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1.  Biomarkers of Secondhand Smoke Exposure in Automobiles 
Tobacco control  2013;23(1):10.1136/tobaccocontrol-2012-050724.
Objectives
The objectives of this study were: (1) to characterize the exposure of nonsmokers exposed to secondhand smoke (SHS) in a vehicle using biomarkers, (2) to describe the time-course of the biomarkers over 24 h, and (3) to examine the relationship between tobacco biomarkers and airborne concentrations of SHS markers.
Methods
Eight nonsmokers were individually exposed to SHS in cars with fully open front windows and closed back windows over an hour from a smoker who smoked 3 cigarettes at 20 min intervals. The nonsmokers sat in the backseat-passenger side, while the smoker sat in the driver’s seat. Plasma cotinine and urine cotinine, 3-hydroxycotinine (3HC), and 4-(methylnitrosoamino)-(3-pyridyl)-1-butanol (NNAL) were compared in samples taken at baseline and several time-points after exposure. Nicotine, particulate matter (PM2.5), and carbon monoxide (CO) were measured inside and outside the vehicle and ventilation rates in the cars were measured.
Results
Average plasma cotinine and the molar sum of urine cotinine and 3HC (COT+3HC) increased 4-fold, urine cotinine increased 6-fold, and urine NNAL increased ~27 times compared to baseline biomarker levels. Plasma cotinine, urine COT+3HC and NNAL peaked at 4–8 hours post-exposure while urine cotinine peaked within 4 hours. Plasma cotinine was significantly correlated to PM2.5 (Spearman correlation (rs = 0.94) and CO (rs = 0.76) but not to air nicotine. The correlations between urine biomarkers, cotinine, COT+3HC, and NNAL and air nicotine, PM2.5, and CO were moderate but non-significant (rs range, 0.31 – 0.60).
Conclusion
Brief SHS exposure in cars resulted in substantial increases in levels of tobacco biomarkers in nonsmokers. For optimal characterization of SHS exposure, tobacco biomarkers should be measured within 4–8 h post-exposure. Additional studies are needed to better describe the relationship between tobacco biomarkers and environmental markers of SHS.
doi:10.1136/tobaccocontrol-2012-050724
PMCID: PMC3670969  PMID: 23349229
Cigarettes; Secondhand smoke; passive smoking; automobiles; motor vehicles; biomarkers; cotinine; tobacco-specific nitrosamines
2.  Factors Associated with Discontinuation of Bupropion and Counseling among African American Light Smokers in a Randomized Clinical Trial 
Background
African Americans are at risk for inadequate adherence to smoking cessation treatment yet little is known about what leads to treatment discontinuation.
Purpose
Examine the factors associated with discontinuation of treatment in African American light smokers (≤10 cigarettes per day).
Methods
Bupropion plasma levels and counseling attendance were measured among 540 African American light smokers in a placebo-controlled randomized trial of bupropion.
Results
By Week 3, 28.0% of subjects in the bupropion arm had discontinued bupropion and only moderate associations were found between plasma levels and self-reported bupropion use (rs=0.38). By Week 16, 36.9% of all subjects had discontinued counseling. Males had greater odds of discontinuing medication (OR=2.02, 95% CI, 1.10–3.71, p=0.02) and older adults had lower odds of discontinuing counseling (OR=0.96, 95% CI, 0.94–0.97, p<0.0001).
Conclusions
Bupropion and smoking cessation counseling are underutilized even when provided within the context of a randomized trial. Future research is needed to examine strategies for improving treatment utilization among African American smokers.
doi:10.1007/s12160-013-9510-x
PMCID: PMC3815499  PMID: 23733379
Smoking cessation; discontinuation of treatment; African Americans
3.  Influence of a Dopamine Pathway Additive Genetic Efficacy Score on Smoking Cessation: Results from Two Randomized Clinical Trials of Bupropion 
Addiction (Abingdon, England)  2013;108(12):10.1111/add.12325.
Aims
To evaluate associations of treatment and an ‘additive genetic efficacy score’ (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled in two randomized clinical trials of smoking cessation therapies.
Design
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.
Setting
Two Hospital-affiliated clinics (Study 1), and two University-affiliated clinics (Study 2).
Participants
N=792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.
Measurements
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 Variable Number of Tandem Repeats polymorphism [DRD4 VNTR], SLC6A3 3' VNTR) analyzed both separately and as part of an AGES, time to first lapse, and point prevalence abstinence at end of treatment.
Findings
Significant associations of the AGES (hazard ratio = 1.10, 95% Confidence Interval [CI] = 1.06–1.14], p=0.0099) and of the DRD4 VNTR (HR = 1.29, 95%CI 1.17–1.41, p=0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β [SE]=−0.18 [0.07], p=0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.
