Prevention of Neonatal Abstinence Syndrome

描述(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，这对怀孕的母亲和她们的婴儿造成了后果。在加利福尼亚州，产妇在分娩时使用阿片类药物的流行率约为1%。新生儿禁欲综合征(NAS)是一系列麻醉药物戒断症状，42%到94%的母亲依赖毒品的婴儿会出现这种症状。对于这种严重的综合征，没有预防性的治疗，这可能导致长时间的住院和在新生儿重症监护病房的治疗。基于一项基因发现，我们证明了在小鼠和人类的实验研究中，给予5-HT3拮抗剂(恩丹西酮)可以预防麻醉药物戒断的症状。由此，我们假设，在分娩前对服用麻醉剂的怀孕母亲服用恩丹西酮，然后对新生儿服用为期3天的恩丹西酮，可以降低NAS症状的发生率或严重性。恩丹西酮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恩丹西酮药代动力学的影响，也很难预测出生时恩丹西酮的药代动力学。因此，我们将首先对恩丹西酮在孕妇和新生儿中的药代动力学进行详细的描述。除了提供有关孕期和新生儿药物代谢差异的重要信息外，这些结果还将确保在随后的疗效研究中选择合适的昂丹西酮剂量用于母亲和新生儿的治疗。在这项研究的第二部分，我们将进行一项多中心、随机、双盲和安慰剂对照试验，以确定昂丹西酮治疗是否会降低服用麻醉药的母亲所生婴儿的NAS的发生率(需要麻醉药物治疗的婴儿的百分比)或严重程度(所需麻醉药物的总量、住院时间、症状严重程度评分)。该项目测试了一种非常新的方法，用于预防麻醉药物滥用引起的与怀孕有关的重要并发症。如果对使用麻醉药的母亲及其婴儿进行短暂的恩丹西酮给药，可以预防或改善新生儿的麻醉药物戒断症状，这将减少人类的痛苦和阿片剂滥用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.