Pharmacological fMRI to Identify New Anxiolytics: A Human Bioassay

药理学功能磁共振成像鉴定新型抗焦虑药：人体生物测定

基本信息

批准号：
7263148
负责人：
MURRAY B. STEIN
金额：
$ 33.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-20 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7263148
关键词：
Acute Agonist Alprazolam Amygdaloid structure Animal Model Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Area Behavioral Benzodiazepines Biological Assay Biological Markers Blood Brain Brain region CRF receptor type 1 Categories Cerebrovascular Circulation Class Clinical Clinical Trials Country Critical Pathways Data Development Dose Emotions Escitalopram Failure Functional Magnetic Resonance Imaging Goals Health Priorities Human Individual Insula of Reil Lead Lorazepam Magnetic Resonance Imaging Measures Medial Mediation Mental disorders Methods Movement Neurosciences Norepinephrine Oxygen Paper Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacotherapy Phase Phase II Clinical Trials Placebo Control Population Positron-Emission Tomography Prefrontal Cortex Probability Procedures Process Property Public Health Purpose Recommendation Research Research Personnel Reservations Risk Sensitivity and Specificity Series Serotonin Signal Transduction Societies Spin Labels Staging Standards of Weights and Measures Structure Techniques Technology Testing Time Translational Research Treatment Protocols United States United States Dept. of Health and Human Services United States Food and Drug Administration Week attenuation behavioral pharmacology blood oxygenation level dependent response design drug development drug discovery healthy volunteer improved in vivo in vivo Bioassay inhibitor/antagonist innovation metabotropic glutamate receptor 2 neuroimaging novel pre-clinical pregabalin programs psychopharmacologic response reuptake size success tool trait

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this application is to validate and optimize a human, in vivo bioassay for dentifying pharmaceutical compounds that are highly likely to have anti-anxiety properties. No new classes of anxiolytic medications have entered the marketplace in the past two decades, and the current drug development pathway suffers from many costly, time-consuming failures of compounds that enter Phase studies. The FDA has pointed to this "pipeline problem" as a significant challenge to drug development in the 21st century. Among their recommendations is the need to invent new drug development tools to enhance the movement along the "critical path" from Phase I to Phase III. This proposal outlines a series of studies aimed at determining whether functional magnetic resonance imaging (fMRI) in conjunction with the administration of pharmacological agents can be used as a human, in vivo bioassay at the juncture between Phase I and Phase II drug development for anxiety disorders. This predictive tool would be used to guide selection of lead compound(s) and optimal dosing, and would increase the prior probability of success in Phase II. In this application, we propose to examine the sensitivity, specificity, and reliability of a two emotion-processing tasks during blood oxygen dependent (BOLD) and arterial spin labeling (ASL) fMRI to probe the activation in amygdala, insula, and medial prefrontal cortex with standard anxiolytic and other psychopharmacological agents. A goal of this line of research is to be able to relate the degree of attenuation of the BOLD-fMRI signal in the target areas to the anxiolytic potential of a novel drug. The studies proposed here over 3 years are intended to establish the utility of these techniques for this purpose. Studies in healthy volunteers will optimize the procedures and paradigms and document their sensitivity and reliability (Aim #1). Dose-response studies in anxious subjects will examine sensitivity and specificity of the procedures to known anxiolytic agents in the contexts of acute dose-response (alprazolam and pregabalin) and subchronic (4 weeks of escitalopram) administration (Aim #2). Anxiety disorders are the most prevalent form of mental disorder in the United States, and are disabling to individuals and costly to society. Current pharmacotherapies fail to provide complete relief to 50% of patients. Enhancing the development of new treatments for anxiety is a public health priority. The projects proposed in this application have the potential to achieve this important aim.

描述（由申请人提供）：本申请的长期目标是验证和优化人体生物测定法，以牙化学化合物，这些化合物很可能具有抗焦虑性。在过去的二十年中，没有任何新的抗焦虑药进入市场，当前的药物开发途径遭受了许多代价，耗时的，耗时的失败，这些化合物进入了阶段研究。 FDA指出，这种“管道问题”是21世纪药物开发的重大挑战。他们的建议之一是需要发明新的药物开发工具，以增强从第一阶段到第三阶段的“关键道路”运动。该提案概述了一系列旨在确定功能磁共振成像（fMRI）与药理学剂的施用是否可以用作人类，在I期和II期药物发展之间的交界处的体内生物测定。该预测工具将用于指导铅化合物和最佳剂量的选择，并增加阶段II成功的先前概率。在此应用中，我们建议研究在血氧依赖性（BOLD）和动脉旋转标签（ASL）fMRI期间进行两项情感处理任务的敏感性，特异性和可靠性，以探测杏仁核，间属和内侧前额叶皮质的激活，并具有标准的抗焦点皮层具有标准的抗焦虑药物和其他心理疗法和其他心理药物学的人。这一研究的目的是能够将目标区域中BOLD-FMRI信号的衰减程度与新药物的抗焦虑潜力联系起来。此处提出的3年旨在为此目的建立这些技术的实用性。健康志愿者的研究将优化程序和范式，并记录其敏感性和可靠性（AIM＃1）。在急性受试者中的剂量反应研究将检查急性剂量反应（Alprazolam和Pregabalin）和亚chronic（Escitalopram的4周）给药的背景下对已知抗焦虑药的敏感性和特异性（AIM＃2）。焦虑症是美国最普遍的精神障碍形式，正在为个人致命，对社会付出了高昂的代价。当前的药物治疗无法完全缓解50％的患者。加强新焦虑疗法的发展是公共卫生的重点。本应用程序中提出的项目有可能实现这一重要目标。