Conclusions
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
doi:10.1111/add.12325
PMCID: PMC3834197  PMID: 23941313
Bupropion; genetic; pharmacogenetic analysis; randomized clinical trial; first lapse
4.  Levels of Cotinine in Dried Blood Specimens from Newborns as a Biomarker of Maternal Smoking Close to the Time of Delivery 
American Journal of Epidemiology  2013;178(11):1648-1654.
The precise quantitation of smoking during pregnancy is difficult in retrospective studies. Routinely collected blood specimens from newborns, stored as dried blood spots, may provide a low-cost method to objectively measure maternal smoking close to the time of delivery. This article compares cotinine levels in dried blood spots to those in umbilical cord blood to assess cotinine in dried blood spots as a biomarker of maternal smoking close to the time of delivery. The California Genetic Disease Screening Program provided dried blood spots from 428 newborns delivered in 2001–2003 with known umbilical cord blood cotinine levels. Cotinine in dried blood spots was measured in 6.35­-mm punches by using liquid chromatography­–tandem mass spectrometry (quantitation limit, 3.1 ng/mL). Repeated measures of cotinine in dried blood spots were highly correlated (R2 = 0.99, P < 0.001) among 100 dried blood spots with cotinine quantitated in 2 separate punches. Linear regression revealed that cotinine levels in dried blood spots were slightly lower than those in umbilical cord blood and predicted umbilical cord blood cotinine levels well (β = 0.95, R2 = 0.80, and P < 0.001 for both cotinine levels in log10 scale). When defining active smoking as a cotinine level of 10 ng/mL or more and using umbilical cord blood cotinine as the criterion standard, we found that measurements of cotinine in dried blood spots had high sensitivity (92.3%) and specificity (99.7%) in the prediction of maternal active smoking. Cotinine levels in dried blood spots are an accurate biomarker of maternal smoking close to the time of delivery.
doi:10.1093/aje/kwt182
PMCID: PMC3842901  PMID: 24068198
cotinine; dried blood spot; maternal smoking; newborn; pregnancy
5.  Nicotelline: A Proposed Biomarker and Environmental Tracer for Particulate Matter Derived from Tobacco Smoke 
Chemical research in toxicology  2013;26(11):1615-1631.
Particulate matter (PM) derived from tobacco smoke contains numerous toxic substances. Since the PM and gas phase of tobacco smoke may distribute differently in the environment, and substances in them may have different human bioavailability, multiple tracers and biomarkers for tobacco smoke constituents are desirable. Nicotelline is a relatively non-volatile alkaloid present in tobacco smoke, and therefore it has the potential to be a suitable tracer and biomarker for tobacco smoke-derived PM. We describe experiments demonstrating that nicotelline is present almost entirely in the PM, in both freshly generated cigarette smoke and aged cigarette smoke. An excellent correlation between the mass of nicotelline and the mass of the PM in aged cigarette smoke was found. We also describe experiments suggesting that the main source of nicotelline in tobacco smoke is dehydrogenation of another little-studied tobacco alkaloid, anatalline, during the burning process. We show that nicotelline metabolites can be measured in urine of smokers, and that nicotelline can be measured in house dust from homes of smokers and non-smokers. We conclude that nicotelline should be useful as a tracer and biomarker for PM derived from tobacco smoke.
doi:10.1021/tx400094y
PMCID: PMC3929594  PMID: 24125094
Cigarettes; Environmental Tobacco Smoke (ETS); Nicotelline; Nicotine; Particulate Matter; Secondhand Smoke (SHS); Settled House Dust; Thirdhand Smoke (THS); Tobacco Alkaloids; Tobacco Smoke
6.  Stability of the Nicotine Metabolite Ratio in Smokers of Progressively Reduced Nicotine Content Cigarettes 
Nicotine & Tobacco Research  2013;15(11):1939-1942.
Introduction:
The nicotine metabolite ratio (NMR), the ratio of trans-3′-hydroxycotinine (3-HC) to cotinine, has been used as a biomarker of the rate of CYP2A6-mediated nicotine metabolism. While stable in smokers who maintain constant smoking consumption, since smoking has been shown to inhibit nicotine metabolism and this inhibition could be mediated by the nicotine in the smoke, NMR could change during nicotine reduction. The objective of this study was to determine the reproducibility (or stability) of plasma NMR in smokers of progressively reduced nicotine content (RNC) cigarettes.
Methods:
We analyzed data from subjects in a clinical trial of smoking progressively RNC cigarettes. Plasma NMR in 30 smokers whose plasma cotinine levels had decreased by at least 50% from the use of the first test cigarette (12mg nicotine content) to the final test cigarette (1mg nicotine content) was measured on 4 occasions over a period of 24 weeks.
Results:
Plasma cotinine and 3-HC decreased by an average of 85% and 84%, respectively, following the use of the first type of RNC cigarette to the last type. Plasma NMR had an average absolute change of 28.5% over the same period. Using repeated measures analysis, changes in plasma NMR over time were not significant with or without controlling for the effects of age, body mass index, gender, and race (p = .24 and p = .23, respectively). The reliability coefficient for repeated measurements of plasma NMR was .72. The average within-subject coefficient of variation for plasma NMR was 21.6% (SD = 12.0%).
