Use of precision deuteration to determine the contribution of norbuprenorphine to buprenorphine-associated neonatal abstinence syndrome

使用精密氘化确定去甲丁丙诺啡对丁丙诺啡相关新生儿戒断综合征的影响

• 批准号: 9980838
• 负责人: Lisa Kaye Brents
• 金额: $ 19万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980838
• 关键词: Acute; Adenylate Cyclase; Adverse effects; Affinity; Agonist; Analgesics; Blood; Brain; Buprenorphine; Charge; Child; Chinese Hamster Ovary Cell; Chronic; Cleaved cell; Data; Development; Dose; Drug Kinetics; Epidemic; Estrogen receptor positive; Exhibits; Exposure to; Female; Female of child bearing age; Fetal Development; Fetal Tissues; Fetus; Funding; Future; GTP-Binding Proteins; Glucuronides; Goals; Harvest; Human; Implant; In Vitro; Incidence; Life; Liquid Chromatography; Long-Term Effects; Measures; Metabolism; Modeling; Modification; Monitor; Mothers; Neonatal Abstinence Syndrome; Newborn Infant; Opiate Addiction; Opioid; Opioid Receptor; Outcome; Parents; Personal Satisfaction; Pharmaceutical Preparations; Physical Dependence; Plasma; Positioning Attribute; Pregnancy; Pregnant Women; Property; Rattus; Research; Research Personnel; Role; Severities; Site; Structure; Substance Withdrawal Syndrome; Testing; Therapeutic; Therapeutic Effect; Time; Umbilical cord structure; Withdrawal; Work; addiction; base; buprenorphine treatment; chemical bond; cognitive function; cost; effective therapy; experimental study; fetal; improved; in vitro Assay; kappa opioid receptors; medication-assisted treatment; mu opioid receptors; offspring; opioid abuse; opioid therapy; opioid treatment program; opioid use disorder; osmotic minipump; pregnant; prenatal; prenatal exposure; subcutaneous; tandem mass spectrometry; tool; treatment duration; treatment strategy

PROJECT SUMMARY/ABSTRACT Buprenorphine (BUP) is an effective treatment for opioid use disorder (OUD); however, treatment with BUP during pregnancy is associated with a high rate of physical dependence in offspring and leads to a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Arguably, BUP is currently the best treatment for OUD during pregnancy because it improves maternal—child outcomes relative to other or no treatments, but the high rate of NAS associated with BUP indicates that improved treatments are needed. Understanding the mechanisms that promote BUP-associated NAS can facilitate the development of improved treatments. Evidence suggests that fetal exposure to a major active metabolite of BUP, called norbuprenorphine (NorBUP), may promote BUP-associated NAS. Moreover, NorBUP does not appear to contribute to the therapeutic effects of BUP, indicating that NorBUP is not vital for BUP treatment. Therefore, reducing or eliminating NorBUP formation is a potential strategy to improve BUP treatment. However, the degree to which NorBUP contributes to NAS is currently undefined because there have been no means to distinguish the effects of BUP and NorBUP following BUP administration. This proposal seeks to develop a new tool, deuterated buprenorphine (BUP-D2), that will distinguish the contributions of NorBUP and BUP in BUP-associated NAS. Preliminary data suggests that BUP-D2 resists metabolism to NorBUP relative to BUP but fully retains the opioid activity of BUP. These properties will elucidate whether fetal exposure to NorBUP substantially contributes to BUP-associated NAS. The experiments proposed in this study will determine whether fetal exposure to NorBUP is reduced following chronic prenatal treatment with BUP-D2 relative to BUP, and will characterize opioid receptor affinity and activity of BUP-D2. We hypothesize that relative to BUP, BUP-D2 will decrease fetal exposure to NorBUP when administered during pregnancy and will retain the opioid activity of BUP. Aim 1 will compare concentrations of NorBUP in fetal brains harvested during late gestation following chronic prenatal treatment with BUP-D2 versus BUP. Aim 1 also will measure concentrations of parent drugs, NorBUP, and other major metabolites in maternal plasma, maternal brain, fetal plasma, and fetal brain to determine if compensatory pharmacokinetics changes occur with these compounds following BUP-D2 administration. Aim 2 will characterize the affinity and activity of BUP-D2 versus BUP with in vitro assays using CHO cells transfected with human mu, delta, or kappa opioid receptors. If BUP- D2 reduces fetal brain exposure to NorBUP and retains the activity of BUP, it will be used in future studies to determine the impact of fetal exposure to NorBUP during prenatal BUP treatment. If NorBUP is confirmed to exert adverse effects on the fetus, BUP-D2 will be investigated as a potential improved therapy for OUD during pregnancy.

项目总结/摘要 丁丙诺啡（BUP）是阿片类药物使用障碍（OUD）的有效治疗;然而， 在怀孕期间与后代的身体依赖率高，并导致退出 新生儿戒断综合征（NAS）。可以说，BUP是目前最好的治疗方法， 妊娠期间使用OUD，因为相对于其他治疗或无治疗，它改善了母婴结局， 与BUP相关的高NAS率表明需要改进治疗。了解 促进BUP相关NAS的机制可以促进改进治疗的发展。 有证据表明，胎儿暴露于BUP的主要活性代谢物，称为去甲丁丙诺啡， （NorBUP），可以促进BUP相关的NAS。此外，NorBUP似乎并不有助于 BUP的治疗效果，表明NorBUP对于BUP治疗不是至关重要的。因此，减少或 消除NorBUP形成是改善BUP治疗的潜在策略。然而， NorBUP对NAS的贡献目前尚未定义，因为没有办法区分 BUP给药后BUP和NorBUP的作用。该提案旨在开发一种新的工具， 氘代丁丙诺啡（BUP-D2），这将区分NorBUP和BUP的贡献， BUP关联NAS。初步数据表明，相对于BUP，BUP-D2抵抗NorBUP的代谢 但完全保留了BUP的阿片样活性。这些特性将阐明胎儿是否暴露于NorBUP 基本上有助于与BUP相关的NAS。本研究中提出的实验将确定 BUP-D2长期产前治疗后胎儿暴露于NorBUP是否减少 相对于BUP，并将表征阿片受体亲和力和BUP-D2的活性。我们假设 相对于BUP，BUP-D2在妊娠期间给药时将减少胎儿对NorBUP的暴露 并将保留BUP的阿片活性。目的1将比较胎仔脑中NorBUP的浓度 在妊娠晚期用BUP-D2与BUP进行长期产前治疗后收获。Aim 1还将 测量母体血浆中母体药物、NorBUP和其他主要代谢物的浓度，母体 脑、胎仔血浆和胎仔脑，以确定这些药物是否发生代偿性药代动力学变化。 BUP-D2给药后的化合物目的2将表征BUP-D2与BUP-D3的亲和力和活性。 使用转染人μ、δ或κ阿片样受体的CHO细胞进行体外测定的BUP。如果BUP- D2减少了胎儿大脑对NorBUP的暴露，并保留了BUP的活性，它将用于未来的研究， 确定产前BUP治疗期间胎儿暴露于NorBUP的影响。如果NorBUP被确认为 对胎儿产生不良影响，将研究BUP-D2作为OUD的潜在改进疗法， 怀孕