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Research on nicotine metabolism has primarily focused on white adults. This study examined associations between nicotine metabolism, tobacco use, and demographic characteristics among Alaska Native adults who smoke cigarettes. Participants (N = 244) were Alaska Native adults who smoked and who provided a plasma sample at baseline (70.1%) or follow-up (29.9%) of a randomized controlled trial of a cardiovascular risk behavior intervention. At baseline, participants self-reported age, sex, Alaska Native heritage, cigarettes per day, time to first cigarette upon wakening, menthol use, perceived difficulty staying quit, tobacco withdrawal symptoms, and past-month tobacco product use, binge drinking, and cannabis use. At 3-, 6-, 12-, and 18-month follow-ups, participants self-reported 7-day point prevalence abstinence from smoking. Height and weight were measured to calculate body mass index (BMI). Participants' nicotine metabolite ratio (NMR), calculated as the ratio of plasma cotinine and trans-3' hydroxycotinine, was log-transformed. The sample (52.0% male, age M = 47.0 years [SD = 13.8], 60.3% of Inupiaq heritage) averaged 12.5 cigarettes per day (SD = 10.5); 64.0% smoked within 30 min of wakening. NMR was not significantly associated with age, sex, Alaska Native heritage, BMI, cigarettes per day, time to first cigarette upon wakening, menthol use, perceived difficulty staying quit, past-month dual tobacco product use, withdrawal symptoms, past-month binge drinking, past-month cannabis use, or abstinence from smoking (all p-values > .050). Characteristics that relate to NMR in Alaska Native adults may differ from those typically identified among white adults. Specifically, results may suggest that Alaska Native adults with slower nicotine metabolism do not titrate their nicotine intake when smoking. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

This narrative review examines the impact of cigarette smoking and the use of other tobacco and nicotine products on cardiovascular disease. Smoking increases the incidence of both acute and chronic cardiovascular diseases, and the harmful effects are substantially and relatively quickly reversible after quitting. Recommended cessation treatment includes offering pharmacotherapy, counseling which should emphasize the rapid risk reduction that occurs after quitting and adequate follow-up contacts. Although most research on cardiovascular disease in relation to tobacco use has focused upon cigarette smoking, we also review available data related to other combustible tobacco products, smokeless tobacco, electronic nicotine delivery systems and second-hand smoke. We discuss the implications of smoking on clinical management of patients with heart disease and newer developments with potential relevance to treatment of such patients.

Author(s): Beard, Emma; Jackson, Sarah E; Anthenelli, Robert M; Benowitz, Neal L; Aubin, Lisa St; McRae, Thomas; Lawrence, David; Russ, Cristina; Krishen, Alok; Evins, A Eden; West, Robert | Abstract: Background and aimsAnalysed using classical frequentist hypothesis testing with alpha set to 0.05, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) did not find enough evidence to reject the hypothesis of no difference in neuropsychiatric adverse events (NPSAEs) attributable to varenicline, bupropion, or nicotine patch compared with placebo. This might be because the null hypothesis was true or because the data were insensitive. The present study aimed to test the hypothesis more directly using Bayes factors.DesignEAGLES was a randomised, double-blind, triple-dummy, controlled trial.SettingGlobal (16 countries across five continents), between November 2011 and January 2015.ParticipantsParticipants were smokers with (nn=n4116) and without (nn=n4028) psychiatric disorders.InterventionsVarenicline (1nmg twice daily), bupropion (150nmg twice daily), nicotine patch (21nmg once daily with taper) and matched placebos.MeasurementsThe outcomes included: (i) a composite measure of moderate/severe NPSAEs; and (ii) a composite measure of severe NPSAEs. The relative evidence for there being no difference in NPSAEs versus data insensitivity for the medications was calculated in the full and sub-samples using Bayes factors and corresponding robustness regions.FindingsFor all but two comparisons, Bayes factors were l1/3, indicating moderate to strong evidence for no difference in risk of NPSAEs between active medications and placebo (Bayes factor = 0.02-0.23). In the psychiatric cohort versus placebo, the data were suggestive, but not conclusive of no increase in NPSAEs with varenicline (Bayes factorn=n0.52) and bupropion (Bayes factorn=n0.71). Here, the robustness regions ruled out an≥7% and ≥8% risk increase with varenicline and bupropion, respectively.ConclusionsSecondary analysis of the Evaluating Adverse Events in a Global Smoking Cessation Study trial using Bayes factors provides moderate to strong evidence that use of varenicline, bupropion or nicotine patches for smoking cessation does not increase the risk of neuropsychiatric adverse events relative to use of placebo in smokers without a history of psychiatric disorder. For smokers with a history of psychiatric disorder the evidence also points to no increased risk but with less confidence.

Introduction Cytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5-mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated the effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability. Methods ORCA-1 was a double-blind, randomized, placebo-controlled clinical trial that provided cytisinicline or placebo tablets plus behavioral support for 25 days. Adult smokers (>10 cigarettes daily) committed to quitting smoking were randomized to compare 2 cytisinicline doses (1.5 mg and 3 mg) versus placebo, and 2 administration schedules [downward titration versus 3 times daily (TID)]. Primary outcome was a reduction in expected cigarettes smoked at end of treatment; secondary outcomes were biochemically confirmed 7-day abstinence at Week 4 and continuous abstinence from Weeks 5 to 8. Results Among 254 participants, those in cytisinicline arms (regardless of dose or schedule) had greater reductions in cigarettes smoked versus placebo, with differences observed in 3 cytisinicline arms statistically significant versus placebo. All cytisinicline arms had statistically significantly higher abstinence rates at Week 4 versus placebo. Both cytisinicline arms using TID schedules had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 compared with placebo. Participants in the cytisinicline 3-mg TID arm had the highest abstinence rate. There were no safety concerns with either 1.5-mg or 3-mg cytisinicline. Conclusion Based on simpler dose scheduling, excellent tolerability, and best-continued abstinence rate, cytisinicline 3-mg TID was selected for future Phase 3 studies. Implications Although the 1.5-mg 25-day titration schedule has been marketed in Central and Eastern Europe for decades, this study explored using a higher dosage and a simplified dosing schedule for impact on cytisinicline efficacy and tolerability. Based on these results, a Phase 3 program was initiated using cytisinicline 3-mg tablets on a TID schedule for potential market approval in the United States.

Author(s): Liakoni, Evangelia; Tyndale, Rachel F; Jacob, Peyton; Dempsey, Delia A; Addo, Newton; Benowitz, Neal L | Abstract: ObjectivesTo investigate if the nicotine metabolite ratio (NMR, the ratio of nicotine metabolites 3'-hydroxycotinine/cotinine) is a reliable phenotypic biomarker for nicotine clearance across races, and as a function of differences in the rate of nicotine, cotinine and 3'-hydroxycotinine glucuronidation and UGT genotypes.MethodsParticipants [Caucasians (Whites), African Americans (Blacks) and Asian-Americans (Asians)] received an oral solution of deuterium-labeled nicotine and its metabolite cotinine. Plasma and saliva concentrations of nicotine and cotinine were used to determine oral clearances. Rates of glucuronidation were assessed from urine glucuronide/parent ratios, and UGT2B10 and UGT2B17 genotypes from DNA.ResultsAmong the 227 participants, 96 (42%) were White, 67 (30%) Asian and 64 (28%) Black. Compared to the other two races, Whites had higher nicotine and cotinine total oral clearance, Blacks had lower nicotine and cotinine glucuronidation rates and Asians had lower 3'-hydroxycotinine glucuronidation rates. A strong positive correlation (correlations coefficients 0.77-0.84; P l 0.001) between NMR and nicotine oral clearance was found for all three races, and NMR remained a strong predictor for the nicotine oral clearance while adjusting for race, sex and age. Neither the metabolite glucuronidation ratios nor the UGT genotypes had significant effects on the ability of NMR to predict nicotine oral clearance.ConclusionNMR appears to be a reliable phenotypic biomarker for nicotine clearance across races, glucuronidation phenotypes and genotypes. Racial differences in the relationships between NMR, smoking behaviors and addiction are unlikely to be related to an inadequate estimation of nicotine clearance on the basis of NMR.

