Oral Nicotine Replacement Research Articles

Varenicline Combined With Oral Nicotine Replacement Therapy and Smartphone-Based Medication Reminders for Smoking Cessation: Feasibility Randomized Controlled Trial.

Varenicline and oral nicotine replacement therapy (NRT) have each been shown to increase the likelihood of smoking cessation, but their combination has not been studied. In addition, smoking cessation medication adherence is often poor, thus, challenging the ability to evaluate medication efficacy. This study examined the effects of combined varenicline and oral NRT and smartphone medication reminders on pharmacotherapy adherence and smoking abstinence among adults enrolled in smoking cessation treatment. A 2×2 factorial design was used. Participants (N=34) were randomized to (1) varenicline + oral NRT (VAR+NRT) or varenicline alone (VAR) and (2) smartphone medication reminder messages (REM) or no reminder messages (NREM) over 13 weeks. Participants assigned to VAR+REM received varenicline reminder prompts, and those assigned to VAR+NRT+REM also received reminders to use oral NRT. The other 2 groups (VAR+NREM and VAR+NRT+NREM) did not receive medication reminders. Participants were not blinded to intervention groups. All participants received tobacco cessation counseling. Smartphone assessments of smoking as well as varenicline and NRT use (if applicable) were prompted daily through the first 12 weeks after a scheduled quit date. Descriptive statistics were generated to characterize the relations between medication and reminder group assignments with daily smoking, daily varenicline adherence, and daily quantity of oral NRT used. Participants completed follow-up assessments for 26 weeks after the quit date. Participants were predominantly White (71%), and half were female (50%). On average, participants were 54.2 (SD 9.4) years of age, they smoked an average of 19.0 (SD 9.0) cigarettes per day and had smoked for 34.6 (SD 12.7) years. Descriptively, participants assigned to VAR+NRT reported more days of smoking abstinence compared to VAR (29.3 vs 26.3 days). Participants assigned to REM reported more days of smoking abstinence than those assigned to NREM (40.5 vs 21.8 days). Participants assigned to REM were adherent to varenicline on more days compared to those assigned to NREM (58.6 vs 40.5 days), and participants assigned to VAR were adherent to varenicline on more days than those assigned to VAR + NRT (50.7 vs 43.3 days). In the subsample of participants assigned to VAR+NRT, participants assigned to REM reported more days where ≥5 pieces of NRT were used than NREM (14.0 vs 7.4 days). Average overall medication adherence (assessed via the Medication Adherence Questionnaire) showed the same pattern as the daily smartphone-based adherence assessments. Preliminary findings indicated that smoking cessation interventions may benefit from incorporating medication reminders and combining varenicline with oral NRT, though combining medications may be associated with poorer adherence. Further study is warranted. ClinicalTrials.gov NCT03722966; https://classic.clinicaltrials.gov/ct2/show/NCT03722966.

Consumer experiences of long-term oral nicotine replacement therapy and related health information-seeking: A qualitative study.

Nicotine replacement therapy (NRT) delivers a therapeutic dose of nicotine to support smoking cessation, and is currently approved for short-term use (typically ≤12 weeks). Yet, research on real-world over-the-counter NRT use indicates that some consumers continue to use these products long-term. This study sought to understand consumers' experiences of long-term oral NRT use, including self-reported reasons for continued use, and health information-seeking regarding long-term use. In-depth semi-structured telephone interviews were conducted between May and June 2021 with 21 current and former NRT consumers aged ≥18 years from across Australia, with oral NRT use of ≥1 year. Interviews were thematically analysed using the Framework Method. The majority of participants reported achieving NRT-assisted smoking cessation and related health benefits (e.g. respiratory health, improved physical appearance). However, nearly all participants reported experiencing addiction to oral NRT, with many attributing their long-term use to dependence on these products. Participants reported low engagement with NRT health information sources; just half reported consulting with a health professional regarding their long-term NRT use, and some reported negative experiences when health professional advice was sought (e.g. perceptions of not being taken seriously, perceived lack of health professional knowledge). Less than half of participants accurately identified the duration of use recommended in NRT consumer medicine information, and some reported actively dismissing this information. Findings highlight consumers' perceived benefits of continued NRT use whilst also identifying two key concerns - the addictive potential of oral NRT, and low health information-seeking and health professional engagement regarding long-term use. While oral NRT is indisputably safer than tobacco smoking, public health strategies to raise consumer and health professional awareness about the safe use of NRT, which acknowledge the current evidence gap regarding safety and efficacy of long-term use, are needed to maximise their benefits as a harm reduction strategy for smoking cessation.

