ORAL OXYTOCIN ANTAGONIST PHARMACODYNAMICS IN PREGNANT/NONPREGNANT RHESUS MONKEY

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 催产素拮抗剂可以帮助延迟早产，早产发生在所有人类怀孕的12%，并导致各种新生儿健康问题。 目前用于药理学抑制子宫收缩的宫缩抑制剂具有副作用和有限的功效。口服活性药物AS 606521以非侵入性方式给药，清除缓慢，对催产素受体具有特异性。 然而，与非妊娠动物相比，具有增加的血容量和改变的循环的妊娠动物可能具有不同的清除率。 直接测试药物在减少妊娠期灵长类动物子宫活动方面的疗效，以及药物经胎盘转移到羊水和胎儿血液中，是未来在女性中使用的重要方面。 恒河猴和人类妊娠的相似性使这项研究对人类医学有潜在的直接益处。 在未妊娠和妊娠恒河猴模型中启动了口服活性催产素拮抗剂AS 606521的药代动力学和药效学研究。 目的是比较AS 606521在妊娠和非妊娠灵长类动物中的药代动力学，以确定阻断妊娠恒河猴中催产素诱导的子宫收缩的有效血浆浓度范围，并确认较高浓度催产素（补救治疗）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).