Use of 'Elf Bar' among youth and young adults who currently vape in England: cross-sectional associations with demographics, dependence indicators and reasons for use.

BACKGROUND AND AIMS: Elf Bar is currently the leading e-cigarette (vape) brand in Great Britain. This study examined youth and young adults' use of Elf Bar, socio-demographic characteristics and dependence indicators and reasons for use over other brands. DESIGN: Cross-sectional survey. SETTING AND PARTICIPANTS: Online 2022 International Tobacco Control Project Youth Tobacco and Vaping Survey (N = 1355 16-29-year-olds in England who had vaped in the past 30 days). MEASUREMENTS: Currently using Elf Bar most often (versus other brands) and associations with: socio-demographics, owning a vaping device, dependence indicators and reasons for brand choice. Logistic regressions were used. FINDINGS: Among 16-29-year-olds who vaped in the past 30 days, 48.4% (n = 732) reported Elf Bar as the brand they used most often. Among 16-17-year-olds, 40.7% used Elf Bar over other brands; this was lower than among 18-19-year-olds (60.1%) and 20-29-year-olds (47.4%) (P ≤ 0.002). Using Elf Bar over other brands was higher among those who were female (55.2 versus 41.5% male), identified as White (53.1 versus 30.9% other/mixed), a student (54.5 versus 44.3% not), did not own a vape (66.7 versus 44.4% who did) and typically vaped 5-8 hours after waking (62.7 versus 36.8% within 5 min) (P ≤ 0.044). Most who vaped but had never smoked used Elf Bar (64.3%), although use did not significantly differ from those who currently (45.4%), formerly (42.3%) or experimentally (48.7%) smoked (all P ≥ 0.060). Popular reasons for choosing Elf Bar over other brands were better flavour/taste (47.5%), less expensive (28.7%), easier to get (26.1%), smoother to inhale (24.0%) and popularity (23.1%). 'Better for quitting smoking' (10.1%) was least frequently selected reason for choosing Elf Bar over other brands. CONCLUSIONS: Elf Bar brand e-cigarettes were used by approximately half of 16-29-year-olds who vaped in England in 2022 and was mainly chosen over other brands for subjective responses (e.g. flavour/taste), rather than for quitting smoking.

Noticing education campaigns or public health messages about vaping among youth in the United States, Canada and England from 2018 to 2022.

Public health campaigns have the potential to correct vaping misperceptions. However, campaigns highlighting vaping harms to youth may increase misperceptions that vaping is equally/more harmful than smoking. Vaping campaigns have been implemented in the United States and Canada since 2018 and in England since 2017 but with differing focus: youth vaping prevention (United States/Canada) and smoking cessation (England). We therefore examined country differences and trends in noticing vaping campaigns among youth and, using 2022 data only, perceived valence of campaigns and associations with harm perceptions. Seven repeated cross-sectional surveys of 16-19 year-olds in United States, Canada and England (2018-2022, n = 92 339). Over half of youth reported noticing vaping campaigns, and noticing increased from August 2018 to February 2020 (United States: 55.2% to 74.6%, AOR = 1.21, 95% CI = 1.18-1.24; Canada: 52.6% to 64.5%, AOR = 1.13, 1.11-1.16; England: 48.0% to 53.0%, AOR = 1.05, 1.02-1.08) before decreasing (Canada) or plateauing (England/United States) to August 2022. Increases were most pronounced in the United States, then Canada. Noticing was most common on websites/social media, school and television/radio. In 2022 only, most campaigns were perceived to negatively portray vaping and this was associated with accurately perceiving vaping as less harmful than smoking among youth who exclusively vaped (AOR = 1.46, 1.09-1.97). Consistent with implementation of youth vaping prevention campaigns in the United States and Canada, most youth reported noticing vaping campaigns/messages, and most were perceived to negatively portray vaping.

Exposure to Tobacco-Specific Nitrosamines Among People Who Vape, Smoke, or do Neither: A Systematic Review and Meta-Analysis.