Nicotine replacement treatment, e-cigarettes and an online behavioural intervention to reduce relapse in recent ex-smokers: a multinational four-arm RCT.

Relapse remains an unresolved issue in smoking cessation. Extended stop smoking medication use can help, but uptake is low and several behavioural relapse prevention interventions have been found to be ineffective. However, opportunistic 'emergency' use of fast-acting nicotine replacement treatment or electronic cigarettes may be more attractive and effective, and an online behavioural Structured Planning and Prompting Protocol has shown promise. The present trial aimed to evaluate the clinical effectiveness and cost-effectiveness of these two interventions. A randomised controlled trial. English stop smoking services and Australian quitlines, Australian social media and St Vincent's Hospital Melbourne, Fitzroy, VIC. Ex-smokers abstinent for at least 4 weeks, with some participants in Australia also recruited from 1 week post quit date. The planned sample size was 1400, but the trial was curtailed when 235 participants were recruited. Participants were randomised in permuted blocks of random sizes to (1) oral nicotine replacement treatment/electronic cigarettes to use if at risk of relapse, plus static text messages (n = 60), (2) the Structured Planning and Prompting Protocol and interactive text messages (n = 57), (3) oral nicotine replacement treatment/electronic cigarettes plus the Structured Planning and Prompting Protocol with interactive text messages (n = 58) or (4) usual care plus static text messages (n = 59). Owing to delays in study set-up and recruitment issues, the study was curtailed and the primary outcome was revised. The original objective was to determine whether or not the two interventions, together or separately, reduced relapse rates at 12 months compared with usual care. The revised primary objective was to determine whether or not number of interventions received (i.e. none, one or two) affects relapse rate at 6 months (not biochemically validated because of study curtailment). Relapse was defined as smoking on at least 7 consecutive days, or any smoking in the last month at final follow-up for both the original and curtailed outcomes. Participants with missing outcome data were included as smokers. Secondary outcomes included sustained abstinence (i.e. no more than five cigarettes smoked over the 6 months), nicotine product preferences (e.g. electronic cigarettes or nicotine replacement treatment) and Structured Planning and Prompting Protocol coping strategies used. Two substudies assessed reactions to interventions quantitatively and qualitatively. The trial statistician remained blinded until analysis was complete. The 6-month relapse rates were 60.0%, 43.5% and 49.2% in the usual-care arm, one-intervention arm and the two-intervention arm, respectively (p = 0.11). Sustained abstinence rates were 41.7%, 54.8% and 50.9%, respectively (p = 0.17). Electronic cigarettes were chosen more frequently than nicotine replacement treatment in Australia (71.1% vs. 29.0%; p = 0.001), but not in England (54.0% vs. 46.0%; p = 0.57). Of participants allocated to nicotine products, 23.1% were using them daily at 6 months. The online intervention received positive ratings from 63% of participants at 6 months, but the majority of participants (72%) completed one assessment only. Coping strategies taught in the Structured Planning and Prompting Protocol were used with similar frequency in all study arms, suggesting that these are strategies people had already acquired. Only one participant used the interactive texting, and interactive and static messages received virtually identical ratings. The inability to recruit sufficient participants resulted in a lack of power to detect clinically relevant differences. Self-reported abstinence was not biochemically validated in the curtailed trial, and the ecological momentary assessment substudy was perceived by some as an intervention. Recruiting recent ex-smokers into an interventional study proved problematic. Both interventions were well received and safe. Combining the interventions did not surpass the effects of each intervention alone. There was a trend in favour of single interventions reducing relapse, but it did not reach significance and there are reasons to interpret the trend with caution. Further studies of both interventions are warranted, using simpler study designs. Current Controlled Trials ISRCTN11111428. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 68. See the NIHR Journals Library website for further project information. Funding was also provided by the National Health and Medical Research Council, Canberra, ACT, Australia (NHMRC APP1095880). Public Health England provided the funds to purchase the nicotine products in England.

