Animal models to inform FDA tobacco regulation: Assessing the relative abuse liability of different classes of tobacco products

为 FDA 烟草监管提供信息的动物模型：评估不同类别烟草产品的相对滥用倾向

• 批准号: 9770827
• 负责人: ANDREW Charles HARRIS
• 金额: $ 42.11万
• 依托单位: HENNEPIN HEALTHCARE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770827
• 关键词: Acetaldehyde; Address; Aerosols; Animal Model; Animals; Area; Attenuated; Behavioral; Characteristics; Chemicals; Cigarette; Data; Detection; Development; Dose; Electronic cigarette; Evaluation; Exhibits; Exposure to; Formulation; Goals; Human; Lead; Liquid substance; Measures; Modeling; Monoamine Oxidase Inhibitors; Nicotine; Pre-Clinical Model; Procedures; Psychological reinforcement; Rattus; Regulation; Reporting; Research; Self Stimulation; Smoke; Smokeless Tobacco; System; Tobacco; Tobacco Dependence; Tobacco use; addiction; analog; cigarette smoke; clinically relevant; design; innovation; nicotine replacement; novel; pre-clinical; response; tobacco abuse; tobacco products; tobacco regulatory science; volatile organic compound

PROJECT SUMMARY/ABSTRACT The goal of this study is to use preclinical models to understand whether non-nicotine constituents unique to cigarette smoke (CS) contribute to differences in abuse liability between conventional cigarettes and non- combusted, alternative nicotine delivery systems (ANDs) in order to inform FDA CTP tobacco regulation. Conventional tobacco cigarettes have greater abuse liability than ANDs, such as electronic cigarettes (ECs), smokeless tobacco (ST), and nicotine replacement therapy (NRT). Non-nicotine constituents associated with CS may contribute to the greater abuse liability of cigarettes because some of these constituents (e.g., monoamine oxidase (MAO) inhibitors, volatile organic compounds (VOCs)) can mimic or enhance the effects of nicotine, or exhibit abuse liability themselves. Evaluating this hypothesis could lead to identification of new Harmful or Potentially Harmful Constituents (HPHCs) and development of addiction-related product standards that extend beyond the FDA's current focus on nicotine. Animal models are needed for this purpose, as they avoid limitations associated with human studies. Animal studies involving exposure to extracts of commercial tobacco products have been consistent with the differential abuse liability between products observed in humans. We have found that the relative abuse liability of ST extract and EC refill liquid is similar to that of nicotine alone, whereas others have found that CS extracts can produce greater addiction-related effects than nicotine alone under certain conditions. This may reflect the higher levels of addiction-relevant non-nicotine constituents in CS extracts. The proposed studies will evaluate this possibility by directly comparing the relative abuse liability of CS, ST, and EC aerosol extracts and nicotine alone (NRT analog) in state-of-the-art, FDA- recommended models for assessing abuse liability. Levels of a range of behaviorally relevant non-nicotine constituents (e.g., MAO inhibitors, acetaldehyde) will be measured and effects of isolated MAO inhibitors and VOCs will be studied to identify the specific constituents that may be responsible for observed differences in abuse liability. In Aim 1, demand for CS extract will be compared to nicotine dose-equivalent concentrations of ST extract, EC extract, and nicotine alone when each is available in isolation or under novel concurrent-choice procedures to determine relative reinforcing efficacy and substitutability of formulations. Aim 2 will compare reinforcement-enhancing and aversive effects between formulations. Aim 3 will evaluate the reinforcement- enhancing and aversive effects of isolated MAO inhibitors and VOCs when administered alone or in combination with nicotine. It is hypothesized that CS extract will have greater addiction-related effects than the other formulations due to its higher levels of behaviorally active non-nicotine constituents (e.g., MAO inhibitors, VOCs). These studies will characterize the impact of a specific tobacco product characteristic (i.e., profile of non-nicotine constituents) in tobacco abuse and inform the FDA CTP on potential compounds to consider for addition to the list of HPHCs. As such, the data will help inform specific regulatory actions of the FDA CTP.

项目摘要/摘要 这项研究的目的是使用临床前模型来了解非纽约胺成分是否特有 香烟烟（CS）导致常规香烟和非 - 燃烧的替代性尼古丁输送系统（和），以告知FDA CTP烟草调节。 传统的烟草香烟的滥用责任比电子烟（例如电子烟）（ECS）， 无烟烟草（ST）和尼古丁替代疗法（NRT）。非纽约胺成分 CS可能会导致香烟的更大滥用责任，因为其中一些成分（例如， 单胺氧化酶（MAO）抑制剂，挥发性有机化合物（VOC）可以模仿或增强效果 尼古丁，或本身表现出虐待责任。评估这一假设可能会导致对新的识别 有害或潜在有害成分（HPHC）和与成瘾相关的产品标准的发展 这超出了FDA目前对尼古丁的关注。为此目的需要动物模型 避免与人类研究相关的局限性。动物研究涉及暴露于商业提取物 烟草产品与观察到的产品之间的差异滥用责任是一致的 人类。我们发现ST提取物和EC补充液体的相对虐待责任与 仅尼古丁，而其他人发现CS提取物可以产生与成瘾相关的效果，而不是 在某些条件下，仅尼古丁。这可能反映了与成瘾相关的非纽约定 CS提取物中的成分。拟议的研究将通过直接比较相对来评估这种可能性 CS，ST和EC气溶胶提取物和尼古丁的滥用责任（NRT Analog）在最新的FDA-中 建议评估滥用责任的模型。一系列与行为相关的非纽约汀的水平 将测量成分（例如，MAO抑制剂，乙醛），分离的MAO抑制剂和效果 将研究VOC，以确定可能导致观察到的差异的特定成分 虐待责任。在AIM 1中，将对CS提取物的需求与尼古丁剂量等效浓度进行比较 单独或在新型并发选择下，单独使用ST提取物，EC提取物和尼古丁 确定配方相对增强功效和替代性的程序。 AIM 2将比较 配方之间的增强增强作用和厌恶作用。 AIM 3将评估加固 - 单独管理或在 结合尼古丁。假设CS提取物将具有比成瘾相关的更大的作用 其他制剂由于其行为活跃的非新核酸成分的较高水平（例如，MAO抑制剂， VOC）。这些研究将表征特定烟草产品特征的影响（即 烟草滥用中的非纽约胺成分），并告知FDA CTP潜在化合物要考虑的化合物 在HPHC列表中增加。因此，数据将有助于告知FDA CTP的特定监管行动。