INTRODUCTION: Smoking exposes people to high levels of Tobacco-Specific Nitrosamines (TSNAs), which include potent carcinogens. We systematically reviewed TSNA exposure between people smoking, vaping, and doing neither. AIMS AND METHODS: Databases were searched between August 2017-March 2022, using vaping-related terms. Peer-reviewed articles reporting TSNA metabolites (NNAL, NNN, NAB, and NAT) levels in bio-samples among adults exclusively vaping, exclusively smoking, or doing neither were included. Where possible, meta-analyses were conducted. RESULTS: Of 12 781 identified studies, 22 were included. TSNA levels fell substantially when people who smoke switched to vaping in longitudinal studies and were lower among people who vaped compared to smoked in cross-sectional studies. Levels of TSNAs were similar when comparing people who switched from smoking to vaping, to those who switched to no use of nicotine products, in longitudinal studies. Levels were higher among people who vaped compared to people who neither vaped nor smoked in cross-sectional studies.When comparing people who vaped to smoked: pooled urinary NNAL was 79% lower across three randomized controlled trials and 96% lower across three cross-sectional studies; pooled NAB was 87% lower and NAT 94% lower in two cross-sectional studies. When comparing people who neither vaped nor smoked to people who vaped, pooled urinary NNAL was 80%, NAB 26%, and NAT 27% lower in two cross-sectional studies. Other longitudinal data, and NNN levels could not be pooled. CONCLUSIONS: Exposure to all TSNAs was lower among people who vaped compared to people who smoked. Levels were higher among people who vaped compared to people who neither vaped nor smoked. IMPLICATIONS: As well as TSNAs, there are many other toxicant exposures from smoking and vaping that can increase the risk of disease. However, it is likely that the reduced exposure to TSNAs from vaping relative to smoking reduces the risk to health of those who use vaping products to quit smoking. Future high-quality research, with robust definitions of exclusive vaping and smoking, and accounting for TSNAs half-lives, is needed to fully assess exposure to TSNAs among people who vape.

Impact of E-liquid Packaging on Vaping Product Perceptions Among Youth in England, Canada, and the United States: A Randomized Online Experiment.

INTRODUCTION: Vaping is not risk-free but can help those who smoke to reduce harm to health and stop smoking. However, packaging of vaping products, including e-liquids, appeals to youth and might facilitate vaping among nicotine-naïve people. Standardized packaging of vaping products could moderate the appeal of vaping among youth. This study assessed how youth interest in trying and perceived health harms of using e-liquids are associated with branded or standardized (white or olive) e-liquid packaging with different nicotine levels displayed. AIMS AND METHODS: A between-subject experiment with three packaging and two nicotine level conditions included youth (n = 13801) aged 16 to 19 from England, Canada, and the United States as a part of a cross-sectional online survey in August-September 2021. Participants' interest in trying and perceived harm of e-liquids were analyzed using logistic and multinomial regressions adjusted for age, sex, race or ethnicity, country, vaping, and smoking status. RESULTS: Compared with branded e-liquid packs, more youth reported no interest in trying e-liquids in white (aOR = 1.48, 95% CI = 1.34 to 1.64) or olive (aOR = 1.62, 95% CI: 1.47 to 1.80) standardized packs. Compared with branded e-liquid packs, more youth inaccurately perceived e-liquids in white (aOR = 1.22, 95% CI: 1.11 to 1.34) or olive (aOR = 1.29, 95% CI: 1.18 to 1.41) standardized packs as equally or more harmful than smoking. E-liquid nicotine levels displayed on packs were not associated with youth interest in trying or harm perceptions of using e-liquids. CONCLUSIONS: Among 16- to 19-year-old youth from England, Canada, and the United States, standardized packaging of e-liquids was associated with lower interest in trying and higher health risk perceptions. IMPLICATIONS: Branded packaging of vaping products appeal to youth and might prompt nicotine use among those who had never smoked. This study suggests that restricting branding elements on e-liquid packaging is associated with youth's lower interest in trying e-liquids and higher misperceptions that vaping is equally or more harmful than smoking. Standardized packaging might reduce appeal of vaping among youth, but its potential to discourage vaping for harm reduction should also be considered.

Associations between smokers' knowledge of causes of smoking harm and related beliefs and behaviors: Findings from the International Tobacco Control (ITC) Four Country Smoking and Vaping Survey.