Conclusion:
The plasma NMR is relatively stable over time as nicotine levels decline in smokers of progressively RNC cigarettes.
doi:10.1093/ntr/ntt065
PMCID: PMC3790625  PMID: 23674838
7.  CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska-Native tobacco users 
Addiction (Abingdon, England)  2013;108(10):1818-1828.
Background and aims
Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and β4 nicotinic receptor subunits, are associated with altered smoking behaviors in European-Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska-Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use, and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska-Native people.
Design, Setting, Participants
A cross sectional study of 400 Alaska-Native individuals including 290 tobacco users.
Measurements
CHRNA5-A3-B4 genotype, body weight, and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE).
Findings
Alaska-Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African-Americans. In 290 Alaska-Native tobacco users, the ‘G’ allele of rs578776, which tagged a 30kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and significantly associated with nicotine intake (20% higher plasma cotinine, P<0.001, 16% higher TNE, P=0.076), while rs16969968 was not associated with nicotine intake. Rs578776 acted in combination with CYP2A6, the main nicotine-metabolizing enzyme, to increase nicotine intake by 1.8 fold compared with the low risk group (P<0.001). Furthermore rs2869950, a single nucleotide polymorphism 5′ to CHRNB4, was significantly associated with increased body mass index (P<0.01) in the tobacco users even after controlling for differences in nicotine intake (P<0.01).
Conclusions
Genetic variants in CHRNA5-A3-B4 alter nicotine intake and body mass index in a population of Alaska-Native people, who have a distinct haplotype structure, smoking behaviors and prevalence of obesity.
doi:10.1111/add.12250
PMCID: PMC3775934  PMID: 23692359
Alaska-Native People; Smoking; CHRNA5-A3-B4; Obesity
8.  Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease 
Circulation  2010;121(2):221-229.
Background
Smoking cessation is a key component of secondary cardiovascular disease prevention. Varenicline, a partial α4β2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with cardiovascular disease are unknown.
Methods and Results
A multicenter, randomized, double-blind, placebo-controlled trial compared the efficacy and safety of varenicline with placebo for smoking cessation in 714 smokers with stable cardiovascular disease. Participants received varenicline (1 mg twice daily) or placebo, along with smoking-cessation counseling, for 12 weeks. Follow-up lasted 52 weeks. The primary end point was carbon monoxide–confirmed continuous abstinence rate for weeks 9 through 12 (last 4 weeks of treatment). The continuous abstinence rate was higher for varenicline than placebo during weeks 9 through 12 (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval [CI], 4.18 to 8.93) and weeks 9 through 52 (19.2% versus 7.2%; odds ratio, 3.14; 95% CI, 1.93 to 5.11). The varenicline and placebo groups did not differ significantly in cardiovascular mortality (0.3% versus 0.6%; difference, −0.3%; 95% CI, −1.3 to 0.7), all-cause mortality (0.6% versus 1.4%; difference, −0.8%; 95% CI, −2.3 to 0.6), cardiovascular events (7.1% versus 5.7%; difference, 1.4%; 95% CI, −2.3 to 5.0), or serious adverse events (6.5% and 6.0%; difference, 0.5%; 95% CI, −3.1 to 4.1). As a result of adverse events, 9.6% of varenicline and 4.3% of placebo participants discontinued study drug.
Conclusions
Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety.
Clinical Trial Registration Information
URL: http://www.clinicaltrials.gov/ct2/show/NCT00282984. Unique identifier: NCT00282984
doi:10.1161/CIRCULATIONAHA.109.869008
PMCID: PMC4096941  PMID: 20048210
cardiovascular diseases; cerebrovascular disorders; peripheral vascular diseases; smoking; trials
9.  The DRD4 Exon III VNTR, Bupropion, and Associations With Prospective Abstinence 
Nicotine & Tobacco Research  2012;15(7):1190-1200.
Introduction:
DRD4 Exon III Variable Number of Tandem Repeat (VNTR) variation was found to interact with bupropion to influence prospective smoking abstinence, in a recently published longitudinal analyses of N = 331 individuals from a randomized double-blind placebo-controlled trial of bupropion and intensive cognitive–behavioral mood management therapy.
Methods:
We used univariate, multivariate, and longitudinal logistic regression to evaluate gene, treatment, time, and interaction effects on point prevalence and continuous abstinence at end of treatment, 6 months, and 12 months, respectively, in N = 416 European ancestry participants in a double-blind pharmacogenetic efficacy trial randomizing participants to active or placebo bupropion. Participants received 10 weeks of pharmacotherapy and 7 sessions of behavioral therapy, with a target quit date 2 weeks after initiating both therapies. VNTR genotypes were coded with the long allele dominant resulting in 4 analysis categories. Covariates included demographics, dependence measures, depressive symptoms, and genetic ancestry. We also performed genotype-stratified secondary analyses.
