QuitNic: A Pilot Randomized Controlled Trial Comparing Nicotine Vaping Products With Nicotine Replacement Therapy for Smoking Cessation Following Residential Detoxification.

INTRODUCTION: The QuitNic pilot trial aimed to test the feasibility of providing a nicotine vaping product (NVP) compared with combination nicotine replacement therapy (NRT) to smokers upon discharge from a smoke-free residential substance use disorder (SUD) treatment service. METHODS: QuitNic was a pragmatic two-arm randomized controlled trial. At discharge from residential withdrawal, 100 clients received telephone Quitline behavioral support and either 12-week supply of NRT or an NVP. Treatment adherence and acceptability, self-reported abstinence, cigarettes smoked per day (CPD), frequency of cravings, and severity of withdrawal symptoms were assessed at 6 and 12 weeks. Results are reported for complete cases and for abstinence outcomes, penalized imputation results are reported where missing is assumed smoking. RESULTS: Retention on was 63% at 6 weeks and 50% at 12 weeks. At 12 weeks, 68% of the NRT group reported using combination NRT while 96% of the NVP group used the device. Acceptability ratings for the products were high in both groups. At 12 weeks, 14% of the NVP group and 18% of the NRT group reported not smoking at all in the last 7 days. Mean CPD among continued smokers decreased significantly between baseline to 12 weeks in both groups; from 19.91 to 4.72 for the NVP group (p < .001) and from 20.88 to 5.52 in the NRT group (p < .001). Cravings and withdrawal symptoms significantly decreased for both groups. CONCLUSIONS: Clients completing residential withdrawal readily engaged with smoking cessation post-treatment when given the opportunity. Further research is required to identify the most effective treatments postwithdrawal for this population at elevated risk of tobacco-related harm. TRIAL REGISTRATION NUMBER: ACTRN12617000849392. IMPLICATIONS: This pilot study showed that smoking cessation support involving options for nicotine replacement and Quitline-delivered cognitive behavioral counseling is attractive to people after they have been discharged from SUD treatment. Both nicotine vaping products and nicotine replacement therapies were highly acceptable and used by participants who reported reductions in cravings for cigarettes and perceptions of withdrawal symptoms and reductions in number of cigarettes smoked. Some participants self-reported abstinence from cigarettes-around one in five reported having quit smoking cigarettes at 12 weeks postdischarge. The results have significant public health implications for providing quit support following discharge from SUD treatment.

Trendy e-cigarettes enter Europe: chemical characterization of JUUL pods and its aerosols.

The popularity and the high nicotine content of the American pod e-cigarette JUUL have raised many concerns. To comply with European law, the nicotine concentration in the liquids of the European version, which has been recently released on the market, is limited to below 20 mg/mL. This limit can possibly be circumvented by technological adjustments that increase vaporization and consequently, elevate nicotine delivery. In this study, we compare vapor generation and nicotine delivery of the initial European version, a modified European version, and the original American high-nicotine variant using a machine vaping set-up. Additionally, benzoic acid and carbonyl compounds are quantified in the aerosol. Further, concentrations of nicotine, benzoic acid, propylene glycol, and glycerol, along with the density and pH value of JUUL e-liquids have been assessed. Whereas the initial European version did not compensate for the low nicotine content in the liquid, we provide evidence for an increased vaporization by the modified European version. As a consequence, nicotine delivery per puff approximates the American original. Notably, this is not associated with an increased generation of carbonyl compounds. Our data suggest a similar addictiveness of the enhanced European version and the original American product.

Concentrations of nicotine, nitrosamines, and humectants in legal and illegal cigarettes in Mexico.

BACKGROUND: Article 10 of the World Health Organization Framework Convention on Tobacco Control states the need for industry disclosure of tobacco contents and emissions. Currently, the profiles of key tobacco compounds in legal and illegal cigarettes are largely unknown. We aimed to analyze and compare concentrations of nicotine, nitrosamines, and humectants in legal and illegal cigarettes collected from a representative sample of smokers. METHODS: Participants of the International Tobacco Control cohort provided a cigarette pack of the brand they smoked during the 2014 wave. Brands were classified as legal or illegal according to the Mexican legislation. Nicotine, nitrosamines, glycerol, propylene glycol, and pH were quantified in seven randomly selected packs of each brand. All analyses were done blinded to legality status. Average concentrations per brand and global averages for legal and illegal brands were calculated. Comparisons between legal and illegal brands were conducted using t tests. RESULTS: Participants provided 76 different brands, from which 6.8% were illegal. Legal brands had higher nicotine (15.05 ± 1.89 mg/g vs 12.09 ± 2.69 mg/g; p < 0001), glycerol (12.98 ± 8.03 vs 2.93 ± 1.96 mg/g; p < 0.001), and N-nitrosanatabine (NAT) (1087.5 ± 127.0 vs 738.5 ± 338 ng/g; p = 0.006) concentrations compared to illegal brands. For all other compounds, legal and illegal brands had similar concentrations. CONCLUSION: Compared to illegal cigarettes, legal brands seem to have higher concentrations of nicotine, NAT, and glycerol. Efforts must be made to implement and enforce Article 10 of the Framework Convention on Tobacco Control to provide transparent information to consumers, regulators, and policy-makers; and to limit cigarette engineering from the tobacco industry.

