Influence of nicotine form and nicotine flux on puffing behavior and mouth-level exposure to nicotine from electronic nicotine delivery systems.

BACKGROUND: Nicotine form (freebase/protonated) and nicotine flux (rate at which nicotine is emitted) are two factors that can affect the dose of nicotine inhaled by individuals using electronic nicotine delivery systems (ENDS) because they can influence puffing behavior. The nicotine dose for each puff also is directly proportional to nicotine flux (i.e., dose/puff=nicotine flux*puff duration). This study examines the effect of nicotine form and flux on puffing parameters and mouth-level nicotine exposure. METHODS: Thirty-two dual ENDS and combustible cigarette participants completed five visits that differed by nicotine form (freebase or protonated) and nicotine flux (14 or 35µg/sec); a zero-nicotine condition was a negative control. Participants used a Subox Mini C ENDS, powered at 20W, during a 10-puff directed bout (B1) followed by a one-hour ad libitum bout (B2). Puffing parameters and mouth-level nicotine exposure were assessed using the American University of Beirut REALTIME instrument. RESULTS: Relative to protonated nicotine, freebase nicotine was associated with lower total puff duration (puff duration*number of puffs), lower flow rate in B1, lower liquid consumption, and lower mouth-level nicotine exposure. Increasing nicotine flux from 14 to 35µg/sec was associated with lower total puff duration in both bouts, as well as lower liquid consumption. Increasing nicotine flux was associated with higher mouth-level nicotine exposure in B1 only. CONCLUSION: ENDS with protonated nicotine may enhance nicotine exposure by promoting longer puffing and thus greater dose delivered. This work highlights the importance of accounting for interactions between nicotine form and flux when considering nicotine regulation for ENDS.

Nicotine flux as a powerful tool for regulating nicotine delivery from e-cigarettes: Protocol of two complimentary randomized crossover clinical trials.

INTRODUCTION: Electronic cigarette (EC) use has increased rapidly in the last decade, especially among youth. Regulating nicotine delivery from ECs could help curb youth uptake and leverage EC use in harm reduction yet is complicated by varying device and liquid variables that affect nicotine delivery. Nicotine flux, the nicotine emission rate, is a parameter that incorporates these variables and focuses on the performance rather than the design of an EC. Nicotine flux therefore could be a powerful regulatory tool if it is shown empirically to predict nicotine delivery and subjective effects related to dependence. METHODS AND ANALYSIS: This project consists of two complementary clinical trials. In Trial I, we will examine the relationship between nicotine flux and the rate and dose of nicotine delivery from ECs, hence, impacting abuse liability. It will also examine the extent to which this relationship is mediated by nicotine form (i.e., freebase versus protonated). At Yale School of Medicine (YSM), study participants will puff EC devices under conditions that differ by flux and form, while arterial blood is sampled in high time resolution. In Trial II, we will assess the relationship between nicotine flux, form, and subjective effects. At the American University of Beirut (AUB), participants will use EC devices with varying nicotine fluxes and forms, while dependency measures, such as the urge to use ECs, nicotine craving, and withdrawal symptoms, will be assessed. We will also monitor puffing intensity and real-time exposure to toxicants. ETHICS AND DISSEMINATION: The protocol of Trial I and Trial II was approved by YSM and AUB IRBs, respectively. We will disseminate study results through peer-reviewed publications and conference presentations. TRIAL REGISTRATION: NCT05706701 for Trial I and NCT05430334 for Trial II.

A Systematic Review of Analytical Methods for the Separation of Nicotine Enantiomers and Evaluation of Nicotine Sources.

