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Modern oral nicotine delivery (MOND) offers potentially reduced harm nicotine delivery for adult smokers who do not wish to quit. Most clinical studies to date have characterised MOND with lower nicotine content, therefore, this study aimed to assess products with higher nicotine strengths. This randomised, open-label, cross-over, confinement study, conducted in Sweden, compared the nicotine pharmacokinetic and subjective effects of three MOND products, zoneX #5 slim (14 mg nicotine/pouch), zoneX #5 (16 mg) and zoneX #6 (20 mg), and a tobacco snus product (Skruf Slim Fresh #5 (16.6 mg)) in 27 adult snus or MOND users. The zoneX #6 product delivered the highest levels of nicotine; however, all products exhibited similar reductions in urge to use nicotine during and following a controlled product use session. Furthermore, the zoneX products generally scored more favourably than the snus on a 7-point Likert product evaluation scale for satisfaction, psychological reward, aversion and relief, assessed 8 h after the start of product use. There was some indication that pouch size may influence nicotine uptake, however, further characterisation is required. All study products demonstrated good short-term tolerability, with no serious adverse events observed. Overall, the findings support that MOND has tobacco harm reduction potential, providing a satisfactory alternative for adult smokers. Clinical Trial identifier: NCT05452278 https://clinicaltrials.gov/ .

The single-dose pharmacokinetics (PK) of a novel, non-tobacco-based nicotine pouch, ZYN, 3 and 6 mg, were compared with 8 mg General snus (part 1) and ZYN 8 mg was compared with 18 mg Longhorn moist snuff (part 2). The present study demonstrates the characteristics of three strengths of a novel tobacco-free oral snus, ZYN, viz. the extraction of nicotine from the oral cavity and its uptake into the systemic blood circulation. Comparison is made to Swedish General snus and American Longhorn moist snuff and from literature 4 mg Nicorette gum and mean of 13 brands of e-cigarettes. A single-dose randomized crossover design was used. In vivo extraction and PK parameters were determined. Part 1. The AUCinf of ZYN 3 mg was 27% smaller than that of 8 mg General and the AUCinf of ZYN 6 mg was 34% larger than that of 8 mg General. Less nicotine was extracted from ZYN 3 mg (1.5 mg) and more from ZYN 6 mg (3.5 mg) than from 8 mg General (2.4 mg). The extracted fractions of nicotine for both ZYN products (56% and 59%) were significantly larger than for 8 mg General (32%). Part 2. Close to identical plasma nicotine curves, AUCinf and Cmax were found for ZYN 8 mg and Longhorn Natural 18 mg moist snuff. The extracted amount of nicotine from ZYN 8 mg (3.8 mg) was larger than the amount extracted from Longhorn Natural 18 mg (3.0 mg), but smaller than the extracted amount of nicotine from General 2 × 8 mg snus pouches (5.0 mg). The extracted fraction of nicotine for ZYN 8 mg (50%) was larger than for Longhorn Natural (19%) and General 2 × 8 mg snus pouches (33%). The two higher doses of ZYN (6 and 8 mg) deliver nicotine as quickly and to a similar extent as existing smokeless products, with no significant adverse effects.