BACKGROUND AND AIMS: CYP2B6, a genetically variable enzyme, converts bupropion to its active metabolite hydroxybupropion. CYP2B6 activity and bupropion-aided cessation differ between women and men. The aim of this study was to determine whether genetically normal (versus reduced) CYP2B6 activity increases bupropion-aided cessation in African American smokers via higher hydroxybupropion concentration, and whether this differs by sex. DESIGN AND SETTING: Secondary analysis of a smoking cessation clinical trial (NCT00666978). PARTICIPANTS/CASES: African American light smokers (≤ 10 cigarettes/day). INTERVENTIONS: Participants were treated with bupropion for 7 weeks. MEASUREMENTS: Participants with detectable bupropion and/or hydroxybupropion concentrations were divided into normal (n = 64) and reduced (n = 109) CYP2B6 activity groups based on the presence of decreased-function CYP2B6*6 and CYP2B6*18 alleles. Biochemically verified smoking cessation was assessed at week 3, end of treatment (7 weeks) and follow-up (26 weeks). FINDINGS: Normal (versus reduced) CYP2B6 activity was associated with increased cessation at week 7, which was mediated by higher hydroxybupropion concentration [odds ratio (OR) = 1.25, 95% confidence interval (CI) = 1.03, 1.78]; this mediation effect persisted at week 26 (OR = 1.23, 95% CI = 1.02, 1.70). The mediation effect was similar in women (n = 116; OR = 1.33, 95% CI = 1.01, 2.30) and men (n = 57; OR = 1.33, 95% CI = 0.92, 3.87). Moreover, sex did not appear to moderate the mediation effect, although this should be tested in a larger sample. CONCLUSIONS: In African American light smokers with verified early bupropion use, genetically normal CYP2B6 activity appears to be indirectly associated with greater smoking cessation success in a relationship mediated by higher hydroxybupropion concentration. The mediating effect of higher hydroxybupropion concentration on smoking cessation persists beyond the active treatment phase and does not appear to differ by sex.

Background Cigarette smoking is associated with an increased risk of developing ARDS. However, whether changes in smoking patterns or processes of care impact this relationship is unclear. Research Question Are changes in smoking and resuscitation patterns associated with changes in the relationship between smoking and ARDS? Study Design and Methods We conducted a prospective cohort study of critically injured adults with blunt trauma from 2005 to 2015. Plasma cotinine, a tobacco biomarker, was measured to categorize patients by smoking status. We used regression to assess the relationship between smoking, resuscitation practices, and ARDS over time. Results In the overall cohort, active (OR, 1.9; 95% CI, 1.0-3.5; P = .046) and passive (OR, 2.6; 95% CI, 1.4-4.8; P = .002) smoking were associated with an increased risk of developing ARDS in multivariate analyses. In contrast to the dose-response relationship in patients enrolled from 2005 to 2008, passive cigarette smoke exposure was associated with the highest risk of developing ARDS in patients enrolled from 2009 to 2015, suggesting a threshold effect. Packed RBC (pRBC) and fresh frozen plasma (FFP) transfusions were associated with an increased risk of developing ARDS, particularly in active smokers (pRBC: OR, 5.6; P Interpretation Despite changes in resuscitation and smoking patterns, cigarette smoking remains associated with an increased risk of developing ARDS. However, this relationship changed over time, with passive smokers at particularly increased risk of developing ARDS in later years, which may be related to changes in smoking patterns or transfusion practices over time. These findings highlight the need for additional mechanistic and epidemiologic studies of the effects of low levels of cigarette smoke exposure on lung health.

Hookah (waterpipe) smoking is a growing tobacco epidemic. Though perceived as a safer tobacco alternative, hookah smoke contains, in addition to tobacco combustion products, large amounts of charcoal combustion products-implicated in cardiovascular disease-from the burning charcoal used to heat the flavored tobacco. To date, little is known on the vascular effects of hookah smoking. The aim of this study was to characterize the peripheral circulatory response to acute hookah smoking in cutaneous and muscular beds. In 21 healthy young adult habitual hookah smokers who did not smoke cigarettes (age 24 ± 1 years, mean ± SE), we measured plasma nicotine, exhaled carbon monoxide, skin blood flow (laser Doppler velocimetry) and calf muscle blood flow (strain-gauge plethysmography) before and for up to 60 minutes after ad lib hookah smoking. In nine subjects, nonsmoking time-control studies were performed. Hookah smoking, which increased plasma nicotine by 5.8 ng/ml (from 0.6 ± 0.1 to 6.4 ± 1.3, p0.001) and exhaled carbon monoxide by 27 ppm (from 2.7 ± 0.2 to 29.5 ± 2.2, p0.001), decreased skin blood flow by 23% (20.1 ± 2.8 to 14.8 ± 1.9 units, p0.001) and increased skeletal muscle blood flow by 34% (2.3 ± 0.1 to 2.9 ± 0.2 units, p = 0.010). These responses required more than one hour to recover after smoking cessation. All cardiovascular parameters were unchanged in the nonsmoking time-control studies. Although perceived to be innocuous, hookah smoking produces acute cutaneous vasoconstriction with skeletal muscle vasodilation, a dissociated pattern of peripheral blood flow responses that is characteristic of nicotine and carbon monoxide. In conclusion, these findings provide objective evidence to challenge the perception that hookah smoking is a safer tobacco alternative.

ObjectiveIn an urban adolescent population, we evaluated sources of exposure to secondhand smoke exposure (SHS), examined differences in exposure by race/ethnicity, age and sex, and determined the relationship between exposure source(s) and the biomarkers cotinine and NNAL.MethodsParticipants were recruited from a public hospital-based outpatient clinic in San Francisco, CA, USA.ResultsOf a sample of N=298 adolescents screened, 235 were biologically confirmed to be exposed to tobacco smoke. Of those, N=16 were active smokers and N=219 were exposed to SHS; 91 (39%) were heavily SHS exposed (median cotinine=0.76 ng/mL) and 128 (54%) had light SHS exposure (median cotinine=0.11 ng/mL). Within those SHS exposed, the most common source of exposure was in a public area. No significant racial/ethnic differences were found, although African American adolescents were more likely to live in a home that allowed smoking. Older adolescents were more likely to be exposed across several difference sources, and females more likely to be exposed in a car and in public areas. Past 7-day exposure in the home, in a car, and current blunt use were significantly related to biomarkers of exposure.ConclusionsUrban adolescents are exposed to SHS across a variety of sources. Although exposure in a public area is most common, exposure in the home and in cars significantly influences tobacco biomarker levels. Interventions to reduce exposure would have the greatest impact in this population if they focused on reducing exposure in the home and in cars. History of blunt use is a strong determinant of tobacco exposure.

Background Nicotine, the pharmacologically active substance in both tobacco and many electronic cigarette (e-cigarette) liquids, is responsible for the addiction that sustains cigarette smoking. With 8 million deaths worldwide annually, smoking remains one of the major causes of disability and premature death. However, nicotine also plays an important role in smoking cessation strategies. Objectives The aim of this study was to develop a comprehensive, whole-body, physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of nicotine and its major metabolite cotinine, covering various routes of nicotine administration, and to simulate nicotine brain tissue concentrations after the use of combustible cigarettes, e-cigarettes, nicotine gums, and nicotine patches. Methods A parent–metabolite, PBPK/PD model of nicotine for a non-smoking and a smoking population was developed using 91 plasma and brain tissue concentration–time profiles and 11 heart rate profiles. Among others, cytochrome P450 (CYP) 2A6 and 2B6 enzymes were implemented, including kinetics for CYP2A6 poor metabolizers. Results The model is able to precisely describe and predict both nicotine plasma and brain tissue concentrations, cotinine plasma concentrations, and heart rate profiles. 100% of the predicted area under the concentration–time curve (AUC) and maximum concentration (Cmax) values meet the twofold acceptance criterion with overall geometric mean fold errors of 1.12 and 1.15, respectively. The administration of combustible cigarettes, e-cigarettes, nicotine patches, and nicotine gums was successfully implemented in the model and used to identify differences in steady-state nicotine brain tissue concentration patterns. Conclusions Our PBPK/PD model may be helpful in further investigations of nicotine dependence and smoking cessation strategies. As the model represents the first nicotine PBPK/PD model predicting nicotine concentration and heart rate profiles after the use of e-cigarettes, it could also contribute to a better understanding of the recent increase in youth e-cigarette use. Electronic supplementary material The online version of this article (10.1007/s40262-020-00880-4) contains supplementary material, which is available to authorized users.