Results:
We observed significant effects of time in longitudinal analyses of both abstinence outcomes, of treatment in individuals with VNTR long allele genotypes for both abstinence outcomes, and of covariates in some analyses. We observed non-significantly larger differences in active versus placebo effect sizes in individuals with VNTR long allele genotypes than in individuals without the VNTR long allele, in the directions previously reported.
Conclusions:
VNTR by treatment interaction differences between these and previous analyses may be attributable to insufficient size of the replication sample. Analyses of multiple randomized clinical trials will enable identification and validation of factors mediating treatment response.
doi:10.1093/ntr/nts245
PMCID: PMC3682839  PMID: 23212438
10.  Race, Gender, and Nicotine Metabolism in Adolescent Smokers 
Nicotine & Tobacco Research  2012;15(7):1311-1315.
Introduction:
Differences in the rate of nicotine metabolism between genders and different races have been hypothesized to contribute to disparities in smoking rate, susceptibility to addiction, and ability to quit smoking. The purpose of this study was to determine the effect of race and gender on the rate of nicotine metabolism as indicated by the nicotine metabolite ratio (NMR) in adolescent smokers.
Methods:
One hundred and fifty-nine adolescent smokers aged 13–17 were given 2mg of deuterium-labeled cotinine (cotinine-d4). The NMR was calculated as the ratio of concentrations of deuterium-labeled 3′-hydroxycotinine (ng/ml) to cotinine-d4 (ng/ml) in saliva and is a validated biomarker of the rate of nicotine metabolism.
Results:
The sample was 67.3% female and racially mixed. On average, Whites had the fastest rates of metabolism compared with both Blacks/African Americans (p < .01) and Asians (p = .01). The NMR was similar between males and females (p = .70). Among the 19 girls who reported using estrogen-containing contraceptives, there was no significant difference in NMR compared with the 83 girls who did not use contraceptives (p = .24) or the 10 who used progestin-only contraceptives (p = .45).
Conclusions:
Among adolescent smokers, racial variations in rates of nicotine metabolism were similar to those that have been reported in adult smokers. In contrast to findings in adult smokers, the NMR did not vary significantly by gender or self-reported hormone use.
doi:10.1093/ntr/nts272
PMCID: PMC3682846  PMID: 23239845
11.  Electronic Cigarettes 
Circulation  2014;129(19):e490-e492.
doi:10.1161/CIRCULATIONAHA.114.008545
PMCID: PMC4074376  PMID: 24821830
12.  Nicotine Reduction: Strategic Research Plan 
Nicotine & Tobacco Research  2012;15(6):1003-1013.
Background:
Reducing nicotine content in cigarettes and other combustible products to levels that are not reinforcing or addictive has the potential to substantially reduce tobacco-related morbidity and mortality. The authority to reduce nicotine levels as a regulatory measure is provided in the U.S. Family Smoking Prevention and Tobacco Control Act and is consistent with the general regulatory powers envisioned under the relevant articles of the World Health Organization’s Framework Convention on Tobacco Control. Many experts have considered reducing nicotine in cigarettes to be a feasible national policy approach, but more research is necessary.
Purpose:
This article describes proceedings from a conference that had the goals of identifying specific research gaps, describing methods and measures to consider for addressing these gaps, and considering ways to foster collaboration.
Results and Conclusion:
Identified research gaps included determining the dose of nicotine that would be optimal for reducing and extinguishing cigarette use, examining approaches for reducing nicotine levels in the general and special populations of smokers, understanding how constituents other than nicotine may contribute to the reinforcing effects of tobacco, and identifying unintended consequences to determine ways to mitigate them. Methods that can be used ranged from brain imaging to large human clinical trials. The development and availability of valid biomarkers of exposure and effect are important. Infrastructures to facilitate collaboration need to be established.
doi:10.1093/ntr/nts214
PMCID: PMC3646645  PMID: 23100460
13.  Genetic and Pharmacokinetic Determinants of Response to Transdermal Nicotine in White, Black and Asian Non-Smokers 
Clinical pharmacology and therapeutics  2013;94(6):10.1038/clpt.2013.159.