The US FDA recommends assessment of abuse liability (AL) for premarket tobacco product applications (PMTAs) to determine whether a new tobacco product is appropriate for the protection of public health (APPH). To assess the AL and nicotine uptake of Vuse Alto electronic nicotine tobacco products (ENDS) which offer e-liquid pods that vary in nicotine concentration, we conducted two clinical laboratory studies. The primary objective of Study 1 was to assess measures of product abuse liability (AL) in real time during and following product use. This was achieved through timed subjective effect questionnaires, physiological measures (blood pressure and heart rate), and pharmacokinetic assessments for Golden Tobacco flavor 2.4% and 5% nicotine concentration Vuse Alto products. Study 2 evaluated PK and Overall Product Liking (OPL) of four Alto flavor variants with 1.8% and 2.4% nicotine concentrations. The studies were designed as open-label, randomized, crossover studies with 9 and 7 days of confinement for Study 1 and Study 2 respectively, were employed to assess nicotine PK, subjective effects, and physiological measures (Study 1 only) for 4 h after a 10-minute ad libitum ENDS product use. Study 1 included high (usual brand [UB] cigarettes) and low abuse liability (nicotine gum) comparators. Nicotine PK of Vuse Alto products were generally similar across the three nicotine concentrations and four flavors tested in these studies. In Study 1, nicotine PK and several subjective effects (product liking, OPL, product positive/negative effects and urge to smoke) for Vuse Alto 2.4% and 5% products were determined to be in between UB cigarettes and nicotine gum. Increases in heart rate, systolic and diastolic blood pressure were observed for both products. In Study 2, nicotine PK and the OPL for Vuse Alto four flavors at 1.8% and Golden Tobacco at 2.4% were similar and comparable to the Alto products tested in Study 1. These results indicate the AL of Vuse Alto, as assessed by nicotine PK and subjective effects measures of Vuse Alto products at three nicotine concentrations and of four flavors, is significantly lower than cigarettes, and higher than nicotine gum. ENDS products deliver nicotine in a manner that satisfies smokers’ preferences while exhibiting lower AL than cigarettes. Compared to pharmaceutical smoking cessation aids, such as nicotine gum, the Vuse Alto products demonstrate nicotine PK profiles characterized by a more rapid onset and higher peak concentrations, with subjective measures such as product liking, fall between those of nicotine replacement therapy gum and combustible cigarettes. Collectively, the AL assessments indicate that Vuse Alto products may support tobacco harm reduction by providing an alternative that may help smokers migrate away from cigarette smoking.

Abstract RationaleElectronic nicotine delivery systems and heated tobacco products are noncombustible alternatives for adult smokers. Evidence suggests sufficient nicotine delivery and satisfying effects are necessary to facilitate switching away from smoking; nicotine delivery varies across electronic nicotine delivery systems within limited nicotine concentrations.ObjectivesTo assess the nicotine delivery and subjective effects of prototype JUUL2 System in two nicotine concentrations, currently-marketed US JUUL System (“JUUL”), IQOS-brand heated tobacco product, and combustible cigarettes.MethodsAdult smokers (N = 40) completed a 5-arm cross-over product-use laboratory confinement study. Nicotine pharmacokinetics and subjective effects were assessed following use of: (1) JUUL2 prototype 18 mg/mL nicotine; (2) JUUL2 prototype 40 mg/mL; (3) JUUL 59 mg/mL; (4) IQOS 18 mg/g; and (5) usual brand combustible cigarette, each evaluated during ad libitum (10 min) and controlled (5 min, 10 standardized puffs) use.ResultsNicotine delivery was greatest for combustible cigarettes, followed by JUUL2 prototype 40 mg/mL, IQOS, JUUL2 prototype 18 mg/mL, and JUUL 59 mg/mL. Nicotine delivery from JUUL2 prototype 18 mg/mL was significantly greater than JUUL 59 mg/mL after ad libitum use. JUUL products were significantly more satisfying and effective at reducing craving than IQOS. JUUL2 prototype 40 mg/mL was significantly more aversive than other JUUL products.ConclusionsPrototype JUUL2 and JUUL 59 mg/mL products were rated higher than IQOS on subjective measures associated with switching away from smoking. The JUUL2 prototype 40 mg/mL produced aversive responses and would require modifications to be a viable product for adult smokers. Nicotine delivery and subjective responses to JUUL2 prototype 18 mg/mL suggest a product based on this prototype may facilitate increased switching among adult smokers.

