Clinical Pharmacology of Electronic Cigarettes

 描述(申请人提供)：电子烟(EC)是一种尼古丁输送装置，它会产生一种含有尼古丁的气雾剂，供使用者吸入。使用者认为EC有助于戒除传统烟草香烟(TC)的吸烟，并假定与TC相比，EC对健康有害影响的风险更低，在公共场所使用的可能性更低，成本更低，而且没有与TC使用相关的有害附着气味。近年来，EC的使用急剧增长，目前估计是一个价值10亿美元的行业，现有超过400个EC品牌，美国三大烟草公司现在营销自己的品牌。FDA已经宣布了对EC进行监管的意图。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，EC将被证明与TC一样容易上瘾，但情况可能并非如此，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的全身性尼古丁暴露将更低；尽管EC的尼古丁摄入量较低，EC的使用者仍将经历类似的奖励，并且与TC相比，不会出现更严重的戒断症状或渴望；EC/TC双重吸烟者不会像TC吸烟者那样滴定他们的每日尼古丁摄入量。我们的建议特别关注那些被认为与成瘾者关系最密切的领域 (2)使用EC的主观影响，包括使用与奖励、戒断和渴求的关系。我们还将研究EC使用的安全性方面(通过评估使用EC的心血管和激素影响以及暴露于潜在有毒成分的生物标记物)，并探索识别和验证可能有助于区分EC和TC使用的生物标记物。研究对象将是TC和EC的双重使用者，这样我们就可以在受试者内设计中比较这两种使用方式在有经验的使用者中。这项研究将包括两个为期一周的时段(仅限EC或仅限TC)，包括4天的门诊临时产品使用，然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、用于评估生物标志物的血液和尿液采集，以及24小时的心血管监测。第二组结束时的另外两天将评估尼古丁产品戒断期间的类似测量。

 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.