DEVELOPMENT OF MEDICATIONS FOR THE PREGNANT OPIATE ADDICT

我们研究的长期目标是改善怀孕阿片成瘾者的治疗及其新生儿的结局。几十年来，这些患者唯一可用的治疗方法是美沙酮方案。这些项目都取得了成功，美沙酮成为治疗海洛因和吗啡成瘾者的“标准”。然而，报告了复发、副作用、药物相互作用和不明原因的临床观察，并促使调查人员寻找替代药物。目前有两种这样的药物，丁丙诺啡(BUP)和L-乙酰美沙醇(LAAM)，但关于它们对孕妇和她的新生儿影响的数据很少，甚至根本不存在。这项调查的目的是为安全使用BUP和LAAM治疗怀孕阿片成瘾者提供所需的基本信息，并帮助理解与这些患者及其在美沙酮计划中的新生儿有关的几个无法解释的观察结果。我们研究的假设是，由于这三种阿片类药物的物理化学性质，可能是通过被动扩散从母体循环到胎儿循环来转运的。然而，人类胎盘在保护胎儿免受药物、外源物质和环境污染物的影响方面发挥着重要作用。这一作用可以通过代谢药物或通过转运体P-糖蛋白(P-gp)将其挤出母体循环来实现。我们的数据将确定这两种功能中的任何一种是否会影响这些阿片类药物向胎儿循环的转移。我们将利用人体胎盘小叶双重灌流技术来获得这些数据。使用的胎盘将从健康的足月妊娠中获得。这项工作的具体目标是：(1)确定BUP、LAAM和美沙酮的胎盘转运参数。(2)确定胎盘组织为每种阿片剂形成的代谢物及其随后在组织、母体和胎儿循环之间的分布。(3)确定哪种阿片类药物是P-gp的底物。所获得的数据可能提供了与这一患者群体的治疗相关的几个无法解释的临床观察的原因。这些包括：在怀孕期间接受BUP或美沙酮治疗的母亲在一些但不是所有新生儿中观察到的戒断症状和严重程度；药物剂量与其母亲血清水平之间缺乏相关性；怀孕患者中阿片剂和代谢物的浓度低于未怀孕患者。识别P-gp的阿片底物将避免药物与其他药物的相互作用，从而避免胎儿过度暴露于两者。总之，所获得的信息将为更好地了解这些阿片类药物在人类胎盘中的转移以及组织在减少胎儿接触药物方面的作用。它还可以根据患者的情况提供治疗个别患者的药物选择，从而改善新生儿结局。

The long term goal of our investigations is to improve on the treatment of the pregnant opiate addict and the outcome of their newborns. For several decades, the only treatment available for these patients were methadone programs. These programs have been successful and methadone became the "standard" for treating the heroin and morphine addict. However, relapses, side effects, drug interactions and unexplained clinical observations were reported and prompted investigators to seek alternative drugs. Two such drugs, buprenorphine (BUP) and L-acetylmethadol (LAAM) are currently available but data on their effects on the pregnant patient and her newborn are scarce to non-existent. The goal of this investigation is to provide the needed basic information on BUP and LAAM for their safe use in treatment of the pregnant opiate addict as well as help understand several unexplained observations associated with these patients and their newborns in methadone programs. The hypothesis for our investigation is that the three opiates, because of their physicochemical properties, may be transported by passive diffusion across the placenta from the maternal to fetal circulation. However, human placenta plays an important role in protecting the fetus from exposure to drugs, xenobiotics and environmental pollutants. This role can be achieved either by metabolizing the drug or extruding it to the maternal circulation by the transporter P-glycoprotein (P-gp). Our data will determine if either of these functions affects the transfer of these opiates to the fetal circulation. The technique of dual perfusion of human placental lobule will be utilized to obtain these data. The placentas utilized will be obtained from full term healthy pregnancies. The specific aims for the proposed work are: (1) Determine the transplacental transfer (TPT) parameters for BUP, LAAM and methadone. (2) Determine the metabolites formed for each opiate by placental tissue and their subsequent distribution between the tissue, maternal and fetal circulations. (3) Identify which of the opiates is a substrate for P-gp. Data obtained may provide the cause for several unexplained clinical observations associated with treatment of this patient population. These include: withdrawal symptoms, and severity, observed in some but not all newborns for mothers treated with BUP or methadone during pregnancy; lack of correlation between dose of the drug and its maternal serum levels; lower concentrations of the opiate and metabolites in pregnant than non-pregnant patients. Identification of the opiate substrate for P-gp will allow avoiding drug interactions with other medications thus avoiding fetal over exposure to both. In summary, the information obtained will provide a better understanding of the transfer of these opiates across human placenta and the role of the tissue in decreasing fetal exposure to the drugs. It may also provide a choice of medications for treating an individual patient according to her condition thus improving neonatal outcome.