Flavour chemicals in electronic cigarette fluids.

BACKGROUND: Most e-cigarette liquids contain flavour chemicals. Flavour chemicals certified as safe for ingestion by the Flavor Extracts Manufacturers Association may not be safe for use in e-cigarettes. This study identified and measured flavour chemicals in 30 e-cigarette fluids. METHODS: Two brands of single-use e-cigarettes were selected and their fluids in multiple flavour types analysed by gas chromatography/mass spectrometry. For the same flavour types, and for selected confectionary flavours (eg, bubble gum and cotton candy), also analysed were convenience samples of e-cigarette fluids in refill bottles from local 'vape' shops and online retailers. RESULTS: In many liquids, total flavour chemicals were found to be in the ∼1-4% range (10-40 mg/mL); labelled levels of nicotine were in the range of 0.6-2.4% (6 to 24 mg/mL). A significant number of the flavour chemicals were aldehydes, a compound class recognised as 'primary irritants' of mucosal tissue of the respiratory tract. Many of the products contained the same flavour chemicals: vanillin and/or ethyl vanillin was found in 17 of the liquids as one of the top three flavour chemicals, and/or at ≥0.5 mg/mL. CONCLUSIONS: The concentrations of some flavour chemicals in e-cigarette fluids are sufficiently high for inhalation exposure by vaping to be of toxicological concern. Regulatory limits should be contemplated for levels of some of the more worrisome chemicals as well as for total flavour chemical levels. Ingredient labeling should also be required.

Trace elements in e-liquids - Development and validation of an ICP-MS method for the analysis of electronic cigarette refills.

Electronic cigarette use has rapidly increased in recent years. In assessing their safety, and in view of coming regulations, trace elements (TE) are among the potentially toxic compounds required to be evaluated in electronic cigarette refill fluids ("e-liquids"). An analytical method using inductively coupled plasma with mass spectrometric detection (ICP-MS) was developed and rigorously validated in order to determine concentrations of 15 TE in 54 e-liquids from a French brand. Despite a significant matrix effect from the main e-liquid constituents, and difficulties related to the current lack of reference materials, our method demonstrated satisfactory linearity, precision and robustness, and permitted the quantification of low concentrations of these 15 elements: lower limits of quantification (LLQ) obtained were ≤4 ppb for all elements except for Ni, Cu and Zn (16 ppb, 20 ppb and 200 ppb, respectively). All TE concentrations in all tested samples were <510 ppb, mostly near or below the LLQs. This method is transposable and is timely for laboratories seeking to meet a prospective demand in light of current or future regulations.

Characterization of potential impurities and degradation products in electronic cigarette formulations and aerosols.

E-cigarettes are gaining popularity in the U.S. as well as in other global markets. Currently, limited published analytical data characterizing e-cigarette formulations (e-liquids) and aerosols exist. While FDA has not published a harmful and potentially harmful constituent (HPHC) list for e-cigarettes, the HPHC list for currently regulated tobacco products may be useful to analytically characterize e-cigarette aerosols. For example, most e-cigarette formulations contain propylene glycol and glycerin, which may produce aldehydes when heated. In addition, nicotine-related chemicals have been previously reported as potential e-cigarette formulation impurities. This study determined e-liquid formulation impurities and potentially harmful chemicals in aerosols of select commercial MarkTen(®) e-cigarettes manufactured by NuMark LLC. The potential hazard of the identified formulation impurities and aerosol chemicals was also estimated. E-cigarettes were machine puffed (4-s duration, 55-mL volume, 30-s intervals) to battery exhaustion to maximize aerosol collection. Aerosols analyzed for carbonyls were collected in 20-puff increments to account for analyte instability. Tobacco specific nitrosamines were measured at levels observed in pharmaceutical grade nicotine. Nicotine-related impurities in the e-cigarette formulations were below the identification and qualification thresholds proposed in ICH Guideline Q3B(R2). Levels of potentially harmful chemicals detected in the aerosols were determined to be below published occupational exposure limits.

