A preventive pharmacotherapy for neonatal abstinence syndrome

新生儿戒断综合征的预防性药物治疗 项目总结/摘要 新生儿阿片类药物依赖是一个巨大的和不断增长的医疗挑战。目标 这项研究的目的是开发一种药物疗法，可以防止阿片类药物依赖在子宫内， 以抑制或减少新生儿戒断（新生儿戒断综合征）。的 受本研究影响的目标人群为临床控制的孕妇 疼痛管理或阿片类药物依赖（如美沙酮）的临床护理 （维护）和他们的孩子。建议的治疗不得干扰 产妇疼痛/依赖的管理。为了实现这一目标，我们正在测试一个 μ-阿片受体的外周选择性中性拮抗剂，6β-纳洛醇（6 BN）。 我们已经在小鼠中证明，药物在10分钟内穿过胎盘进入胎儿大脑。 高水平，但被血脑屏障相对排除在母体大脑之外 （BBB）。因此，我们的疗法利用了未发育的胎儿血脑屏障。我们还 表明这种药物以高水平进入发育中的小鼠大脑， 出生后第14天，药物可以预防出生后早期的依赖行为， 当在吗啡施用期间共同施用时具有高效力。的第一个进球 建议对6 BN和美沙酮进行详细的药代动力学（PK）分析 (MTD)妊娠小鼠（目标1A）。将开发房室模型，以更好地 评估和预测药物暴露。第二个目标是进行初步研究， 在小鼠中测定6 BN的药效学（PD）和MTD以确定6 BN的剂量范围 预防新生儿/青少年依赖（无BBB），但不影响母体/成人 疼痛缓解（BBB）（目的1B）。最终的目标是将小鼠的结果转化为 更适合人类新生儿发育状态的模型：即恒河猴 猴子.将启动有限的PK分析，以确定是否可以优先使用6 BN 如在小鼠中一样，递送至胎猴脑，这是治疗的核心（目的2）。的 该项目汇集了基础研究人员和临床医生的多元化团队， 互补的技能、专业知识、资源和经验，以解决这一重大问题。 社会问题。

A preventive pharmacotherapy for neonatal abstinence syndrome PROJECT SUMMARY/ABSTRACT Neonatal opioid dependence is an enormous and growing medical challenge. The goal of this study is to develop a drug therapy that can prevent opioid dependence in utero in order to suppress or reduce neonatal withdrawal (neonatal abstinence syndrome). The target population affected by this research is pregnant women under clinically controlled pain management or under clinical care for opioid dependence (such as methadone maintenance), and their babies. The proposed therapy must not interfere with management of maternal pain/dependence. To achieve this goal we are testing a peripherally-selective neutral antagonist of the mu-opioid receptor, 6β-naltrexol (6BN). We have shown in mice that the drug crosses the placenta and enters the fetal brain at high levels, but is relatively excluded from the maternal brain by the blood brain barrier (BBB). Thus our therapy takes advantage of the undeveloped fetal BBB. We have also shown that the drug enters the developing mouse brain at high levels until at least postnatal day 14, and that the drug can prevent early postnatal dependence behaviors at high potency when co-administered during morphine administration. The first goal of the proposal is to conduct a detailed pharmacokinetic (PK) analysis of 6BN and methadone (MTD) in pregnant mice (Aim 1A). Compartmental models will be developed to better assess and predict drug exposures. The second goal is to perform initial studies of the pharmacodynamics (PD) of 6BN and MTD in mice to determine a dose range of 6BN that prevents neonatal/juvenile dependence (no BBB), but does not affect maternal/adult pain alleviation (with BBB) (Aim 1B). The final goal is to translate the results in mice to a more appropriate model of the human neonatal developmental state: namely, rhesus monkey. A limited PK analysis will be initiated to determine if 6BN can be preferentially delivered to the fetal monkey brain as in mice, the core of the therapy (Aim 2). The project brings together a diverse team of basic researchers and clinicians with complementary skills, expertise, resources and experience to tackle this substantial societal problem.