Pharmacology of Drugs of Abuse During Pregnancy

怀孕期间滥用药物的药理学

基本信息

批准号：
10688212
负责人：
JASHVANT D Unadkat
金额：
$ 153.99万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10688212
关键词：
18 year old Address Adolescence Affect American Animals Brain CNR1 gene Cannabinoids Cannabis Cells Child Clinical Trials Consensus Consumption Controlled Clinical Trials Data Development Discipline of obstetrics Dose Drug Kinetics Drug Transport Ethics Exposure to Fetal Liver Fetus Frequencies Funding Future Gestational Age Glucuronides Goals Gynecology Human Impairment In Vitro Infant Infection Inhalation Knowledge Link Marijuana Maternal Exposure Mental disorders Meta-Analysis Metabolic Metabolism Methods Molecular Profiling Morbidity - disease rate Mus Neurologic Neurons Odds Ratio Organ Outcome Perfusion Pharmaceutical Preparations Pharmacology Placenta Plasma Pregnancy Pregnant Women Prevalence Proteomics Public Health Race Recommendation Risk Rodent Schizophrenia Schools Signal Transduction System THC concentration Testing Tetrahydrocannabinol Tissues Tobacco Toxic effect United States National Institutes of Health Visual attention adverse outcome age related animal data axon growth clinically relevant college data integration design developmental neurotoxicity drug disposition drug of abuse fetal fetal marijuana exposure human data illicit drug use in vivo innovation marijuana use marijuana use in pregnancy maternal marijuana use metabolome metabolomics models and simulation neonatal death neonatal morbidity neonatal outcome novel perpetrators pharmacokinetic model physiologically based pharmacokinetics placental transfer pregnant prenatal prenatal exposure programs risk prediction statistics tool unethical visual memory

项目摘要

Use of marijuana (cannabis) among pregnant women in the US is increasing with prevalence as high as 14% among 12–18 year old pregnant women. The American College of Obstetrics and Gynecology recommends that pregnant women avoid marijuana due to evidence that it affects the fetus and may interfere with brain development. Studies in animals appear to support this recommendation. Although other constituents of marijuana cannot be discounted, the general scientific consensus is that ∆9-tetrahydrocannabinol (THC), the most abundant and psychoactive component in marijuana, is the likely perpetrator of the developmental neurotoxicity of marijuana. However, these animal and in vitro studies were conducted at high THC doses or concentrations and therefore their applicability to humans, where THC plasma concentrations are sub-micromolar, is unknown. On the other hand, human data on fetal and infant developmental outcomes due to marijuana use during pregnancy are limited, confounded by other factors and remain controversial. Conducting a controlled clinical trial to determine if marijuana results in negative fetal/neonatal outcomes is unethical. Therefore, alternative approaches to determine fetal outcomes of marijuana use during pregnancy need to be explored. However, this can only be achieved when the fetal exposure to THC and its active metabolite,11-OH-THC, has been addressed and accurately predicted. To achieve this goal, we propose a systems pharmacology approach to begin to address this significant public health problem and test the central hypothesis: Maternal-fetal exposure for THC/11-OH-THC during pregnancy can be predicted through innovative in vitro and in vivo studies integrated through maternal-fetal PBPK modeling and simulation (m-f-PBPK M & S). Fetal exposure to THC/11-OH-THC will be dependent on their maternal disposition, placental transport/metabolism and fetal clearance. Fetal exposure to THC/11-OH-THC will drive their fetal toxicity. Therefore, the projects of this P01 are designed to: 1) understand fetal exposure to THC/11-OH-THC by characterizing metabolism and transport of THC/11-OH-THC in maternal organs, placenta and fetus (Project 1); 2) predict the changes in maternal exposure to THC and its comprehensive metabolome including 11-OH-THC, 11-nor-COOH-THC and the glucuronides, throughout pregnancy, and the mechanistic basis for these changes (Project 2); and 3) predict and verify gestational age- dependent placental-fetal exposure to THC/11-OH-THC through PBPK M & S by integrating the data from the above two projects (Project 3). In addition, in an exploratory manner, we will determine whether these cannabinoids produce any molecular signatures indicative of short or long-term developmental neurotoxicity in humans (Project 3). Our approach uses novel and innovative tools (e.g. m-f-PBPK model, development of an inhalational m-f-PBPK model, perfused human placenta, quantitative targeted proteomics and metabolomics) to address a compelling public health question.

在美国，在孕妇中使用大麻（大麻）的患病率高在12-18岁的孕妇中有14％。美国妇产金学院妇产科建议孕妇避免大麻，因为证据表明它会影响胎儿和可能会干扰大脑发育。动物的研究似乎支持了这一点推荐。尽管大麻的其他成分不能打折，但一般科学共识是Δ9-四氢大麻酚（THC），是最丰富和精神活性的成分大麻是大麻发育神经毒性的可能犯罪者。但是，这些动物并以高分毒剂量或浓度进行体外研究，因此适用于人类，THC血浆浓度是亚微摩尔的，尚不清楚。另一方面，人类数据关于胎儿和婴儿在怀孕期间使用大麻的发育结果的有限其他因素并保持争议。进行对照临床试验以确定大麻是否导致负胎儿/新生儿结局是不道德的。因此，确定胎儿结局的替代方法需要探索怀孕期间大麻的使用。但是，只有在胎儿时才能实现已经解决并准确地预测了暴露于THC及其活性代谢产物11-OH-THC。到实现这一目标，我们提出了一种系统药理学方法，以开始解决这一重要的公众健康问题和检验中心假设：THC/11-OH-THC的母亲娱乐暴露可以通过创新的体外和体内研究来预测怀孕母亲 - 宠儿PBPK建模和仿真（M-F-PBPK M＆S）。胎儿暴露于THC/11-OH-THC将取决于其母体性格，占地运输/代谢和胎儿清除率。胎儿暴露到THC/11-OH-THC将推动其胎儿毒性。因此，该P01的项目被设计为：1）通过表征代谢和THC/11-OH-THC的运输来了解胎儿暴露于THC/11-OH-THC 在孕产妇器官中，胎盘和胎儿（项目1）； 2）预测产妇暴露于THC及其的变化全面代谢组，包括11-OH-THC，11-Nor-COOH-THC和葡萄糖醛酸苷怀孕和这些变化的机械基础（项目2）； 3）预测和验证妊娠年龄通过整合来自PBPK M＆S的依赖性位置接触到THC/11-OH-THC 以上两个项目（项目3）。另外，我们将以探索方式确定大麻素产生的任何分子特征表明在短期或长期发育神经毒性中产生任何分子特征。人类（项目3）。我们的方法使用新颖和创新的工具（例如M-F-PBPK模型，开发吸入的M-F-PBPK模型，灌注的人物，定量靶向保护植物学和代谢组学）解决一个令人信服的公共卫生问题。