Repurposing cholinesterase inhibitors for smoking cessation

重新利用胆碱酯酶抑制剂来戒烟

• 批准号: 9040135
• 负责人: Rebecca Ashare
• 金额: $ 15.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040135
• 关键词: Abstinence; Acetylcholine; Acetylcholinesterase Inhibitors; Address; Adverse effects; Alzheimer' s Disease; Area; Attention; Attenuated; Cholinesterase Inhibitors; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Complement; Coupled; Data; Development; Development Plans; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Elements; Ensure; Environment; Evaluation; FDA approved; Financial Support; Funding; Galantamine; Gender; Genes; Genetic; Goals; Health; Human; Incentives; Institutional Review Boards; Interdisciplinary Study; Internships; Knowledge; Laboratory Study; Link; Measures; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Modeling; Moods; Neurobehavioral Manifestations; Neuropharmacology; Neurosciences; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Participant; Patients; Pennsylvania; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Pharmacy facility; Phase; Phase III Clinical Trials; Placebos; Postdoctoral Fellow; Procedures; Psychiatry; Psychologist; Psychophysiology; Qualifying; Randomized; Relapse; Research; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Resources; Rewards; Rodent; Safety; Sample Size; Schedule; Scientist; Secure; Self Administration; Short-Term Memory; Smoker; Smoking; Smoking Behavior; Testing; Therapeutic; Time; Training; Universities; Variant; Withdrawal; Withdrawal Symptom; Withholding Treatment; Work; addiction; arm; base; biological adaptation to stress; career; career development; cognitive function; cognitive neuroscience; cognitive performance; cognitive testing; collaborative environment; craving; critical period; data management; dependence relapse; flexibility; improved; novel; patient oriented research; phase 2 study; primary outcome; professor; programs; relapse risk; response; screening; secondary outcome; skills; smoking cessation; smoking relapse; success; therapeutic target

DESCRIPTION (provided by applicant): As a clinical psychologist, my long-term career goal is to establish an independent career in patient-oriented research (POR), which focuses on the development and evaluation of more efficacious treatments for nicotine dependence, specifically treatments that reduce withdrawal-related cognitive deficits (referred to as pro-cognitive treatments). My prior training has enabled me to develop skills in delivering FDA-approved smoking cessation treatments and conducting human laboratory studies. My graduate and internship training focused primarily on psychophysiology, stress responses, and nicotine dependence. As a postdoctoral fellow, I have extended this training to nicotine dependence treatment research and neuro-cognitive research. However, to achieve my long-term career goal, it is essential that I address critical gaps in my knowledge and training. On July 1, 2012, I will be appointed Assistant Professor in the Department of Psychiatry at UPenn, which will allow me to begin my pursuit of an independent career in POR on cognition and smoking cessation treatment. The K23 mechanism will enable me to focus at least 90% of my time and effort to develop a career as an independent clinical researcher. My training objectives progress in a logical fashion to prepare me for the transition to an independent research career in this area. These include: 1) acquiring new knowledge in neuro-pharmacology and cognitive neuroscience to understand the mechanisms of efficacy of nicotine dependence treatments, particularly pro- cognitive medications; 2) conducting a research project to evaluate whether a pro-cognitive medication reverses withdrawal-related cognitive deficits and improves quit rates; and 3) developing the skills necessary to communicate my research findings, to secure subsequent research funding, and to collaborate in an interdisciplinary environment. I will accomplish these training objectives through relevant coursework, guidance from my mentor and mentorship committee, attendance at seminars and workshops, and applied hands-on research training. This multi-modal approach will enable me to acquire new knowledge in areas essential to my career goals (e.g., neuro-pharmacology and cognitive neuroscience), implement the proposed research plan, and build an independent research program with the goal of receiving an R01 prior to the end of the K23 award. The research project is a proof-of-concept study designed to examine the effects on smoking cessation of a novel pharmacological treatment, galantamine, an acetylcholinesterase inhibitor (ACHEI) that is FDA-approved to treat the cognitive symptoms of Alzheimer's disease. The scientific rationale for testing galantamine is based on evidence that: (a) cognitive deficits predict smoking relapse; (b) galantamine reduces nicotine self- administration and attenuates withdrawal-related cognitive deficits in rodents; and (c) galantamine has pro- cognitive effects in Alzheimer's disease patients. Further, my preliminary data using galantamine with treatment-seeking smokers supports this approach for smoking cessation treatment. The proposed study utilizes a Phase II model of short-term quitting that has been shown to be clinically valid for early human screening of smoking cessation medications. In this randomized, parallel-arm trial, I will compare the effects of galantamine with placebo on withdrawal-related cognitive deficits and short-term quitting success in treatment- seeking smokers. Because existing FDA-approved treatments for smoking cessation have limited efficacy, this project could have an important clinical impact. The environment at the Center for Interdisciplinary Research on Nicotine Addiction (CIRNA) at the University of Pennsylvania (UPenn) is uniquely equipped to support my training needs. I will be mentored by Caryn Lerman, Ph.D. (CIRNA Director, primary mentor) and Henry Kranzler, M.D. (Co-Director, Center for Studies of Addiction, co-mentor). My mentorship committee includes scientists in the areas of neuropharmacology, genetics, and neuroscience. Mentorship will be complemented by focused coursework and participation in seminars and workshops at UPenn. In addition to these intellectual resources, CIRNA will provide the practical resources needed to conduct my research, including use of an extensive infrastructure for participant recruitment, medical screening, data management, and biostatistical support. Additional financial support provided through CIRNA will enable me to have 90% protected time as a new Assistant Professor in the Department of Psychiatry to conduct the proposed training and research and to develop my career. This comprehensive, interdisciplinary mentored approach will enhance my clinical research skills and my ability to compete successfully for R01 funding and establish an independent program of research.