BACKGROUND: Most smokers know that smoking is harmful to health, but less is known about their understanding of what causes the harms. The primary aim was to examine smokers' perceptions of the relative contributions to smoking-related morbidity from combustion products, nicotine, other substances present in unburned tobacco, and additives. A secondary aim was to evaluate the association of these perceptions with nicotine vaping product use intentions, and quitting motivation/intentions. METHODS: Participants were current smokers and recent ex-smokers from Australia, Canada, England and the United States (N = 12,904, including 8511 daily smokers), surveyed in the 2018 International Tobacco Control Four Country Smoking and Vaping Survey. Respondents reported on how much they thought combustion products, nicotine, chemicals in the tobacco and additives in cigarettes contribute to smoking-related morbidity (none/very little; some but less than half; around half; more than half; all or nearly all of it; don't know). RESULTS: Overall, 4% of participants provided estimates for all four component causes that fell within the ranges classified correct, with younger respondents and those from England most likely to be correct. Respondents who rated combustion as clearly more important than nicotine in causing harm (25%) were the least likely to be smoking daily and more likely to have quit and/or to be vaping. Among daily smokers, all four cause estimates were independently related to overall health worry and extent of wanting to quit, but the relative rating of combustion compared to nicotine did not add to prediction. Those who answered 'don't know' to the sources of harm questions and those suggesting very little harm were consistently least interested in quitting. CONCLUSIONS: Most smokers' knowledge of specific causes of harm is currently inadequate and could impact their informed decision-making ability.

Perceptions of cannabis use risk to mental health among youth in Canada, England and the United States from 2017 to 2021.

BACKGROUND: There is little research examining perceptions of cannabis use risk to mental health in countries with differing cannabis regulations. This study therefore examines such perceptions among youth between 2017 and 2021 in Canada (non-medical cannabis legalized in October 2018), England (highly-restricted medical cannabis legalized November 2018), and the US (non-medical cannabis legal in some states). METHODS: Seven repeat cross-sectional online surveys were conducted between July 2017 to August 2021 among youth aged 16-19 in Canada (N=29,420), England (N=28,155), and the US (N=32,974). Logistic regression models, stratified by country, were used to examine perceptions of cannabis use risk to mental health over time, adjusting for age group, sex, race/ethnicity, cannabis use and, for the US only, state-level cannabis legalization. RESULTS: Perceptions that cannabis use posed "no risk" to mental health decreased between July 2017 and August 2021 in Canada (6.1-4.4%; AOR=0.64, 95% CI=0.52-0.78) and the US (14.0-11.3%; AOR=0.74, 0.65-0.84) but not England (3.7-4.5%; AOR=1.21, 0.97-1.52). No significant changes were observed from immediately before (August 2018) to after (August 2019) legalization of non-medical cannabis in Canada (AOR=0.99, 0.83-1.20) or highly-restricted medical cannabis in England (AOR=0.90, 0.70-1.17). In the US, perceptions of "no risk" were more likely in states where cannabis use was illegal (15.0%) compared with legal non-medical (12.2%) (AOR=0.68, 0.63-0.74). CONCLUSION: There were modest decreases in perceptions that cannabis use poses no risk to mental health in Canada and the US between 2017 and 2021 but no clear association with cannabis legalization status.

Marketing claims on the websites of leading e-cigarette brands in England.

INTRODUCTION: Exposure to electronic cigarette (EC) marketing is associated with EC use, particularly among youth. In England, the Tobacco and Related Products Regulations and Committee of Advertising Practice (CAP) regulate EC marketing to reduce appeal to youth; however, there are little published data on EC marketing claims used online. This study therefore provides an overview of marketing claims present on the websites of EC brands popular in England. METHODS: From January to February 2022, a content analysis of 10 of England's most popular EC brand websites was conducted, including violation of CAP codes. RESULTS: Of the 10 websites, all presented ECs as an alternative to smoking, 8 as a smoking cessation aid and 6 as less harmful than smoking. Four websites presented ECs as risk-free. All mentioned product quality, modernity, convenience, sensory experiences and vendor promotions. Nine featured claims about flavours, colours, customisability and nicotine salts. Seven featured claims concerning social benefits, personal identity, sustainability, secondhand smoke and nicotine strength. Six featured claims about fire safety. Some claimed ECs are cheaper than tobacco (n=5), cited health professionals (n=4) or featured collaborations with brands/icons (n=4). All were assessed by the research team to violate one or more CAP code(s) by featuring medicinal claims (n=8), contents which may appeal to non-smokers (n=7), associations with youth culture (n=6), depictions of youth using ECs (n=6) or media targeting youth (n=5). CONCLUSION: Among 10 top EC brand websites in England, marketing elements that might appeal to youth were commonly identified and CAP code compliance was low.

