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.

项目摘要/摘要 该项目根据NIH探索性/发展研究赠款计划编号：PA- 20-195。 Mitragyna Speciosa Korth。（通常称为Kratom）是东南亚的一棵树。叶子 Kratom及其市售产品是自我规定的，以治疗疼痛，增强情绪和减轻 阿片类药物戒断症状。据报道，在 美国，包括育龄女性。有阿片类药物史的妇女将kratom摄取 怀孕期间治疗他们的疼痛和阿片类药物的戒断症状，​​并认为草药的替代品 传统的阿片类药物将使他们的孩子更安全。根据已发表的案例报告和新生儿的讨论 医学专家，接触Kratom可能会影响胎儿发育，而阿片类药物戒断症状有 在新生儿中观察到。但是，大多数在怀孕期间食用kratom的母亲的病史 非法物质摄入量，没有明确的科学证据，即 新生儿的症状。迫切需要了解Kratom生物碱是否可以越过胎盘屏障 并导致新生儿的严重戒断症状。我们认为评估子宫内效应很重要 不仅是mitragynine和7-羟基甲基苯胺，而且是传统的kratom制剂（作为冻干的 茶）和商业使用的产品（OPMS黄金）。在大鼠中，我们将建立胎儿暴露和代谢 Mitragynine和代谢产物以及其他主要的Kratom生物碱。我们可以同时量化11 Kratom生物碱和/或Mitragynine及其在生物基质中的三个主要代谢产物。在 基于药代动力学的特定目标1，我们将在口服剂量后建立Kratom生物碱的胎儿暴露 Mitragynine，冻干茶和商业使用的产品（OPMS金）。我们将检查系统性 通过分析胎儿尿液，通过分析Mitragynine，7-羟基甲酸和其他Kratom生物碱的排泄。 羊水。我们将建立一个多门室药代动力学模型，以描述浓度 - 母亲和胎儿的时间数据。在基于药效的特定目标2中，我们将测试在子宫内是否暴露 Kratom生物碱导致新生儿的戒断症状。我们将评估纳曲酮沉淀阿片类药物 出生后立即出现幼崽的戒断症状。我们还将进行免疫组织化学研究 提取特异性生物标志物（NR2B，ARC，GFAP和C-FOS）。两年后，我们将建立直接关系 在怀孕期间的kratom摄入量及其对新生儿的后果之间。如果认为合理，毯子 可以发出警告以停止妊娠期间使用kratom的使用，并将进行进一步的研究 评估kratom对子宫对后代长期记忆和学习能力的影响。