Prevention of Neonatal Abstinence Syndrome

描述（由申请人提供）：滥用阿片类药物成瘾已成为美国增长最快的毒品问题，这对孕妇及其婴儿产生了影响。在加州，产妇在分娩时使用阿片类药物的比例约为1%。新生儿戒断综合征（NAS）是一系列的麻醉药物戒断症状，在依赖麻醉药物的母亲所生的婴儿中，有42%至94%的婴儿会出现这种症状。目前还没有针对这种严重综合征的预防性治疗方法，这可能导致长期住院和在新生儿重症监护病房治疗。基于遗传发现，我们在小鼠和人类的实验研究中证明，施用5-HT3拮抗剂（昂丹司琼）可以预防麻醉药物戒断症状。由此，我们假设在分娩前给服用麻醉药的孕妇服用昂丹司琼，然后给新生儿服用昂丹司琼3天，可以降低NAS症状的发生率或严重程度。昂丹司琼是一种广泛使用的药物，在孕妇中有大量的安全记录，但我们不知道怀孕对昂丹司琼的药代动力学有什么影响，而且很难预测出生时的昂丹司琼药代动力学。因此，我们将首先对孕妇和新生儿的昂丹司琼药代动力学进行详细的表征。除了提供妊娠期和新生儿药物代谢差异的重要信息外，这些结果将确保在随后的疗效研究中选择合适的昂丹司琼剂量用于治疗母亲和新生儿。在本研究的第二部分，我们将进行一项多中心、随机、双盲、安慰剂对照试验，以确定昂丹西琼治疗是否会降低使用麻醉药母亲所生婴儿NAS的发生率（需要麻醉药物治疗的婴儿百分比）或严重程度（所需麻醉药物总量、住院时间、症状严重程度评分）。该项目测试了一种非常新颖的方法，用于预防与麻醉药品滥用有关的一种重要妊娠并发症。如果使用麻醉药品的母亲及其婴儿在短时间内服用昂丹司琼，可以预防或改善新生儿出现的麻醉药品戒断症状，这将减少人类的痛苦和阿片类药物滥用带来的日益增长的社会成本。

DESCRIPTION (provided by applicant): The misuse of an addiction to opioid medications has become the most rapidly increasing drug problem in the US, which has consequences for pregnant mothers and their babies. The prevalence of maternal opioid drug use at the time of delivery in California is approximately one percent. The neonatal abstinence syndrome (NAS) is a constellation of narcotic drug withdrawal symptoms that develops in 42 to 94 percent of infants born to narcotic dependent mothers. There are no preventative treatments for this severe syndrome, which can result in a prolonged hospitalization and treatment in a neonatal intensive care unit. Based upon a genetic discovery, we demonstrated that administration of a 5-HT3 antagonist (ondansetron) prevented the symptoms of narcotic drug withdrawal in experimental studies in mice and in humans. From this, we hypothesize that ondansetron administration to pregnant narcotic-using mothers just prior to delivery, followed by a 3-day period of ondansetron administration to the neonate, could reduce the incidence or severity of NAS symptoms. Ondansetron is a broadly utilized drug with a substantial safety record in pregnant women, but we do not know what effect pregnancy may have on ondansetron pharmacokinetics and it is hard to predict ondansetron pharmacokinetics at birth. Therefore, we will first perform a detailed characterization of ondansetron pharmacokinetics in pregnant mothers and in neonates. Besides providing important information about differences in drug metabolism during pregnancy and in neonates, these results will ensure that appropriate ondansetron doses are selected for treatment of the mothers and neonates in the subsequent efficacy study. In the second part of this study, we will conduct a multi-center, randomized, double blind, and placebo-controlled trial to determine whether ondansetron treatment will reduce the incidence (percentage of infants requiring narcotic drug treatment) or severity (total amount of narcotic drug required, length of hospitalization, symptom severity scores) of NAS in babies born to narcotic-using mothers. This project tests a very novel approach for preventing an important pregnancy-related complication of narcotic drug abuse. If a brief period of ondansetron administration to the mothers that use narcotic drugs, and to their babies, can prevent or ameliorate the development of narcotic drug withdrawal symptoms in neonates, this would reduce human suffering and the growing societal cost of opiate abuse.