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。根据现行 资金，我们已经通过开发和应用方法， 更精确地绘制出个体患者手术后的恢复速度。此外，我们还表明， 如果手术发生在分娩前后，动物和人类手术后的恢复会更快， 加速恢复反映了催产素（OXT）的作用。虽然OXT对多种神经系统疾病的影响 已经在动物中进行了探索，但人类的翻译测试受到给药途径的阻碍 （鼻内[i.n.]）在大脑或周围的分布不确定。项目3将建立在这些基础上 在项目1和2的指导下，在PK/PD核心的支持下， OXT对躯体感觉以及疼痛的感觉和情感维度的作用。具体而言： 目标1.创建IV和i.n.给药后血浆中OXT的PK模型。给药和试验协变量 该目的将确定IV和i.n.在血浆中给药， 测试关键生物学变量（性别、年龄、体重、人种、种族）是否影响这种倾向。这些数据将 用于确定外周或中枢药物作用（包括疼痛缓解）靶部位的适当剂量。 目的2：定义躯体感觉外周部位的OXT作用 使用来自5分钟热刺激的疼痛报告或由瑞典人测试的范例， 合作者（在他们的资助下，由瓦伦堡基金会在本P01之外），我们将创建和验证一个 OXT对躯体感觉（包括外周疼痛）的PK/PD（药效学）模型。这种模式的 在瑞典的一个子奖项下指导OXT给药，以直接测试OXT对感觉传入的影响， 显微神经摄影记录和我们测试的影响，OXT轻触摸以及疼痛纤维。 目的3：将海马作为OXT作用的衡量指标，并将IV研究与鼻内给药联系起来 我们将首次建立催产素在脑内的PK/PD模型，使用瞳孔直径 振荡（海马）作为结果测量。然后，我们将运用目标1和2中的知识， i.n.后疼痛缓解和中枢神经系统作用的PK/PD模型OXT给药。这些模型 将指导未来i.n. OXT治疗疼痛和其他神经系统疾病。

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.