Associations between smoking and vaping prevalence, product use characteristics, and mental health diagnoses in Great Britain: a population survey.

BACKGROUND: Rates of diseases and death from tobacco smoking are substantially higher among those with a mental health condition (MHC). Vaping can help some people quit smoking, but little is known about vaping among people with MHCs or psychological distress. We assessed the prevalence and characteristics (heaviness, product type) of smoking and/or vaping among those with and without a history of single or multiple MHC diagnoses and with no, moderate or serious psychological distress. METHODS: Data from 27,437 adults in Great Britain surveyed between 2020 and 2022. Multinomial regressions analysed associations between smoking, vaping and dual use prevalence, smoking/vaping characteristics and (a) history of a single or multiple MHC and (b) moderate or serious psychological distress, adjusted for age, gender, and socioeconomic status. RESULTS: Compared with people who had never smoked, those who currently smoked were more likely to report a history of a single (12.5% vs 15.0%, AOR=1.62, 95% CI=1.46-1.81, p<.001) or multiple MHCs (12.8% vs 29.3%, AOR=2.51, 95% CI=2.28-2.75, p<.001). Compared with non-vapers, current vapers were more likely to report a history of a single (13.5% vs 15.5%, AOR=1.28, 95% CI=1.11-1.48, p<.001) or multiple MHCs (15.5% vs 33.4%, AOR=1.66, 95% CI=1.47-1.87, p<.001). Dual users were more likely to report a history of multiple MHCs (36.8%), but not a single MHC than exclusive smokers (27.2%) and exclusive vapers (30.4%) (all p<.05). Similar associations were reported for those with moderate or serious psychological distress. Smoking roll-your-own cigarettes and smoking more heavily, were associated with a history of single or multiple MHCs. There were no associations between vaping characteristics and a history of MHCs. Frequency of vaping, device type and nicotine concentration differed by psychological distress. CONCLUSIONS: Smoking, vaping and dual use were substantially higher among those with a history of MHC, especially multiple MHC, and experiencing past month distress than those not having a history of MHC or experiencing past month distress respectively. Analysis used descriptive epidemiology and causation cannot be determined.

Pattern and prevalence of vaping nicotine and non-nicotine drugs in the United Kingdom: a cross-sectional study.

OBJECTIVES: Electronic vaping devices are being used to consume nicotine and non-nicotine psychoactive drugs. We aimed to determine the pattern and prevalence of using vaping devices for nicotine and/or non-nicotine drug administration in the United Kingdom and how these differ by drug type and individual sociodemographic characteristics. We explored reasons for vaping onset and continuation. DESIGN: An online cross-sectional survey PARTICIPANTS: A convenience sample of adults (aged ≥18 years) in the UK. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was prevalence of current use (within the last 30 days) of a vaping device to administer either nicotine or 18 types of non-nicotine drugs. We additionally evaluated reasons for onset and continuation of vaping. Sociodemographic characteristics were compared between the UK general population using census data and those vaping non-nicotine drugs. RESULTS: We recruited 4027 participants of whom 1637 (40.7%) had ever used an electronic vaping device; 1495 (37.1%) had ever vaped nicotine and 593 (14.7%) had ever vaped a non-nicotine drug. Overall, 574 (14.3%) currently vaped nicotine and 74 (1.8%) currently vaped a non-nicotine drug. The most common currently vaped non-nicotine drug was cannabis (n=58, 1.4%). For nicotine, people's modal reasons to start and continue vaping was to quit smoking tobacco. For almost all other drugs, people's modal reason to start vaping was curiosity and to continue was enjoyment. Compared with the general population, the population who had ever vaped a non-nicotine drug were significantly younger, had more disabilities and fewer identified as white, female, heterosexual or religious. CONCLUSIONS: A non-trivial number of people report current use and ever use of an electronic vaping device for non-nicotine drug administration. As vaping technology advances and drug consumption changes, understanding patterns of use and associated behaviours are likely to be increasingly important to both users and healthcare professionals.

Awareness and use of short-fill e-liquids by youth in England in 2021: findings from the ITC Youth Tobacco and Vaping Survey.