Oral health and nicotine replacement therapy product

AbstractNicotine replacement therapy (NRT) products are used extensively for assisting users in achieving cessation goals through the substitution of pure nicotine with tobacco-less products. Awareness of the adverse oral effects of nicotine replacement products is important for health practitioners. This review highlights the potential effects of NRT products on the oral tissues and management of these adverse effects. Cochrane, PubMed, and MEDLINE electronic databases were utilized in search of the relevant literature related to NRT. The review highlights various adverse effects on oral health status from NRT products, with the underlying mechanisms for these effects remaining inconclusive. There is a need for more education of health professionals in oral health promotion and maintenance in these cases. NRT products have many potential adverse effects on oral health, and it is the responsibility of dental professionals to consider these in the management of patients to optimize a beneficial clinical outcome.

Feasibility and acceptability of Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy multicomponent implementation intervention and study design for Australian Indigenous pregnant women: A pilot cluster randomised step-wedge trial

BackgroundMany health providers (HPs) lack knowledge, confidence, optimism and skills in addressing smoking with pregnant women. This study aimed to explore the feasibility and acceptability of a) a co-designed multi-component intervention for HPs at Aboriginal Medical Services (AMSs) in culturally-targeted pregnancy-specific smoking cessation care and b) the study design. MethodsUsing a randomised step-wedge cluster design, the Indigenous Counselling And Nicotine (ICAN) QUIT in Pregnancy Trial was evaluated across six AMSs in three Australian states. HPs were provided educational resource packages including live interactive webinars, treatment manuals, patient resources, carbon monoxide (CO) meters, and oral Nicotine Replacement Therapy (NRT). Feasibility was assessed through recruitment and retention rates of both pregnant women (12-weeks) and HPs (end of study) as well as the potential to improve women's quit rates. Qualitative interviews with staff post-trial explored acceptability of the intervention and study, based on capability, opportunity and motivation from the Behaviour Change Wheel. ResultsPregnant women (n = 22; 47% (95% CI: 32%, 63%) eligible) and HPs (n = 50; 54% (95% CI: 44%, 64%) eligible) were recruited over 6 months with retention rates of 77% (95% CI: 57%, 90%) and 40% (95% CI: 28%, 54%) respectively. Self-reported 12-week 7-day point-prevalence abstinence was 13.6% (n = 3) and validated abstinent with CO readings ≤6 ppm. Staff interviewed regarding intervention implementation highlighted the importance of provision and use of resources, including training materials, patient resources, CO meters and oral NRT. Resources helped increase capability and opportunity, restructure the environment, and provided social comparison and modelling. Staff were motivated by greater engagement with pregnant women and seeing the women's reductions in CO readings. Having the intervention at the AMSs improved organisational capacity to engage with pregnant women. Staff reported changes to their routine practice that were potentially sustainable. Recommendations for improvement to the implementation of the intervention and research included reducing training length and the tasks related to conducting the study. ConclusionICAN QUIT in Pregnancy was a pilot study with the ability to enrol Indigenous women. It was feasible to implement and acceptable to most staff of the AMSs in three states, with modifications recommended. Smoking in pregnancy is a key challenge for Indigenous health. The intervention needs to be evaluated through a methodologically rigorous fully-powered study to determine the efficacy of outcomes for women. Trial registrationAustralian and New Zealand Clinical Trials Registry, ACTRN12616001603404. Registered 21 November 2016 - retrospectively registered, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=371778

The Indigenous Counselling and Nicotine (ICAN) QUIT in Pregnancy Pilot Study protocol: a feasibility step-wedge cluster randomised trial to improve health providers' management of smoking during pregnancy

IntroductionIndigenous women have the highest smoking prevalence during pregnancy (47%) in Australia. Health professionals report lack of knowledge, skills and confidence to effectively manage smoking among pregnant women in general....

Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

Heavy-Drinking Smokers: Pathophysiology and Pharmacologic Treatment Options

Effectiveness of oral health education versus nicotine replacement therapy for tobacco cessation- a parallel randomized clinical trial.

