An abuse liability assessment of the glo tobacco heating product in comparison to combustible cigarettes and nicotine replacement therapy.

Tobacco heating products (THPs) have reduced emissions of toxicants compared with cigarette smoke, and as they expose user to lower levels than smoking, have for a role to play in tobacco harm reduction. One key concern of Public Health is that new tobacco and nicotine products should not be more addictive than cigarettes. To assess their abuse liability, we determined nicotine pharmacokinetics and subjective effects of two THPs compared with conventional cigarettes and a nicotine replacement therapy (Nicotine inhaler). In a randomised, controlled, open-label, crossover study healthy adult smokers used a different study product in a 5 min ad libitum use session in each of four study periods. Product liking, overall intent to use again, urge for product and urge to smoke questionnaires were utilised to assess subjective effects. Nicotine uptake was greater for the cigarette (Cmax = 22.7 ng/mL) than for either THP (8.6 and 10.5 ng/mL) and the NRT (2.3 ng/mL). Median Tmax was significantly longer for the NRT (15.03 min) than for the tobacco products (4.05-6.03 min). Product liking and overall intent to use again was highest for the cigarette, and higher for the THPs than the NRT. Urge to smoke was reduced more by the cigarette than by the other three products. Urge to use the THPs was greater than the NRT. These findings suggest that the abuse liability of the THPs lies between that of subjects usual brand cigarettes and the NRT.

Pharmacokinetic and subjective assessment of prototype JUUL2 electronic nicotine delivery system in two nicotine concentrations, JUUL system, IQOS, and combustible cigarette.

RATIONALE: Electronic nicotine delivery systems and heated tobacco products are noncombustible alternatives for adult smokers. Evidence suggests sufficient nicotine delivery and satisfying effects are necessary to facilitate switching away from smoking; nicotine delivery varies across electronic nicotine delivery systems within limited nicotine concentrations. OBJECTIVES: To assess the nicotine delivery and subjective effects of prototype JUUL2 System in two nicotine concentrations, currently-marketed US JUUL System ("JUUL"), IQOS-brand heated tobacco product, and combustible cigarettes. METHODS: Adult smokers (N = 40) completed a 5-arm cross-over product-use laboratory confinement study. Nicotine pharmacokinetics and subjective effects were assessed following use of: (1) JUUL2 prototype 18 mg/mL nicotine; (2) JUUL2 prototype 40 mg/mL; (3) JUUL 59 mg/mL; (4) IQOS 18 mg/g; and (5) usual brand combustible cigarette, each evaluated during ad libitum (10 min) and controlled (5 min, 10 standardized puffs) use. RESULTS: Nicotine delivery was greatest for combustible cigarettes, followed by JUUL2 prototype 40 mg/mL, IQOS, JUUL2 prototype 18 mg/mL, and JUUL 59 mg/mL. Nicotine delivery from JUUL2 prototype 18 mg/mL was significantly greater than JUUL 59 mg/mL after ad libitum use. JUUL products were significantly more satisfying and effective at reducing craving than IQOS. JUUL2 prototype 40 mg/mL was significantly more aversive than other JUUL products. CONCLUSIONS: Prototype JUUL2 and JUUL 59 mg/mL products were rated higher than IQOS on subjective measures associated with switching away from smoking. The JUUL2 prototype 40 mg/mL produced aversive responses and would require modifications to be a viable product for adult smokers. Nicotine delivery and subjective responses to JUUL2 prototype 18 mg/mL suggest a product based on this prototype may facilitate increased switching among adult smokers.

Assessment of Drug Delivery Kinetics to Epidermal Targets In Vivo.

It has proven challenging to quantify 'drug input' from a formulation to the viable skin because the epidermal and dermal targets of topically applied drugs are difficult, if not impossible, to access in vivo. Defining the drug input function to the viable skin with a straightforward and practical experimental approach would enable a key component of dermal pharmacokinetics to be characterised. It has been hypothesised that measuring drug uptake into and clearance from the stratum corneum (SC) by tape-stripping allows estimation of a topical drug's input function into the viable tissue. This study aimed to test this idea by determining the input of nicotine and lidocaine into the viable skin, following the application of commercialised transdermal patches to healthy human volunteers. The known input rates of these delivery systems were used to validate and assess the results from the tape-stripping protocol. The drug input rates from in vivo tape-stripping agreed well with the claimed delivery rates of the patches. The experimental approach was then used to determine the input of lidocaine from a marketed cream, a typical topical product for which the amount of drug absorbed has not been well-characterised. A significantly higher delivery of lidocaine from the cream than from the patch was found. The different input rates between drugs and formulations in vivo were confirmed qualitatively and quantitatively in vitro in conventional diffusion cells using dermatomed abdominal pig skin.