The aim of the study was to examine genetic, pharmacokinetic and demographic factors that influence sensitivity to nicotine in never smokers. Sixty never smokers, balanced for gender and race (Caucasian, Blacks and Asian), wore 7 mg nicotine skin patches for up to 8 hours. Serial plasma nicotine concentrations and subjective and cardiovascular effects were measured, and genetic variation in the CYP2A6 gene, the primary enzyme responsible for nicotine metabolism, was assessed. Nicotine toxicity requiring patch removal developed in 9 subjects and was strongly associated with rate of rise and peak concentrations of plasma nicotine. Toxicity, subjective and cardiovascular effects of nicotine were associated with the presence of reduced function CYP2A6 alleles, presumably reflecting slow nicotine metabolic inactivation. This study has implications for understanding individual differences in responses to nicotine medications, particularly when the latter are used for treating medical conditions in non-smokers, and possibly in vulnerability to developing nicotine dependence.
doi:10.1038/clpt.2013.159
PMCID: PMC3834081  PMID: 23933970
14.  Comparison of Nicotine and Carcinogen Exposure with Water pipe and Cigarette Smoking 
Background
Smoking tobacco preparations in a water pipe (hookah) is widespread in many places of the world and is perceived by many as relatively safe. We investigated biomarkers of toxicant exposure with water pipe compared to cigarette smoking.
Methods
We conducted a cross-over study to assess daily nicotine and carcinogen exposure with water pipe and cigarette smoking in 13 people who were experienced in using both products.
Results
While smoking an average of 3 water pipe sessions compared to smoking 11 cigarettes per day, water pipe use was associated with a significantly lower intake of nicotine, greater exposure to carbon monoxide and a different pattern of carcinogen exposure compared to cigarette smoking, with greater exposure to benzene and high molecular weight PAHs, but less exposure to tobacco-specific nitrosamines, 1,3-butadiene and acrolein, acrylonitrile, propylene oxide, ethylene oxide, and low molecular weight PAHs.
Conclusions
A different pattern of carcinogen exposure might result in a different cancer risk profile between cigarette and water pipe smoking. Of particular concern is the risk of leukemia related to high levels of benzene exposure with water pipe use.
Impact
Smoking tobacco in water pipes has gained popularity in the United States and around the world. Many believe that water pipe smoking is not addictive and less harmful than cigarette smoking. We provide data on toxicant exposure that will help guide regulation and public education regarding water pipe health risk.
doi:10.1158/1055-9965.EPI-12-1422
PMCID: PMC3650103  PMID: 23462922
15.  Determination of Tobacco Smoke Exposure by Plasma Cotinine Levels in Infants and Children Attending Urban Public Hospital Clinics 
Objective
To determine the prevalence of secondhand smoke (SHS) exposure among infants and young children who received preventive care at pediatric preventative care clinics associated with an urban public hospital. Cotinine, a metabolite of nicotine, has been used to study SHS exposure in population-based studies of children 3 years of age or older.
Design
Retrospective study using a convenience sample.
Setting
Urban county pediatric primary care clinics in San Francisco, California.
Participants
A total of 496 infants and children (mean [SD] age, 2.4 [1.9] years).
Interventions
Discarded plasma samples (which were routinely collected for lead screening) were tested, and medical records were reviewed, for SHS exposure.
Main Outcome Measure
Secondhand smoke exposure based on cotinine plasma level and history of exposure in the medical record.
Results
Thirteen percent of parents reported that their child was exposed to SHS, yet biochemical testing detected cotinine in 55% of samples, at a geometric mean (SD) of 0.23 (3.55) ng/mL. There were no significant sex or age differences. African American children had much higher mean cotinine levels than did Latino children (geometric mean difference, 6.07 ng/mL [95% CI, 4.37 to 8.43 ng/mL]).
Conclusion
In a city with a low smoking rate (12%) and public smoking bans, we documented 55% exposure among infants and young children, using a plasma biomarker, compared with 13% exposure reported by parents. Because SHS is associated with significant respiratory diseases and parents underreport exposure, routine biochemical screening should be considered as a tool to identify and reduce SHS exposure.
doi:10.1001/archpediatrics.2012.170
PMCID: PMC3997061  PMID: 22566513
16.  The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race and sex 
Background
Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine and carcinogen exposure. However a given cotinine level may not represent the same tobacco exposure; for example, African Americans have higher cotinine levels than Caucasians after controlling for exposure.
Methods
Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal which are both mediated by the enzyme CYP2A6. Since CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal were measured in non-smoking Caucasians (Study 1, n=181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n=163).
Results
Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P=0.01), or 1.39 and 1.12 in males and females (P=0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by ≥25% in CYP2A6 reduced metabolizers (≈2 fold between some genotypes) and in males.
Conclusions
In people with slower, relative to faster, CYP2A6 activity cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.
Impact
Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e. African Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels) or between the sexes.
doi:10.1158/1055-9965.EPI-12-1234-T
PMCID: PMC3617060  PMID: 23371292
Tobacco; Cotinine; CYP2A6; Polycyclic aromatic hydrocarbons; NNAL
17.  Racial differences in the relationship between tobacco dependence and nicotine and carcinogen exposure 
Addiction (Abingdon, England)  2012;108(3):607-617.
Aims
To investigate the relationships between tobacco dependence, biomarkers of nicotine and carcinogen exposure, and biomarkers of nicotine and carcinogen exposure per cigarette in Black and White smokers.