BackgroundIndia has millions of tobacco users. It is the leading cause of deaths due to oral cancer and hence needs effective strategies to curb it. Hence the aim of present study was to evaluate and compare the effectiveness of Oral Health Education (OHE) and Nicotine Replacement Therapy (NRT) in tobacco cessation.Material and MethodsThe clinical trial consisted of Manohar Lal Kapoor (MLK) factory workers (n= 40) giving history of tobacco consumption (smoking/smokeless) within past 30 days. They were randomized into OHE (n=20) and NRT (n=20) groups. Baseline evaluation (demographic, smoking/ smokeless behaviour) was done. Fagerstrom test was used for Nicotine Dependence (FTND) and to assess nicotine addiction level. Follow up was done at an interval of 1week, 2 weeks, 1 month, 2 months and 3 months to assess the reduction in the mean FTND score. “Nano-CheckTM Rapid Nicotine test” was used for the qualitative detection of cotinine in human urine. Appropriate statistical analysis was performed (Paired and Unpaired t test).ResultsIn both OHE and NRT group there was a significant reduction (p< 0.00001) in mean Fagerstrom score at every follow up but when both the groups were compared mean Fagerstrom score reduction was more in NRT than OHE at all time interval though it was not statistically significant (p>0.05).ConclusionsNRT is better than OHE when both the groups were compared. However, it was found that any intervention given to tobacco users either NRT or OHE is helpful for the patients in the process of quitting tobacco. Key words:Tobacco cessation, nicotine replacement therapy, oral health education, fagerstrom test, urine cotinine.

Relationships of PROP Taste Phenotype, Taste Receptor Genotype, and Oral Nicotine Replacement Use.

Recommended dosage of oral nicotine replacement therapy (NRT) product is often not achieved in smoking cessation attempts. n-6-propylthiouracil (PROP) bitter taste phenotype may be a potential risk factor for non-adherence to oral NRT products due to their bitter taste. There is limited literature on this phenotype in the context of smoking and none in relation to oral NRT pharmacotherapy. The association of PROP taste phenotype with NRT usage and sensory response to products was examined. In a cross-over experimental design, 120 participants received a 1 week supply of nicotine inhalers and 1 week of nicotine lozenges with random assignment to order. Mixed effects linear model analyses were conducted. PROP taste phenotype and taste receptor genotype were not associated with NRT usage or sensory response to NRT, after adjusting for other factors. However, PROP non-tasters used a higher number of lozenges per day (continuous exposure) than nicotine cartridges (intermittent exposure). Unexpectedly, half of baseline PROP non-tasters shifted to taster phenotype 2 weeks after smoking cessation or reduction. Menthol cigarette smokers identified higher NRT strength of sensation scores than nonmenthol smokers. Taste receptor genotype was related to PROP taste phenotype (Kendall τ = .591, p = .0001). A nonsignificant relationship of PROP phenotype and NRT usage may be associated with NRT under-dosing and limited variance in the outcome variable. PROP non-tasters' greater use of lozenges is consistent with nicotine exposure being less aversive to non-tasters. Further research of this and other factors impacting NRT usage are warranted to effectively inform smoking cessation pharmacotherapy.

Gradual versus abrupt quitting among French treatment-seeking smokers

ObjectiveThis study examined the prevalence and predictors of gradual quitting among treatment-seeking smokers. MethodThis study examined quit attempts among 28,156 adult smokers who attended French smoking cessation services nationwide between 2007 and 2010. Predictors of gradual quitting were determined using multivariate regression models. ResultsOnly 4.4% quit gradually whereas 48.7% quit abruptly and 46.9% continued smoking. 34.1% of abrupt quitters and 31.9% of gradual quitters were abstinent at 1month post-quit (p=0.108). Gradual quitting was associated with: older age, heavy smoking at baseline, no previous quit attempts, low self-efficacy, baseline intake of anxiolytics, symptoms of depression and history of depressive episodes. Gradual quitters had a similar anxio-depressive profile than continued smokers but were more educated and more likely to have reported previous quit attempts. Prescription of oral nicotine replacement therapy (NRT) only as opposed to combination NRT doubled the odds of gradual quitting. Likelihood of gradual quitting compared with continued smoking improved with the number of follow-up visits. ConclusionOur findings suggest that hard-to-treat smokers may be more likely to quit gradually than abruptly. However, intense follow-up with adapted treatment appears to be crucial to achieve cessation gradually in French smoking cessation services.