BACKGROUND: Refillable e-cigarettes were popular among youth in England in 2021. The UK Tobacco and Related Products Regulations (TRPR) limits e-liquids to 20 mg/mL of nicotine in a 10 mL bottle. Short-fill e-liquids, which are not covered by TRPR regulations, are typically nicotine-free and come in larger, underfilled bottles allowing customisation with the addition of 'nicotine shots'. This paper investigates awareness, use, and reasons for use of short-fill e-liquids among youth in England. METHODS: Data are from the online 2021 International Tobacco Control Youth Survey, comprising 4224 youth (aged 16-19 years) in England. Weighted logistic regression models investigated associations between awareness and past 30-day use of short-fills by smoking status, vaping status, nicotine strength vaped and participant demographics. Reasons for use were also reported. RESULTS: Approximately one-quarter (23.0%) of youth in England reported awareness of short-fill e-liquids. Among youth who had vaped in the past 30 days, 22.1% had used short-fills in the past 30 days; use was most prevalent among those who were also smoking (43.2%) and those who reported usually vaping nicotine concentrations of 2.1% (21 mg/mL) or more (40.8%). 'Convenience of a bigger bottle' was the most selected reason for use (45.0%), followed by 'less expensive than regular e-liquids' (37.6%). CONCLUSIONS: Awareness of short-fills was common among youth in 2021, including among those who had never vaped or smoked. Among youth who vaped in the past 30 days, short-fill use was more prevalent among those who also smoked and those who vaped nicotine-containing e-liquids. Integration of short-fill products into existing e-cigarette regulations should be considered.

Association of Fully Branded and Standardized e-Cigarette Packaging With Interest in Trying Products Among Youths and Adults in Great Britain.

Importance: e-Cigarette vaping among youths and adults has increased in Great Britain. The design of e-cigarette packaging may appeal to youths. Regulations that reduce the appeal of e-cigarettes to youths may deter adult smokers from trying e-cigarettes to help them quit smoking. Objective: To examine the association of fully branded and standardized e-cigarette packaging with interest in trying products among youths and adults in Great Britain. Design, Setting, and Participants: In this survey study comprising 2 surveys, the online Action on Smoking and Health Smokefree Great Britain survey collected data between March 25 and April 16, 2021, from a representative sample of 2469 youths (aged 11-18 years) and between February 18 and March 18, 2021, from a representative sample of 12 046 adults (aged ≥18 years). Interventions: A between-individuals experimental design was used to examine participants' perceptions of e-cigarette packs that were digitally altered to remove brand imagery and color. Participants were randomly assigned to view a set of 3 e-cigarette packs from 1 of 3 different packaging conditions: (1) fully branded packs (control), (2) white standardized packs with brand name, or (3) green standardized packs with brand name. Main Outcomes and Measures: Youth participants were asked which product people their age would be most interested in trying, while adult participants were asked which product they would be most interested in trying. All participants could respond "no interest" or "don't know." Logistic regression models tested whether reporting no interest in trying the e-cigarettes differed between the pack conditions. Results: This study included 2469 youths (1286 female youths [52.1%]; mean [SD] age, 15.0 [2.3] years) and 12 046 adults (6412 female [53.2%]; mean [SD] age, 49.9 [17.4] years). Youths had higher odds of reporting no interest among people their age in trying the e-cigarettes packaged in green (292 of 815 [35.8%]; adjusted odds ratio [AOR], 1.37; 95% CI, 1.10-1.71; P = .005) but not white (264 of 826 [32.0%]; AOR, 1.16; 95% CI, 0.93-1.44; P = .20) standardized packaging compared with the fully branded packaging (238 of 828 [28.7%]). Adults had lower odds of reporting no interest in trying e-cigarettes in green standardized packaging (3505 of 4040 [86.8%]; AOR, 0.85; 95% CI, 0.73-0.99; P = .046) but not white packaging (3532 of 4006 [88.2%]; AOR, 1.05; 95% CI, 0.89-1.23; P = .59) compared with branded packaging (3526 of 4000 [88.1%]). Youths who had never vaped (275 of 699 [39.3%]; AOR, 1.34; 95% CI, 1.07-1.69; P = .01) and youths who had never smoked (271 of 676 [40.1%]; AOR, 1.38; 95% CI, 1.10-1.75; P = .006) were more likely to report no interest in trying e-cigarettes in green packaging compared with branded packaging (224 of 688 [32.6%] never vaping; 216 of 662 [32.6%] never smoking). There were no significant differences by vaping or smoking status among adults. Conclusions and Relevance: The findings of this survey study suggest that standardized packaging measures may reduce the appeal of e-cigarettes among youths without reducing their appeal among adults.