Design and participants
204 healthy Black (n=69) and White (n=135) smokers were enrolled in two clinical studies.
Measurement
Nicotine equivalents (nicotine and its metabolites), 4-(methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL), and polycyclic aromatic hydrocarbon (PAH) metabolites were measured in urine. The Fagerström Test for Nicotine Dependence (FTND) and time to first cigarette (TFC) measured tobacco dependence.
Findings
Average TFC and FTND for Blacks and Whites were not significantly different. Urine NNAL and nicotine equivalents increased with increasing FTND in Whites but did not increase in Blacks (race x FTND interaction, both p<0.031). The interaction term was not significant for PAHs. An inverse relationship was seen between FTND and nicotine equivalents, NNAL, and PAH metabolites per cigarette in Blacks but remained flat in Whites (race x FTND interaction, all p≤0.039). Regardless of dependence (low dependence, TFC>15 minutes; high dependence, TFC≤15 minutes), FTND and TFC were not significantly correlated with urine nicotine equivalents and carcinogen exposure in Blacks. We found moderate correlations between FTND and TFC and nicotine equivalents and carcinogen exposure among Whites of low dependence and non-significant correlations among Whites of high dependence.
Conclusion
In the US, tobacco dependence measures were linearly related to nicotine intake and carcinogen exposure in White but not in Black smokers. The relationship between dependence measures and tobacco biomarkers in Black smokers regardless of level of dependence resembled highly dependent White smokers.
doi:10.1111/j.1360-0443.2012.04077.x
PMCID: PMC3553231  PMID: 22971134
Tobacco dependence; nicotine addiction; carcinogen exposure; FTND; time to first cigarette (TFC); racial differences; NNAL; PAH
18.  Predictors of cessation in African American light smokers enrolled in a bupropion clinical trial 
Addictive behaviors  2012;38(3):1796-1803.
Background
This is the first study to examine predictors of successful cessation in African American (AA) light smokers treated within a placebo-controlled trial of bupropion.
Methods
We analyzed data from a randomized, double-blind, placebo-controlled trial of bupropion and health education for 540 African American light smokers. African American light smokers (≤ 10 cigarettes per day, cpd) were randomly assigned to receive 150mg bid bupropion SR (n=270) or placebo (n=270) for 7 weeks. All participants received health education counseling at Weeks 0, 1, 3, 5 and 7. Using chi-square tests, two sample t-tests, and multiple logistic regression analyses, we examined baseline psychosocial and smoking characteristics as predictors of cotinine-verified 7-day point prevalence smoking abstinence among study participants at the end treatment (week 7) and at the end of follow up (week 26).
Results
Participants who received bupropion were significantly more likely to quit smoking compared to those who received placebo (OR = 2.72, 95% CI = 1.60–4.62, P = 0.0002). Greater study session attendance (OR = 2.47, 95% CI = 1.76–3.46, P = 0.0001), and smoking non-menthol cigarettes increased the likelihood of quitting (OR = 1.84, 95% CI = 1.01–3.36, P = 0.05); while longer years of smoking (OR = 0.98, 95% CI = 0.96–1.00, P = 0.05) and higher baseline cotinine (OR = 0.97, 95% CI = 0.95–0.99, P = 0.002) significantly reduced the odds of quitting at Week 7. Conversely, at the end of follow-up (week 26), treatment with bupropion vs. placebo (OR =1.14, 95% CI = 0.65–2.02, P = 0.64) was not significantly associated with quitting and type of cigarette smoked (menthol vs. non-menthol) did not appear in the final logistic regression model. Greater study session attendance (OR = 1.96, 95% CI = 1.44–2.66, P = 0.0001); BMI (OR = 1.03, 95% CI = 1.00–1.07, P = 0.04); and weight efficacy (OR = 1.03, 95% CI = 1.01–1.05, P = 0.01) increased the likelihood of quitting at Week 26. Similar to our findings at Week 7, longer years of smoking (OR = 0.96, 95% CI = 0.94–0.99, P = 0.01) and higher baseline cotinine (OR = 0.97, 95% CI = 0.95–0.99, P = 0.02) significantly reduced the odds of quitting at Week 26.
Conclusions
Baseline cotinine levels, number of years smoked and study session attendance are associated with both short- and long-term smoking cessation, while bupropion and the type of cigarette smoked were associated with quitting on short term only.
doi:10.1016/j.addbeh.2012.11.010
PMCID: PMC3558614  PMID: 23254230
African American; light smokers; bupropion; cotinine; menthol; smoking cessation
19.  Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state 
Pharmacogenetics and genomics  2013;23(3):135-141.
Background
Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6.
Objectives
To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants.
Methods
In a genotype-guided study of 42 healthy subjects we measured plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion (TB) and erythrohydrobupropion (EB) after 7 days of sustained release bupropion dosing.
Results
CYP2B6*6 and *18 gene variants were associated with approximately 33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex.
