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.

项目摘要/摘要 丁丙诺啡（BUP）是阿片类药物使用障碍（OUD）的有效治疗方法；但是，用BUP治疗 怀孕期间与后代的身体依赖率高有关，并导致撤离 综合征称为新生儿戒毒综合征（NAS）。可以说，BUP目前是最好的治疗方法 怀孕期间的Oud是因为它改善了母子 - 相对于其他治疗或没有治疗的孩子的结局，但 与BUP相关的NAS的高率表明需要改进的治疗方法。了解 促进与bup相关的NA的机制可以促进改善治疗的发展。 有证据表明，胎儿暴露于主要的活性代谢产物，称为Norbuprenorphine （NORBUP），可以促进与BUP相关的NAS。而且，诺尔布普似乎没有贡献 BUP的治疗作用，表明NORBUP对于BUP治疗并不重要。因此，减少或 消除Norbup形成是改善BUP治疗的潜在策略。但是，在以上的程度 NORBUP目前有助于NAS，因为没有任何区分 BUP给药后BUP和NORBUP的影响。该建议旨在开发一种新工具， 氘化丁丙诺啡（BUP-D2），将区分Norbup和Bup的贡献 与BUP相关的NAS。初步数据表明，BUP-D2相对于bup抵抗Norbup的新陈代谢 但完全保留了bup的阿片类药物活性。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NA。本研究提出的实验将确定 慢性产前治疗bup-d2后，胎儿暴露于NORBUP是否会减少 相对于BUP，将表征阿片受体的亲和力和BUP-D2的活性。我们假设 相对于BUP，BUP-D2在怀孕期间给药时会减少胎儿暴露于Norbup 并将保留BUP的阿片类药物活动。 AIM 1将比较胎儿大脑中的Norbup浓度 在妊娠晚期妊娠后，用BUP-D2与BUP相比，在妊娠晚期收获。 AIM 1也将 测量母体血浆中母体药物，NORBUP和其他主要代谢产物的浓度 大脑，胎儿血浆和胎儿大脑，以确定是否发生了代偿性药代动力学的变化 BUP-D2给药后的化合物。 AIM 2将表征BUP-D2的亲和力和活动 使用人类MU，三角洲或Kappa阿片受体转染的CHO细胞进行体外测定的BUP。如果bup- D2减少胎儿脑暴露于Norbup并保留BUP的活性，将来将在以后的研究中使用它 确定在产前BUP治疗期间胎儿暴露于NORBUP的影响。如果确认诺布普 对胎儿执行不良影响，将研究bup-d2，以改进对OUD的潜在治疗 怀孕。