Creating PK/PD models for oxytocin action in humans and bridging to intranasal delivery

项目3摘要 手术使大多数患者受益，但对一些人来说，它会导致慢性疼痛和残疾。欠电流 资金，我们通过开发和应用方法来推动这一领域的研究状况 更准确地绘制出手术后个别患者的恢复速度。此外，我们已经表明， 如果手术发生在分娩前后，动物和人类的手术后恢复更快，而这 加速恢复反映了催产素(Oxt)的作用。尽管奥施康定对多种神经功能障碍的作用 已经在动物身上进行了探索，在人类身上的翻译测试受到了一种给药途径的阻碍 (鼻腔[I.N.])在大脑或外周的分布不确定。项目3将建立在这些基础上 观察和翻译，在项目1和2的指导下，在PK/PD核心的支持下，进行关键测试 OXT对躯体感觉的作用以及疼痛的感觉和情感维度。具体地说，就是： 目的1.建立静脉注射和静脉注射后血浆中OXT的PK模型。管理和测试协变量 这一目的将确定静脉注射和静脉注射后催产素的药代动力学(PK)。在血浆和血浆中给药 测试关键的生物变量(性别、年龄、体重、种族、民族)是否会影响这种倾向。这些数据将是 用于确定外周或中枢药物作用的目标部位的适当剂量，包括止痛。 目标2：确定OXT在躯体感觉周围部位的作用 使用5分钟热刺激的疼痛报告或由我们的瑞典人测试的范例 合作者(在瓦伦堡基金会的资助下)，我们将创建并验证 OXT包括外周疼痛在内的躯体感觉PK/PD(药效学)模型。这款车型将 根据瑞典的一项次级奖励指导OXT剂量直接测试OXT对感觉神经传入的影响 显微神经学记录，并由我们测试OXT对轻触和疼痛纤维的影响。 目标3：验证髋关节作为OXT作用的衡量标准，并将IV研究与鼻腔给药联系起来 我们将首次使用瞳孔直径建立脑内催产素的PK/PD模型 震荡(臀部)作为结果衡量标准。然后我们将应用目标1和目标2中的知识来创建 静脉注射后疼痛缓解和中枢神经系统活动的PK/PD模型。OXT管理。这些型号 将指导未来的I.N临床试验的剂量。OXT用于治疗疼痛和其他神经疾病。

Project 3 Summary Surgery benefits most patients, but for some, it results in chronic pain and disability. Under current funding, we have moved the state of research in this area forward by developing and applying methods to more precisely map the speed of recovery in individual patients after surgery. In addition, we have shown that recovery after surgery in animals and humans is quicker if surgery occurs around the time of delivery, and this hastened recovery reflects oxytocin (OXT) actions. Although OXT’s effects on multiple neurologic disorders have been probed in animals, translational testing in humans is hampered by a route of administration (intranasal [i.n.]) with undetermined distribution in the brain or the periphery. Project 3 will build on these observations and translate, with guidance by Projects 1 and 2 and support by the PK/PD Core, critical testing of OXT’s actions on somatosensation and the sensory and affective dimensions of pain. Specifically: Aim 1. Create PK models of OXT in plasma after IV and i.n. administration and test covariates This Aim will determine oxytocin pharmacokinetics (PK) after IV and i.n. administration in plasma and test whether key biologic variables (sex, age, weight, race, ethnicity) affect this disposition. These data will be used to determine appropriate dosing to target sites of peripheral or central drug action, including pain relief. Aim 2: Define OXT actions at peripheral sites of somatosensation Using either pain report from a 5 minute heat stimulus or paradigms to be tested by our Swedish collaborators (under their funding by the Wallenberg Foundation outside this P01), we will create and validate a PK/PD (pharmacodynamic) model for OXT on somatosensation including pain in the periphery. This model will guide OXT dosing under a subaward in Sweden to directly test the effects of OXT on sensory afferents using microneurographic recording and by us to test the effects of OXT on light touch as well as pain fibers. Aim 3: Validate hippus as a measure of OXT action and bridge IV studies to intranasal administration We will for the first time establish a PK/PD model for oxytocin in the brain, using pupil diameter oscillations (hippus) as an outcome measure. We will then apply knowledge from Aims 1 and 2 to create PK/PD models for pain relief and central nervous system action after i.n. OXT administration. These models will guide dosing for future clinical trials of i.n. OXT to treat pain and other neurologic disorders.