Abuse liability of two electronic nicotine delivery systems compared with combustible cigarettes and nicotine gum from an open-label randomized crossover study.

An assessment of the likelihood of use and abuse potential for new tobacco products is an important part of tobacco product regulation in the United States and abroad. This paper reports the results of a randomized, open-label, crossover clinical study that assessed factors related to product adoption and abuse liability (AL), comparing two closed electronic nicotine delivery system (ENDS) products to combustible cigarettes and nicotine gum, high- and low-AL comparator products, respectively. During an 11-day confinement period that included multiple product familiarization sessions, healthy adult smokers participated in AL test sessions to evaluate the abuse liability of each product. During these test sessions, changes in subjective measures; speed and amount of nicotine uptake; and maximum changes in physiological effects before, during, and after use of each assigned product were assessed over 4 h. Positive subjective effects measures scores such as product-liking and overall intent to use again were highest for cigarettes, followed by the Vuse ENDS, with nicotine gum consistently having the lowest scores. The PK results (Cmax and Tmax) of the Vuse ENDS products are between UB cigarettes and nicotine gum, which correlates with the subjective effects. All nicotine uptake measures for the Vuse ENDS products were lower than that of usual brand (UB) cigarettes, including peak nicotine uptake and overall nicotine uptake, and were either similar to or lower than nicotine gum. The time course of nicotine uptake after use of the ENDS was more similar to that of combustible cigarettes than nicotine gum. The results indicate that the AL of each ENDS product is lower than that of UB cigarettes and similar to that of nicotine gum.

Changes in Biomarkers of Exposure and Potential Harm in Smokers Switched to Vuse Vibe or Vuse Ciro Electronic Nicotine Delivery Systems.

Electronic nicotine delivery systems (ENDS) have the potential to provide nicotine to tobacco consumers while reducing exposure to combustion-related toxicants. Here, we report changes in biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in smokers who completely switched to Vuse Vibe and Vuse Ciro ENDS products, or to smoking abstinence in a randomized, controlled clinical study. Thirteen BoE (12 urinary and one blood) that indicate exposure to harmful and potentially harmful toxicants (HPHCs) were evaluated at baseline on day 5. Urinary BoPH linked to oxidative stress, platelet activation, and inflammation were also assessed at baseline, and on day 5 and day 7. Nicotine exposure was lower in Vuse Vibe and Vuse Ciro groups compared to baseline values. Urinary non-nicotine BoE decreased significantly (52.3-96.7%) in the Vuse ENDS groups, and the reductions were similar in magnitude to those observed in the abstinence group. Blood carboxyhemoglobin decreased 52.8-55.0% in all study groups. Decreases (10-50%) in BoPH were observed in all study groups. Thus, smokers who switch exclusively to Vuse Vibe or Vuse Ciro products or completely abstain from smoking are exposed to substantially lower levels of HPHCs, and experience improvements in BoPH of oxidative stress and inflammation pathways.

Part two: an unblinded, parallel, randomized study to assess nicotine pharmacokinetics of four Vuse Solo ENDS flavors in smokers.

We report the findings from a randomized, parallel study designed to evaluate nicotine pharmacokinetics (PK) following 10 min of ad libitum use of electronic nicotine delivery system (ENDS) in four flavor variants. Subjects were randomized an investigational product (IP) and blood samples were collected for PK assessments during a test session. Primary endpoints were baseline-adjusted values of maximum plasma nicotine concentration (Cmax) and area under the nicotine concentration-vs-time curve up to 60 min (AUCnic0-60). Baseline-adjusted mean Cmax ranged from 6.53 to 8.21 ng/mL, and mean AUCnic0-60 ranged from 206.87 to 263.52 ng min/mL for all ENDS IPs. Results of geometric mean Cmax and AUCnic0-60 values were within 95% confidence intervals (CI) among the ENDS IP flavor variants tested.

Part one: abuse liability of Vuse Solo (G2) electronic nicotine delivery system relative to combustible cigarettes and nicotine gum.

Abuse liability (AL) of electronic nicotine delivery systems (ENDS) is relevant as the category increases in popularity as a potentially less-harmful alternative to cigarette smoking. AL assessments are important to the FDA in determining if a new product is appropriate for the protection of public health. This paper reports the results for Vuse Solo (G2 cartridge design) compared to high and low AL-comparators evaluated in an open-label, randomized crossover confinement AL study. The confinement design was adapted from previous ambulatory studies of Vuse Solo (G1 cartridge design) and included product familiarization sessions before each four-hour test session in which subjective measures, nicotine pharmacokinetics (PK), and physiological endpoints were assessed following a single 10-min ad libitum product use session. Product liking, intent to use again, suppression of urge to smoke, and nicotine PK were lower after use of Vuse Solo compared to cigarettes and higher after use of Vuse Solo compared to nicotine gum. No significant differences in blood pressure or heart rate were observed between the products pre- to post-product use. These data reinforce previous research and provide the scientific evidence to support regulatory decisions demonstrating that Vuse Solo has an AL profile lower than that of combustible cigarettes but higher than that of nicotine gum and, therefore, may be a suitable replacement for cigarette smoking for some adult smokers.

Part three: a randomized study to assess biomarker changes in cigarette smokers switched to Vuse Solo or Abstinence.

