DISPOSITION & PHARMACODYNAMICS OF COCAINE IN PREGNANCY

可卡因是一种具有积极强化作用的强效兴奋剂， 很多孕妇都在使用。 之甚少 了解该药物的处置和药效学 在怀孕期间，除了它很容易穿过 胎盘并可能导致间歇性宫内缺氧， 早产和可能的长期发育问题。 在 本研究拟以妊娠母羊为模型进行研究 怀孕期间使用可卡因的某些特征，包括 可卡因处置的广泛药代动力学分析 母羊和胎儿。 研究药物暴露的决定因素将 i）母体和胎儿清除率，ii）剂量; iii）给药途径 给药（静脉内与吸入挥发的游离- 碱（快克）可卡因）; iv）母体和胎儿血浆蛋白 可卡因的结合; v）以及 可卡因代谢物 我们将比较血浆蛋白结合， 母羊和胎羔羊与孕妇和脐带静脉血 在交付时获得。 将在以下方面寻求相关性： 可卡因的药代动力学以及母体和胎儿 心血管反应和血气，母体和胎儿 血浆儿茶酚胺和胎儿行为状态。 考虑到 母亲服用可卡因会影响 胎儿发育和新生儿行为，我们将确定当地 胎儿脑能量代谢的研究 （14 C）-2-脱氧葡萄糖利用率。 最后，我们将确定如何 心血管、神经生理和神经化学指标 胎儿和产妇的健康受到同时发生的 注射可卡因和吸入热解和 大麻的燃烧产物 本研究的目标是 描述可卡因在母胎中的药代动力学 单位，并通过药效学分析，形成一个更清晰的 了解可卡因对人体的急性和慢性影响 神经系统功能的一个特殊群体的风险， 子宫内的胎儿 本研究将着重于基本机制， 可卡因使用的作用、影响和生理危害。

Cocaine, a powerful stimulant with positive reinforcing actions, is used by a significant number of pregnant women. Very little is known about the disposition and pharmacodynamics of this drug during pregnancy, apart from the facts that it easily crosses the placenta and may cause intermittent intrauterine hypoxia, preterm labor, and possible long-term developmental problems. In this proposal we plan to use the pregnant ewe as a model to study certain features of cocaine use in pregnancy, including an extensive pharmacokinetic analysis of cocaine disposition in the ewe and fetus. Determinants of drug exposure to be studied will be i) maternal and fetal clearance, ii) dose; iii) route of administration (intravenous versus inhalation of volatilized free- base (crack) cocaine); iv) maternal and fetal plasma protein binding of cocaine; v) and formation and placental transfer of cocaine metabolites. We will compare plasma protein binding in ewe and fetal lamb with pregnant women and cord venous blood obtained at delivery. Correlations will be sought between the pharmacokinetics of cocaine and maternal and fetal cardiovascular response and blood gases, maternal and fetal plasma catecholamines, and fetal behavioral state. In view of the observations that maternally administered cocaine influences fetal development and neonatal behavior, we will determine local cerebral energy metabolism in fetal brain using the technique of (14C)-2-deoxyglucose utilization. Finally, we will determine how cardiovascular, neurophysiologic and neurochemical indexes of fetal and maternal health are altered by the simultaneous injection of cocaine and the inhalation of pyrolytic and combustion products of marijuana. The goals of this research are to describe the pharmacokinetics of cocaine in the maternal-fetal unit, and through pharmacodynamic analyses, to form a clearer understanding of the acute and chronic effects of cocaine on the function of the nervous systems of a special population at risk, fetuses in utero. This study will focus on basic mechanisms of action and effects and physiological hazards of cocaine use.