Chemical, physical, and in vitro characterization of research cigarettes containing denicotinized tobacco.

The use of very low nicotine tobacco cigarettes is currently being investigated as a possible harm reduction strategy. Here, we report the smoke chemistry, toxicity, and physical characteristics of very low nicotine cigarettes that were made using blended tobacco processed through a supercritical CO2 fluid extraction, which resulted in elimination of 96% of nicotine content (denicotinized (denic) tobacco). Three types of test cigarettes (TCs) were manufactured with tobacco filler containing 100% denic tobacco (TC100), 50% denic tobacco and 50% unextracted tobacco (TC50/50), and 100% unextracted tobacco (TC0). Mainstream smoke (MS) was generated for measurement of 46 analytes and cytotoxicity and mutagenicity determination. Analysis of physical characteristics of TCs demonstrated they were well made with <5% variability among cigarettes for most parameters measured. We observed significant changes in the levels of smoke constituents, including decreases in formaldehyde, nitrosamines, and phenol, and increases in aliphatic hydrocarbons, aliphatic nitrogen compounds, aromatic amines, halogen compounds, and metals. Use of denic tobacco resulted in changes in the chemical composition of MS, but these changes did not modify biological activity as measured in the mutagenicity and cytotoxicity assays.

Fatality following a suicidal overdose with varenicline.

The smoking cessation agent varenicline acts as a partial agonist on α(4)ß(2) nicotinic acetylcholine receptors. Although debated, several reports have linked varenicline therapy to an increased risk of suicidal thoughts and/or suicide. In addition, several non-fatal overdose cases have been reported. In this report, we utilised a sample preparation procedure suitable for postmortem samples and gas chromatography coupled to mass spectrometry to analyse samples obtained from a suicidal case in which ingestion of an overdose of varenicline had occurred. Extremely high concentrations of varenicline (>250 ng/ml) were detected in the blood of the deceased, in addition to high concentrations in urine and vitreous humour. To the best of our knowledge, similar high concentrations have not been reported yet. Although, with respect to the mechanism of death in this case, confounding factors were concomitant ethanol consumption and, importantly, potentially fatal hypothermia, this is the first report of a fatality associated with the ingestion of an overdose of varenicline.

A new radioligand binding assay to measure the concentration of drugs in rodent brain ex vivo.

We have developed a new radioligand binding assay method to measure the concentration of nonradiolabeled drugs in the brain ex vivo. This new method fuses the concepts of standard competition and saturation binding assays and uses a transformed version of the Cheng-Prusoff equation (Biochem Pharmacol 22:3099-3108, 1973) to calculate the drug concentration. After testing the validity of this method, we demonstrated its utility by measuring the brain concentration of sazetidine-A, a newly developed nicotinic receptor ligand, and its elimination rate after a single subcutaneous administration. Our results indicate that sazetidine-A reaches brain concentrations that are known to occupy and desensitize the majority of neuronal nicotinic acetylcholine receptor binding sites. Furthermore, using this method, we estimated the half-life of sazetidine-A in the rat brain to be ∼65 min. It is important to note that the method described here to measure sazetidine-A in brain should be generalizable to other drugs acting at any receptor that can be reliably measured with a radiolabeled ligand.

Determination of six neonicotinoid insecticides residues in spinach, cucumber, apple and pomelo by QuEChERS method and LC-MS/MS.

A modified QuEChERS and LC-MS/MS method has been developed for the simultaneous determination of residues of six neonicotinoids in various crops, including spinach, cucumber, apple and pomelo. The method showed good linearity (R(2) ≥ 0.9995) and precision (RSD ≤ 14.0%). Average recoveries of the six neonicotinoids ranged between 73.7% and 103.8% at spiking levels 0.005, 0.1 and 1 mg kg(-1). The LODs and LOQs were in the ranges of 0.20-0.85 µg kg(-1) and 0.66-2.84 µg kg(-1), respectively. The method was satisfactorily validated for the analysis of 50 agricultural samples. Imidacloprid and imidaclothiz were detected at concentration levels ranging from 7 to 5.3 µg kg(-1).

The role of nicotine content information in smokers' subjective responses to nicotine and placebo inhalers.

