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

创建人体催产素作用的 PK/PD 模型并桥接鼻内递送

• 批准号: 10332265
• 负责人: James Eisenach
• 金额: $ 33.3万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10332265
• 关键词: Acute; Acute Pain; Affect; Affective; Age; Animals; Area; Arthritis; Biological; Biological Assay; Biological Markers; Brain; Caliber; Childbirth; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; Conflict (Psychology); Contracts; Controlled Clinical Trials; Cross-Over Studies; Data; Dimensions; Discipline of obstetrics; Disease; Dose; Double-Blind Method; Drug Kinetics; Eligibility Determination; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Fiber; Foundations; Frequencies; Functional disorder; Funding; Future; Grant; Human; Injury; International; Intranasal Administration; Intravenous infusion procedures; Knee; Knowledge; Laboratories; Light; Maps; Measures; Mechanoreceptors; Methods; Modeling; Nerve; Nervous system structure; Neuraxis; Neurohormones; Nociception; Nociceptors; Operative Surgical Procedures; Outcome Measure; Oxytocin; Pain; Pathology; Patients; Penetration; Perception; Peripheral; Persons; Pharmacodynamics; Pharmacology; Placebo Control; Plasma; Pregnant Uterus; Productivity; Protocols documentation; Psychophysics; Pupil; Race; Randomized; Recovery; Reporting; Research; Rodent; Route; Self Administration; Sensory; Series; Site; Speed; Stimulus; Sweden; Testing; Time; Touch sensation; Translating; Validation; Weight; Woman; Work; absorption; appropriate dose; base; chronic pain; clinical pain; cognitive neuroscience; desensitization; disability; drug action; experimental study; heat stimulus; individual patient; injury recovery; intravenous injection; knee replacement arthroplasty; liquid chromatography mass spectrometry; men; nervous system disorder; novel; pain reduction; pain relief; pharmacodynamic model; pharmacokinetic model; postoperative recovery; pre-clinical; pressure; protective effect; sex; simulation; social neuroscience; tool; vibration; volunteer

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.

项目3摘要 手术使大多数患者受益，但就某些患者而言，这会导致慢性疼痛和残疾。在当前 资金，我们通过开发和应用方法来推动该领域的研究状态 更精确地绘制了手术后个别患者的恢复速度。此外，我们已经表明 如果手术在分娩时进行手术，则在动物和人类手术后恢复会更快，这 加速恢复反映了催产素（OXT）的作用。尽管OXT对多种神经系统疾病的影响 在动物中已证明，人类的翻译测试受到管理途径的阻碍 （鼻内[I.N.]）在大脑或周围的分布不确定。项目3将基于这些 在项目1和2的指导下进行观察和翻译，并由PK/PD核心支持，关键测试 OXT对疼痛的感官和情感维度的行为。具体来说： AIM 1。在IV和I.N.之后的血浆中创建OXT的PK模型。管理和测试协变量 此目的将确定IV和I.N.之后的氧气药代动力学（PK）。血浆和 测试关键的生物学变量（性别，年龄，体重，种族，种族）是否影响这种处置。这些数据将是 用于确定对周围或中央药物作用的目标部位的适当剂量，包括缓解疼痛。 AIM 2：在体验的外围部位定义oxt动作 使用5分钟的热刺激或范式通过我们的瑞典语测试的疼痛报告 合作者（在P01以外的Wallenberg基金会的资助下），我们将创建并验证 PK/PD（药效学）模型，用于体验，包括外周的疼痛。这个模型将 在瑞典的一个子宣告下引导oxt剂量，直接使用使用 微图记录，并通过我们测试OXT对轻触感和疼痛纤维的影响。 AIM 3：验证河马作为对OXT动作的度量和桥梁内给药的桥梁IV研究 我们将首次使用瞳孔直径建立大脑中氧气的PK/PD模型 振荡（Hippus）作为结果度量。然后，我们将利用目标1和2的知识来创建 I.N.后的PK/PD模型用于缓解疼痛和中枢神经系统动作OXT管理。这些模型 将指导I.N.将来的临床试验剂量治疗疼痛和其他神经系统疾病的OXT。