ORAL OXYTOCIN ANTAGONIST PHARMACODYNAMICS IN PREGNANT/NONPREGNANT RHESUS MONKEY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 催产素拮抗剂可能有助于推迟早产，早产发生在高达12%的人类怀孕中，并导致各种新生儿健康问题。目前用于药物抑制子宫收缩的宫缩酵解剂都有副作用，疗效有限。口服活性AS606521以非侵入性方式给药，清除缓慢，并且是催产素受体的特异性药物。然而，与未怀孕的动物相比，血液容量增加和循环改变的怀孕动物可能有不同的清除能力。直接测试药物在妊娠期间减少灵长类动物子宫活动的疗效，以及胎盘将药物转移到羊水和胎儿血液中，是妇女未来使用的重要方面。恒河猴和人类怀孕的相似性使这项研究对人类医学具有潜在的直接好处。对口服催产素拮抗剂AS606521在恒河猴非妊娠和妊娠模型上的药代动力学和药效学进行了研究。目的是比较AS606521在怀孕和未怀孕灵长类动物体内的药代动力学，建立阻断催产素引起的妊娠恒河猴子宫收缩的有效血药浓度范围，并确认高浓度催产素(抢救疗法)抑制这种抑制的可逆性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Oxytocin antagonists could help delay preterm labor, which occurs in up to 12% of all human pregnancies and contributes to a variety of neonatal health problems. Current tocolytic agents for the pharmacological inhibition of uterine contractions have side-effects and limited efficacy. The orally active AS606521 is administered in a non-invasive manner, has a slow clearance, and is specific for the oxytocin receptor. However, pregnant animals, with increased blood volume and altered circulation, may have a different clearance compared to non-pregnant animals. The direct testing of drug efficacy in reducing uterine activity in primates during pregnancy, as well as placental transfer of the drug into amniotic fluid and fetal blood, are important aspects for future use in women. The similarity of rhesus and human pregnancy allows this study to have potential direct benefits to human medicine. A pharmacokinetic and pharmacodynamic study on the orally-active oxytocin antagonist AS606521 in a nonpregnant and pregnant rhesus monkey model was initiated. The goals are to compare the pharmacokinetics of AS606521 in pregnant and non-pregnant primates, to establish the effective plasma concentration ranges for blocking oxytocin-induced uterine contractions in pregnant rhesus monkeys and to confirm the reversibility of the inhibition by higher concentrations of oxytocin (rescue therapy).