ObjectivesTo measure the short-term effects of an electronic nicotine delivery device (“e cigarette”, ENDD) on desire to smoke, withdrawal symptoms, acceptability, pharmacokinetic properties and adverse effects.DesignSingle blind randomised repeated measures cross-over trial of the Ruyan V8 ENDD.SettingUniversity research centre in Auckland, New Zealand.Participants40 adult dependent smokers of 10 or more cigarettes per day.InterventionsParticipants were randomised to use ENDDs containing 16 mg nicotine or 0 mg capsules, Nicorette nicotine inhalator or their usual cigarette on each of four study days 3 days apart, with overnight smoking abstinence before use of each product.Main outcome measuresThe primary outcome was change in desire to smoke, measured as “area under the curve” on an 11-point visual analogue scale before and at intervals over 1 h of use. Secondary outcomes included withdrawal symptoms, acceptability and adverse events. In nine participants, serum nicotine levels were also measured.ResultsOver 60 min, participants using 16 mg ENDD recorded 0.82 units less desire to smoke than the placebo ENDD (p=0.006). No difference in desire to smoke was found between 16 mg ENDD and inhalator. ENDDs were more pleasant to use than inhalator (p=0.016) and produced less irritation of mouth and throat (p<0.001). On average, the ENDD increased serum nicotine to a peak of 1.3 mg/ml in 19.6 min, the inhalator to 2.1 ng/ml in 32 min and cigarettes to 13.4 ng/ml in 14.3 min.ConclusionsThe 16 mg Ruyan V8 ENDD alleviated desire to smoke after overnight abstinence, was well tolerated and had a pharmacokinetic profile more like the Nicorette inhalator than a tobacco cigarette. Evaluation of the ENDD for longer-term safety, potential for long-term use and efficacy as a cessation aid is needed.Trial registrationNo.12607000587404, Australia and New Zealand Clinical Trials Register

Smokers who switch completely to e-cigarettes may reduce their relative risk of tobacco-related disease. Effective nicotine delivery from e-cigarettes is important in consumer acceptance. We assessed whether protonated nicotine and e-cigarette devices delivering greater aerosol mass increase nicotine delivery and product liking. A randomised controlled non-blinded eight-arm crossover study was used to assess plasma nicotine pharmacokinetics and product liking for two e-cigarettes (Vype ePen3 and Vype ePen) with various nicotine e-liquid formulations and a conventional cigarette among 24 healthy dual-users of cigarettes and e-cigarettes. Product use and puff count were also assessed. Results show that nicotine bioavailability was greater for Vype ePen3 with greater aerosol mass delivery than for Vype ePen (C max , p  = 0.0073; AUC 0–120 min , p  = 0.0102). Protonated nicotine (18 mg/mL, medium protonation) e-liquid yielded higher nicotine bioavailability than unprotonated nicotine (18 mg/mL) e-liquid (C max , p  = 0.0001; AUC 0–120 min , p  = 0.0026). There was no significant difference in T max between e-liquids. Nicotine bioavailability did not differ between nicotine benzoate formulation (30 mg/mL nicotine, high protonation) and combustible cigarettes (C max , p  = 0.79; AUC 0–120 min , p  = 0.13). Vype ePen3 with protonated nicotine delivers nicotine more efficiently with the potential to increase product liking relative to earlier devices using unprotonated e-liquid.

Abuse liability (AL) of electronic nicotine delivery systems (ENDS) is relevant as the category increases in popularity as a potentially less-harmful alternative to cigarette smoking. AL assessments are important to the FDA in determining if a new product is appropriate for the protection of public health. This paper reports the results for Vuse Solo (G2 cartridge design) compared to high and low AL-comparators evaluated in an open-label, randomized crossover confinement AL study. The confinement design was adapted from previous ambulatory studies of Vuse Solo (G1 cartridge design) and included product familiarization sessions before each four-hour test session in which subjective measures, nicotine pharmacokinetics (PK), and physiological endpoints were assessed following a single 10-min ad libitum product use session. Product liking, intent to use again, suppression of urge to smoke, and nicotine PK were lower after use of Vuse Solo compared to cigarettes and higher after use of Vuse Solo compared to nicotine gum. No significant differences in blood pressure or heart rate were observed between the products pre- to post-product use. These data reinforce previous research and provide the scientific evidence to support regulatory decisions demonstrating that Vuse Solo has an AL profile lower than that of combustible cigarettes but higher than that of nicotine gum and, therefore, may be a suitable replacement for cigarette smoking for some adult smokers.