ENDS are evolving quickly with increasing use in the U.S. More recently, e-hookahs have been introduced as healthier alternatives to the traditional hookah-flavored tobacco smoking. To date, virtually all studies of ENDS have focused on e-cigarettes; consequently, little is known about e-hookah use.Data were drawn from the 2014-2015 Wave 2 Population Assessment of Tobacco and Health study, a nationally representative sample of adults aged ≥18 years (n=28,362) and youth aged 12-17 years (n=12,172). Weighted analyses, conducted in 2018-2019, estimated the prevalence of e-hookah versus e-cigarette and examined comparisons among users and sociodemographics, patterns of use, and co-use of tobacco products and substances.Overall, 4.6% of adults reported ever e-hookah use; of these, more than a quarter (26.8%) reported current use. For e-cigarettes, 22.5% reported ever use with 24.8% reporting current use. Among youth, 7.7% reported ever e-hookah use versus 14.3% for e-cigarette use. Comparing e-hookah versus e-cigarette only users, the majority were young adults aged 18-24 years versus ≥25 years (60.5% vs 17.3%, p0.0001) with the majority being female (58.8% vs 46.0%, p0.0001). Although alcohol and marijuana were the most common substances used among e-hookah and e-cigarette users, both adult and youth e-hookah only users had a higher prevalence of use than e-cigarette only users.Although e-hookahs are used less commonly than e-cigarettes, e-hookah use is not rare. Compared with e-cigarette users, e-hookah users have a different profile in terms of user demographics and co-use of substances. Given the rapid uptake of ENDS by young adults, these findings suggest the need to understand e-hookah products' distinct characteristics and users' smoking patterns and behaviors to help inform tobacco regulation specific to hookah.

Background As of March 2019, JUUL electronic cigarettes are the most popular e-cigarette on the U.S. market, but little is known of nicotine exposure and dependence on JUUL and user experience. Methods JUUL users participated in a community-based study involving questionnaires, saliva collection and a qualitative interview. Results Fifteen participants were enrolled (80% male, 53% White) and had an average age of 29.8 (standard deviation = 10) years. Daily exposure to nicotine assessed via salivary cotinine was similar to those reported for other e-cigarette and tobacco cigarette users in general. The majority reported low to moderate nicotine dependence. Qualitative interview themes included: the importance of social networks in adoption and use of the product; device features such as small size and vapor cloud reinforced product use; the product provided satisfaction compared to a tobacco cigarette; and a perceived sense of addiction to the product. Conclusions JUUL e-cigarettes expose users to levels of nicotine similar to other e-cigarettes but may be more satisfying due to unique device features. JUUL may be quite acceptable to tobacco cigarette smokers who are seeking to quit. However, it holds addictive potential and can reinforce long-term nicotine use.

Author(s): Hatsukami, Dorothy K; Luo, Xianghua; Heskin, Alisa K; Tang, Mei Kuen; Carmella, Steven G; Jensen, Joni; Robinson, Jason D; Vandrey, Ryan; Drobes, David J; Strasser, Andrew A; al'Absi, Mustafa; Leischow, Scott; Cinciripini, Paul M; Koopmeiners, Joseph; Ikuemonisan, Joshua; Benowitz, Neal L; Donny, Eric C; Hecht, Stephen S | Abstract: AimA previous study showed significantly greater reductions in number of cigarettes smoked and biomarkers of toxicant and carcinogen exposure in smokers assigned to immediate reduction of nicotine in cigarettes to very low levels versus gradually over time or continued smoking of normal nicotine content cigarettes. This study examines the effects of these approaches on selected biomarkers associated with harmful biological effects.DesignThree-arm, randomized controlled trial.SettingTen United States academic institutional sites.ParticipantsDaily smokers uninterested in quitting smoking with a mean age of 45.1 [standard deviation (SD)n=n13.4)] years and smoking 17.1 (SDn=n8.5) cigarettes/day; 43.9% (549 of 1250) female; 60.6% (758 of 1250) white ethnicity.Interventions(1) Smoking cigarettes where nicotine content was immediately reduced to very low levels (nn=n503); (2) smoking cigarettes where nicotine content was gradually reduced, with dose changes occurring monthly (nn=n498); and (3) continued smoking with normal nicotine content cigarettes (nn=n249).MeasurementsSmokers were assessed at baseline while smoking their usual brand cigarettes, and again at 4, 8, 12, 16 and 20nweeks. Outcomes were areas under the concentration time curve (AUC) for the period of study of biomarkers of inflammation, oxidative stress and hematological parameters.FindingsNo consistent significant differences were observed across groups (Bayes factors showing data to be insensitive), with the only exception being red blood cell size variability, which was observed to be lower in the immediate versus gradual nicotine reduction [mean differencen=nn-0.11; 95% confidence interval (CI)n=n-0.18, -0.04, Pn=n0.004] and normal nicotine control groups (mean differencen=n-n0.15, 95% CIn=n-0.23, -0.06, Pn=n0.001).ConclusionIt remains unclear whether switching to very low nicotine cigarettes leads to a short-term reduction in biomarkers of tobacco-related harm.

Introduction Approximately the same percentage of male high school students in the United States currently uses conventional smokeless tobacco as smokes cigarettes, resulting in toxin exposure. Methods This study assessed tobacco product use (smokeless, combustible, and electronic cigarettes) and nicotine and carcinogen exposures in a sample of 594 male rural high school baseball players—a population traditionally at risk for smokeless tobacco use. Salivary specimens were assayed for cotinine (a biomarker of nicotine exposure) and urine specimens for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a biomarker of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) using liquid chromatography–tandem mass spectrometry. Results The prevalence of past 30-day use of any tobacco product was 29%. Past 7-day smokeless tobacco use (prevalence: 13%) was associated with the highest levels of cotinine and NNAL observed in the sample, whether smokeless tobacco was used exclusively (geometric means: cotinine 11.1 ng/mL; NNAL 31.9 pg/mg-creatinine) or in combination with combustible products (geometric means: cotinine 31.6 ng/mL; NNAL 50.0 pg/mg creatinine). Cotinine and NNAL levels were incrementally higher in each increasing category of smokeless tobacco use frequency. However, observed levels were lower than previously reported for adults, likely reflecting less smokeless use per day among adolescents. Conclusions Based on these biomarker observations, adolescents who use conventional smokeless tobacco products are exposed to substantial levels of nicotine and NNK. Although exposed to lower levels than adult smokeless users, the findings are concerning given the young age of the sample and tendency for smokeless tobacco users to increase use intensity over time. Implications This study demonstrates that adolescents using smokeless tobacco are exposed to levels of nicotine and NNK that increase with use frequency and that exceed exposures among peers using other tobacco products. Youth smokeless tobacco use in the United States has not declined along with youth smoking prevalence, giving greater importance to this health concern. To reduce youth (and adult) exposures, needed actions include effective smokeless tobacco use prevention, potentially in combination with reducing the levels of harmful and potentially harmful chemicals in smokeless tobacco products currently popular among adolescents.

Aims To review cytisine's history of use, pre-clinical evidence, clinical pharmacokinetics, efficacy, adverse reactions (ARs) and safety for smoking cessation. Methods A synoptic review of the use of cytisine as a smoking cessation medication, mechanism of action, pharmacokinetics and safety. Relevant literature on data included in these sections were identified through a search of 11 databases with additional literature obtained from reports and monographs. Three databases (PubMed, EMBASE and www.elibrary.ru) were systematically searched for studies published from 2012 to August 2018 in any language to provide an updated meta-analysis of cytisine's efficacy and ARs for smoking cessation compared with placebo. We pooled the relative risks (RR) of abstinence in the efficacy analysis and RR of ARs, either reported by the authors or calculated from the reports. Results Cytisine has been in use since 1964 and is currently marketed in 18 countries. Systemic bioavailability from oral ingestion is high and clearance is primarily renal, with minimal or no metabolism. Brain uptake in animal models is moderate. The plasma half-life averages 4.8 hours. Eight studies were included for meta-analysis of efficacy. With heterogeneous results, the overall RR versus placebo of successful continuous abstinence at the longest follow-up was 1.74 [95% confidence interval (CI) = 1.38-2.19]. Nausea, vomiting, dyspepsia, upper abdominal pain and dry mouth that were mild or moderate were the most common ARs, with RR versus placebo 1.10 (95% CI = 0.95-1.28). The cost of cytisine in eastern and central Europe is several-fold less than that of other smoking cessation medications. Conclusions Cytisine is a low-cost medication found to increase the likelihood of smoking cessation. The most frequently reported ARs of cytisine involve gastrointestinal symptoms that are mostly reported as either mild or moderate in severity.

