Tobacco-Related Alterations in Airway Gene Expression are Rapidly Reversed Within Weeks Following Smoking-Cessation.

The physiologic response to tobacco smoke can be measured by gene-expression profiling of the airway epithelium. Temporal resolution of kinetics of gene-expression alterations upon smoking-cessation might delineate distinct biological processes that are activated during recovery from tobacco smoke exposure. Using whole genome gene-expression profiling of individuals initiating a smoking-cessation attempt, we sought to characterize the kinetics of gene-expression alterations in response to short-term smoking-cessation in the nasal epithelium. RNA was extracted from the nasal epithelial of active smokers at baseline and at 4, 8, 16, and 24-weeks after smoking-cessation and put onto Gene ST arrays. Gene-expression levels of 119 genes were associated with smoking-cessation (FDR < 0.05, FC ≥1.7) with a majority of the changes occurring by 8-weeks and a subset changing by 4-weeks. Genes down-regulated by 4- and 8-weeks post-smoking-cessation were involved in xenobiotic metabolism and anti-apoptotic functions respectively. These genes were enriched among genes previously found to be induced in smokers and following short-term in vitro exposure of airway epithelial cells to cigarette smoke (FDR < 0.05). Our findings suggest that the nasal epithelium can serve as a minimally-invasive tool to measure the reversible impact of smoking and broadly, may serve to assess the physiological impact of changes in smoking behavior.

Greater reductions in nicotine exposure while smoking very low nicotine content cigarettes predict smoking cessation.

OBJECTIVE: Reducing the nicotine content of cigarettes is a potential regulatory strategy that may enable cessation. The present study investigated the effect of nicotine exposure while smoking very low nicotine content (VLNC) cigarettes on cessation outcomes. The roles of possible sources of nicotine were also explored, including the VLNC cigarette and co-use of cigarettes with normal nicotine content. METHODS: A secondary data analysis of two analogous randomised trials of treatment seeking, adult daily smokers (n=112) who were instructed to smoke VLNC cigarettes for 6 weeks and then make a quit attempt. Controlling for baseline demographic and smoking features, the association between reductions in nicotine exposure during the 6-week trial, assessed by urinary total cotinine and biomarker-confirmed smoking abstinence 1 month later, was tested. Subsequent analyses controlled for the effects of the frequency of VLNC and normal nicotine content cigarette use and the nicotine yield of the VLNC cigarette (0.05 vs 0.09 mg). RESULTS: Greater reductions in nicotine exposure while smoking VLNC cigarettes predicted abstinence independent of individual differences in baseline smoking, cotinine, dependence, gender and study. Nicotine reduction was largest among individuals who were assigned to smoke a VLNC cigarette with lower nicotine yield and who smoked fewer normal nicotine content and VLNC cigarettes. CONCLUSIONS: In the context of nicotine regulations and corresponding research, factors that undermine nicotine reduction must be addressed, including the availability and use of cigarettes with normal nicotine content and not sufficiently reducing the nicotine yield of cigarettes. Maximising nicotine reduction may facilitate smoking cessation. TRIAL REGISTRATION NUMBERS: NCT 01050569 and NCT 00777569.

Sex differences in response to reduced nicotine content cigarettes.

BACKGROUND: When switching from usual brand cigarettes, very low nicotine content (VLNC) cigarettes lead to a reduction in the number of cigarettes smoked, toxicant exposure, withdrawal symptoms and dependence. One area that has been relatively unexplored is what factors might moderate the effects of VLNC cigarettes. This exploratory analysis focuses on sex differences in responses to VLNC cigarettes and nicotine replacement therapy. METHODS: An exploratory secondary analysis of a randomized trial of 235 participants (58% female, mean age 47 years) comparing a) 0.05-0.09 mg nicotine yield cigarettes; b) 21 mg nicotine patch and 3) 0.05-0.09 nicotine yield cigarettes with 21 mg nicotine patch was conducted. We focused on sex differences in product use, and impact of products on withdrawal response from usual brand cigarettes and abstinence by randomized group. RESULTS: The combination of VLNC cigarettes and nicotine patch was more effective in reducing use of VLNC cigarettes and withdrawal symptoms among males than females, whereas females were equally responsive to VLNC cigarettes with and without the nicotine patch. Females were more likely to quit smoking than males when assigned to either of the conditions that incorporated the VLNC cigarettes; however, males were more likely to quit smoking in the nicotine patch alone condition than females. CONCLUSION: Sex of the smoker may be an important determinant for effects of VLNC cigarettes and nicotine patch. Future large randomized trials to confirm these results are needed.

Reduced nicotine content cigarettes and nicotine patch.

BACKGROUND: Reduced nicotine content (RNC) cigarettes have led to smoking fewer cigarettes, withdrawal relief, and facilitation of cessation. The aim of this study is to examine the effects RNC cigarettes with and without nicotine patch and patch alone on smoking behavior, toxicant exposure, withdrawal discomfort, and as an exploratory analysis, on long-term abstinence. METHODS: This study involved a randomized, parallel arm design and six weeks of: (i) 0.05-0.09 mg nicotine yield cigarettes (N = 79); (ii) 21 mg nicotine patch (N = 80), or (iii) 0.05-0.09 nicotine yield cigarettes with 21 mg nicotine patch (N = 76); all groups received six weeks of additional behavioral treatment with follow-ups up to six months. RESULTS: Combination approach led to lower rates of smoking assigned cigarettes and hence lower carbon monoxide levels than RNC cigarettes alone. In addition, the combination approach was associated with less withdrawal severity when switching from usual brand to assigned product, and less smoking of usual brand cigarettes during treatment, but not after treatment compared with the other approaches. CONCLUSION: Combining very low nicotine content cigarettes with nicotine patch may improve the acute effects resulting from switching to either of these products alone. IMPACT: These findings may have implications for smoking cessation treatment or a policy measure to reduce nicotine content in cigarettes.