OBJECTIVE: A growing body of evidence suggests that non-pharmacological factors may play an important role in smoking cessation outcomes using nicotine replacement therapies. This study examined the role of information about nicotine content in smokers' subjective responses to nicotine and placebo inhalers, using the four conditions of the balanced-placebo design in a mixed within/between-subjects design. METHODS: Twenty-four adult smokers (12 male) completed two laboratory sessions following overnight abstinence from smoking. Participants were randomly assigned to receive either nicotine inhalers or placebo inhalers in both sessions but were told that they received a nicotine-containing inhaler in one session and a nicotine-free inhaler in the other. In each session participants completed subjective assessments before and after inhaler administration using visual analogue scales and the Brief Questionnaire of Smoking Urges. RESULTS: While neither nicotine content nor information about it significantly affected cigarette craving associated with withdrawal relief, participants reported a greater reduction in craving associated with intention to smoke when told the inhalers contained nicotine than when told the inhalers were nicotine-free, regardless of actual nicotine content. CONCLUSIONS: Findings suggest that psychological factors play an important role in smokers' subjective responses to nicotine inhalers, the effects of which cannot be solely attributed to the direct pharmacological effects of nicotine.

Nicotine Content from Cigarettes Submerged in Soda.

INTRODUCTION: Cigarettes and other tobacco products may be extinguished by submersion in liquids in beverage cans or bottles. Cases of nicotine poisoning in children have been reported following ingestion of such liquids. The aim of this study is to analyze the variability of nicotine concentrations with respect to number of cigarettes immersed and the duration of immersion in a soda can METHODS: One unsmoked cigarette was immersed in a cola containing soda can. Three separate samples of the mixture were obtained at different intervals of time post immersion up to 1 week. At the same time, a set of four cola cans were immersed with an increasing number of unsmoked cigarettes and samples obtained. All the samples were then analyzed for nicotine concentrations using liquid chromatography-mass spectrometry. RESULTS: The mean concentration of nicotine measured over the course of 6 hours from one full cigarette in 55 ml of a cola beverage was 0.48 mg/ml. Nicotine concentrations steadily increased in the first 6 hours following submersion, after which, the levels plateaued (r = 0.530, n = 18, p = 0.024). There was a strong positive correlation between nicotine concentrations and the number of cigarettes (r = 0.967, n = 12, p = 3e-7). CONCLUSIONS: The mean concentration of nicotine measured over the course of 6 hours from one immersed cigarette can be potentially toxic especially to children. Nicotine concentrations are positively correlated with the number of cigarettes and time of immersion.

Approaches, challenges, and experience in assessing free nicotine.

Delivery of nicotine in the most desirable form is critical in maintaining people's use of tobacco products. Interpretation of results by tobacco industry scientists, studies that measure free-base nicotine directly in tobacco smoke, and the variability of free-base nicotine in smokeless tobacco products all indicate that the form of nicotine delivered to the tobacco user, in addition to the total amount, is an important factor in whether people continue to use the product following their initial exposure. The physiological impact of nicotine varies with the fraction that is in the free-base form and this leads to continued exposure to other toxic tobacco contents and emissions. In addition to evaluating the total nicotine delivered to the user, measuring the fraction of nicotine in the free-base form is critical in understanding and controlling the influence of nicotine on tobacco use.

Toxicological analysis of low-nicotine and nicotine-free cigarettes.

Low-nicotine and nicotine-free cigarettes are commercially available under the brand-name Quest. Some consumers may believe that these are safer cigarettes, and they may smoke more cigarettes or inhale more smoke to compensate for low nicotine yields. Thus, we have studied the toxicological effects of these two cigarettes and compared them with the Kentucky reference cigarette 2R4F. Also, the availability of nicotine-free cigarettes allows for the assessing the role of nicotine in cigarette smoke. In addition to nicotine, some tobacco-specific nitrosamines, aldehydes, and volatile organic compounds were also reduced in the Quest cigarettes compared to the 2R4F. However, aromatic amines were higher in the nicotine-free compared with low nicotine cigarettes. The Ames test revealed that cigarette smoke condensates from the nicotine-free (CSC-F), low nicotine (CSC-L) and 2R4F (CSC-R) cigarettes had a similar mutagenic potency. Exposure to any CSC caused a similar dose-dependent LDH leakage from normal human bronchial epithelial cells. However, CSC-F had more inhibitory effects on the cell growth than CSC-L and CSC-R. Adding nicotine to the CSC-F attenuated this inhibition. Both Quest CSCs decreased gap junction intercellular communication and caused cell cycle arrest. CSC exposure increased cytoplasmic nucleosomes, sub-G1/G0 population and apoptotic comet tails. Proapoptotic protein Bax increased independent of p53 induction after exposure to CSC-F. In conclusion, these studies are not consistent with a perception that low-nicotine or nicotine-free cigarettes may have less toxicity in human cells. Nicotine, as it exists in CSC, attenuates cytotoxicity possibly in part through inhibition of apoptotic pathways.

