Repurposing cholinesterase inhibitors for smoking cessation

重新利用胆碱酯酶抑制剂来戒烟

• 批准号: 8641335
• 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/8641335
• 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; 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; Performance; 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; Risk; 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; craving; critical period; data management; dependence relapse; flexibility; improved; novel; patient oriented research; phase 2 study; primary outcome; professor; programs; public health relevance; 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在面向患者的研究（patient-oriented research， POR）领域建立独立的职业生涯，专注于开发和评估更有效的尼古丁依赖治疗方法，特别是减少戒断相关认知缺陷的治疗方法（称为前认知治疗）。我之前的培训使我能够发展提供fda批准的戒烟治疗和进行人体实验室研究的技能。我的研究生和实习训练主要集中在心理生理学、应激反应和尼古丁依赖方面。作为博士后，我将这一培训扩展到尼古丁依赖治疗研究和神经认知研究。然而，为了实现我的长期职业目标，我必须解决我在知识和培训方面的关键差距。2012年7月1日，我