Introduction Accurate measurement of nicotine exposure from cigarette smoke is important in studying disease risk and level of dependence. Urine total nicotine equivalents, the molar sum of nicotine and six metabolites (NE7), accounts for more than 90% of a nicotine dose and is independent of individual metabolic differences. However, measuring NE7 is technically difficult and costly. We compared NE7, the gold standard of nicotine intake, with different combinations of fewer urinary nicotine metabolites. We also examined the impact of individual differences in nicotine metabolic rate, sex, and race on strength of association with NE7. Methods Urine samples from 796 daily smokers, who participated across five clinical studies, were assayed for nicotine and/or metabolites. Associations with NE7 were assessed by regression and Bland–Altman analyses. Results Overall, the molar sum of urine [cotinine + 3′-hydroxycotinine (3HC)] (NE2) and [nicotine + cotinine + 3HC] (NE3) were strongly correlated with NE7 (r = .97 and .99, respectively). However, in slow metabolizers NE2 was less predictive of NE7, whereas NE3 was equally robust. Urine total cotinine was also strongly correlated with NE7 (r = .87). Conclusions Urine NE3 is a robust biomarker of daily nicotine intake, independently of individual metabolic differences, whereas NE2 is less accurate in slow metabolizers. Our findings inform the selection of more rigorous and cost-effective measures to assess nicotine exposure in tobacco research studies. Implications The molar sum of urine total nicotine, cotinine and 3HC (NE3) is a robust biomarker of daily nicotine intake, independently of individual metabolic differences, and performs as well as measuring seven nicotine metabolites (NE7). The sum of cotinine and 3HC (NE2) is less accurate in slow metabolizers. Our findings inform the selection of more rigorous and cost-effective measures to assess nicotine exposure in tobacco research studies.

Background Black-white differences in smoking abstinence are not well understood. This trial sought to confirm previously reported differences in quitting between blacks and whites and to identify factors underlying this difference. Methods During enrollment, 224 black and 225 white low-income smokers were stratified on race and within race on age and sex to ensure balance on these factors known to impact abstinence. The intervention included varenicline for 12 weeks and six guideline-based smoking cessation counseling sessions. The primary endpoint was cotinine-verified 7-day point prevalence smoking abstinence at week 26. A priori socioeconomic, smoking, treatment process (eg, treatment utilization, side effects, withdrawal relief), psychosocial, and biological factors were assessed to investigate race differences in abstinence. Unadjusted odds ratios (OR) were used to compare abstinence between blacks and whites. Adjusted odds ratios from logistic regression models were used to examine predictors of abstinence. All statistical tests were two-sided. Results Blacks were less likely to achieve abstinence at week 26 (14.3% vs 24.4%, OR = 0.51, 95% confidence interval [CI] = 0.32 to 0.83, P = .007). Utilizing best subsets logistic regression, five factors associated with race jointly predicted abstinence: home ownership (yes/no, OR = 3.03, 95% CI = 1.72 to 5.35, P Conclusions The race difference in abstinence was fully explained by lack of home ownership, lower income, greater neighborhood problems, higher baseline cotinine, and higher visit completion, which were disproportionately represented among blacks. Findings illuminate factors that make it harder for blacks in the United States to quit smoking relative to whites and provide important areas for future studies to reduce tobacco-related health disparities.

Author(s): Liu, Jia; Benowitz, Neal L.; Hatsukami, Dorothy K.; Havel, Christopher M.; Lazcano-Ponce, Eduardo; Strasser, Andrew A.; Jacob, Peyton | Abstract: In studies of tobacco toxicology, including comparisons of different tobacco products and exposure to secondhand or thirdhand smoke, exposure assessment using biomarkers is often useful. Some studies have indicated that most of the toxicity of tobacco smoke is due to gas-phase compounds. 3-Ethenylpyridine (3-EP) is a major nicotine pyrolysis product occurring in the gas phase of tobacco smoke. It has been used extensively as an environmental tracer for tobacco smoke. 3-EP would be expected to be a useful tobacco smoke biomarker as well, but nothing has been published about its metabolism and excretion in humans. In this Article we describe a solid-phase microextraction (SPME) GC-MS/MS method for determination of 3-EP in human urine and its application to the determination of 3-EP in the urine of smokers and people exposed to secondhand smoke. We conclude that 3-EP is a promising biomarker that could be useful in studies of tobacco smoke exposure and toxicology. We also point out the paucity of data on 3-EP toxicity and suggest that additional studies are needed.Graphical Abstract

Background Electronic hookah (e‐hookah) vaping has increased in popularity among youth, who endorse unsubstantiated claims that flavored aerosol is detoxified as it passes through water. However, e‐hookahs deliver nicotine by creating an aerosol of fine and ultrafine particles and other oxidants that may reduce the bioavailability of nitric oxide and impair endothelial function secondary to formation of oxygen‐derived free radicals. Methods and Results We examined the acute effects of e‐hookah vaping on endothelial function, and the extent to which increased oxidative stress contributes to the vaping‐induced vascular impairment. Twenty‐six healthy young adult habitual hookah smokers were invited to vape a 30‐minute e‐hookah session to evaluate the impact on endothelial function measured by brachial artery flow‐mediated dilation (FMD). To test for oxidative stress mediation, plasma total antioxidant capacity levels were measured and the effect of e‐hookah vaping on FMD was examined before and after intravenous infusion of the antioxidant ascorbic acid (n=11). Plasma nicotine and exhaled carbon monoxide levels were measured before and after the vaping session. Measurements were performed before and after sham‐vaping control experiments (n=10). E‐hookah vaping, which increased plasma nicotine (+4.93±0.92 ng/mL, P P =0.479), increased mean arterial pressure (11±1 mm Hg, P P P P =0.002). All parameters were unchanged during sham studies. Conclusions E‐hookah vaping has adverse effects on vascular function, likely mediated by oxidative stress, which overtime could accelerate development and progression of cardiovascular disease. Registration URL: https://ClinicalTrials.gov . Unique identifier: NCT03690427.

ObjectiveIt is unclear why Black smokers in the United States have elevated risk of some tobacco-related diseases compared to White smokers. One possible causal mechanism is differential intake of tobacco toxicants, but results across studies are inconsistent. Thus, we examined racial differences in biomarkers of toxic volatile organic compounds (VOCs) present in tobacco smoke.MethodWe analyzed baseline data collected from 182 Black and 184 White adult smokers who participated in a randomized clinical trial in 2013-2014 at 10 sites across the United States. We examined differences in urinary levels of ten VOC metabolites, total nicotine equivalents (TNE), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), controlling for covariates such as cigarettes per day (CPD), as well as differences in VOCs per TNE to assess the extent to which tobacco exposure, and not metabolic factors, accounted for racial differences.ResultsConcentration of metabolites of acrolein, acrylonitrile, ethylene oxide, and methylating agents were significantly higher in Blacks compared to Whites when controlled for covariates. Other than the metabolite of methylating agents, VOCs per TNE did not differ between Blacks and Whites. Concentrations of TNE/CPD and VOCs/CPD were significantly higher in Blacks. Menthol did not contribute to racial differences in VOC levels.ConclusionsFor a given level of CPD, Black smokers likely take in higher levels of acrolein, acrylonitrile, and ethylene oxide than White smokers. Our findings are consistent with Blacks taking in more nicotine and toxicants per cigarette smoked, which may explain their elevated disease risk relative to other racial groups.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.

Electronic nicotine delivery systems (ENDS) such as e-cigarettes and heated tobacco products are novel battery-operated devices that deliver nicotine without combustion of tobacco. Because cigarette smoking is sustained by nicotine addiction and the toxic combustion products are mainly responsible for the harmful effects of smoking, ENDS could be used to promote smoking cessation while exposing users to lower levels of toxicants compared with conventional cigarettes. The currently available evidence from clinical and observational studies indicates a potential role of e-cigarettes as smoking cessation aids, although many continue to use e-cigarettes long after quitting smoking. Nicotine and toxicant delivery vary considerably by device and depend on the characteristics of the e-liquid formulation. Because smokers tend to titrate their nicotine intake to maintain their desired pharmacologic effects, device and liquid characteristics need to be considered when using ENDS as an aid to quit smoking. Factors potentially limiting their use are the currently still unknown long-term safety of these products and concerns regarding widespread use among youth. Implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration are discussed.

Nicotine is inactivated by the polymorphic CYP2A6 enzyme to cotinine and then to 3′hydroxycotinine. The Nicotine Metabolite Ratio (NMR; 3′hydroxycotinine/cotinine) is a heritable nicotine metabolism biomarker, varies with sex and ancestry, and influences smoking cessation and disease risk. We conducted sex-stratified genome-wide association studies of the NMR in European American (EA) and African American (AA) smokers (NCT01314001, NCT00666978). In EA females (n = 389) and males (n = 541), one significant (P CYP2A6 (intronic), for C vs. T: females: beta = 0.67, P = 7.5e−22, 21.8% variation explained; males: beta = 0.75, P = 1.2e−37, 26.1% variation explained). In AA females (n = 503) and males (n = 352), the top variant was found on chromosome 19 but differed by sex (females: rs11878604, CYP2A6 (~ 16 kb 3′), for C vs. T: beta = − 0.71, P = 6.6e−26, 16.2% variation explained; males: rs3865454, CYP2A6 (~ 7 kb 3′), for G vs. T: beta = 0.64, P = 1.9e−19, 18.9% variation explained). In AA females, a significant region was found on chromosome 12 (top variant: rs12425845: P = 5.0e−9, TMEM132C (~ 1 Mb 5′), 6.1% variation explained) which was not significant in AA males. In AA males, significant regions were found on chromosomes 6 (top variant: rs9379805: P = 4.8e−9, SLC17A2 (~ 8 kb 5′), 8.0% variation explained) and 16 (top variant: rs77368288: P = 3.5e−8, ZNF469 (~ 92 kb 5′), 7.1% variation explained) which were not significant in AA females. Further investigation of these associations outside of chromosome 19 is required, as they did not replicate. Understanding how sex and ancestry influence nicotine metabolism genetics may improve personalized approaches for smoking cessation and risk prediction for tobacco-related diseases.