Relapse prevention interventions for smoking cessation

A number of treatments can help smokers make a successful quit attempt, but many initially successful quitters relapse over time. Several interventions have been proposed to help prevent relapse. To assess whether specific interventions for relapse prevention reduce the proportion of recent quitters who return to smoking. We searched the Cochrane Tobacco Addiction Group trials register in May 2013 for studies mentioning relapse prevention or maintenance in title, abstracts or keywords. Randomized or quasi-randomized controlled trials of relapse prevention interventions with a minimum follow-up of six months. We included smokers who quit on their own, were undergoing enforced abstinence, or were participating in treatment programmes. We included trials that compared relapse prevention interventions with a no intervention control, or that compared a cessation programme with additional relapse prevention components with a cessation programme alone. Studies were screened and data extracted by one review author, and checked by a second. Disagreements were resolved by discussion or by referral to a third review author. Sixty-three studies met inclusion criteria but were heterogeneous in terms of populations and interventions. We considered 41 studies that randomly assigned abstainers separately from studies that randomly assigned participants before their quit date.Upon looking at studies of behavioural interventions that randomly assigned abstainers, we detected no benefit of brief and 'skills-based' relapse prevention methods for women who had quit smoking because of pregnancy, or for smokers undergoing a period of enforced abstinence during hospitalisation or military training. We also failed to detect significant effects of behavioural interventions in trials in unselected groups of smokers who had quit on their own or through a formal programme. Amongst trials randomly assigning smokers before their quit date and evaluating the effects of additional relapse prevention components, we found no evidence of benefit of behavioural interventions or combined behavioural and pharmacotherapeutic interventions in any subgroup. Overall, providing training in skills thought to be needed for relapse avoidance did not reduce relapse, but most studies did not use experimental designs best suited to the task and had limited power to detect expected small differences between interventions. For pharmacological interventions, extended treatment with varenicline significantly reduced relapse in one trial (risk ratio (RR) 1.18, 95% confidence interval (CI) 1.03 to 1.36). Pooling of six studies of extended treatment with bupropion failed to detect a significant effect (RR 1.15, 95% CI 0.98 to 1.35). Two small trials of oral nicotine replacement treatment (NRT) failed to detect an effect, but treatment compliance was low, and in two other trials of oral NRT in which short-term abstainers were randomly assigned, a significant effect of intervention was noted. At the moment, there is insufficient evidence to support the use of any specific behavioural intervention to help smokers who have successfully quit for a short time to avoid relapse. The verdict is strongest for interventions focused on identifying and resolving tempting situations, as most studies were concerned with these. Little research is available regarding other behavioural approaches.Extended treatment with varenicline may prevent relapse. Extended treatment with bupropion is unlikely to have a clinically important effect. Studies of extended treatment with nicotine replacement are needed.

Pharmacokinetic and Pharmacodynamics Studies of Nicotine After Oral Administration in Mice: Effects of Methoxsalen, a CYP2A5/6 Inhibitor

The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years. Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration. Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively. Additionally, methoxsalen potentiated nicotine-induced antinociception and hypothermia as evidenced by leftward shifts in nicotine's dose-response curve. Furthermore, this prolongation of nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter pharmacological effects of nicotine given orally. We have shown that the pharmacological effects of inhibiting nicotine's metabolism after oral administration in mice are profound. Our results suggest that inhibiting nicotine metabolism can be used to dramatically enhance nicotine's bioavailability and its resulting pharmacology, which further supports this inhibitory approach for clinical development of an oral nicotine replacement therapy.

Sevrage tabagique, mise au point sur la prise en charge actuelle et ses résultats

Tobacco prevention is the most effective prevention of cancer. Daily smoking promotes tumor progression, increases the risk of second cancer and decreases survival. The diagnosis of smoking and support for cessation and preventing recurrence is an integral part of cancer treatment. Smoking increases side effects of chemotherapy and surgery and reduces the effectiveness of radiotherapy and chemotherapy. Smokers with cancer do not smoke by life-style choice but because they are highly addicted and are suffering from a chronic relapsing disease: tobacco dependence, which justifies intensive medical management. The oncologist himself may perform this support or coordinate with other physicians in charge of the patient or with a tobacco cessation clinic, but patients are often unable to stop alone, as evidenced by the continued to use tobacco despite a cancer diagnosis. Treatment will always include a therapeutic education, compartmental behavioral therapy and medication. The patches and oral nicotine replacement or varenicline are the two most effective treatments that can be prescribed to smokers suffering of cancer, without including those with any motivation to quit. Smoking reducing occurred in a few days or weeks on treatment will allow them to reconsider the judgment. The full stop is always the goal for the doctor, even if it is not the patient initial goal. After stopping, the patient is not cured but still a patient with tobacco dependence who does not smoke. The risk of relapse in the year being 50%. The cancer patient management will use every visit to the point tobacco dependence and prevent relapse, alone or with assistance of a specialist. There is a lack of data on smoking cessation in cancer patients, but no item calls for a three-month quit rate of 50% as observed in the general population after an optimal management of tobacco cessation.

Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans.

We recently reported that certain amounts of the carcinogen N'-nitrosonornicotine (NNN) can be formed endogenously from nicotine and/or nornicotine in some users of oral nicotine replacement therapy products. Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH. To test the hypothesis that endogenous formation of NNN could occur in the oral cavity, we investigated nitrosation of nicotine and nornicotine in human saliva. To specifically identify NNN as derived from precursors added to saliva, we incubated saliva samples with [pyridine-D(4)]nicotine and [pyridine-D(4)]nornicotine, with and without the addition of nitrite, and subsequently analyzed [pyridine-D(4)]NNN by liquid chromatography-tandem mass spectrometry. Consistent with kinetic studies on nicotine and nornicotine nitrosation, incubation of saliva with [pyridine-D(4)]nornicotine alone produced detectable amounts of [pyridine-D(4)]NNN, whereas only traces of [pyridine-D(4)]NNN were found in samples incubated with [pyridine-D(4)]nicotine and sodium nitrite. Incubation of saliva samples from 10 nonsmoking volunteers with [pyridine-D(4)]nornicotine resulted in the formation of [pyridine-D(4)]NNN in 8 samples, with yields ranging from 0.003% to 0.051% of the added alkaloid. Our results demonstrate that NNN can be formed from nornicotine in human saliva without deliberate addition of any other substance. Therefore, nornicotine, as present in tobacco or in nicotine replacement products, is a carcinogen precursor.

Abstract 4650: Nornicotine nitrosation in human saliva and its relation to endogenous formation of N′-nitrosonornicotine in oral nicotine replacement therapy users

Abstract We recently reported occasional significant increases in urinary biomarkers of the potent human carcinogen N′-nitrosonornicotine (NNN) in some users of oral nicotine replacement therapy (NRT) products, such as nicotine gum or lozenge, compared with baseline smoking levels in the same subjects. We hypothesized that this is due to endogenous synthesis of NNN through the reaction of nicotine and/or nornicotine that is metabolically formed from nicotine or originally present in NRT products, with nitrosating agents supplied by diet. While the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction can also occur in the oral cavity in the presence of bacteria that catalyzes nitrosation at neutral pH. To test the hypothesis that endogenous formation of NNN can occur in the oral cavity of NRT users, we investigated nitrosation of nicotine and nornicotine in human saliva. To specifically identify NNN as derived from the precursors added to saliva, we used [pyridine-D4]nicotine and [pyridine-D4]nornicotine and subsequently analyzed [pyridine-D4]NNN by liquid chromatography-tandem mass spectrometry. Aliquots of pooled saliva from nonsmoking volunteers were incubated for 30 min at 37 °C with either [pyridine-D4]nicotine or [pyridine-D4]nornicotine, in the presence of various concentrations of sodium nitrite. [Pyridine-D4]NNN was not detected in the blank saliva aliquot that was added as a negative control. Incubation of saliva with 50 ng of [pyridine-D4]nornicotine alone produced 38 pg [pyridine-D4]NNN, or 0.08% yield. The aliquot incubated with 200 ng of [pyridine-D4]nornicotine and 7 mg of sodium nitrite formed 5,503 pg of [pyridine-D4]NNN (nearly 150-fold increase). Only traces of [pyridine-D4]NNN were detected in samples incubated with [pyridine-D4]nicotine. These results are in agreement with kinetic studies on nicotine and nornicotine nitrosation. To investigate the effect of natural inter-individual variations in salivary nitrite and/or oral microflora on the amount of orally synthesized NNN, saliva samples from 10 nonsmoking volunteers were incubated with deuterium-labelled nicotine and nornicotine. Formation of [pyridine-D4]NNN was observed in 6 samples treated with [pyridine-D4]nornicotine, with yields ranging from 0.001 to 0.037% of the added alkaloid. Trace amounts of [pyridine-D4]NNN were detected in some samples incubated with [pyridine-D4]nicotine. In summary, our results demonstrate that NNN can be formed in human saliva in the presence of nornicotine, supporting the hypothesis that NNN can be synthesized endogenously in oral NRT users. Removal of nornicotine from NRT products could improve the safety of these products. Additional studies are needed to evaluate the contribution of metabolically formed nornicotine to the endogenous formation of NNN in oral NRT users. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4650. doi:10.1158/1538-7445.AM2011-4650

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

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