Assessment of priority tobacco additives per the requirements of the EU Tobacco Products Directive (2014/40/EU): Part 3, Smoking behavior and plasma nicotine pharmacokinetics.

This publication is part of a series of 3 publications and describes the clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU under which Member States require manufacturers and importers of cigarettes and Roll Your Own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies (European Union, 2016). In our clinical study, two distinct end points were investigated, namely measuring plasma nicotine pharmacokinetics as a measure of nicotine uptake, and analyses of changes in smoker puffing behavior as a measure of cigarette smoke inhalation. This clinical study indicated that the inclusion of none of the priority additives either as single additive or as part of a chemical mixture, facilitated nicotine uptake. Furthermore, the data did not suggest that differences in the inhalation pattern of cigarette smoke of any of the Priority Additives tested occurred when compared to the additive-free reference cigarette. Finally, it is concluded that neither the scientific literature nor our study gave circumstantial indications of increased addictiveness for cigarettes containing these priority additives.

To quit or not: Vulnerability of women to smoking tobacco.

Tobacco smoking is currently on the rise among women, and can pose a greater health risk. In order to understand the nature of the increase in smoking prevalence among women, we focused on the vulnerability of women to smoking behaviors--smoking cessation or tobacco addiction--and performed a systematic review of the socioeconomic and intrinsic factors as well as tobacco ingredients that affect women's susceptibility to smoking tobacco. We observed that nicotine and other tobacco components including cocoa-relatives, licorice products, and menthol aggravate tobacco addiction in women rather than in men. Various genetic and epigenetic alterations in dopamine pathway and the pharmaco-kinetics and -dynamic factors of nicotine also showed potential evidences for high susceptibility to tobacco addiction in women. Therefore, we suggest systemic approaches to prevent tobacco smoking-related health risks, considering gene-environment-gender interaction.

Scientific assessment of the use of sugars as cigarette tobacco ingredients: a review of published and other publicly available studies.

Sugars, such as sucrose or invert sugar, have been used as tobacco ingredients in American-blend cigarettes to replenish the sugars lost during curing of the Burley component of the blended tobacco in order to maintain a balanced flavor. Chemical-analytical studies of the mainstream smoke of research cigarettes with various sugar application levels revealed that most of the smoke constituents determined did not show any sugar-related changes in yields (per mg nicotine), while ten constituents were found to either increase (formaldehyde, acrolein, 2-butanone, isoprene, benzene, toluene, benzo[k]fluoranthene) or decrease (4-aminobiphenyl, N-nitrosodimethylamine, N-nitrosonornicotine) in a statistically significant manner with increasing sugar application levels. Such constituent yields were modeled into constituent uptake distributions using simulations of nicotine uptake distributions generated on the basis of published nicotine biomonitoring data, which were multiplied by the constituent/nicotine ratios determined in the current analysis. These simulations revealed extensive overlaps for the constituent uptake distributions with and without sugar application. Moreover, the differences in smoke composition did not lead to relevant changes in the activity in in vitro or in vivo assays. The potential impact of using sugars as tobacco ingredients was further assessed in an indirect manner by comparing published data from markets with predominantly American-blend or Virginia-type (no added sugars) cigarettes. No relevant difference was found between these markets for smoking prevalence, intensity, some markers of dependence, nicotine uptake, or mortality from smoking-related lung cancer and chronic obstructive pulmonary disease. In conclusion, thorough examination of the data available suggests that the use of sugars as ingredients in cigarette tobacco does not increase the inherent risk and harm of cigarette smoking.

Assessment of chronic exposure to cigarette smoke and its change during pregnancy by segmental analysis of maternal hair nicotine.