Conclusions
Since HB is active and steady state concentrations of HB are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Due to the large individual variation within genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary.
doi:10.1097/FPC.0b013e32835d9ab0
PMCID: PMC3763712  PMID: 23344581
20.  CYP2A6 Genotype but not Age Determines Cotinine Half-life in Infants and Children 
Clinical pharmacology and therapeutics  2013;94(3):10.1038/clpt.2013.114.
The formation of cotinine, the main proximate metabolite and a biomarker of nicotine exposure, is mediated primarily by CYP2A6. Our aim was to determine if higher cotinine levels in young children exposed to secondhand smoke (SHS) are a result of age-related differences in pharmacokinetics. Forty-nine participants, 2 to 84 months old, received oral deuterium-labeled cotinine, with daily urine samples for up to 10 days for cotinine half-life measurement. DNA from saliva was used for CYP2A6 genotyping. The estimate of half-life using a mixed effect model was 17.9 hrs (95%CI: 16.5, 19.3), similar to that reported in adults. There was no statistically significant effect of sex, race, age, or weight. Children with normal activity CYP2A6*1/*1 genotypes had a shorter half-life than those with 1–2 reduced activity variant alleles. Our data suggest that higher cotinine levels in SHS-exposed young children compared to adults are due to greater SHS exposure rather than different cotinine pharmacokinetics.
doi:10.1038/clpt.2013.114
PMCID: PMC3820275  PMID: 23714690
21.  NICOTINE METABOLISM AND ADDICTION AMONG ADOLESCENT SMOKERS 
Addiction (Abingdon, England)  2012;108(2):406-412.
AIMS
The purpose of this study was to determine the association between the nicotine metabolic rate and smoking behavior, including addiction, in adolescent smokers.
DESIGN
Baseline data from a prospective study of adolescent smoking behaviors and nicotine metabolism.
SETTING
The setting was an outpatient university hospital in San Francisco.
PARTICIPANTS
Adolescent smokers (n=164) aged 13–17 years old.
MEASUREMENTS
Participants completed self-report measures of smoking behavior and nicotine dependence (modified Fagerström Tolerance Questionnaire, mFTQ). The nicotine metabolite ratio (NMR), a phenotypic marker of the rate of nicotine metabolism, was calculated using the ratio of concentrations of deuterium-labeled 3’-hydroxycotinine to cotinine-d4.
FINDINGS
Participants reported smoking a mean of 2.86 cigarettes per day (CPD) (median= 1.78, SD=3.35) for 1.37 years (median= 1.0, SD=1.36). Results from multivariate analyses accounting for age, race/ethnicity, gender and duration of smoking indicated that slower metabolizers smoked more CPD than faster metabolizers (the NMR was inversely related to CPD; p=.02). Slower metabolizers also showed greater dependence on the mFTQ (NMR was negatively associated with the mFTQ; p=.02).
CONCLUSIONS
In adolescence, slower clearance of nicotine may be associated with greater levels of addiction, perhaps mediated by a greater number of cigarettes smoked.
doi:10.1111/j.1360-0443.2012.04026.x
PMCID: PMC3504133  PMID: 22823143
22.  High Dose Transdermal Nicotine for Fast Metabolizers of Nicotine: A Proof of Concept Placebo-Controlled Trial 
Nicotine & Tobacco Research  2012;15(2):348-354.
Introduction:
Smokers with a faster rate of nicotine metabolism, estimated using the ratio of 3′-hydroxycotinine (3-HC) to cotinine, have lower plasma nicotine levels and are more likely to relapse with 21 mg nicotine patch therapy, than smokers with slower rates of nicotine metabolism. Thus, faster metabolizers of nicotine may require a higher nicotine patch dose to achieve cessation.
Methods:
This proof of concept randomized placebo-controlled trial evaluated the efficacy and safety of 8 weeks of 42 mg transdermal nicotine versus 21 mg, among 87 fast metabolizers of nicotine (3-HC/cotinine ≥ 0.18).
Results:
After 1 week of treatment, an intent-to-treat (ITT) analysis showed that participants treated with 42 mg nicotine had significantly higher expired-air carbon monoxide (CO)-confirmed 24-hr abstinence (75% vs. 58.1%; OR = 3.21; 95% CI: 1.12–9.24, p = .03) but not 7-day abstinence (50% vs. 34.9%; OR = 2.02; 95% CI: 0.82–4.94, p = .13). After 8 weeks of treatment, ITT analysis showed that participants treated with 42 mg nicotine had marginally higher rates of CO-confirmed 24-hr abstinence (45.5% vs. 30.2%; OR = 2.32; 95% CI: 0.92–5.92, p = .08) but not 7-day abstinence (29.6% vs. 23.3%; OR = 1.52, 95% CI: 0.57–4.07, p = .41). Percent nicotine and cotinine replacement were significantly greater for 42 mg nicotine versus 21 mg (p < .005). There were no significant differences between treatment arms in the frequency of severe side effects and serious adverse events or blood pressure during treatment (p > .10).
