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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.

The purpose of this study was to assess the effect of bupropion on cytochrome P450 2D6 (CYP2D6) activity. Twenty-one subjects completed this repeated-measures study in which dextromethorphan (30-mg oral dose) was administered to smokers at baseline and after 17 days of treatment with either bupropion sustained-release (150 mg twice daily) or matching placebo. Subjects quit smoking 3 days before the second dextromethorphan administration. To assess CYP2D6 activity, urinary dextromethorphan/dextrorphan metabolic ratios were calculated after an 8-hour urine collection. Thirteen subjects received bupropion, and 8 received placebo. In those receiving active medication, the dextromethorphan/dextrorphan ratio increased significantly at the second assessment relative to the first (0.012 +/- 0.012 vs. 0.418 +/- 0.302; P < 0.0004). No such change was observed in those randomized to placebo (0.009 +/- 0.010 vs. 0.017 +/- 0.015; P = NS). At baseline, all subjects were phenotypically extensive CYP2D6 metabolizers (metabolic ratio <0.3); after treatment, 6 of 13 subjects receiving bupropion, but none of those receiving placebo, had metabolic ratios consistent with poor CYP2D6 metabolizers. Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6.

The University of Minnesota Transdisciplinary Tobacco Use Research Center has been examining the multiple dimensions and the scientific evidence required to determine the feasibility of tobacco harm reduction as a means to reduce tobacco-related mortality and morbidity. Because of the complexity associated with exploring this area, an interdisciplinary approach is necessary. The research components that have been of particular focus at our center include (a) developing and validating biomarkers of tobacco-related exposure and toxicity, (b) developing animal models and designing studies with humans to assess a variety of smoking reduction approaches and potential reduced exposure products, and (c) determining individual differences in response to these interventions and products. A description of the ongoing activities and challenges in these areas is provided, along with projected directions for the future.

Key Words reduced risk, reduced exposure products, harm reduction s Abstract Tobacco harm reduction approaches are gaining increased attention.Much of this attention is due to a growing concern that significant populations of smokers either do not want to quit or believe they are unable to quit smoking, and to a concern over tobacco-industry attempts to produce tobacco products that claim to result in less toxin exposure. Decreasing tobacco toxin exposure as a method for reducing mortality and morbidity may be a reasonable tobacco control strategy. However, the impact of this strategy must be explored both on individual and population levels. A significant amount of independent research is needed to inform policy decisions. Regulatory authority over potential reduced exposure products is also essential.

Objective: To compare nicotine pharmacokinetics and subjective effects of three new smokeless tobacco potential reduced exposure products (PREPs; Ariva, Revel and Stonewall) with moist snuff (Copenhagen) and medicinal nicotine (Commit lozenge). Methods: 10 subjects completed a randomised, within-subject, crossover study. Subjects used one product for 30 min at each of the five laboratory sessions. Maximal nicotine concentration (C max ) was determined and area under the concentration time curve (AUC) was calculated for a 90-min period (during use and 60 min after use). Nicotine craving, withdrawal symptoms and ratings of product effects and liking were measured during product use. Results: Nicotine AUC and C max were higher for Copenhagen than for any other product (p,0.002) and higher for Commit than for either Ariva or Revel (p,0.001). C max for Commit was also higher than for Stonewall (p = 0.03). Craving was lowest during use of Copenhagen (p,0.03). Craving during use of Stonewall, Ariva and Commit was lower than during use of Revel (p,0.05). Withdrawal symptom score during use of Copenhagen was lower than during use of Revel (p = 0.009). Copenhagen scores were higher (p,0.005) than all other products in several measures of drug effects and liking (feel good effects, satisfaction, liking and desire for product, and strength of product). Conclusion:The new smokeless tobacco PREPs result in lower nicotine concentrations and equivalent or lower reductions in subjective measures compared with medicinal nicotine. Since health effects of PREPs are largely unknown, medicinal nicotine should be preferentially encouraged for smokers or smokeless tobacco users wishing to switch to lower-risk products.

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