The introduction of synthetic nicotine by the tobacco industry, also promoted as tobacco-free nicotine, presented new challenges for analytical chemists working in tobacco regulatory science to develop and optimize new methods to assess new nicotine parameters, namely enantiomer ratio and source. We conducted a systematic literature review of the available analytical methods to detect the nicotine enantiomer ratio and the source of nicotine using PubMed and Web of Science databases. Methods to detect nicotine enantiomers included polarimetry, nuclear magnetic resonance, and gas and liquid chromatography. We also covered methods developed to detect the source of nicotine either indirectly via determining the nicotine enantiomer ratio or the detection of tobacco-specific impurities or directly using the isotope ratio enrichment analysis by nuclear magnetic resonance (site-specific natural isotope fractionation and site-specific peak intensity ratio) or accelerated mass spectrometry. This review presents an accessible summary of all these analytical methods.

Flavor-Toxicant Correlation in E-cigarettes: A Meta-Analysis.

Flavors in electronic cigarette (ECIG) liquids may increase ECIG aerosol toxicity via intact distillation or chemical transformation. For this report, we performed a meta-analysis of the literature to categorize the compounds found in flavored ECIG liquids into a few chemical classes and to predict their possible chemical transformations upon ECIG liquid aerosolization. This analysis allowed us to propose specific correlations between flavoring chemicals and aerosol toxicants. A literature search was conducted in November 2019 using PubMed. Keywords included terms related to ECIGs and flavors. Studies were included if they reported chemical ingredients of flavored liquids and clearly stated the commercial names of these liquids. The obtained data were visualized on a network diagram to show the common chemical compounds identified in flavored ECIG liquids and categorize them into different chemical classes. The systematic literature review included a total of 11 articles. Analysis of the data reported gave a total of 189 flavored liquids and 173 distinct chemical compounds that were categorized into 22 chemical classes according to their functional groups. The subsequent prediction of chemical transformations of these functional groups highlighted the possible correlation of flavor compounds to aerosol toxicants.

Comparative study between the effect of topical tazarotene 0.1 gel alone vs its combination with tioconazole nail paint in treatment of onychomycosis.

Onychomycosis (OM) is a chronic fungal infection of the nail caused by dermatophytes, yeasts, and nondermatophytes. Tioconazole is one of the topical antifungal belonging to imidazole derivatives. Tazarotene is a synthetic retinoid, with immunomodulating properties and anti-inflammatory activity. To evaluate the efficacy of tazarotene 0.1% gel alone in comparison with its combination with tioconazole nail paint in the treatment of onychomycosis. Forty patients presented with onychomycosis, subjected to a full history taking, clinical examination, and nail examination, which includes a clinical, dermoscopic, assessment of severity by using Onychomycosis Severity Index (OSI), KOH examination, and fungal culture. There was a statistically significant increase in the response of treatment in patients treated by a combination of tazarotene and tioconazole compared to tazarotene alone through (decrease in OSI, dermoscopic features, and mycological clearance). Tazarotene had antifungal activity specially against Aspergillus niger while its combination with tioconazole gave better results and can be used as an adjuvant to the standard systemic or topical antifungal treatment for OM.

A comparison of the electrical characteristics, liquid composition, and toxicant emissions of JUUL USA and JUUL UK e-cigarettes.

In 2018, JUUL entered the UK market, where EU regulations limit liquid nicotine concentration to 20 mg/mL, approximately one-third the level of JUUL products sold in the USA. We hypothesized that JUUL's UK product was engineered to deliver greater electrical power and boost liquid vaporization such that the net nicotine delivery rate was similar to the US version. We compared electrical characteristics, liquid composition, and aerosol emissions of JUUL devices procured in the USA and the UK. Study outcomes included electrical power, total and freebase nicotine, propylene glycol/vegetable glycerin ratio, carbonyls, and reactive oxygen species. Liquids and aerosols were analyzed by GCMS, HPLC, and fluorescence. Compared to the US version, JUUL UK had approximately one-third the liquid nicotine concentration in the liquid (5.4 vs. 1.6 wt.%) and aerosol (4.7 and 1.3 wt.%). Other than nicotine concentration and yield, we found no differences in any other study outcome, including electrical power. Currently, JUUL UK emits nicotine at a far lower rate than the US product, offering an opportunity to study how this factor impacts user behavior, JUUL uptake, and other population-level outcomes across the two markets.