Conclusions:
Further examination of the efficacy of 42 mg nicotine patch therapy for fast metabolizers of nicotine is warranted.
doi:10.1093/ntr/nts129
PMCID: PMC3545715  PMID: 22589423
23.  Nicotinic Acetylcholine Receptor Variation and Response to Smoking Cessation Therapies 
Pharmacogenetics and genomics  2013;23(2):94-103.
Objective
Evaluate nicotinic acetycholine receptor (nAChR) single nucleotide polymorphism (SNP) association with seven day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies (RCTs) in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.
Methods
We quantified association of four SNPs at three nAChRs with abstinence in eight RCTs. Participants were 2,633 outpatient treatment-seeking, self-identified European ancestry individuals smoking ≥10 cigarettes per day, recruited via advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment (EOT) and six month (6MO) abstinence, with demographic, behavioral and genetic covariates.
Results
“Risk” alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the placebo pharmacotherapy group (PG) at 6MO [for rs588765 OR (95%CI) 0.41 (0.17–0.99)], and at EOT and at 6MO [for rs1051730, 0.42 (0.19–0.93) and 0.31 (0.12–0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765 2.07 (1.11–3.87) and for rs1051730 2.54 (1.29–4.99)]. We observed significant heterogeneity in rs1051730 effects (F=2.48, P=0.021) between PGs.
Conclusions
chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with placebo treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.
doi:10.1097/FPC.0b013e32835cdabd
PMCID: PMC3563676  PMID: 23249876
logistic regression; mediation analysis; nAChR variation; nicotine dependence; pharmacotherapy; randomized clinical trials
24.  Tobacco Use Among Southwestern Alaska Native People 
Nicotine & Tobacco Research  2012;15(2):401-406.
Introduction:
We examined the characteristics, attitudes, beliefs, and exposure to tobacco products in a cohort of rural dwelling Alaska Native (AN) people.
Methods:
We conducted a study of 400 of AN adult tobacco users and nonusers living in Southwestern Alaska. Questionnaires covered variables such as demographics, tobacco-use history, current tobacco use and dependence scales, general health status, attitudes and beliefs about tobacco, and quitting history.
Results:
The study population smoked 7.8 cigarettes per day compared with 16.8 on average for the U.S. population: a significant proportion of the population engaged in dual use of cigarettes and smokeless tobacco products. Over one third (40.9%), first tried tobacco at age 11 or younger. The mean measures of tobacco addiction (e.g., Fagerstrom Test for Nicotine Dependence, Severson Scale of Smokeless Tobacco Dependence) scores were lower compared with other U.S. populations.
Conclusions:
Very high tobacco-use prevalence, dual product use, and early tobacco use are observed in Southwestern AN people. Unexpectedly these did not appear to be correlated with heavier individual tobacco use or higher levels of addiction in this population.
doi:10.1093/ntr/nts137
PMCID: PMC3612002  PMID: 22949573
25.  Cigarette Smoke Toxins Deposited on Surfaces: Implications for Human Health 
PLoS ONE  2014;9(1):e86391.
Cigarette smoking remains a significant health threat for smokers and nonsmokers alike. Secondhand smoke (SHS) is intrinsically more toxic than directly inhaled smoke. Recently, a new threat has been discovered – Thirdhand smoke (THS) – the accumulation of SHS on surfaces that ages with time, becoming progressively more toxic. THS is a potential health threat to children, spouses of smokers and workers in environments where smoking is or has been allowed. The goal of this study is to investigate the effects of THS on liver, lung, skin healing, and behavior, using an animal model exposed to THS under conditions that mimic exposure of humans. THS-exposed mice show alterations in multiple organ systems and excrete levels of NNAL (a tobacco-specific carcinogen biomarker) similar to those found in children exposed to SHS (and consequently to THS). In liver, THS leads to increased lipid levels and non-alcoholic fatty liver disease, a precursor to cirrhosis and cancer and a potential contributor to cardiovascular disease. In lung, THS stimulates excess collagen production and high levels of inflammatory cytokines, suggesting propensity for fibrosis with implications for inflammation-induced diseases such as chronic obstructive pulmonary disease and asthma. In wounded skin, healing in THS-exposed mice has many characteristics of the poor healing of surgical incisions observed in human smokers. Lastly, behavioral tests show that THS-exposed mice become hyperactive. The latter data, combined with emerging associated behavioral problems in children exposed to SHS/THS, suggest that, with prolonged exposure, they may be at significant risk for developing more severe neurological disorders. These results provide a basis for studies on the toxic effects of THS in humans and inform potential regulatory policies to prevent involuntary exposure to THS.
doi:10.1371/journal.pone.0086391
PMCID: PMC3906039  PMID: 24489722

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