Tobacco heating products (THPs) have reduced emissions of toxicants compared with cigarette smoke, and as they expose user to lower levels than smoking, have for a role to play in tobacco harm reduction. One key concern of Public Health is that new tobacco and nicotine products should not be more addictive than cigarettes. To assess their abuse liability, we determined nicotine pharmacokinetics and subjective effects of two THPs compared with conventional cigarettes and a nicotine replacement therapy (Nicotine inhaler). In a randomised, controlled, open-label, crossover study healthy adult smokers used a different study product in a 5 min ad libitum use session in each of four study periods. Product liking, overall intent to use again, urge for product and urge to smoke questionnaires were utilised to assess subjective effects. Nicotine uptake was greater for the cigarette (C max  = 22.7 ng/mL) than for either THP (8.6 and 10.5 ng/mL) and the NRT (2.3 ng/mL). Median T max was significantly longer for the NRT (15.03 min) than for the tobacco products (4.05–6.03 min). Product liking and overall intent to use again was highest for the cigarette, and higher for the THPs than the NRT. Urge to smoke was reduced more by the cigarette than by the other three products. Urge to use the THPs was greater than the NRT. These findings suggest that the abuse liability of the THPs lies between that of subjects usual brand cigarettes and the NRT.

We report the findings from a randomized, parallel study designed to evaluate nicotine pharmacokinetics (PK) following 10 min of ad libitum use of electronic nicotine delivery system (ENDS) in four flavor variants. Subjects were randomized an investigational product (IP) and blood samples were collected for PK assessments during a test session. Primary endpoints were baseline-adjusted values of maximum plasma nicotine concentration (C max ) and area under the nicotine concentration-vs-time curve up to 60 min (AUC nic0–60 ). Baseline-adjusted mean C max ranged from 6.53 to 8.21 ng/mL, and mean AUC nic0–60 ranged from 206.87 to 263.52 ng min/mL for all ENDS IPs. Results of geometric mean C max and AUC nic0–60 values were within 95% confidence intervals (CI) among the ENDS IP flavor variants tested.

Background This randomized, partially single-blinded, 6-period crossover clinical study of adult smokers compared the nicotine pharmacokinetics, impacts on smoking urge and tolerability of various formulations of one brand of e-cigarettes with that of a tobacco cigarette. Methods Five e-cigarettes with different e-liquid formulations containing 1.6 % and 2.4 % nicotine and a conventional tobacco cigarette were randomized among 24 subjects under two exposure sessions consisting of a 30-min controlled and a one-hour ad lib use period to assess plasma nicotine levels, impacts on smoking urge and adverse events. The 30-min controlled use session comprised an intensive use of the e-cigarettes with a total of 50 puffs taken every 30 s for comparison to a single conventional cigarette having a typical machine-measured nicotine yield (~0.8 mg). Ad lib product use conditions provided insight into more naturalistic product use behaviors and their accompanying smoking urge reductions. Adverse events (AEs) were assessed by the Principal Investigator. Results Significant ( p  < 0.05) increases in plasma nicotine concentrations occurred within 10 min of controlled e-cigarette use and significant ( p  < 0.001) reductions from baseline smoking urge were observed within 5 min. E-cigarette and cigarette nicotine plasma levels were comparable for up to one hour of use. After both sessions (90 min), nicotine exposure was the highest for the cigarette, with all e-cigarettes showing 23 % to 53 % lower plasma concentrations. During controlled use, peak reduction in smoking urge for e-cigs occurred later than for the cigarette. After completion of both sessions, significant smoking urge reduction persisted for most of the tested e-cigarettes, albeit at levels lower than that provided by the tobacco cigarette. Nicotine content, vehicle differences, and the presence of menthol did not significantly affect smoking urge reduction by the e-cigarettes. No subjects were discontinued due to AEs. The most frequently reported AEs events included cough, throat irritation, headache, and dizziness. Conclusions Blood plasma nicotine levels obtained from short-term use of e-cigarettes containing 1.6 % and 2.4 % nicotine were significant, but lower than those of conventional tobacco cigarettes, yet the reduction in craving symptoms were broadly comparable. The types of AEs were consistent with other research studies of longer duration that have reported that use of e-cigarettes by adult smokers is well-tolerated. Trial Registration http://ClinicalTrials.gov identifier: NCT02210754 . Registered 8 August 2014.