Clinical Pharmacology of Electronic Cigarettes

 描述（由申请人提供）：电子烟（EC）是一种尼古丁输送装置，可产生供用户吸入的含尼古丁气雾剂。用户认为 EC 有助于戒掉传统烟草卷烟 (TC)，并且与 TC 相比，其对健康产生不良影响的风险较低，具有在公共场所使用的潜力，降低了成本，并且没有与 TC 使用相关的有害粘着气味。近年来，EC 的使用急剧增长，目前估计是一个价值 10 亿美元的产业，现有 400 多个 EC 品牌，美国三大烟草公司现在都在营销自己的品牌。 FDA 已宣布有意对 EC 进行监管。与 FDA 监管相关的关键问题包括 EC 的成瘾性和安全性。许多人认为 EC 的功能与 TC 一样，都是尼古丁输送装置，而且 EC 将被证明与 TC 一样容易上瘾，但事实可能并非如此，因为这些产品的设计和使用方法存在根本差异。例如，我们假设与 TC 相比，EC 的全身尼古丁暴露量较低；尽管尼古丁摄入量较低，但与 TC 相比，EC 使用者将获得相似的奖励，并且不会出现更大的戒断症状或渴望；并且 EC/TC 双重使用者不会像使用高尼古丁 TC 和低尼古丁 TC 的 TC 吸烟者那样调整每日尼古丁摄入量。我们的建议特别关注被认为与成瘾最密切相关的领域 EC 的潜力，即： (1) EC 作为尼古丁输送装置，涵盖尼古丁摄入量和药代动力学、使用时间模式和尼古丁滴定等问题； (2) EC 使用的主观影响，包括使用与奖励、戒断和渴望的关系。我们还将研究 EC 使用的安全性方面（通过评估使用的心血管和激素影响以及暴露于潜在有毒成分的生物标志物），并探索可能有助于区分 EC 与 TC 使用的生物标志物的识别和验证。研究对象将是 TC 和 EC 的双重用户，以便我们可以在对象内设计中比较经验丰富的用户的两种使用方式。该研究将包括两个为期 1 周的区块（仅 EC 或仅 TC 条件），其中 4 天门诊随意使用产品，随后在临床研究病房使用 3 天，包括一次性药代动力学研究、产品使用监测、主观评估、采集血液和尿液以评估生物标志物以及 24 小时心血管监测。第二组结束时的另外两天将评估戒除尼古丁产品期间的类似测量结果。

 DESCRIPTION (provided by applicant): Electronic cigarettes (EC) are nicotine delivery devices that generate a nicotine-containing aerosol which is inhaled by the user. EC are perceived by users to be useful in helping quitting smoking of conventional tobacco cigarettes (TC) as well as having a presumed lower risk of adverse health effects compared to TC, the potential for use in public places, reduced cost, and lack of the noxious clinging odors associated with TC use. The use of EC has dramatically grown in recent years and is currently estimated to be a billion dollar industry, with over 400 existing brands of EC and the three major U.S. tobacco companies now marketing their own brands. The FDA has announced the intention to regulate EC. Key questions relevant to FDA regulation include the addictiveness and safety of EC. Many believe that EC function as nicotine delivery devices in the same way as TC, and that EC will prove to be just as addictive as TC, but this may not be the case because of fundamental differences in the design and method of use of these products. For example, we hypothesize that systemic nicotine exposure will be lower with EC compared to TC; that despite lower nicotine intake EC users will experience similar reward and no greater withdrawal symptoms or craving compared to TC; and that dual EC/ TC users will not titrate their daily intake of nicotine in the same way that TC smokers of high- vs low-yield nicotine TC do. Our proposal specifically focuses on the areas that are thought to most closely relate to the addictive potential of EC, namely: (1) EC as nicotine delivery devices, covering issues of nicotine intake and pharmacokinetics, temporal patterns of use and titration of nicotine; and (2) subjective effects of EC use, including relationship of use to reward, withdrawal and craving. We will also examine aspects of safety of EC use (by assessment of cardiovascular and hormonal effects of use and of biomarkers of exposure to potentially toxic constituents) and explore the identification and validation of biomarkers that may be useful in distinguishing EC from TC use. Study subjects will be dual users of TC and EC so that we may compare both modalities of use in experienced users in a within-subject design. The study will consist of two 1-week blocks (EC-only or TC-only conditions) with 4 days of outpatient ad libitum product use followed by 3 days in a clinical research ward to include a single-use pharmacokinetic study, monitoring of product use, subjective assessments, blood and urine collections to assess biomarkers, and a 24-hour period of cardiovascular monitoring. Two additional days at the end of the 2nd block will assess similar measurements during a period of nicotine-product abstention.