Background Cardiovascular safety is an important consideration regarding the benefits versus risks of electronic cigarette use (EC) for public health. The single‐use cardiovascular effects of EC have been well studied but may not reflect effects of ad libitum use throughout the day. We aimed to compare the circadian hemodynamic effects as well as 24‐hour biomarkers of oxidative stress, and platelet aggregation and inflammation, with ad libitum cigarette smoking (CS) versus EC versus no tobacco product use. Methods and Results Thirty‐six healthy dual CS and EC users participated in a crossover study in a confined research setting. Circadian heart rate, blood pressure and plasma nicotine levels, 24‐hour urinary catecholamines, 8‐isoprostane and 11‐dehydro‐thromboxane B2, and plasma interleukin‐6 and interleukin‐8 were compared in CS, EC, and no nicotine conditions. Over 24 hours, and during daytime, heart rate and blood pressure were higher in CS and EC compared with no tobacco product conditions ( P P Conclusions CS and EC had similar 24‐hour patterns of hemodynamic effects compared with no tobacco product, with a higher average heart rate with CS versus EC, and similar effects on biomarkers of inflammation. EC may pose some cardiovascular risk, particularly to smokers with underlying cardiovascular disease, but may also provide a harm reduction opportunity for smokers willing to switch entirely to EC. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT02470754.

Key Points Question What is the effect of using nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) for replacing cigarettes (ie, switching) on biomarkers of tobacco exposure and potential harm among cigarette smokers? Findings In this randomized clinical trial including 186 African American and Latinx adult smokers, those randomized to the e-cigarette condition maintained their cotinine levels and significantly reduced urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and carbon monoxide levels and respiratory symptoms compared with controls smoking as usual at week 6. Lung function and blood pressure remained unchanged. Meaning This randomized clinical trial found that switching to NSPS e-cigarettes among adult smokers did not increase nicotine exposure and led to short-term reduction in the major pulmonary carcinogen, NNAL, compared with continued smoking., This randomized clinical trial examines biomarkers of carcinogen exposure in African American and Latinx smokers who switch to electronic cigarettes vs smoking as usual., Importance Fourth-generation nicotine salt pod system (NSPS) electronic cigarettes (e-cigarettes) are the leading class of e-cigarettes. They contain high nicotine concentrations, which may facilitate switching among smokers, but could also lead to increased exposure to nicotine and biomarkers of potential harm. African American and Latinx smokers experience significant tobacco-related health disparities. The potential of NSPS e-cigarettes to reduce smoking-related harm among these groups is unknown. Objective To compare the harm reduction potential of NSPS e-cigarette vs combustible cigarettes. Design, Setting, and Participants This unblinded randomized clinical trial compared 6 weeks of e-cigarette use vs cigarettes as usual from to 2018 to 2019 among smokers in the San Diego, California, and Kansas City, Missouri, areas. Participants included African American and Latinx adult combustible cigarette smokers who smoked at least 5 cigarettes/d on at least 25 of the past 30 days for at least 6 months and were interested in switching to e-cigarettes. Data were analyzed from September 18, 2019, to September 4, 2020. Interventions 6 weeks of e-cigarette use in a choice of pod flavors (5% nicotine) along with brief education, training, and action planning to completely switch to e-cigarettes from combustible cigarettes. The control group smoked combustible cigarettes as usual. Main Outcomes and Measures The primary outcome was reduction in urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) concentration at week 6. Secondary outcomes were change in urinary cotinine, expired carbon monoxide (CO), respiratory symptoms, lung function, blood pressure, past 7-day consumption of combustible cigarettes, and switching rates (e-cigarette group only) at weeks 2 and 6. Results This study included 186 participants, including 92 African American participants and 94 Latinx participants. The mean (SD) age was 43.3 (12.5) years, and 75 (40.3%) were women. Participants smoked a mean (SD) of 12.1 (7.2) cigarettes/d on 6.8 (0.6) d/wk at baseline. A total of 125 participants were randomized to the e-cigarette group and 61 were randomized to the control group. At baseline, median (interquartile range) NNAL was 124 (45-197) pg/mL in the e-cigarette group and 88 (58-197) pg/mL in the control group. At week 6, the e-cigarette group had significantly greater reductions in NNAL (relative risk [RR], 0.36 [95% CI, 0.23-0.54]; P

With patented nicotine salt technology, JUUL dominates the e-cigarette market. We reviewed studies of JUUL’s nicotine pharmacokinetic profile and studies quantifying nicotine in a JUULpod, emitted in the aerosol and absorbed by users. Examined in eight studies, JUUL’s peak nicotine levels were half to three-quarters that of a combustible cigarette in industry-conducted studies with JUUL-naïve users, while comparable to or greater than combustible cigarettes in independent studies of experienced e-cigarette users. JUUL Labs reports each 5% (nicotine-by-weight) cartridge contains approximately 40 mg nicotine per pod and is ‘approximately equivalent to about 1 pack of cigarettes.’ In five independent studies, nicotine in the liquid in a JUULpod ranged from 39.3 to 48.3 mg. Seven studies measured nicotine delivery via vaping-machine generated aerosols, varying in puffing regimes and equipment. One study estimated 68% transfer efficiency to the aerosol, measuring 28.8 mg nicotine per JUULpod. The other studies reported nicotine values ranging from 72 to 164 µg/puff. At 200 puffs, this is 14.4–32.8 mg of nicotine per pod with equivalence to 13–30 cigarettes. A study measuring nicotine levels in JUUL users during a 5-day controlled switch found equivalence to 18 cigarettes. One JUULpod appears capable of delivering the nicotine equivalent to smoking about a pack of cigarettes, with variability. In JUUL-naïve smokers, JUUL’s nicotine boost was lower than that of combustible cigarettes; while in experienced users, JUUL was comparable. Minimising harshness and adaptive to user experience, JUUL’s design facilitates initiation to a high nicotine, and ultimately, highly addictive vaping product.

OBJECTIVE: Evaluate efficacy and safety of varenicline, bupropion, and nicotine replacement therapy (NRT) for smoking cessation in smokers with schizophrenia spectrum disorders in post-hoc analyses of EAGLES data. METHODS: Smokers with a schizophrenia spectrum disorder (n=390) and without a psychiatric illness (controls) (n=4,028) were randomly assigned to varenicline, bupropion, NRT, or placebo for 12 weeks. Outcomes included abstinence rates during treatment and follow-up, number needed to treat (NNT) for abstinence, incidence of neuropsychiatric adverse events, and temporal relationship between neuropsychiatric adverse events and abstinence status. RESULTS: Smokers with schizophrenia smoked more, had greater dependence, and fewer prior trials of cessation pharmacotherapy. At each timepoint, on varenicline, smokers with schizophrenia had significantly greater odds of abstinence than placebo and comparable NNT with controls. Bupropion and NRT increased odds of abstinence, though confidence intervals included one for some comparisons and produced greater NNT in smokers with schizophrenia than controls. No treatment was associated with significantly more neuropsychiatric adverse events than placebo in either cohort. The estimated neuropsychiatric adverse event rate was 5% (95% CI=3.0–7.7) in smokers with schizophrenia and 1% (95% CI=.6–2.1) in controls. Over one-third of neuropsychiatric adverse events occurred during partial or full abstinence, suggesting a multifactorial nature of neuropsychiatric adverse events. CONCLUSIONS: In smokers with schizophrenia, varenicline was associated with significantly higher abstinence rates than NRT, bupropion, and placebo, and had NNT comparable with smokers without psychiatric disorders. A significant proportion of neuropsychiatric adverse events occurred during early abstinence. No treatment significantly increased neuropsychiatric adverse event prevalence.