Biomarkers of exposure (BoE) can help evaluate exposure to combustion-related, tobacco-specific toxicants after smokers switch from cigarettes to potentially less-harmful products like electronic nicotine delivery systems (ENDS). This paper reports data for one (Vuse Solo Original) of three products evaluated in a randomized, controlled, confinement study of BoE in smokers switched to ENDS. Subjects smoked their usual brand cigarette ad libitum for two days, then were randomized to one of three ENDS for a 7-day ad libitum use period, or to smoking abstinence. Thirteen BoE were assessed at baseline and Day 5, and percent change in mean values for each BoE was calculated. Biomarkers of potential harm (BoPH) linked to oxidative stress, platelet activation, and inflammation were also assessed. Levels decreased among subjects randomized to Vuse Solo versus Abstinence, respectively, for the following BoE: 42-96% versus 52-97% (non-nicotine constituents); 51% versus 55% (blood carboxyhemoglobin); and 29% versus 96% (nicotine exposure). Significant decreases were observed in three BoPH: leukotriene E4, 11-dehydro-thromboxane B2, and 2,3-dinor thromboxane B2 on Day 7 in the Vuse Solo and Abstinence groups. These findings show that ENDS use results in substantially reduced exposure to toxicants compared to smoking, which may lead to reduced biological effects.

Biomarkers of Tobacco Exposure Decrease After Smokers Switch to an E-Cigarette or Nicotine Gum.

INTRODUCTION: The aerosol composition of electronic cigarettes (ECs) suggests that exposure to toxicants during use is greatly reduced compared to exposure from combustible cigarettes (CCs). METHODS: This randomized, parallel-group, clinical study enrolled smokers to switch to Vuse Solo (VS) Digital Vapor Cigarettes (Original or Menthol) or Nicorette 4 mg nicotine gum (NG) in a controlled setting. Subjects who smoked CCs ad libitum for 2 days during a baseline period were then randomized to ad libitum use of either VS or NG for 5 days. Biomarkers of 23 toxicants were measured in 24-hour urine samples and blood collected at baseline and following product switch. RESULTS: A total of 153 subjects completed the study. Total nicotine equivalents decreased in all groups, but higher levels were observed in the VS groups compared to the NG groups, with decreases of 38% and 60%-67%, respectively. All other biomarkers were significantly decreased in subjects switched to VS, and the magnitude of biomarker decreases was similar to subjects switched to NG. Decreases ranged from 30% to greater than 85% for constituents such as benzene and acrylonitrile. CONCLUSIONS: These results indicate that exposure to toxicants when using VS is significantly reduced compared to CC smoking, and these reductions are similar to those observed with use of NG. Although statistically significantly decreased, nicotine exposure is maintained closer to CC smoking with VS use compared to NG use. This research suggests that use of VS exposes consumers to fewer and lower levels of smoke toxicants than CCs while still providing nicotine to the consumer. IMPLICATIONS: This is the first study to report changes in nicotine delivery and biomarkers of tobacco exposure following a short-term product switch from CCs to either an EC or NG in a controlled environment. The study shows that nicotine exposure decreased in both groups but was maintained closer to CC smoking with the EC groups. Biomarkers of tobacco combustion decreased to similar levels in both EC and gum groups.

Nicotine pharmacokinetics of electronic cigarettes: A review of the literature.

E-cigarettes are battery-powered electronic devices from which users can inhale nicotine following its aerosolisation from a liquid solution. Some regulators and public health bodies consider e-cigarettes as potentially playing a major role in tobacco harm reduction. Their ability to provide nicotine to smokers in both amount and in a manner and form generally similar to cigarette smoking have been proposed as key components to help smokers reduce or cease the use of combustible cigarettes. Nicotine pharmacokinetic studies of e-cigarettes have been performed for a number of years and are beginning to show how nicotine delivery is evolving as the products themselves evolve. In this review, we provide a critical overview of the literature to describe what is known about nicotine delivery from e-cigarettes. We will discuss how the progression of e-cigarette design, development, and user familiarity has allowed increases in nicotine availability to the user, in the context of how much and how rapidly nicotine is delivered during acute-use periods. This review will also provide insight into current research gaps and highlight the potential utility of modelling and the standardisation of methodologies used to assess nicotine delivery to facilitate identification of products that are best suited to displace cigarette smoking among adult smokers.

Intestinal signaling to GABAergic neurons regulates a rhythmic behavior in Caenorhabditis elegans.

The Caenorhabditis elegans defecation motor program (DMP) is a highly coordinated rhythmic behavior that requires two GABAergic neurons that synapse onto the enteric muscles. One class of DMP mutants, called anterior body wall muscle contraction and expulsion defective (aex) mutants, exhibits similar defects to those caused by the loss of these two neurons. Here, we demonstrate that aex-2 encodes a G-protein-coupled receptor (GPCR) and aex-4 encodes an exocytic SNAP25 homologue. We found that aex-2 functions in the nervous system and activates a G(s)alpha signaling pathway to regulate defecation. aex-4, on the other hand, functions in the intestinal epithelial cells. Furthermore, we show that aex-5, which encodes a pro-protein convertase, functions in the intestine to regulate the DMP and that its secretion from the intestine is impaired in aex-4 mutants. Activation of the G(s)alpha GPCR pathway in GABAergic neurons can suppress the defecation defect of the intestinal mutants aex-4 and aex-5. Lastly, we demonstrate that activation of GABAergic neurons using the light-gated cation channel channelrhodopsin-2 is sufficient to suppress the behavioral defects of aex-2, aex-4, and aex-5. These results genetically place intestinal genes aex-4 and aex-5 upstream of GABAergic GPCR signaling. We propose a model whereby the intestinal genes aex-4 and aex-5 control the DMP by regulating the secretion of a signal, which activates the neuronal receptor aex-2.