This study aimed to investigate the association between biomarkers of fetal exposure to smoking during the whole pregnancy, nicotine in maternal and newborns hair samples, and quantitative measurement of smoking intake and exposure evaluated by maternal self-reported questionnaire. Study subjects were 150 mothers and their newborns from a hospital in Barcelona. A questionnaire including smoking habits was completed in the third trimester of pregnancy and on the day of delivery. Nicotine content was measured in two subsequent segments of maternal hair accounting for the first and last months of pregnancy, and in fetal hair. The geometric mean of nicotine concentration in maternal hair discriminated between nonexposition (3.84 and 2.80 ng/mg in distal and proximal hair segment, respectively) and exposition to cigarette smoke during pregnancy (6.06 and 4.30 ng/mg in distal and proximal hair segment, respectively) (P<0.05), and between these two classes and active smoking (14.40 and 11.08 ng/mg in distal and proximal hair segment, respectively). Maternal hair nicotine was able to differentiate levels of exposure to tobacco smoke and levels of intake. Nicotine concentration in hair from newborns did not differentiate between exposure and nonexposure to environmental tobacco smoke (ETS) in nonsmoking mothers. Finally, chronic exposure to cigarette smoke during pregnancy, assessed by maternal hair nicotine, correlated negatively with anthropometric parameters of newborns.

Environmental tobacco smoke and lung cancer: a reappraisal.

It is biologically plausible that environmental tobacco smoke (ETS) has a contributory role in the induction of lung cancer in nonsmoking individuals. However, recent findings have strengthened previous assumptions that a major part of the observed increase in lung cancer risk reported from epidemiological studies on ETS-exposed nonsmokers can be related to misclassification of smoking status and inappropriate selection of controls as well as to certain confounding factors related to life-style, and possibly also to hereditary disposition. Dose-response extrapolation-supported by a more solid database for active smokers-reflects a possible increase in lung cancer that appears to be more than one order of magnitude lower than indicated by the epidemiological studies that have been used to support regulatory action in the United States. The epidemiological studies on ETS conducted so far lack the required sensitivity to confirm increases in risk of such low magnitudes. Self-reported information on exposure to tobacco smoke has been found to be unreliable, and data from interviews with proxy respondents even more so. In addition, determination of cotinine to establish smoking status is inadequate for use in this context, i.e., to assure that misclassification in the range 5-10% does not occur; due to genetically based differences in the rate of nicotine metabolism, some active smokers will not be detected. Further, due the short half-life of cotinine in the organism, a self-reported nonsmoker may, in principle, have been a lifelong heavy smoker until just before the sampling takes place. For some of the major studies, preferential inclusion of disease-prone individuals of very low socioeconomic status among cases seems to have been present to a varying extent. Due to inclusion of this group, life-style and hereditary disposition may result in a disproportionally large impact on the recorded overall lung cancer rate. Further, a possible major confounder causing inflated risk estimates, and that was not controlled for, is apparently a high intake of saturated fat, which to a varying extent is coupled to inadequate intake of anticarcinogens present in certain foods of plant origin. The one-sided preoccupation with ETS as a causative factor of lung cancer in nonsmokers may seriously hinder the elucidation of the multifactorial etiology of these tumors.

Menthol and nonmenthol cigarettes and smoke exposure in black and white women.

Purposes of this investigation were to compare smoke constituent exposure (CO and nicotine boosts) and smoking topography parameters between black and white women, and between women regularly using menthol or nonmenthol cigarettes. A two-factor factorial design with a sample of 37 women stratified by race and menthol or nonmenthol cigarette use was implemented. There were significant main and interaction effects of race and menthol/nonmenthol use on CO boost. Black women had a mean CO boost of 10.1 ppm vs. 7.2 ppm for white women, while women using nonmenthol cigarettes had a higher CO boost (mean = 10.6 ppm) compared to those regularly using menthol cigarettes mean = 6.5 ppm). White menthol smokers had the lowest CO boost of all subgroups. There was a trend for black women to have higher nicotine boost than white women (21.4 ng/ml vs. 15.9 ng/ml). Black women had nonsignificantly higher puff volumes compared to white women (mean = 48.4 vs. 43.5 ml), while nonmenthol smokers had nonsignificantly higher puff volumes than menthol smokers (mean = 48.5 vs. 42.7 ml). Lower CO boost with mentholated cigarettes suggests factors beyond mentholation may affect elevated smoke constituent exposure among black women.

Kinetic analysis of regional (S)(-)11C-nicotine binding in normal and Alzheimer brains--in vivo assessment using positron emission tomography.