Author(s): Epperson, Anna E; Crouch, Maria; Skan, Jordan; Benowitz, Neal L; Schnellbaecher, Matthew; Prochaska, Judith J | Abstract: IntroductionApproximately 9 million American adults use two or more tobacco products regularly, referred to as dual or poly tobacco users. In Alaska, where tobacco is not native, approximately 20% of the population smokes cigarettes, and among smokers, 10% use two or more tobacco products. Previous research suggests that dual tobacco product use may be especially high among Alaska Native people. The current study examined cultural and demographic characteristics associated with dual tobacco use.MethodsAlaska Native adults reporting daily smoking and identified with high blood pressure or cholesterol were recruited in the Norton Sound region of Alaska between 2015-2019 as part of a treatment trial targeting cardiovascular disease risk factors. Participants reported their tribal group, level of identification with their Alaska Native heritage, speaking of their tribal language, basic demographic characteristics, and past 30-day use of tobacco products in addition to smoking cigarettes.ResultsParticipants (n=299) were 48.5% female and identified as Yup'ik (31.1%), Inupiat (60.5%), and other or multiple tribal group(s) (8.4%). Most participants (85.3%) strongly identified with their Alaska Native heritage. Past 30-day dual tobacco use was reported by 10.0%, specifically 9.0% chew/snuff, 1.3% e-cigarettes, and 0.7% Iq'mik. Multivariate regression models indicated that dual tobacco use was more likely among men (OR=3.35; 95% CI: 1.30-8.64), younger participants (OR range: 10.97-12.35; 95% CI: 2.33-57.86), those identifying as Yup'ik (OR=2.86; 95% CI: 1.13-7.19), and those who identified very little or not at all with their Alaska Native heritage (OR=2.98; 95% CI: 1.14-7.77).ConclusionsYoung men identifying as Yup'ik were more likely to use dual forms of tobacco. Stronger identification with one's Alaska Native heritage was associated with lower risk of dual tobacco use. The findings highlight cultural and demographic factors for further consideration and attention in tobacco cessation treatment interventions.

Introduction We illustrate the differential impact of common analysis approaches to handling urinary creatinine, a measure for urine dilution, on relationships between race, gender, and biomarkers of exposure measured in spot urine. Methods In smokers, spot urine levels of total nicotine equivalents (TNE, sum of total nicotine, total cotinine, and total 3′-hydroxycotinine) and total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) overall and per cigarette were examined. Relationships between race (African Americans [AA] n = 373, Whites n = 758) or gender (males n = 629, females n = 502) and TNE or NNAL were examined using the following approaches to handling creatinine: (1) unadjusted/unstandardized; (2) standardization; (3) adjustment as a covariate. Significance was considered at p < .05 Results Creatinine was higher in AA versus Whites (1.19 vs. 0.96 mg/mL; p < .0001) and in males versus females (1.21 vs. 0.84 mg/mL; p < .0001). Independent of how creatinine was handled, TNE was lower among AA than Whites (TNE ratios AA vs. Whites: 0.67–0.84; p’s < .05). Unadjusted TNE per cigarette was higher among AA versus Whites (ratio 1.12; p = .0411); however, the relationship flipped with standardization (ratio 0.90; p = .0360) and adjustment (ratio 0.95; p = .3165). Regarding gender, unadjusted TNE was higher among males versus females (ratio 1.13; p = .0063), but the relationship flipped with standardization (ratio 0.79; p < .0001) or adjustment (ratio 0.89; p = .0018). Unadjusted TNE per cigarette did not differ across gender (ratio 0.98; p = .6591), but lower levels were found in males versus females with standardization (ratio 0.68; p < .0001) and adjustment (ratio 0.74; p < .0001). NNAL displayed similar patterns. Conclusions Relationships between race, gender, and spot urine levels of biomarkers of exposure can vary greatly based on how creatinine is handled in analyses. Implications Lack of appropriate methods can lead to discrepancies across reports on variability of urinary biomarkers by race and gender. We recommend that for any analyses of biomarkers of exposure measure in spot urine samples across race, gender, or other population subgroups that differ in urinary creatinine levels, sensitivity analyses comparing the different methods for handling urinary creatinine should be conducted. If methods result in discrepant findings, this should be clearly noted and discussed.

Author(s): Harvanko, Arit M; St Helen, Gideon; Nardone, Natalie; Addo, Newton; Benowitz, Neal L | Abstract: Background and aimsRelative pharmacological effects of e-cigarettes and cigarettes during 24nhours of ad-libitum use have not been described. In this study, 24-hour blood plasma nicotine concentrations and 48-hour subjective effects with use of cigarettes and e-cigarettes were measured among dual users.DesignTwo-arm within-subject cross-over design with preferred e-cigarette or cigarette ad-libitum use over 48nhours.SettingHospital research ward in San Francisco, California, USA.ParticipantsThirty-six healthy dual users of e-cigarettes and cigarettes (nn=n8, 25% females).MeasurementsTwenty-four-hour blood plasma nicotine and cotinine concentrations and 48-hour self-reported nicotine withdrawal symptoms and rewarding effects.FindingsAnalyses used analysis of variance (ANOVA)-based mixed models with order of product (e-cigarette or cigarette) and product type (combustible cigarette or type of e-cigarette) as fixed effects, and subject as a repeated effect. During a 24-hour period, e-cigarettes produced lower nicotine exposure than cigarettes for the majority of users, although 25% received more nicotine from e-cigarettes, which was predicted by more frequent e-cigarette use or greater dependence. Compared to cigarette smoking, nicotine exposure for variable-power tank users was similar, while cig-a-like (t(30) n=n2.71, Pn=n0.011, dn=n0.745) and fixed-power tank users (t(30) n=n3.37, Pn=n0.002, dn=n0.993) were exposed to less nicotine. Cigarettes were rated higher than e-cigarettes on some desirable subjective effects (e.g. psychological reward, t(322) n=n7.24 Pnln0.001, dn=n0.432), but withdrawal symptom reduction was comparable. No differences were found between e-cigarette types, but Bayes factors indicate that these measures were insensitive.ConclusionsDuring a 24-hour period in a hospital setting in the United States, nicotine exposure for dual users of e-cigarettes and cigarettes was similar when using cigarettes or variable-power tank devices only but was lower for those using cig-a-like or fixed-power devices only. Despite lower nicotine levels, all types of e-cigarette were effective in preventing withdrawal symptoms. E-cigarettes were rated less rewarding than cigarettes.

School children may be exposed to secondhand smoke (SHS) either at home, in transit or in social gatherings permitting smoking in their presence. Questionnaires about SHS often underestimate prevalence and extent of exposure. A more accurate tool is the use of biomarkers such as cotinine (COT) and trans-3'-hydrocycotinine (3HC) as biomarkers of SHS exposure, alongside 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a reduction product in the body of the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), both potent carcinogens. We measured urinary COT, 3HC and total NNAL using sensitive and specific high-performance LC-MS/MS methods. The limit of quantification (LOQ) for each assay were 0.05ng/mL, 0.1ng/mL and 0.25pg/mL respectively. The aim of this study was to evaluate the exposure to SHS of school children (9-11 years), from five public schools in the island of Malta, from questionnaire information about smoking at home and verify it by urinary biomarker data of COT, 3HC and NNAL. These biomarkers were measurable in 99.4%, 95.4% and 98.3% of the participating children respectively. From the children reporting smoking at home, 11% had a history of asthma and had COT, 3HC and NNAL geometric mean concentrations double compared to the non-asthmatic group. In has been confirmed that non-smokers exposed to SHS and THS have a higher NNAL/COT ratio than the group identified as smokers according to specific and defined COT threshold levels (despite the fact that a priori, the entire study group was composed of non-smokers). The implication of high measured levels of urinary NNAL in children should be of concern given its potency. A main effects multifactor ANOVA model was developed and the children's house and school locations and the smoking frequency were statistically significant to predict the levels of the three metabolites. For 3HC only, the status of the employment of the mother was also an important predictor.

Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among youth and smoking cessation among established smokers are key for reducing smoking prevalence and the associated negative health consequences. Proven tobacco cessation treatment includes pharmacotherapy and behavioral support, which are most effective when provided together. First-line medications (varenicline, bupropion, and nicotine replacement) are effective and safe for patients with CVD. Clinicians who care for patients with CVD should give as high a priority to treating tobacco use as to managing other CVD risk factors. Broader tobacco control efforts to raise tobacco taxes, adopt smoke-free laws, conduct mass media campaigns, and restrict tobacco marketing enhance clinicians' actions working with individual smokers.