Pharmacological and chemical effects of cigarette additives.

We investigated tobacco industry documents and other sources for evidence of possible pharmacological and chemical effects of tobacco additives. Our findings indicated that more than 100 of 599 documented cigarette additives have pharmacological actions that camouflage the odor of environmental tobacco smoke emitted from cigarettes, enhance or maintain nicotine delivery, could increase the addictiveness of cigarettes, and mask symptoms and illnesses associated with smoking behaviors. Whether such uses were specifically intended for these agents is unknown. Our results provide a clear rationale for regulatory control of tobacco additives.

Evaluation of nicotine in tobacco-free-nicotine commercial products.

Recently, a variety of new tobacco-free-nicotine, TFN, products have been commercialized as e-liquids. Tobacco-derived nicotine contains predominantly (S)-(-)-nicotine, whereas TFN products may not. The TFN products are said to be cleaner, purer substances, devoid of toxic components that come from the tobacco extraction process. A variety of commercial tobacco and TFN products were analyzed to identify the presence and composition of each nicotine enantiomer. A rapid and effective enantiomeric separation of nicotine has been developed using a modified macrocyclic glycopeptide bonded to superficially porous particles. The enantiomeric assay can be completed in <2 min with high resolution and accuracy using high performance liquid chromatography with electrospray ionization mass spectrometry. The results of this study suggest the need for pharmacological studies of (R)-(+)-nicotine, which is present in much greater quantities in commercial TFN products compared to commercial tobacco-derived products. Such studies are required by the FDA for new enantiomeric pharmacological products. Copyright © 2016 John Wiley & Sons, Ltd.

Cotinine concentration in smokers from different countries: relationship with amount smoked and cigarette type.

This four-country study examined salivary cotinine as a marker for nicotine intake and addiction among smokers in relation to numbers and types of cigarettes smoked. Smoking characteristics of cigarette smokers in Brazil, China, Mexico, and Poland were identified using a standard questionnaire. Cotinine concentration was measured using a saliva sample from each participant; its relationship with numbers and types of cigarettes smoked was quantified by applying regression techniques. The main outcome measure was salivary cotinine level measured by gas chromatography. In all four countries, cotinine concentration increased linearly with cigarettes smoked up to 20 per day [11.3 ng/mL (95% confidence interval, 10.5-12.2)] and then stabilized as the number of cigarettes exceeded 20 [6.8 ng/mL per cigarette (95% confidence interval, 6.3-7.4) for up to 40 cigarettes]. On average, smokers of regular cigarettes consumed more cigarettes and had higher cotinine levels than light cigarette smokers. Cotinine concentration per cigarette smoked did not differ between regular and light cigarette smokers. Results suggest a saturation point for daily nicotine intake and minimal or no reduction in nicotine intake by smoking light cigarettes.

Relative toxicities and neuromuscular nicotinic receptor agonistic potencies of anabasine enantiomers and anabaseine.

Anabasine occurring in wild tree tobacco (Nicotiana glauca) and anabaseine occurring in certain animal venoms are nicotinic receptor agonist toxins. Anabasine lacks the imine double bond of anabaseine; the two possible enantiomers of anabasine occur in N. glauca. A comparision of the relative potencies of S- and R-anabasine has not been previously reported. We separated the enantiomers of anabasine by reaction of the racemic N. glauca natural product with 9-fluorenylmethoxycarbonyl-L-alanine (Fmoc-L-Ala-OH) to give diastereomers, which were separated by preparative reversed phase HPLC. The S- and R-anabasine enantiomer fractions were then obtained by Edman degradation. A mouse bioassay was used to determine the relative lethalities of S- and R-enriched anabasine enantiomers. The intravenous LD50 of the (+)-R-anabasine rich fraction was 11 +/- 1.0 mg/kg and that of the (-)-S-anabasine-rich fraction was 16 +/- 1.0 mg/kg. The LD50 of anabaseine was 0.58 +/- 0.05 mg/kg. Anabaseine was significantly more toxic in the mouse bioassay than S-anabasine (27-fold) and R-anabasine (18-fold). The relative agonistic potencies of these three alkaloids on human fetal nicotinic neuromuscular receptors were of the same rank order: anabaseine>>R-anabasine>S-anabasine.