Changes in responses to nicotine vaping product warnings and leaflets in England compared with Canada, the US and Australia: findings from the 2016-2018 ITC Four Country Smoking and Vaping Surveys.

BACKGROUND AND AIMS: In May 2017, black-and-white text nicotine addiction warning labels ('warnings') and health and safety leaflets ('leaflets') became mandatory for nicotine vaping products (NVPs) in England, in accordance with the European Union's Tobacco Products Directive. We compared changes over time in noticing warnings and leaflets, recall of warnings about nicotine and concerns about using NVP due to noticing warnings in England, compared with Canada, the US and Australia, where no warnings and leaflets were mandated. DESIGN: 19 005 adult (aged 18+) NVP users, smokers and quitters of cigarettes and NVP from the 2016 and 2018 International Tobacco Control Four Country Smoking and Vaping Surveys in England, Canada, the US and Australia, recruited via probability and non-probability sampling. FINDINGS: Noticing warnings increased in England from 4.9% (2016) to 9.4% (2018) (adjusted OR/AOR=1.64, 95% CI=1.15-2.36); this change was larger than changes in Canada (AOR=2.51, 95% CI=1.71-3.69) and the US (AOR=2.22, 95% CI=1.45-3.39). Recall of a nicotine warning increased in England from 86% (2016) to 94.9% (2018) (AOR=5.50, 95% CI=1.57-19.27) but not significantly elsewhere. Noticing leaflets increased in England from 14.6% (2016) to 19.1% (2018) (AOR=1.42, 95% CI=1.15-1.74); this change was larger than in Canada (AOR=1.42, 95% CI=1.12-1.79), the US (AOR=1.55, 95% CI=1.17-2.06) and Australia (AOR=1.51, 95% CI=1.02-2.22). Among those noticing warnings, concern about NVP use did not change significantly between 2016 and 2018 (all countries p>0.081). CONCLUSIONS: Introduction of mandatory NVP warnings and leaflets in England was associated with small increases in noticing them but not with changes in concerns about NVP use.

Associations Between Noticing Nicotine Vaping Product Health Warning Labels, Harm Perceptions, and Use Among Adult Vapers, Current and Former Smokers. Findings From the 2018 ITC Four Country Smoking and Vaping Survey.

BACKGROUND: The number of countries mandating a nicotine addiction warning label ("warnings") on nicotine vaping products (NVPs) has been increasing. This study examined associations between noticing NVP warnings, perceptions of NVPs, and intentions to use NVPs. AIM AND METHODS: Cross-sectional analysis of 12 619 adult NVP users, cigarette smokers, concurrent users of both cigarettes and NVPs, and quitters who participated in the 2018 International Tobacco Control (ITC) Project Four Country Smoking and Vaping Survey (England, Australia, Canada, USA). Logistic regression analyses examined associations between noticing warnings in the past 30 days and perceptions of nicotine harm, NVP harm relative to cigarettes, and NVP addictiveness relative to cigarettes. Associations were also explored between noticing warnings and intentions to use NVPs. RESULTS: Noticing warnings was higher among NVP users (18.8%) than nonusers (2.1%). Noticing warnings was associated with perceiving nicotine to pose little or no harm to health among NVP users, but there was no association among nonusers. There was little evidence of an association between noticing warnings and perceptions of NVP harms relative to smoking among NVP users and non-users. Noticing warnings was associated with perceiving NVPs as less addictive than cigarettes among nonusers but not NVP users. Among exclusive smokers, noticing warnings was associated with intending to start using NVPs. Among NVP users, there was little evidence of an association between noticing warnings and intentions to continue using/stopping NVPs. CONCLUSIONS: Noticing NVP warnings was not associated with increased NVP and nicotine harm perceptions or decreased intentions to use NVPs among adult smokers and vapers. IMPLICATIONS: Our findings suggest that noticing NVP warnings may not influence NVP risk perceptions or deter NVP use among adult smokers and vapers. Future research should investigate the impact of warnings on youth and adults who have never smoked or vaped.

Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study.