James L. Januzzi Jr, MD, FACC, Chair Tariq Ahmad, MD, MPH, FACC Brendan Everett, MD, FACC William Hucker, MD, PhD Dharam J. Kumbhani, MD, SM, FACC Joseph E. Marine, MD, FACC Pamela B. Morris, MD, FACC Robert N. Piana, MD, FACC Sunil V. Rao, MD, FACC Marielle Scherrer-Crosbie, MD, PhD

Introduction The availability of electronic cigarettes (e-cigarettes) has profoundly changed the tobacco product landscape. In the United States, almost 6 million adults use both combustible and e-cigarettes (ie, dual users). The goal of this study was to understand how smokers and dual users differ in terms of demographics, cigarette dependence, and exposure to carcinogens. Methods An observational cohort (smokers, n = 166, ≥5 cigarettes/day for 6 months and no e-cigarette use in 3 months; dual users, n = 256, smoked daily for 3 months and used e-cigarettes at least once/week for the past 3 months) completed baseline assessments of demographics, tobacco use, and dependence. They also provided breath samples for carbon monoxide (CO) assay and urine samples for cotinine, 3-hydroxycotinine, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) assays. Results Compared to smokers, dual users (mean e-cigarette use = 5.5 days/week [SD = 1.9]) were significantly younger and more likely to be white, have more education, report a history of psychiatric co-morbidity, and smoke fewer cigarettes per day. There were no differences in CO, cotinine, or 3-hydroxycotinine levels; however, dual users had significantly lower levels of NNAL than did smokers. Most smokers and dual users had no plans to quit smoking within the next year; 91% of dual users planned to continue using e-cigarettes for at least the next year. Conclusions In this community sample, dual users are supplementing their smoking with e-cigarette use. Dual users, versus smokers, smoked fewer cigarettes per day and delayed their first cigarette of the day, but did not differ in quitting intentions. Implications This comparison of a community sample of established dual users and exclusive smokers addresses key questions of dependence and health risks of dual use in real-world settings. Dual users were more likely to be white, younger, have more than a high school education and have a psychiatric history. Dual users also smoked significantly fewer cigarettes and had lower levels of NNAL (a carcinogen), but they did not differ from exclusive smokers in CO or cotinine levels, suggesting that they supplemented their nicotine intake via e-cigarettes.

This study investigated the influence of the rate of nicotine metabolism, as indicated by the nicotine metabolite ratio (NMR), on tobacco dependence. We stratified 136 smokers on the basis of saliva NMR as fast (n = 65) and slow (n = 71) metabolizers. Two “loading cigarettes” were smoked after overnight, and a “reward cigarette” was smoked after 6 hours of daytime, abstinence. Blood nicotine concentrations, expired carbon monoxide, withdrawal/craving, and reward questionnaires were collected before/after smoking and during daytime abstinence. Compared with slow metabolizers, fast metabolizers had a shorter nicotine elimination half-life (P < 0.001), lower plasma nicotine concentrations (P < 0.001), and higher withdrawal/craving scores (P < 0.05) for most times during daytime abstinence, indicating that fast metabolizers are likely smoking more to relieve withdrawal symptoms (negative reinforcement). Reward/satisfaction scores were similar in fast and slow metabolizers, suggesting that faster nicotine metabolism, assessed by NMR, is not associated with greater positive reinforcement. CYP2A6 normal (n = 82) and reduced (n = 42) genotype predicted plasma nicotine concentrations but not withdrawal symptoms.

Background: Biomarkers of tobacco exposure have a central role in studies of tobacco use and nicotine intake. The most significant exposure markers are nicotine itself and its metabolites in urine. Therefore, it is important to evaluate the performance of laboratories conducting these biomarker measurements. Methods: This report presents the results from a method performance study involving 11 laboratories from 6 countries that are currently active in this area. Each laboratory assayed blind replicates of seven human urine pools at various concentrations on three separate days. The samples included five pools blended from smoker and nonsmoker urine sources, and two additional blank urine samples fortified with pure nicotine, cotinine, and hydroxycotinine standards. All laboratories used their own methods, and all were based on some form of liquid chromatography/tandem mass spectrometry. Results: Overall, good agreement was found among the laboratories in this study. Intralaboratory precision was good, and in the fortified pools, the mean bias observed was < + 3.5% for nicotine, approximately 1.2% for hydroxycotinine, and less than 1% for cotinine (1 outlier excluded in each case). Both indirect and direct methods for analyzing the glucuronides gave comparable results. Conclusions: This evaluation indicates that the experienced laboratories participating in this study can produce reliable and comparable human urinary nicotine metabolic profiles in samples from people with significant recent exposure to nicotine. Impact: This work supports the reliability and agreement of an international group of established laboratories measuring nicotine and its metabolites in urine in support of nicotine exposure studies. Cancer Epidemiol Biomarkers Prev; 27(9); 1083–90. ©2018 AACR.

BackgroundNew electronic heated tobacco products are being introduced in the global market and are gaining popularity. In 2016, Philip Morris International, Inc. (PMI) submitted a modified risk tobacco product (MRTP) application to the Food and Drug Administration (FDA) to market IQOS in the USA with claims of reduced exposure and reduced risk.MethodsWe examined PMI’s MRTP application, specifically sections on aerosol chemistry and human exposure assessment, to assess the validity of PMI’s claims of reduced exposure and risk.FindingsPMI reported levels for only 40 of 93 harmful and potentially harmful constituents (HPHCs) on FDA’s HPHC list in IQOS mainstream aerosol. All substances in PMI’s list of 58 constituents (PMI-58) were lower in IQOS emissions compared with mainstream smoke of 3R4F reference cigarettes. However, levels of 56 other constituents, which are not included in the PMI-58 list or FDA’s list of HPHCs, were higher in IQOS emissions; 22 were >200% higher and seven were >1000% higher than in 3R4F reference cigarette smoke. PMI’s studies also show significantly lower systemic exposure to some HPHCs from use of IQOS compared with smoking combustible cigarettes.ConclusionPMI’s data appear to support PMI’s claim that IQOS reduces exposure to HPHCs. However, PMI’s data also show significantly higher levels of several substances that are not recognised as HPHCs by the FDA in IQOS emissions compared with combustible cigarette smoke. The impact of these substances on the overall toxicity or harm of IQOS is not known.

Tobacco use is the leading preventable cause of death worldwide and is a major risk factor for cardiovascular disease (CVD). Both prevention of smoking initiation among youth and smoking ce...

Objective The primary objective of this pilot study was to describe the impact of e-cigarette liquid flavors on experienced e-cigarette users’ vaping behavior. Methods 11 males and 3 females participated in a 3-day inpatient crossover study using e-cigarettes with strawberry, tobacco, and their usual brand e-liquid. Nicotine levels were nominally 18 mg/mL in the strawberry and tobacco e-liquids and ranged between 3–18 mg/mL in the usual brands. On each day, participants had access to the study e-cigarette (KangerTech mini ProTank 3, 1.5 Ohms, 3.7 V) and the assigned e-liquid during a 90-minute videotaped ad libitum session. Results Average puff duration was significantly longer when using the strawberry e-liquid (3.2 ± 1.3 s, mean ± SD) compared to the tobacco e-liquid (2.8 ± 1.1 s) but the average number of puffs was not significantly different (strawberry, 73 ± 35; tobacco, 69 ± 46). Compared to the strawberry- and tobacco-flavored e-liquids, average puff duration was significantly longer (4.3 ± 1.6 s) and the average number of puffs was significantly higher (106 ± 67 puffs) when participants used their usual brand of e-liquid. Participants generally puffed more frequently in small groups of puffs (1–5 puffs) with the strawberry compared to the tobacco e-liquid and more frequently in larger groups (>10 puffs) with their usual brand. The strength of the relationship between vaping topography and nicotine intake and exposure were not consistent across e-liquids. Conclusion Vaping behavior changes across e-liquids and influences nicotine intake. Research is needed to understand the mechanisms that underlie these behavioral changes, including e-liquid pH and related sensory effects, subjective liking, and nicotine effects.

Background A non-invasive phenotypic indicator of the rate of nicotine metabolism is nicotine metabolite ratio (NMR) defined as a ratio of two major metabolites of nicotine – trans-3′-hydroxycotinine/cotinine. The rate of nicotine metabolism has important clinical implications for the likelihood of successful quitting with nicotine replacement therapy (NRT). We conducted a study to measure NMR among Polish smokers. Methods In a cross-sectional study of 180 daily cigarette smokers (42% men; average age 34.6 ± 13.0), we collected spot urine samples and measured trans-3′-hydroxycotinine (3-HC) and cotinine levels with LC–MS/MS method. We calculated NMR (molar ratio) and analyzed variations in NMR among groups of smokers. Results In the whole study group, an average NMR was 4.8 (IQR 3.4–7.3). The group of women below 51 years had significantly greater NMR compared to the rest of the population (6.4; IQR 4.1–8.8 vs. 4.3; IQR 2.8–6.4). No differences were found among group ages of male smokers. Conclusions This is a first study to describe variations in nicotine metabolism among Polish smokers. Our findings indicate that young women metabolize nicotine faster than the rest of population. This finding is consistent with the known effects of estrogen to induce CYP2A6 activity. Young women may require higher doses of NRT or non-nicotine medications for most effective smoking cessation treatment.

