Marketing of nicotinamide as nicotine replacement in electronic cigarettes and smokeless tobacco.

In the United States, the Food and Drug Administration (FDA) requires tobacco product manufacturers to submit Premarket Tobacco Product Applications (PMTA) for new products, granting marketing approval only if deemed appropriate for the protection of public health. Historically, the tobacco industry has exploited loopholes in the Tobacco Control Act (TCA), especially related to the definitions of nicotine, tobacco product and characterizing flavors, to circumvent the PMTA requirement. In 2023, the industry introduced several 'PMTA-exempt' e-cigarette and smokeless products, including products containing 6-methyl nicotine, a synthetic nicotine analog that is pharmacologically more potent than nicotine. In late 2023 and early 2024, the major US e-cigarette suppliers Nicotine River and ECBlend introduced 'PMTA-exempt' products with the brand names 'Nixamide' or 'Nixodine' or 'Nixotine', with nicotinamide as the main active ingredient. Nicotinamide is a form of vitamin B3 with no known pharmacological activity at nicotinic receptors. Here, we report that the marketing claims for these products, suggesting them and be nicotine substitute products designed to target nicotinic receptors and provide the same experience as nicotine, is deceptive and misleading to consumers. We also inform that these products have evolved further to contain a combination of nicotinamide and 6-methyl nicotine. The regulatory implications of these newly introduced products are discussed.

Variability in Constituents of E-Cigarette Products Containing Nicotine Analogues.

This study characterizes and quantifies constituents in 2 e-cigarette products to assess product consistency and inform future risk assessments.

High Variability in Nicotine Analog Contents, Misleading Labeling, and Artificial Sweetener in New E-Cigarette Products Marketed as "FDA-Exempt".

The recent introduction of electronic cigarette products containing a synthetic nicotine analog, 6-methyl nicotine (6MN), challenges FDA's tobacco regulatory authority. A similar strategy is pursued by vendors of recently introduced e-cigarette liquids containing nicotinamide (NA), marketed as 'Nixotine' or 'Nixamide'. Compared to nicotine, 6MN is pharmacologically more potent at nicotinic receptors, and more toxic, raising concerns about increased addictiveness and adverse effects. Here, combinations of gas chromatography, high performance liquid chromatography and mass spectrometry were used to determine nicotine analogs, flavor and sweetener contents of e-cigarette liquids of the brands "SpreeBar" and ECBlend "Nixotine" products. All SpreeBar products, labelled as containing 5% 6-methyl nicotine, contained only 0.61-0.64% 6-methylnicotine, while "Nixotine" samples contained 7-46% less of the declared nicotinamide contents. Although "Nixotine" product labels did not list 6MN as an ingredient, small amounts of 6-methyl nicotine were detected. All 'SpreeBar' samples contained the artificial sweetener neotame (0.20-0.86µg/mg). Results identified significant discrepancies between declared and measured constituents of e-cigarette products containing nicotine alternatives. The discrepancy is misleading for consumers and raises concerns about production errors. 'SpreeBar' products also contained neotame, a high-intensity sweetener with high heat stability, likely increasing appeal to young and first-time users. Novel e-cigarette products with misleading labels containing nicotine analogs instead of nicotine on the US market is concerning and should be urgently addressed by lawmakers and regulators.

Artificial Sweeteners in US-Marketed Oral Nicotine Pouch Products: Correlation with Nicotine Contents and Effects on Product Preference.