BACKGROUND: Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus. METHODS: We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18-40 years to receive one of five doses of Ad4-H5-Vtn (10(7) viral particles [VP], 10(8) VP, 10(9) VP, 10(10) VP, 10(11) VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 µg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798. FINDINGS: We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6-17) and three of 41 placebo recipients (7%, 2-20) seroconverted. HAI GMT was 6 (95% CI 5-7) for vaccinees, and 5 (5-6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 10(11) VP cohort (100%; 95% CI 82-100) and eight of 22 placebo recipients (36%; 17-59); 17 of 19 participants in the 10(11) VP cohort (89%; 67-99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5-40); GMT was 135 (89-205) with 10(11) VP, compared with 13 (7-21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16·8%] of 125 vs one [2·4%] of 41, p=0·017; 24 [19·2%] of 125 vs two [4·9%] of 41, p=0·027; 41 [32·8%] of 125 vs six [14·6%] of 41, p=0·028; respectively). No serious treatment-related adverse events occurred. INTERPRETATION: Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1. FUNDING: Wellcome Trust Foundation, PaxVax.

Pharmacology of N-desmethylclozapine.

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.

Protection of sensory function in diabetic rats by Neotrofin.

We investigated the ability of Neotrofin, an agent that enhances endogenous nerve growth factor (NGF) levels, to prevent phenotypic, functional and structural changes that occur in the peripheral nerve of streptozotocin-diabetic rats. Eight weeks of Neotrofin treatment prevented depletion of NGF protein in plantar foot skin and sciatic nerve of diabetic rats and increased NGF protein in associated skeletal muscles. These effects were accompanied by maintenance of normal nerve levels of the neuropeptides substance P and calcitonin gene related peptide. Thermal hypoalgesia and conduction slowing of large sensory fibres in diabetic rats were ameliorated by Neotrofin treatment, whereas there was no effect on conduction slowing in large motor fibres or on reduced myelinated fibre axonal calibre. Enhancing endogenous production of neurotrophic factors using small molecules may be an alternative to either exogenous treatment with neurotrophic factors or gene therapy as a therapeutic approach to treating diabetic neuropathy.

Reversal of cycloheximide-induced memory disruption by AIT-082 (Neotrofin) is modulated by, but not dependent on, adrenal hormones.

RATIONALE: AIT-082 (Neotrofin), a hypoxanthine derivative, has been shown to improve memory in both animals and humans. In animals, adrenal hormones modulate the efficacy of many memory-enhancing compounds, including piracetam and tacrine (Cognex). OBJECTIVE: To investigate the role of adrenal hormones in the memory-enhancing action of AIT-082. METHODS: Plasma levels of adrenal hormones (corticosterone and aldosterone) in mice were significantly reduced by surgical or chemical (aminoglutethimide) adrenalectomy or significantly elevated by oral administration of corticosterone. The effects of these hormone level manipulations on the memory-enhancing activity of AIT-082 and piracetam were evaluated using a cycloheximide-induced amnesia/passive avoidance model. RESULTS: As previously reported by others, the memory enhancing action of piracetam was abolished by adrenalectomy. In contrast, the memory enhancement by 60 mg/kg AIT-082 (IP) was unaffected. However, a sub-threshold dose of AIT-082 (0.1 mg/kg, IP) that did not improve memory in control animals did improve memory in adrenalectomized animals. These data suggested that, similar to piracetam and tacrine, the memory enhancing action of AIT-082 might be inhibited by high levels of adrenal hormones. As expected, corticosterone (30 and 100 mg/kg) inhibited the action of piracetam, however no dose up to 100 mg/kg corticosterone inhibited the activity of AIT-082. CONCLUSIONS: These data suggest that while AIT-082 function is not dependent on adrenal hormones, it is modulated by them. That memory enhancement by AIT-082 was not inhibited by high plasma corticosterone levels may have positive implications for its clinical utility, given that many Alzheimer's disease patients have elevated plasma cortisol levels.

Neotrofin increases heme oxygenase-1 selectively in neurons.