描述（由申请人提供）：作为一名临床心理学家，我的长期职业目标是建立独立的以患者为导向的研究（POR），该职业重点是对尼古丁依赖性更有效治疗的开发和评估，特别是减少戒断相关的认知缺陷（称为亲认知治疗）。我先前的培训使我能够发展提供FDA批准的戒烟治疗和进行人类实验室研究的技能。我的毕业和实习培训主要关注心理生理学，压力反应和尼古丁依赖性。作为博士后研究员，我将这种培训扩展到尼古丁依赖治疗研究和神经认知研究。但是，为了实现我的长期职业目标，我必须解决自己的知识和培训中的关键差距。 2012年7月1日，我 将被任命为UPenn精神病学系的助理教授，这将使我能够开始从事认知和戒烟治疗的独立职业。 K23机制将使我至少将90％的时间和精力集中在培养独立临床研究人员的职业中。我的培训目标以逻辑方式进展，使我为过渡到该领域的独立研究事业做好准备。其中包括：1）获取神经药理学和认知神经科学领域的新知识，以了解尼古丁依赖治疗疗效的机制，尤其是获得性认知药物； 2）进行一个研究项目，以评估亲认知药物是否会逆转与戒断相关的认知缺陷并提高戒烟率； 3）开发传达我的研究结果所需的技能，以确保随后的研究资金并在跨学科环境中进行协作。我将通过相关课程，导师和指导委员会的指导，参加研讨会和讲习班的指导以及应用动手研究培训来实现这些培训目标。这种多模式的方法将使我能够在我的职业目标（例如神经药理学和认知神经科学）中获得重要领域的新知识，实施拟议的研究计划，并建立一个独立的研究计划，以便在K23奖项结束之前获得R01。该研究项目是一项概念验证研究，旨在检查对新型药理治疗，甘氨酸，乙酰胆碱酯酶抑制剂（ACHEI）的戒烟的影响，该治疗因FDA批准以治疗阿尔茨海默氏病的认知症状。测试甘氨酸的科学原理是基于：（a）认知缺陷预测吸烟复发的证据； （b）甘氨酸减少尼古丁自我给药，并减轻啮齿动物中与戒断相关的认知缺陷； （c）甘氨酸对阿尔茨海默氏病患者具有积极认知作用。此外，我的初步数据使用甘氨酸和寻求治疗的吸烟者支持这种戒烟治疗方法。拟议的研究利用了短期戒烟的II期模型，该模型已证明对吸烟药物的早期筛查在临床上有效。在这项随机的平行臂试验中，我将比较甘氨酸与安慰剂对戒断相关的认知缺陷的影响以及在寻求吸烟者方面的短期退出成功。由于现有的FDA批准用于戒烟的治疗方法有限，因此该项目可能会产生重要的临床影响。宾夕法尼亚大学（UPENN）的尼古丁成瘾（CIRNA）跨学科研究中心的环境具有独特的能力，可以满足我的培训需求。我将由Caryn Lerman博士指导。 （CIRNA主管，小学导师）和医学博士Henry Kranzler（成瘾研究中心联合主任，联合学中心）。我的指导委员会包括神经药理学，遗传学和神经科学领域的科学家。指导将与Upenn的专注课程以及参加研讨会和研讨会的参与相辅相成。除这些智力资源外，CIRNA还将提供进行我研究所需的实用资源，包括使用广泛的基础设施来招募参与者，医疗筛查，数据管理和生物统计学支持。通过CIRNA提供的额外财务支持将使我能够在精神病学系的新助理教授中获得90％的保护时间，以进行拟议的培训和研究并发展我的职业。这种全面的跨学科指导方法将提高我的临床研究技能，并能够成功争夺R01资金并建立独立的研究计划。