DEVELOPMENT OF MEDICATIONS FOR THE PREGNANT OPIATE ADDICT

我们研究的长期目标是改善妊娠阿片类药物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计划。这些方案取得了成功，美沙酮成为治疗海洛因和吗啡成瘾者的“标准”。然而，复发，副作用，药物相互作用和无法解释的临床观察报告，并促使研究人员寻求替代药物。目前有两种这样的药物，丁丙诺啡（BUP）和L-乙酰美沙酮（LAAM），但关于它们对孕妇及其新生儿影响的数据很少或不存在。本调查的目的是提供所需的基本信息BUP和LAAM的安全使用在治疗怀孕的阿片类药物成瘾者，以及帮助了解一些无法解释的观察与这些患者和他们的新生儿在美沙酮计划。我们的研究假设是，这三种阿片类药物，因为它们的物理化学性质，可能是通过被动扩散，从母体到胎儿的胎盘循环。然而，人类胎盘在保护胎儿免受药物、外源性物质和环境污染物的暴露方面起着重要作用。这一作用可以通过药物代谢或通过转运蛋白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些功能是否影响这些阿片类药物转移到胎儿循环。将利用人胎盘小叶的双重灌注技术来获得这些数据。使用的胎盘将从足月健康妊娠中获得。具体工作如下：（1）确定BUP、LAAM和美沙酮的经胎盘转运（TPT）参数。(2)确定胎盘组织形成的每种阿片类药物的代谢产物及其随后在组织、母体和胎儿循环中的分布。(3)确定哪种阿片类药物是P-gp的底物。获得的数据可能提供与该患者人群治疗相关的几个无法解释的临床观察结果的原因。这些包括：戒断症状和严重程度，在一些但不是所有的新生儿中观察到的母亲在怀孕期间接受BUP或美沙酮治疗; 药物剂量与其母体血清水平之间缺乏相关性;妊娠患者中阿片剂和代谢物的浓度低于非妊娠患者。鉴定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，获得的信息将提供更好的了解这些阿片类药物通过人胎盘的转移和组织在减少胎儿暴露于药物中的作用。它还可以根据患者的病情提供治疗个体患者的药物选择，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.