There is evidence that heme oxygenase plays a role in cellular defense against reactive oxygen species and thereby has neuroprotective effects. We examined the interaction of Neotrofin, a cognitive-enhancing and neuroprotective drug, with the heme oxygenase system. In adult rats, both a single administration or seven daily injections of Neotrofin at 10, 30 or 100 mg/kg intraperitoneally increased HO-1 immunoreactivity in neurons of the hippocampal formation and its connections including CA1-4, fornix, septal nuclei, hippocampal commissure, septohippocampal nucleus, fimbria, anteroventral thalamic nucleus, frontal and parietal cortex. Prominent HO-1 staining of neuronal cells in the proximity of blood vessels and circumventricular organs was also observed. Increasing doses of Neotrofin resulted in an increase in the number of neuronal populations expressing HO-1 with 100 mg/kg evoking a widespread neuronal cell response in brain. Quantification by ELISA confirmed that intraperitoneal administration of 100 mg/kg Neotrofin caused a significant increase in HO-1 protein expression in the hippocampus. The increase was evident by 6 h post-injection, peaked at 24 h with a 4-fold increase, and persisted for at least 48 h. Similarly, oral administration of 100 mg/kg Neotrofin produced a 5-fold increase in HO-1 protein 24 h post-administration. The effect of Neotrofin on HO-1 appears to be at the transcriptional level, as suggested by an increase in HO-1 mRNA levels. Neotrofin treatment was also associated with a significant increase in HO-2 mRNA levels in whole brain homogenate. These data may explain the neuroprotective effects of Neotrofin in models of excitotoxic neuronal injury.

Neotrofin is transported out of brain by a saturable mechanism: possible involvement of multidrug resistance and monocarboxylic acid transporters.

Neotrofin (AIT-082; leteprinim potassium) is transported out of brain by a saturable mechanism and in this study the mechanisms mediating this efflux were evaluated. Intracerebroventricular coadministration of [(14)C]Neotrofin with verapamil, a P-glycoprotein inhibitor, probenecid, an organic anion transporter inhibitor, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571), a multidrug resistance-associated protein inhibitor, and salicylate or benzoate, both monocarboxylic acid transporter substrates, inhibited the efflux of [(14)C]Neotrofin. Additionally, Neotrofin inhibited the efflux of [(3)H]quinidine from brain. Compounds can diffuse from cerebrospinal fluid (CSF) into extracellular fluid of brain parenchyma and thus, efflux of [(14)C]Neotrofin after intracerebroventricular administration may indicate active transport across choroid plexus epithelium, brain capillary endothelium, or both. To determine whether [(14)C]Neotrofin efflux occurs at the brain capillary endothelium, experiments were performed in which [(14)C]Neotrofin was administered intraparenchymally. The t(1/2) for [(14)C]Neotrofin disappearance from brain after intraparenchymal administration was significantly lower than that for [(3)H]sucrose and the efflux of Neotrofin was inhibited by 600-fold excess of unlabeled Neotrofin, verapamil, MK571, and salicylate. Together, these data suggest that a saturable mechanism for the efflux of Neotrofin is located at the blood-brain barrier and possibly the blood-CSF barrier. It is likely that multiple transporters are involved in the efflux of Neotrofin and these may include multidrug resistance and monocarboxylic acid transporters. These data are discussed in detail with respect to the site of transporter expression, the recent identification of numerous multidrug resistance-associated protein and monocarboxylic acid transporter homologs, the existence of other potential brain efflux transporters, and the availability of specific pharmacological agents with which to distinguish these transporters.

The impact of efflux transporters in the brain on the development of drugs for CNS disorders.

The development of drugs to treat disorders of the CNS requires consideration of achievable brain concentrations. Factors that influence the brain concentrations of drugs include the rate of transport into the brain across the blood-brain barrier (BBB), metabolic stability of the drug, and active transport out of the brain by efflux mechanisms. To date, three classes of transporter have been implicated in the efflux of drugs from the brain: multidrug resistance transporters, monocarboxylic acid transporters, and organic ion transporters. Each of the three classes comprises multiple transporters, each of which has multiple substrates, and the combined substrate profile of these transporters includes a large number of commonly used drugs. This system of transporters may therefore provide a mechanism through which the penetration of CNS-targeted drugs into the brain is effectively minimised. The action of these efflux transporters at the BBB may be reflected in the clinic as the minimal effectiveness of drugs targeted at CNS disorders, including HIV dementia, epilepsy, CNS-based pain, meningitis and brain cancers. Therefore, modulation of these efflux transporters by design of inhibitors and/or design of compounds that have minimal affinity for these transporters may well enhance the treatment of intractable CNS disorders.