A compartment model has been developed and validated for the kinetic analysis of (S)(-)11C-nicotine binding in the brain including a compensation for the influence of regional cerebral blood flow (rCBF). The model was applied to eight patients with Alzheimer disease (AD) and three age-matched healthy volunteers who received intravenous injections of (S)(-)11C-nicotine and 11C-butanol. The uptake and time course of radioactivity in different brain regions were assessed by positron emission tomography (PET). The rate constant k2* was formulated by dividing the K2 rate constant for 11C-nicotine with the K1 rate constant for 11C-butanol and thereby minimizing the influence of CBF on the quantitated binding of 11C-nicotine. The rate constant k2* for 11C-nicotine giving a quantitative measure of binding in the brain tissue was significantly higher in the temporal and frontal cortices as well as in the hippocampus of AD brains as compared with controls, indicating deficits in specific nicotinic binding in these brain areas of AD patients. A significant and negative correlation was obtained between cognitive function (Mini-Mental State Examination) and k2* of 11C-nicotine in the temporal and frontal cortices as well as in the hippocampus. The described kinetic model allowed in vivo quantification of nicotinic receptor binding in brain, which will be of importance in the future for evaluation of diagnosis, progress of disease, as well as the therapeutic effects in the treatment of AD.

The pros and cons of transdermal nicotine therapy.

OBJECTIVE: To review current knowledge of the efficacy, safety and cost of transdermal nicotine therapy for smoking cessation. DATA SOURCES AND STUDY SELECTION: 1. Published and unpublished reports of randomised, double-blind trials of at least 12 weeks' duration, in smokers motivated to cease smoking, identified by a search of the MEDLINE database, article and book bibliographies, Current contents, and by a request to the Medical Department of Ciba-Geigy (Australia) Ltd. 2. A clinical trial of 1500 smokers using transdermal nicotine (S Gourlay, unpublished data). DATA SYNTHESIS: Transdermal nicotine more than doubles the success rates of smoking cessation attempts in motivated subjects who smoke at least 10-15 cigarettes per day (odds ratio 12 months after quitting, 2.3; 95% confidence interval, 1.6-3.4). Application site reactions are not uncommon (erythema or burning < or = 16%, transient itch < or = 50%) and cause discontinuation of therapy in up to 10% of subjects. Sleep disturbance due to nocturnal nicotine absorption occurs in up to 13% of subjects when patches are worn overnight. Smoking or nicotine chewing gum used concurrently with transdermal nicotine could raise peak nicotine levels but is unlikely to adversely affect individuals with established tolerance to nicotine. Smoking and (theoretically) nicotine replacement therapies should be avoided in pregnancy or patients with unstable coronary artery disease. In such patients, the risk-benefit ratio of nicotine replacement therapies may be favourable for nicotine-dependent smokers unable to cease smoking by alternative methods. CONCLUSIONS: Transdermal nicotine is an effective smoking cessation therapy for motivated, nicotine-dependent smokers. As most smokers can cease smoking on their own, and the patches are costly, they should be recommended only for smokers who are unable to quit by simpler means and those likely to suffer severe nicotine withdrawal symptoms.

Tobacco dependence and the nicotine patch. Clinical guidelines for effective use.

OBJECTIVE: A comprehensive review of transdermal nicotine treatment for tobacco dependence, with recommendations derived from the research literature. DATA SOURCES: English-language clinical trials. STUDY SELECTION: Clinical trials using placebo-controlled, double-blind methodology (11 studies) with at least 6 months of follow-up after treatment (eight studies) and biochemical verification of smoking status. DATA SYNTHESIS: Nicotine patches produce end-of-treatment smoking cessation rates that range from 18% to 77%; these rates are about twice those of placebo-treated subjects. Nicotine patches produced 6-month abstinence rates of 22% to 42%, while placebo patches produced quit rates of 5% to 28%. Nicotine patches appear to reduce some, but not all, nicotine withdrawal symptoms. For instance, while the patch reduces craving for cigarettes and negative moods, it does not appear to reduce hunger or weight gain. The clinical trials literature suggests that proper adjuvant smoking cessation counseling is crucial in determining successful long-term outcome with the nicotine patch, and suggests that 6 to 8 weeks of patch therapy may be an adequate duration for most patients. CONCLUSIONS: Nicotine patches are an effective aid to tobacco dependence treatment. However, success rates vary greatly across research studies and may be influenced highly by the nature and intensity of adjuvant smoking cessation counseling. More research is needed to identify optimal duration, dosage, and individualization of patch therapy. The impact of nicotine patches (more than 5 million users with $1 billion in sales for 1992) also raises important ethical and public health issues.