Clinical Pharmacology of Electronic Cigarettes

 描述（由申请人提供）：电子烟（EC）是尼古丁输送装置，可产生由用户吸入的含尼古丁气雾剂。使用者认为EC有助于戒烟传统烟草卷烟（TC），并且与TC相比，EC具有较低的不良健康影响风险，可用于公共场所，降低成本，并且缺乏与TC使用相关的有害附着气味。近年来，EC的使用急剧增长，目前估计是一个十亿美元的产业，现有400多个EC品牌，美国三大烟草公司现在销售自己的品牌。FDA已经宣布了监管EC的意图。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作为尼古丁输送装置的功能与TC相同，并且EC将被证明与TC一样上瘾，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使用者将体验到类似的奖励，并且没有更大的戒断症状或渴望;并且EC/ TC双重使用者不会以与高产量与低产量尼古丁TC吸烟者相同的方式滴定其每日尼古丁摄入量。我们的建议特别关注被认为与成瘾性最密切相关的领域 EC的潜力，即：（1）EC作为尼古丁输送装置，涵盖尼古丁摄入和药代动力学、使用时间模式和尼古丁滴定等问题;以及（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效应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和TC使用的生物标志物的识别和验证。研究受试者将是TC和EC的双重使用者，因此我们可以在受试者内设计中比较经验丰富的使用者的两种使用方式。本研究将包括两个为期1周的区组（仅EC或仅TC条件），其中4天为门诊患者随意使用产品，随后3天为临床研究病房，包括单次使用药代动力学研究、产品使用监测、主观评估、血液和尿液采集以评估生物标志物以及24小时心血管监测。在尼古丁产品停药期间，在第二个区组结束时再增加两天，评估类似的测量结果。

 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.