In the United States, the Food and Drug Administration (FDA) has initiated a public dialogue about reducing the nicotine content of cigarettes. A reduced-nicotine standard could increase withdrawal symptoms among current smokers. We examined the impact of switching smokers to cigarettes that varied in nicotine content on withdrawal symptoms over 6 weeks. A secondary analysis (N = 839) of a 10-site, double-blind clinical trial of nontreatment-seeking smokers was completed. Participants were instructed to smoke study cigarettes, containing 0.4 to 15.8 mg of nicotine/g of tobacco, for 6 weeks and were then abstinent overnight. Using latent growth curves, trajectories of individual withdrawal symptoms were compared between the reduced nicotine content (RNC) conditions and a normal nicotine content (NNC) condition. Path analyses compared symptoms after overnight abstinence. Relative to NNC cigarettes, participants smoking RNC cigarettes had increased anger/irritability/frustration and increased appetite/weight gain during the initial weeks, but the symptoms resolved by Week 6. Individuals who were biochemically verified as adherent with using only the 0.4 mg/g cigarettes had higher sadness levels (Cohen's d = .40) at Week 6 compared with the NNC condition, although symptoms were mild. After a post-Week 6 overnight abstinence challenge, some RNC conditions relative to NNC condition exhibited reduced withdrawal. Individuals who were biochemically confirmed as adherent to the lowest nicotine condition experienced only mild and transient symptom elevations. Thus, a reduced-nicotine standard for cigarettes produced a relatively mild and temporary increase in withdrawal among nontreatment-seeking smokers (ClinicalTrials.gov No. NCT01681875). (PsycINFO Database Record

INTRODUCTION:While adherence to medication in smoking cessation clinical trials is strongly associated with clinical outcome, very few studies have evaluated the validity of pill count as a measure of adherence relative to a biological assay, and evaluated a broad range of correlates of adherence. METHODS:In a smoking cessation clinical trial of varenicline, we compared pill counts collected over 4 different time periods to varenicline salivary levels taken after 2weeks of treatment, as well as evaluated predictors of adherence to varenicline. RESULTS:Using a binary measure of adherence based on salivary varenicline levels, adherence was higher among older, white, and more educated participants. Relative to 3, 7, and 14-day pill count, 12-week pill count was the only significant measure able to discriminate adherence as defined by salivary varenicline levels (assessed by area under the receiver operating characteristic curve; AUC=0.59, p=0.004). Seventy-two percent of participants who indicated adherence on 12-week pill count were classified as adherent based on varenicline saliva levels (sensitivity=0.80; specificity=0.40). There was modest variability in the relationship between 12-week pill count and varenicline levels across race and rate of nicotine metabolism. Lastly, General Estimating Equation models demonstrated that longitudinal changes in withdrawal, craving, negative and positive affect, and side effect count and severity were not related to adherence based on salivary varenicline levels. CONCLUSIONS:These results indicate that 12-week pill count was the best, albeit a relatively weak, measure of varenicline adherence; additional factors associated with treatment adherence need to be identified.

BACKGROUND AND AIMS: The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. DESIGN: Genome-wide association study (GWAS). SETTING: Multiple sites within Canada and the United States. PARTICIPANTS: AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n = 504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n = 450). MEASUREMENTS: Genome-wide SNP genotyping, the NMR (phenotype) and population substructure and NMR covariates. FINDINGS: Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190 and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P = 1.47e-39; beta = 0.59 per C (versus T) allele, SE = 0.045), located ~9.5 kb 3' of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in individuals of European descent. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n = 480). None of the hits were in UGT or OCT2 genes. CONCLUSIONS: Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours and tobacco-related disease risk.

Non-cigarette other tobacco products (OTP; e.g., cigarillos, little cigars) are typically used in combination with cigarettes, but limited data exists on the tobacco toxicant exposure profiles of dual cigarette-OTP (Cig-OTP) users. This study examined biomarkers of nicotine and carcinogen exposure in cigarette smokers who used or did not use OTP.111 Cig-OTP and 111 cigarette only (Cig Only) users who smoked equivalent cigarettes per day were matched on age (40,=40), race (African American, White), and gender. Participants reported past 7-day daily use of cigarettes and OTP and provided urine for nicotine, cotinine, total nicotine equivalents (TNE) and total NNAL concentrations.Cig-OTP users reported greater past 7-day tobacco use (15.9 versus 13.0 products/day, p0.01) but had significantly lower creatinine-normalized nicotine (606 versus 1301ng/mg), cotinine (1063 versus 2125ng/mg), TNE (28 versus 57 nmol/mg) and NNAL (251 versus 343pg/mg) than Cig Only users (p0.001).Cig-OTP users had lower levels of nicotine and metabolites of a lung carcinogen relative to Cig-Only users, but concentrations of toxicants among Cig-OTP users were still at levels that place smokers at great risk from the detrimental health effects of smoking.Our study finds that nicotine and carcinogen exposure in Cig-OTP users are lower compared to cigarette only users, but still likely to be associated with substantial harm. A better understanding of why toxicant levels may be lower in Cig-OTP is an important area for future study.

To describe the effect of e-liquid flavors on nicotine intake and pharmacology of e-cigarettes.11 males and 3 females participated in a 3-day inpatient crossover study with strawberry, tobacco, and their usual flavor e-liquid. Nicotine levels were nominally 18mg/mL in the strawberry (pH 8.29) and tobacco (pH 9.10) e-liquids and ranged between 3-18mg/mL in the usual brands (mean pH 6.80). Each day consisted of a 15-puff session followed by 4h of abstinence, then 90min of ad libitum use. Subjects used a KangerTech mini ProTank 3.After 15 puffs, the amount of nicotine inhaled and systemically retained were not significantly different between the strawberry and tobacco e-liquids but plasma AUC(0→180) was significantly higher with the strawberry e-liquid. While not significantly different, Cmax was 22% higher and various early time point AUCs to measure rate of rise of nicotine in blood ranged between 17 and 23% higher with the strawberry e-liquid compared to the tobacco e-liquid. During ad libitum use, systemic exposure to nicotine (AUC(0→90)) was the same for the tobacco and usual brand e-liquids but were both significantly lower than after using the strawberry e-liquid. The usual flavors were more liked and satisfying than the strawberry and tobacco e-liquids.Flavors influence nicotine exposure through flavor liking, may affect rate of nicotine absorption possibly through pH effects, and contribute to heart rate acceleration and subjective effects of e-cigarettes. E-cigarette users titrate their nicotine exposure but the extent of titration may vary across flavors.

Background Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat. Case Report We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. Why Should an Emergency Physician Be Aware of This? Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal.

Author(s): Taghavi, Taraneh; St Helen, Gideon; Benowitz, Neal L; Tyndale, Rachel F | Abstract: ObjectivesNicotine metabolism rates differ considerably among individuals, even after controlling for variation in the major nicotine-metabolizing enzyme, CYP2A6. In this study, the impact of genetic variation in alternative metabolic enzymes and transporters on nicotine and cotinine (COT) pharmacokinetics and smoking was investigated.MethodsWe examined the impact of UGT2B10, UGT2B17, FMO3, NAT1, and OCT2 variation on pharmacokinetics and smoking (total nicotine equivalents and topography) before and after stratifying by CYP2A6 genotype in 60 African American (AA) smokers who received a simultaneous intravenous infusion of deuterium-labeled nicotine and COT.ResultsVariants in UGT2B10 and UGT2B17 were associated with urinary glucuronidation ratios (glucuronide/free substrate). UGT2B10 rs116294140 was associated with significant alterations in COT and modest alterations in nicotine pharmacokinetics. These alterations, however, were not sufficient to change nicotine intake or topography. Neither UGT2B10 rs61750900, UGT2B17*2, FMO3 rs2266782, nor NAT1 rs13253389 altered nicotine or COT pharmacokinetics among all individuals (n=60) or among individuals with reduced CYP2A6 activity (n=23). The organic cation transporter OCT2 rs316019 significantly increased nicotine and COT Cmax (P=0.005, 0.02, respectively) and decreased nicotine clearance (P=0.05). UGT2B10 rs116294140 had no significant impact on the plasma or urinary trans-3'-hydroxycotinine/COT ratio, commonly used as a biomarker of CYP2A6 activity.ConclusionWe found that polymorphisms in genes other than CYP2A6 represent minor sources of variation in nicotine pharmacokinetics, insufficient to alter smoking in AAs. The change in COT pharmacokinetics with UGT2B10 rs116294140 highlights the UGT2B10 gene as a source of variability in COT as a biomarker of tobacco exposure among AA smokers.