Improving Outcome in Neonatal Abstinence Syndrome

改善新生儿戒断综合症的治疗效果

• 批准号: 8690003
• 负责人: Jonathan M. Davis
• 金额: $ 69.3万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690003
• 关键词: ABCB1 gene; Adult; Affect; Age; Age-Months; Agonist; Best Pharmaceuticals for Children Act; Candidate Disease Gene; Catechol O-Methyltransferase; Cells; Consensus; DNA; Data; Development; Diagnosis; Double-Blind Method; Early identification; Fetus; Functional disorder; Genes; Genetic; Genetic Variation; Genotype; Goals; Growth; Heritability; Hospitals; Incidence; Infant; Infant Development; Intervention; Length; Length of Stay; Long-Term Effects; Medical; Metabolism; Methadone; Methyltransferase Gene; Morphine; Mothers; Multi-Drug Resistance; Narcotics; National Institute of Drug Abuse; Neonatal Abstinence Syndrome; Neuraxis; Neurodevelopmental Impairment; Newborn Infant; Opiate Addiction; Opiates; Opioid; Outcome; Pathogenesis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacotherapy; Play; Pregnancy; Pregnant Women; Prenatal care; Psychotropic Drugs; Public Health; Randomized; Randomized Controlled Trials; Regimen; Resources; Role; Safety; Saliva; Severities; Single Nucleotide Polymorphism; Substance-Related Disorders; Symptoms; Therapeutic; Therapeutic Intervention; Twin Studies; Umbilical Cord Blood; United States National Institutes of Health; common treatment; design; high risk; high risk infant; improved; in utero; indexing; infant outcome; mu opioid receptors; neonate; neurobehavioral; neurodevelopment; opioid misuse; pregnant; primary outcome; prospective; public health relevance; secondary outcome; therapy development

DESCRIPTION (provided by applicant): Misuse of opioids and other psychoactive drugs during pregnancy is a significant problem in the US. Neonatal abstinence syndrome (NAS) affects most infants exposed to opioids in utero, although its expression is variable. Optimal treatment of NAS has not been established, with studies limited to short term outcomes, with longer term safety and efficacy undefined. In addition, genetic factors that may contribute to the severity of NAS have not been studied in newborns. The goals of this proposal are: 1) to demonstrate short and long term benefits of pharmacotherapy of NAS in the newborn period (leading to FDA approval) and; 2) to explore how genetic variations in narcotic metabolism and pharmacodynamics contribute to the pathogenesis of NAS. Results should significantly improve our understanding of NAS and elucidate how different therapeutic regimens can influence immediate and long term neurodevelopmental outcome. First, 184 term infants needing treatment for NAS will be randomized to receive either morphine or methadone in a double blind, double dummy design. It is hypothesized that morphine treated infants will require significantly fewer days in the hospital compared to methadone treated infants. Next, the effects of NAS treatment on infant neurodevelopment at 18 months of age will be assessed using the Bayley III Scales of Infant Development. It is hypothesized that morphine treated infants will have better neurodevelopmental outcome at 18 months compared to methadone treated infants. Finally, single nucleotide polymorphisms (SNPs) in the multi-drug resistance (MDR1), mu opioid receptor (OPRM1), and/or catechol-O-methyltransferase (COMT) genes (pharmacogenetic modulators of opioid action) will be analyzed and correlated with short term outcomes and neurodevelopment assessments to determine if genetic variation is important in the pathogenesis of NAS. Preliminary data does suggest that genetic variation does influence the incidence and severity of NAS. The results of these studies will enhance our understanding of the pathogenesis of NAS, define best treatment practices, promote early identification of those at highest risk for neurodevelopmental impairment, and facilitate targeted interventions to improve outcome in these high risk infants.

描述（由申请人提供）：在怀孕期间滥用阿片类药物和其他精神活性药物是美国的一个重大问题。新生儿禁欲综合征（NAS）会影响大多数暴露于子宫内阿片类药物的婴儿，尽管其表达是可变的。尚未建立对NAS的最佳治疗方法，其研究仅限于短期结局，长期安全性和功效不确定。此外，在新生儿尚未研究可能导致NAS严重程度的遗传因素。该提案的目标是：1）在新生儿时期证明NAS药物治疗的短期和长期益处（导致FDA批准）； 2）探索麻醉代谢和药效学的遗传变异如何有助于NAS的发病机理。结果应显着提高我们对NAS的理解，并阐明不同的治疗方案如何影响直接和长期的神经发育结果。首先，需要进行NAS治疗的184名婴儿将被随机分配，以在双盲，双假设计中接收吗啡或美沙酮。假设与美沙酮治疗的婴儿相比，接受吗啡治疗的婴儿在医院需要大量的天数。接下来，将使用婴儿发育的Bayley III量表评估NAS治疗对婴儿神经发育的影响。假设吗啡治疗的婴儿与美沙酮治疗的婴儿相比将在18个月时具有更好的神经发育结局。最后，在多药耐药性（MDR1），MU阿片受体（OPRM1）和/或Catechol-O-O-甲基转移酶（COMT）遗传（药物遗传学调节剂）中，与短期概念的概念相关的单个核苷酸多态性（SNP）将被分析，并纠正属于属性的概念，并与之相互吻合nas。初步数据确实表明遗传变异确实会影响NAS的发病率和严重性。这些研究的结果将增强我们对NAS发病机理的理解，定义最佳治疗方法，促进对神经发育障碍最高风险的最高风险的鉴定，并促进有针对性的干预措施以改善这些高风险婴儿的结果。