MATERNAL/FETAL PHARMACOKINETICS AND PHARMACODYNAMICS

这一部分的总体目标是鉴定阿片肽类似物 具有镇痛作用，对母亲或胎儿没有不良影响。 这一目标可以通过寻找不交叉的肽类似物来实现。 胎盘，对母体的影响最小。或者，它可以是 有可能找到穿过胎盘的肽，但没有显著的 母体或胎儿的影响。在过去的两年里，我们能够 鉴定某些合成阿片肽类似物， 分布在整个胎盘中，对胎儿几乎没有不良影响。 然而，我们的发现也促使我们重新评估我们的假设， 指导我们对未来五年的方法进行一些修改 多年来，这个项目。我们的药效学结果与两个亩激动剂 （DAMGO和DALDA）对母体心血管有显著影响， 静脉推注感染后的功能，但对胎儿的不良影响很小。 我们假设这些潜在的阿片类药物不良反应可能是 通过连续静脉输注或鞘内（IT）给药使其最小化。 我们的药效学结果与两个δ阿片肽类似物（DPDPE 和DELT）显示出显著的心血管和呼吸影响， 母亲，不介导的阿片受体，以及显着 对胎儿的不良影响。我们假设δ阿片肽 不具有这些非阿片样作用的类似物可能是理想的药物 用于全身给药。这一部分的具体目标是 因此，进行系统的药代动力学研究 μ和δ阿片样肽类似物的药理学和药效学 母胎单位我们的第一个具体目标是确定 这些μ和δ阿片肽类似物的抗伤害感受作用， 静脉注射给药，并在啮齿动物体内给药。第二个具体目标是 测定新型μ和δ阿片肽的药代动力学 iv和给药后未妊娠和妊娠绵羊中的类似物 并确定胎儿药物暴露的程度第三个具体目标是 为了检测μ和δ阿片肽类似物对 心血管、呼吸和代谢功能， 妊娠和胎羊静脉注射后，并确定 是否有阿片受体介导的作用具体 本部分提出的目标将由司徒博士共同执行 和克拉普博士在各自的实验室里的实力 组分是药代动力学-药效学联合方法， 在相同的动物模型中进行。这一部分将发挥重要作用， 在实现PPG总体目标方面发挥作用。

The overall goal of this component is to identify opioid peptide analogs that are analgesic and have no adverse effects on the mother or fetus. This goal can be accomplished by finding peptide analogs that do not cross the placenta and have minimal maternal effects. Alternatively, it may be possible to find peptides that cross the placenta but have no significant maternal or fetal effects. Over the past two years, we have been able to identify certain synthetic opioid peptide analogs that have limited distribution across the placenta and little adverse effects in the fetus. However, our findings have also led us to re-assess our hypotheses, and guides us to a number of modifications in our approach to the next five years of this project. Our pharmacodynamic results with two mu agonists (DAMGO and DALDA) showed significant effects on maternal cardiovascular function after iv bolus infection but little adverse effect on the fetus. We hypothesize that these potentially adverse opioid effects may be minimalized by continuous iv infusion or intrathecal (it) administration. Our pharmacodynamic results with two delta opioid peptide analogs (DPDPE and DELT) showed significant cardiovascular and respiratory effects in the mother that are not mediated by opioid receptors, as well as significant adverse effects on the fetus. We hypothesize that delta opioid peptide analogs that do not possess these non-opioid effects may be ideal drugs for systemic administration. The specific aim of this component is therefore to carry out a systematic investigation of the pharmacokinetics and pharmacodynamics of mu and delta opioid peptide analogs in the maternal-fetal unit. Our first specific aim is to determine the antinociceptive action of these mu and delta opioid peptide analogs when administered iv and it in the rodent. Our second specific aim is to determine the pharmacokinetics of novel mu and delta opioid peptide analogs in non-pregnant and pregnant sheep after iv and it administration and determine the extent of fetal drug exposure. Our third specific aim is to examine the effects of mu and delta opioid peptide analogs on cardiovascular, respiratory and metabolic function in non-pregnant, pregnant and fetal sheep after iv and it administration, and determine whether any of the effects are mediated by opioid receptors. The specific aims proposed in this Component will be carried out jointly by Dr. Szeto and Dr. Clapp in their respective laboratories. The strength of this component is the combined pharmacokinetic-pharmacodynamic approach being carried out in the same animal model. This Component will play an integral role in achieving the overall goal of the PPG.