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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

基本信息

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
项目类别：
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

项目摘要

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总结