， 医学专家，接触kratom可能会影响胎儿发育和阿片类药物戒断症状， 在新生儿中观察到。然而，大多数在怀孕期间食用kratom的母亲都有 非法物质的摄入，没有明确的科学证据，如果kratom可以直接连接到退出 新生儿的症状。迫切需要了解Kratom生物碱是否可以穿过胎盘屏障 并导致新生儿出现严重的戒断症状我们认为评估子宫内的影响是很重要的 不仅是mitragynine和7-hydroxymitragynine，而且还有传统的kratom制剂（作为冻干的 茶）和商业上使用的产品（OPMS Gold）。在大鼠中，我们将建立胎儿暴露和代谢 mitragynine和代谢物沿着与其他主要kratom生物碱。我们可以同时量化11个 Kratom生物碱和/或mitragynine沿着及其在生物基质中的三种主要代谢物。中 基于药代动力学的具体目标1，我们将确定口服给药后kratom生物碱的胎仔暴露量 的mitragynine，冻干茶和商业使用的产品（OPMS金）。我们会检查系统 通过分析胎儿尿中的mitragynine，7-hydroxymitragynine和其他kratom生物碱的排泄， 羊水我们将建立一个多房室药代动力学模型来描述浓度- 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 kratom生物碱导致新生儿出现戒断症状。我们将评估纳洛酮沉淀阿片类药物 幼鼠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（NR 2B、Arc、GFAP和C-fos）。2年后，我们将建立直接关系 怀孕期间摄入kratom及其对新生儿的影响之间的关系。如果认为合理， 可以发出警告，在妊娠期停止使用kratom，并将进行进一步的研究 评估子宫内暴露kratom对后代长期记忆和学习能力的影响。