A preventive pharmacotherapy for neonatal abstinence syndrome

新生儿禁欲综合征的预防性药物治疗 项目摘要/摘要 新生儿阿片类药物依赖是一个巨大的且不断增长的医学挑战。目标是 这项研究的目的是开发一种药物疗法，可以预防子宫内阿片类药物依赖 以抑制或减少新生儿戒断(新生儿禁欲综合征)。这个 这项研究影响的目标人群是接受临床控制的孕妇 疼痛管理或阿片类药物依赖(如美沙酮)的临床护理 赡养费)，以及他们的孩子。建议的疗法不能干扰 产妇痛苦/依赖的管理。为了实现这一目标，我们正在测试一个 阿片受体的外周选择性中性拮抗剂，6β-纳曲醇(60N)。 我们已经在老鼠身上证明了这种药物通过胎盘进入胎儿大脑的时间是 高水平，但相对地被血脑屏障排除在母亲的大脑之外 (Bbb)。因此，我们的治疗方法利用了未发育的胎儿血脑屏障。我们还有 表明这种药物以高水平进入发育中的小鼠大脑，直到至少 出生后第14天，该药物可以预防出生后早期依赖行为在 在吗啡给药过程中同时给药时的高效力。第一个目标是 建议对60亿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)。分区模式将发展到更好的 评估和预测药物暴露。第二个目标是对 60BN和MTD在小鼠体内的药效学(PD)，以确定60BN的剂量范围 这可防止新生儿/青少年依赖(无血脑屏障)，但不会影响母亲/成人 缓解疼痛(使用BBB)(目标1B)。最终目标是将老鼠身上的结果转化为 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60亿是否可以优先 被注射到胚胎猴子的大脑中，就像在老鼠身上一样，这是治疗的核心(目标2)。这个 该项目汇集了不同的基础研究人员和临床医生团队， 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.