Introduction: Artificial sweeteners are listed as ingredients of oral nicotine pouches (ONPs), a new product category with rapidly growing market share. The exact sweetener contents of ONPs remain unknown. Artificial sweeteners in ONPs may facilitate initiation and encourage consumption behavior. Aims and Methods: Artificial sweetener contents in major US-marketed ONP brands (Zyn, on!, Velo) were determined by Liquid Chromatography-Mass Spectrometry (LC-MS). Sweetener effects during the initiation of ONP consumption were modeled in single- and two-bottle tests, offering mice ONP extracts calibrated to contain nicotine levels similar to saliva of people who use smokeless tobacco. To examine the contribution of sweet taste perception, consumption behavior was compared between wild-type mice and mice deficient in the sweet taste receptor (Tas1r2-/-). Results: Acesulfame-K was detected in on!, Zyn and Velo ONPs (~0.3-0.9 mg/pouch), including products marketed as "Unflavored" or "Flavor ban approved". In Velo ONPs, sweetened with sucralose (0.6-1.2 mg/pouch), higher nicotine strength products contained higher sucralose levels. Tas1r2-/- mice consumed less ONP extracts than wild-type mice in both sexes. ONP extracts with both higher nicotine and sweetener strengths were tolerated by wild-type mice, but produced stronger aversion in Tas1r2-/- mice. Conclusions: ONPs contain significant amounts of artificial sweeteners, with some brands adding more sweetener to ONPs with higher nicotine strengths. Artificial sweeteners, at levels present in ONPs, increase nicotine consumption. Increasing sweetener contents facilitates consumption of ONPs with higher nicotine strengths. Sweetness is a key determinant of ONP use initiation, likely reducing the aversive sensory effects of nicotine and other ONP constituents. Implications: Artificial sweeteners such as acesulfame-K or sucralose reduce aversion and facilitate initiation and continued consumption of ONPs. The marketing of some artificially sweetened ONPs as "Unflavored" of "Flavor ban-approved" suggests that the tobacco industry rejects sweet taste as a determinant for the presence of a characterizing flavor. Sweetness as imparted by artificial sweeteners in tobacco products needs to be addressed by regulators as a component of a characterizing flavor, with the aim to reduce product appeal and initiation by never users, and especially youth attracted to sweet flavors.

Recapitulation of human pathophysiology and identification of forensic biomarkers in a translational model of chlorine inhalation injury.

Chlorine gas (Cl2) has been repeatedly used as a chemical weapon, first in World War I and most recently in Syria. Life-threatening Cl2 exposures frequently occur in domestic and occupational environments, and in transportation accidents. Modeling the human etiology of Cl2-induced acute lung injury (ALI), forensic biomarkers, and targeted countermeasures development have been hampered by inadequate large animal models. The objective of this study was to develop a translational model of Cl2-induced ALI in swine to understand toxico-pathophysiology and evaluate whether it is suitable for screening potential medical countermeasures and to identify biomarkers useful for forensic analysis. Specific pathogen-free Yorkshire swine (30-40 kg) of either sex were exposed to Cl2 (≤240 ppm for 1 h) or filtered air under anesthesia and controlled mechanical ventilation. Exposure to Cl2 resulted in severe hypoxia and hypoxemia, increased airway resistance and peak inspiratory pressure, and decreased dynamic lung compliance. Cl2 exposure resulted in increased total leucocyte and neutrophil counts in bronchoalveolar lavage fluid, vascular leakage, and pulmonary edema compared with the air-exposed group. The model recapitulated all three key histopathological features of human ALI, such as neutrophilic alveolitis, deposition of hyaline membranes, and formation of microthrombi. Free and lipid-bound 2-chlorofatty acids and chlorotyrosine-modified proteins (3-chloro-l-tyrosine and 3,5-dichloro-l-tyrosine) were detected in plasma and lung tissue after Cl2 exposure. In this study, we developed a translational swine model that recapitulates key features of human Cl2 inhalation injury and is suitable for testing medical countermeasures, and validated chlorinated fatty acids and protein adducts as biomarkers of Cl2 inhalation.NEW & NOTEWORTHY We established a swine model of chlorine gas-induced acute lung injury that exhibits several features of human acute lung injury and is suitable for screening potential medical countermeasures. We validated chlorinated fatty acids and protein adducts in plasma and lung samples as forensic biomarkers of chlorine inhalation.

An electronic cigarette pod system delivering 6-methyl nicotine, a synthetic nicotine analog, marketed in the United States as "PMTA exempt".