Effect of oral snus and medicinal nicotine in smokers on toxicant exposure and withdrawal symptoms: a feasibility study.

BACKGROUND: Smokeless, spitless tobacco products are being introduced and marketed as cigarette substitutes. Data are needed regarding how smokers interested in cessation would use these products, the levels of resultant toxicant exposure, and the feasibility of using these products as aids for tobacco cessation. METHODS: Smokers were randomized to receive Camel Snus (n = 51), Taboka (n = 52), or medicinal nicotine (n = 27) and required to quit smoking for 4 weeks. Measures of toxicant exposure and symptoms of craving and withdrawal were assessed prior to and during product use. RESULTS: Concentrations of exhaled carbon monoxide, urinary cotinine, urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and urinary N'-nitrosonornicotine and its glucuronide (total NNN) were significantly (P values <0.05) lower at the end of treatment in each group except for total NNN in those receiving Camel Snus (P = 0.066). A significant group × time effect was observed for total NNAL concentrations (P = 0.002) with the decrease greatest in the medicinal nicotine group and smallest decrease in the Camel Snus group. No significant differences between groups were found in craving and withdrawal symptoms. CONCLUSIONS: Enrolling smokers into a cessation study utilizing newer smokeless tobacco products is feasible. Camel Snus and Taboka use was not found to be superior to medicinal nicotine in reducing withdrawal symptoms but decreases in NNAL were smaller in users of Camel Snus. IMPACT: This study demonstrates the feasibility of conducting a smoking cessation study utilizing these newer tobacco products. An appropriately powered study is needed to assess smoking cessation rates using these newer products compared with established, safer products such as medicinal nicotine.

Reduced nicotine content cigarettes: effects on toxicant exposure, dependence and cessation.

AIMS: To examine the effects of reduced nicotine cigarettes on smoking behavior, toxicant exposure, dependence and abstinence. DESIGN: Randomized, parallel arm, semi-blinded study. Setting University of Minnesota Tobacco Use Research Center. INTERVENTIONS: Six weeks of: (i) 0.05 mg nicotine yield cigarettes; (ii) 0.3 mg nicotine yield cigarettes; or (iii) 4 mg nicotine lozenge; 6 weeks of follow-up. Measurements Compensatory smoking behavior, biomarkers of exposure, tobacco dependence, tobacco withdrawal and abstinence rate. FINDINGS: Unlike the 0.3 mg cigarettes, 0.05 mg cigarettes were not associated with compensatory smoking behaviors. Furthermore, the 0.05 mg cigarettes and nicotine lozenge were associated with reduced carcinogen exposure, nicotine dependence and product withdrawal scores. The 0.05 mg cigarette was associated with greater relief of withdrawal from usual brand cigarettes than the nicotine lozenge. The 0.05 mg cigarette led to a significantly higher rate of cessation than the 0.3 mg cigarette and a similar rate as nicotine lozenge. CONCLUSION: The 0.05 mg nicotine yield cigarettes may be a tobacco product that can facilitate cessation; however, future research is clearly needed to support these preliminary findings.

Presence of the carcinogen N'-nitrosonornicotine in the urine of some users of oral nicotine replacement therapy products.

N'-nitrosonornicotine (NNN) is a strong carcinogen present in unburned tobacco and cigarette smoke. We here analyze data obtained in two studies, in which a biomarker of exposure to NNN--the sum of NNN and its pyridine-N-glucuronide, called total NNN--was quantified in the urine of people who had stopped smoking and used various nicotine replacement therapy (NRT) products. In 13 of 34 nicotine gum or lozenge users from both studies, total NNN at one or more time points after biochemically confirmed smoking cessation was comparable with, or considerably higher than, the baseline levels. For most of the subjects who used the nicotine patch as a smoking cessation aid, urinary total NNN at all post-quit time points was <37% of their mean baseline levels. These results indicate that endogenous formation of significant amounts of NNN may occur sporadically in some users of oral NRT. Given the carcinogenicity of NNN and the frequent use of nicotine gum as a smoking cessation aid, further studies are needed so that preventive measures can be developed.

Exposure to a tobacco-specific lung carcinogen in adolescent versus adult smokers.

BACKGROUND: Previous studies with adult smokers have shown an association between number of cigarettes smoked per day (CPD) and levels of biomarkers of exposure to the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). This study compared carcinogen and nicotine exposure in adolescent and adult smokers across categories of CPD. METHOD: Baseline smoking history and biomarker data were merged from six studies to make two samples: one of adolescent smokers and one of adult smokers. Metabolites of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and its glucuronides (NNAL-Gluc) and total cotinine were quantified in urine. RESULTS: CPD was stratified into categories of 5 to 10, 11 to 15, and 16 to 20 CPD. Adolescents tended to have lower mean levels of NNAL plus NNAL-Glucs (total NNAL) compared with adults, although differences were not significant overall. Adolescent mean levels of NNAL/CPD were significantly lower than adult levels only in the 11 to 15 CPD category (P = 0.045). However, a significant positive relationship was observed for total NNAL/CPD by age. No significant differences between adolescents and adults were found in mean levels of total cotinine or cotinine/CPD. A subsample of urines from adolescents and adults were analyzed for NNAL-Glucs and NNAL. Adolescents and adults did not significantly differ in the ratio of NNAL-Glucs to NNAL. CONCLUSIONS: Adolescent uptake of NNK and nicotine tends to be lower although not statistically different from adults. The lack of significant differences may be due to the wide variation in exposure in adolescents. Some adolescent smokers are exposed to lung carcinogens at levels similar to those of adults.