MATERNAL/FETAL PHARMACOKINETICS AND PHARMACODYNAMICS

这一部分的总体目标是确定阿片肽类似物 这是止痛药，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多肽类似物来实现 胎盘，对母体的影响最小。或者，它可能是 可能找到穿过胎盘的多肽，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，它们具有有限的 在胎盘中的分布，在胎儿中几乎没有不良影响。 然而，我们的发现也促使我们重新评估我们的假设，以及 指导我们在接下来的五年中对方法进行一些修改 这个项目已经持续了好几年了。我们两种MU激动剂的药效学结果 (DAMGO和DALDA)对产妇心血管有显著影响 静脉推注感染后功能正常，对胎儿不良反应小。 我们推测，这些潜在的阿片类药物不良影响可能是 通过持续静脉输注或鞘内(It)给药将其降至最低。 两种Delta阿片肽类似物(DPDPE)的药效学结果 和DELT)显示出显著的心血管和呼吸作用 母亲不是由阿片受体介导的，以及显著的 对胎儿的不良影响。我们假设德尔塔阿片肽 不具有这些非阿片类药物作用的类似物可能是理想的药物。 用于系统管理。此组件的具体目标是 因此，要开展系统的药代动力学研究 Mu和Delta阿片肽类似物在大鼠体内的药效学 母胎单位。我们的第一个具体目标是确定 这些Mu和Delta阿片肽类似物的抗伤害性作用 给啮齿类动物静脉注射和注射。我们的第二个具体目标是 新型Mu和Delta阿片肽的药代动力学研究 未孕和怀孕绵羊静脉注射及给药后的类似物 并确定胎儿接触药物的程度。我们的第三个具体目标是 目的：研究Mu和Delta阿片肽类似物对大鼠脑内血管紧张素转换酶的影响。 非孕者的心血管、呼吸和代谢功能 妊娠羊和胎羊静脉注射及其给药后，测定 是否有任何影响是由阿片受体介导的。具体的 本部分建议的目标将由司徒华议员共同执行 和克拉普博士在各自的实验室里。这一点的力量 成分是药代动力学和药效学相结合的方法 在相同的动物模型中进行。该组件将起到一个整体的作用 在实现PPG的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.