As of April 14, 2022, the United States Food and Drug Administration (FDA) has been authorized to regulate tobacco products containing nicotine from any source, including synthetic, requiring manufacturers to submit a premarket tobacco product application (PMTA). A recent report by the World Health Organization (WHO) warned that non-nicotine tobacco alkaloids or other synthetic nicotine analogs could be used by manufacturers to bypass regulatory schemes focusing on nicotine alone. From October 2023 on, vape stores in the United States started selling a new electronic cigarette pod system, named Spree Bar, advertised as "PMTA exempt", with youth-appealing flavors and advertising. The products are marketed as containing "Metatine", a trademarked name for 6-methyl nicotine, a synthetic nicotine analog patented by a Chinese electronic cigarette manufacturer. Here we used liquid chromatography-mass spectrometry (LCMS) to confirm the presence of a chemical species with the molecular weight of 6-methyl nicotine in Spree Bar e-liquids. The FDA needs to determine whether, in its view, 6-methyl nicotine is a form of "nicotine" within the meaning of the Tobacco Control Act, or whether 6-methyl nicotine can be regulated as a drug under the Federal Food, Drug, and Cosmetic Act (FDCA).

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16178. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Synthetic Cooling Agent and Other Flavor Additives in "Non-Menthol" Cigarettes Marketed in California and Massachusetts After Menthol Cigarette Bans.

This study uses a bioassay and chemical analysis to determine the proportion of newly introduced "non-menthol" cigarette brands with sensory cooling effects, cooling agents added, and any other flavor additives after menthol cigarette bans.

Synthetic Cooling Agent and Candy Flavors in California-marketed "non-Menthol" Cigarettes.

RATIONALE: The ban of menthol cigarettes is one of the key strategies to promote smoking cessation in the United States. Menthol cigarettes are preferred by young beginning smokers for smoking initiation. Almost 90% of African American smokers use menthol cigarettes, a result of decades-long targeted industry marketing. Several states and municipalities already banned menthol cigarettes, most recently California, effective on December 21, 2022. In the weeks before California's ban took effect, the tobacco industry introduced several "non-menthol" cigarette products in California, replacing previously mentholated brands. Here, we hypothesize that tobacco companies replaced menthol with synthetic cooling agents to create a cooling effect without using menthol. Similar to menthol, these agents activate the TRPM8 cold-menthol receptor in sensory neurons innervating the upper and lower airways. METHODS: Calcium microfluorimetry in HEK293t cells expressing the TRPM8 cold/menthol receptors was used to determine sensory cooling activity of extracts prepared from these "non-menthol" cigarette brands, and compared to standard menthol cigarette extracts of the same brands. Specificity of receptor activity was validated using TRPM8-selective inhibitor, AMTB. Gas chromatography mass spectrometry (GCMS) was used to determine presence and amounts of any flavoring chemicals, including synthetic cooling agents, in the tobacco rods, wrapping paper, filters and crushable capsule (if present) of these "non-menthol" cigarettes. RESULTS: Compared to equivalent menthol cigarette extracts, several California-marketed "non-menthol" cigarette extracts activated cold/menthol receptor TRPM8 at higher dilutions and with stronger efficacies, indicating substantial pharmacological activity to elicit robust cooling sensations. Synthetic cooling agent, WS-3, was detected in tobacco rods of several of these "non-menthol" cigarette brands. Crushable capsules added to certain "non-menthol" crush varieties contained neither WS-3 nor menthol but included several "sweet" flavorant chemicals, including vanillin, ethyl vanillin and anethole. CONCLUSION: Tobacco companies have replaced menthol with the synthetic cooling agent, WS-3, in California-marketed "non-menthol" cigarettes. WS-3 creates a cooling sensation similar to menthol, but lacks menthol's characteristic "minty" odor. The measured WS-3 content is sufficient to elicit cooling sensations in smokers, similar to menthol, that facilitate smoking initiation and act as a reinforcing cue. Regulators need to act quickly to prevent the tobacco industry from bypassing menthol bans by substituting menthol with synthetic cooling agents, and thereby thwarting smoking cessation efforts.